1
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Report on a
Symposium held to
celebrate the
centenary of the
birth of Lionel
Penrose
held
& 13th March 1998
Generously supported by University College London,
The Clinical Genetics Society and The Genetical
Society.
Published by the Centre for Human Genetics at UCL
Penrose: Pioneer in Human Genetics 1
Contents
(left- to right) Roger Penrose, Shirley Hodgson,
Oliver Penrose, Jonathan Penrose.
Programmes of
Symposia Introduction
.............................................................................................................................. 3
................................................................................................................................. 3
4
by Sue Povey
8
Lionel Penrose: Colleague and Father by Roger Penrose..................................................................................
Lionel Penrose FRS, Human geneticist and human being by Oliver Penrose ..................................................
Lionel Penrose as Galton Professor by E.B. Robson ........................................................................................
The origin of trisomy in humans by Terry Hassold .........................................................................................
Preimptantation genetics of Down syndrome by Joy D.A. Delhanty ...............................................................
The Fragile X Syndromes by Patricia A Jacobs ................................................................................................
50 years on - linkage by N.E. Morton ...............................................................................................................
Memories of Lionel Penrose by Cedric Smith ...................................................................................................
Penrose and sib-pairs by J. H. Edwards ...........................................................................................................
Genetics of Autism by A P Monaco and The International Molecular Genetics of Autism Consortium ...............
15
17
19
20
21
21
24
25
25
Lionel Penrose by Shirley Hodgson .................................................................................................................. 26
Epiloia by Sue Povey .........................................................................................................................................
Thanks for Moomin by Marco Fraccaro ............................................................................................................
Penrose in Canada by Peggy Thompson ............................................................................................................
27
28
31
35
The Galton Laboratory 1952-53 by Barton Childs ....................................
Lionel Penrose As Scientist and Mentor: Recollections and Lifelong Legacies by G R Fraser ......................
40
42
From Eugenics to Human Genetics by Ursula Mittwoch ...........................
Reminiscences of Orlando Jack Miller about Lionel Penrose and the Galton Laboratory ........................... 43
by Orlando Jack Miller
43
Reminiscences of Robert Sokal by Robert Sokal
45
Remembrances of Professor Penrose and the Galton, 1961-62 by James
E Bowman .....................................
An extract by Gillian Ingall by Gillian Inge ......................................................................................................
Reminiscences of the Galton Laboratory and Lionel Penrose 1957-1958 by Arno G. Motulsky .....................
The Penrose Club by Ann Gath .........................................................................................................................
L.S. Penrose and J.B. S. Haldane by Krishna R. Dronamraju ..........................................................................
Acknowled
45
47
47
49
............................................................................................................................................... 50
gements .....................................................................................................................................................
The Gallery
Participants List.........................................................................................................................................
Penrose: Pioneer in Human Genetics 2
51
Penrose: Pioneer in Human Genetics
December 1998
Programme
Introduction
13 th March 1998:
organised by Sue Povey and Shirley Hodgson
By Sue Povey.
Welcome: Sir Derek Roberts, Provost of UCL
Unconventional genetic
mechanisms and an unconventional
General Introduction
geneticist
Sir Roger Penrose, University of Oxford.
Prof Bette Robson, University College London.
50 years on - Mental Handicap
Chair: Professor Jean Frezal, HOpital des Enfants Malades and
GENATLAS, Paris
Dr Terry Hassold, Case Western Reserve University, Ohio:
"Genetic recombination and the origin of Down syndrome".
Prof Joy Delhanty, Galton Laboratoty, University College London:
"Preimplantation genetics of Down syndrome".
Prof Pat Jacobs, University of Southampton: "The Fragile X
syndrome".
50 years on - Linkage
Chair: Professor Newton Morton, University of Southampton.
Prof Cedric Smith, University College London: "Memories of
Lionel Penrose".
Prof John Edwards, University of Oxford: "Sib pairs revisited".
Dr Tony Monaco, Wellcome Centre for Human Genetics, Oxford:
"The genetics of Autism".
Chair: Dr Shirley Hodgson, Guy's Hospital, London
Professor Sue Povey, University College London, "Tuberous
Sclerosis (formerly Epiloia)".
Summing up Professor Marco Fraccaro, University of Pavia, Italy
12 t h March 1998:
organised by Prof Pat Jacobs as part of The Clinical Genetics Society Spring
meeting.
Introduction: Prof Pat Jacobs, Wessex Regional Genetics Lab,
Salisbury, UK
Dr Peggy Thompson, The Hospital for Sick Children, Toronto.
Canada. "Penrose in Canada".
Dr Barton Childs, Johns Hopkins Hospital. Baltimore. USA. Life
at the Galion 1952Dr George Fraser. ICRF Cancer Genetic Clinic. Oxford Radcliffe
Hospital, 'Penrose a5 a Mentor-.
Prof Ursula Mittwoch, Queen Man: and Westfield College
University o- London. From Eugenics to Human Genetics".
Lionel Sharples Penrose, FRS, born June
1898 began his major contributions to
human genetics especially in the field of
mental handicap in 1931, at the Eastern
Counties Institution at Colchester. He spent
a period in Canada, where he concentrated
on mental illness and also inspired a
generation of geneticists. He then returned
to the Galton Chair of (then) Eugenics at
University College London. His
tremendous influence on our attitudes and
understanding in relation to human genetics
comes partly from his wide-ranging
personal research. This included for
example his discovery of the maternal age
effect in Down Syndrome and many
theoretical contributions including the
suggestion of sib-pairs as a tool for linkage
analysis. In addition, the stream of students
and post-doctoral fellows who came to
work with Penrose at the Galton Laboratory
from all over the world have ensured that
his approach lives on. Many of those who
remember came to celebrate his centenary
both with tributes and with memories, and
to hear discussion of modern discoveries
which build on his work in the past. Many
young people found food for thought and
stimulation in contemplating the ideas of
this unconventional geneticist! This
booklet has been put together both from the
formal program (see left) and from those at
the celebration whose lives have, in some
way, been touched and influenced by
Penrose. A list of attendees appears at the
back.
Virtually all the photos were taken on the
13th March 1998.EB
Penrose: Pioneer in Human Genetics 3
Lionel Penrose: Colleague
and Father
Roger Penrose
Mathematical Institute, U.K.
1. Early influences
I should like to make a few comments about my father,
Lionel Penrose, from my own rather particular perspective.
He certainly had a great influence on my scientific career.
From him I obtained an enthusiasm for science and for
mathematics. I recall especially, from an early age, that the
family would frequently go for long walks where he would
explain about the workings of nature, or he might share with
us his excitement about some mathematical puzzle. Indeed,
science, mathematics, puzzles, chess, music, painting, and the
like, were immensely important to him, and they provided
him with continual sources of enjoyment. This sense of
enjoyment was infectious, and his three sons and daughter
were themselves all infected by it in one way or another.
In my own case, above all else, I think that it was the joy of
mathematics that most significantly came through to me. It
was something that seemed special, and that I could share
with him, and it provided me with a vehicle whereby it was
possible to relate to him in a personal way. I should say that,
within the family, it was very hard to relate to him about
actual personal matters - almost impossible, in fact.
(Anything of a remotely personal nature had to be attempted
through the intermediary of Margaret, my mother.) But
through science, mathematics, or puzzles (or chess, in the
case of my two brothers), it was possible for us to have a
close and warm relationship with him.
renovated before the war, later donating it to the Nationa
Trust), where one of my brothers would stride far out in front
he would himself be in the middle, and the other brothe
would be trailing far behind. I shall come to my own
positioning in relation to this precession in a minute. Th
three of them we re playing the game kriegspiel in their heads
Kriegspiel is a version of chess in which each player i
allowed to know where his own pieces are positioned, but can
only infer, by examining which of his own moves are lega
where his opponents pieces might be. In addition there is a
umpire who has complete knowledge of the details of th
game as it is played. Usually this game is played with thre
separate chess sets. This is hard enough. But on thes
occasions all three of them would keep all their information in
their heads, with no actual chess board or pieces at all. M
brothers played each other, with my father acting as th
umpire (so only he had the full information of the game). M
own job was to be the runner carrying moves from one brothe
to my father and then to run back to one or the other brother
As opposed to the activities of the other three, my own jo
presented no intellectual challenge, but I got the best exercise!
2. Self-replicating machines
Later in life, from the period when I was a pure-mathematica
research student in Cambridge, I had the honour to collaborat
with my father in three rather unusual pieces of work. Th
first originated when the family went to Switzerland to visi
my mother's mother, who lived at that time in Chateau d'Oex
On the train journey there, Lionel brought up with me th
question of designing a simple mechanical device that migh
be able to reproduce itself. I believe that we had both bee
aware of the w ork of J o h n v o n Neu ma n n, w ho h ad
I recall one occasion (when we lived in Canada) when he had
demonstrated the theoretical possibility of constructing
to leave on a business trip for a few days, he left with us the
mechanical self-replicating machine. (At least I had been
problem of constructing a three-dimensional model providing
aware of it at the time.) But von Neumann's mechanisms wer
the projection, into three-dimensional space, of a fourexceedingly complicated. If one were trying to model the typ
dimensional hypercube from the direction of one of its
of self-reproduction that would have been going on in the ver
corners. I recalled that we failed in this task, but he
early stages of life on Earth, then one would require somethin
constructed the appropriate model out of wire upon his
that was, on the other hand, very simple. My recollection i
return. Later, there was the occasion (when I was at school,
that we had various discussions on the train and then on
back in England) when I told him that my mathematics
walk in the Swiss countryside. As a result of our discussions
master had informed us that he would teach us the essentials
I produced a model in which there was just one (rathe
of the calculus on the next day. Immediately, Lionel took me
inelegant) kind of piece, but he came up with a mor
aside and told me himself the essentials of the calculus. He
satisfactory version in which there were two distinct but ver
could not bear to have me learn from someone else these
simple pieces. After we returned to England, he constructe
delights; he was determined to have the pleasure of doing this
various versions of these pieces, mainly in wood (a material
himself - which he did, just in the nick of time!
with which Lionel had a considerable affinity). Shortl
afterwards, we jointly published the two-piece version i
I never took a particular interest in chess, but my other two
brothers were extremely keen. I clearly recall the many long
Nature.'. (The pieces are placed randomly and separately in
walks that Lionel and his three young sons used to take
linear track and shaken. They remain separate. But when
through the Suffolk countryside (near Thorington Hall, the
linked pair is introduced, the shaking causes other pairs to link
th
in just the same way as the original pair is linked. There are
16 century mansion that he had bought and had had
Penrose: Pioneer in Human Genetics 4
two distinct ways of linking a pair, but the reproduction is always true. See Fig 1. below)
tiodil, tb $how it etf-rt
Tii$
d i4(rIm
$ , - v P i > i t me t 4
Oto 4e3creptioo
Ar. A . xm l 6 ,
sivt o
by L.. S. & R. Per
Not...rr : 79
.
1157) i t a$.
In fact, this work started my father on a lengthy and, no doubt, energy -consuming activit}. He to spend innumerable hours, in
a little workshop at the back of our house in Golders Green, sawing up little pieces of wood. which were to be the component
parts of his more and more complicated mechanical self-reproducing machines-. The workshop and the little pedal-powered
jigsaw that he kept in it had the previous purpose of constructing puzzles and to:, 7.7
:le made for his children, grandchildren,
friends, and relatives.) In some of his later models, he tried to imitate the behaviou:
DNA_ with a double chain of units and a
facility for reproducing information in the manner of nucleotide pairing. I rernembe: :177:ti I used to worry that the early purpose
Penro'e: Pioneer i n E
Genec_s
Penrose: Pioneer in Human Genetics 6
of constructing a self-reproducing machine for which the basic pieces were simple had been somewhat obscured in all this later
complication.
(i)A—A—A— a a a
(ii)
A—A—A
ctio
/*
A—A-
,
A—
a
ft v't_ A—A—A—
tv)
rt
Fig, 3. Salf-hopyiag chain with separation. A—A—
A— old chain of activated unit (seed). The new chain, built in
response to presenee of old chain, after separation becomes
active tilte the sated.
a unattached neutral unit.
point on chain where a neutral unit can be capteived and made part
of a new chain.
— Linkage between units.
. , direction of alignment of units,
Figure 2: Self-copying chain with separation
But then he hit on a very simple device 3 (for single chain replication)
which one could well imagine was indeed simple enough to have been
employed, in some manifestation, by very early life forms. This is
illustrated in Fig. 2. The key idea is that when a second ("daugh ter")
chain begins to build up along the side of a given ("mother") chain, the
attaching link between the two chains is always at a point just beyond
the length of the (growing) daughter chain. He referred to this as a
"diagonal link". The advantage of the diagonal link is that it
automatically disappears just at the moment that the daughter chain
reaches the same length as the mother. In this way he was able to find a
very simple and elegant solution to one of the most awkward
problems of mechanical replication: how does the growth procedure
"know" when to stop? He had the idea that early life could conceivably
hit on this type of solution also. He regarded as his work on
mechanical self-reproducing machines as possibly supplying some
insights into how nature herself might actually have solved some of
these fundamental early problems of the creation of life. Of course, in
the early history of the Earth, there were no little mechanical wooden
pieces lying around. Accordingly, my father tried to produce a
chemical version of this simple self-replicating machine.
This
employed phosphate chains linked by pentose with purine or
pyrimidine bases (see Fig. 3.). He published this in New Biology.' I have
no idea whether this (or something similar) could have worked, but it
certainly strikes me as a very ingenious and original approach to the
question of the origin of life.
3. Impossible objects
In the construction of these self-replicating machines, my own role was
clearly a very subsidiary one. I had some (not entirely insignificant)
input into the original simplest model, but the later developments were
carried out completely independently from any input from me (apart
from the occasional discussion). On the other hand there were two other
areas of my fathers later interests for which my input into our
collaboration was much more substantial. One of these was assembly
puzzles, where up until my final period as an undergraduate at University
College, London, just before going to Cambridge as a research student. I
constructed three 6-piece assembly puzzles, which constructed a
dodecahedron, a tetrahedron, and an octahedron. The octahedron
assembly employed a procedure whereby it was necessary to put three
pairs of pieces together simultaneously. This aspect of the puzzle
intrigued Lionel particularly, and he embarked on the design and
construction of a large number of puzzle designs of his own which
employed this principle. He registered the design of one particularly
ele gant construction, a six-pointed star shape with three pieces that had
to be held carefully in an extreme position before sliding the pieces
0
pra-
40—
St
Figure3:Suggested chemical mechanism for replication of a
single molecular chain.
S, pentose; R1, R2. R3, purine or pyrimidine base.
....... direction of alignment. Self-copying chain with
together simultaneously. A modified version of this puzzle is still being sold, under the name of "Pandora's Box", by the well known puzzle company Pentangle.
The other main area in which I appear to have had an effect in stimulating one of my father's later interests was that of
impossible objects (or, perhaps more correctly, "impossible figures"). I had attended the International Congress of
Mathematicians in Amsterdam in the summer of 1954, at the end of my second year as a Cambridge research student. There, I
attended an exhibition of the works of the Dutch artist M.C. Escher, of whom I had never heard, prior to that meeting. I was
astounded by what I saw, particularly Escher's extraordinary use of mutually inconsistent images. Upon my return to England I
set about trying to draw something "impossible" myself, though different from the ideas that Eschcr actually used, and
eventually I simplified this notion that I had in mind down to the impossible triangle that has subsequently become known as
the "tribar". I showed this to my father who immediately threw himself into the design as numerous other "impossible
structures". I recall, particularly, what he referred to as his "impossible college". Eventually, he came up with his "imposs ible
staircase" which it is possible to ascend indefinitely by going one way around, and to descend indefinitely the other way around.
We then got together and wrote a joint paper on the subject, which we decided was on the subject of psychology and published it
in the British Journal of Psychology'. We sent a copy of this paper to Escher (in which we acknowledged Escher's influence via
a reference to the catalogue for the Amsterdam exhibition. Escher subsequently made use of my father's staircase and of my
triangle in two of his best-known prints "Ascending and Descending" and "Waterfall", and he was generous in his
acknowledgement for the source of these particular ideas. (His lithograph "Belvedere" makes use of a very similar impossible figure notion. This appeared after the Amsterdam exhibition but before our paper appeared. For a history of earlier impossible
figures, see Bruno Ernst's account referenced below")
One particular feature of such impossible figures seems not to have been exploited by others than ourselves . We explained this,
rather enigmatically, in the solution of the third puzzle of a collection that we presented in another joint article, this ti me in The
New Scientist, entitled "Puzzles for Christmas"'. The fact is that if an impossible figure (of the k ind that I have been discussing)
is drawn correctly with perspective,' then there is an additional anomaly with regard to sizes. If objects that are close together
on the impossible structure are drawn locally consistently with one another, then it is foun d that there is a global inconsistency
when the "impossibility" is traversed. For example, if creatures are pictured consistently mounting the stairs of an impossib le
staircase (drawn with perspective), then there will be a size inconsistency when they go all the way around.
My father made use of this "illusion" in a remarkable model that he made of an impossible staircase on which he placed some
plaster model dogs (of two sizes-although this was not apparent) in which the dogs seemed to grow in size when t hey mounted
the staircase. There is a (somewhat inferior) photograph of this in an article of mine, referenced below'. In fact, in our or iginal
article on impossible objects°, there is a photograph of a model of the impossible staircase, made by my father. (There is a
"break" in the actual model, which is subtly disguised in the photograph.) It is less well known that he also made a
corresponding model of the impossible triangle.
Such models were later made by Richard
Gregory and others.
In our "puzzles for Christmas" article', we also
exhibited a number of other types of puzzle,
some that I have not seen elsewhere, that were
the result of many hours of most enjoyable
interaction between my father and me, and
sometimes with others. I think that it was the
sense of fun in working with things of this
nature that had the most lasting impression on
me. For Lionel, there was no dividing line
between fun and work!
References
An impossible staircase.
Penrose, L.S. and Penrose, R. (1957) A selfreproducing analogue Nature 179, 1183-4.
2
see, for example, Penrose, L.S. (1958) Mechanics of self-reproduction Ann. Hunt Genet. Lond. 23, 59, (1959)
Automatic mechanical self-reproduction New Biology 28, 92,
3
Penrose, L.S. (1960) Developments in the theory of self-replication New Biology 31, 5'-66.
4
Penrose. L.S. and Penrose, R. (1958) Impossible Objects: A Special Type of Visual Elusion Brit.J.Psych. 49, 31-3.
Penrose, R. (1986) Escher and the visual representation of mathematical ideas.. in Af.C.Escher: Art and Science (ed.
1-1.S.M.Coxeter. NI_Emmer. R.Penrose and NI.E.Teuber, Elsevier Science Publishers 8.1"., Amsterdam pp.143-57).
Penrose: Pioneer in Human Genetics 8
6
Ernst, B. (1986) Escher's impossible figure prints in a new context, in M.C.Escher: Art and Science (ed. H.S.M.Coxeter,
M.Emmer, R.Penrose and M.L.Teuber,
Elsevier Science Publishers B. V., Amsterdam pp.125-34).
7 Penrose,
L.S. and Penrose, R. (1958) Puzzles for Christmas New Scientist (Dec. 25).
8
Penrose, R. (1991) On the cohomology of impossible figures [La cohomologie des figures impossibles] Structural Topology
[Topologie structurale] 17, 11-16.
9
Penrose, R. (1995) Mathematics of the impossible; in The Artful Eye. Eds. R. Gregory, J. Harris, P. Heard. D. Rose (Oxford
University Press); Chapter 16, pp. 324-34.
Lionel Penrose FRS, Human
geneticist and human being.
Oliver Penrose FRS
My father was born on 11 June 1898. He was given the name
Lionel Sharpies Penrose, after his maternal grandmother Eliza
Sharples, who had died
when Lionel's mother was
only 3.
Lionel Penrose as
a boy
Figure 1: Oxhey Grange
In 1908, when my father
was 10 years old, moved
to a big house in the
country
c alled O x hey Gr a n ge . I t wa s c l o se t o Wa tf ord , in
Hertfordshire. I leave it to you to speculate what effect it
would have on impressionable
extraordinary
young minds to live in such an
building (Fig. 1).
The four brothers
went to Quaker
boarding schools,
first a prep school
ne ar
Mal ver n
called the Downs,
and then one at
Reading
called
Figure 2: Lionel Penrose and his
brothers
Leighton Park. In the holidays they used to visit grandfather
Peckover here in Wisbech. Here's a picture of them from
around that time (Fig. 2) Lionel is on the right.
Already when he was at school, some of Lionel's unusual
qualities must have been evident. He loved malting up
puzzles, particularly ones involving spatial imagination, and
he was also good at drawin g and painting. There are a couple
of his puzzles from that time. The "elephant keeper"
puzzle
(Fig 3) was intended to be made out of wood; the puzzle is
to chop the man across with one cut and put the pieces
together to make his pet elephant. Fig 4 shows how it is
done. In the "treasure in the castle" puzzle (Fig 5) the
traveller has to get to the top of the tower without
letting go of the string, in such a way that it is not looped
through any of the arches.
For example it is no good to go through the nearest
arch, cross the river by the bridge at C and then climb
the stairs to the top; this would leave the string linked with
the nearest arch. The solution is given in Fig 6 (overleaf).
Figure 3: The "elephant
keeper" puzzle.
Figure 5: The traveller's mystery.
Figure 4: The solution.
Figure 7:Margaret and
Lionel Penrose.
of the
hideous
shouts.
women
lunatics
Peace?"
the
and
and
into
is
Psychology and psychoanalysis
Figure 6: Solution.
It must also have been during his schooldays that he first
became interested in the game of chess. Chess was one of
the few approved Sunday pastimes in the Penrose and
Peckover families, and Lord Peckover was a keen chess
player; incidentally one of Lord Peckover's chess
opponents was a man called Aylmer Maude who did the
first English translations of Tolstoy, and indeed Aylmer
Maude played at least one chess game with Tolstoy
himself. (Later on, Aylmer Maude became a close friend
of the birth-control pioneer Marie Stopes). My father
enjoyed chess all his life, and besides being a good player
he was a first-rate chess problem composer. In later life he
also took great pleasure in the chess exploits of his
youngest son Jonathan, who among other successes won
the British Chess Championship 10 times.
When my father was 16, the First World War broke out.
True to his Quaker background he was a pacifist, so he did
not fight, but on leaving school he went to France with an
ambulance train run for the British Red Cross by the
Society of Friends (Quakers). One day he managed to
take some leave and attend a lecture about Freud's theory
of dreams, and this seems to have captured his
imagination; as he wrote later, he was "astonished to hear
that some fairly reasonable explanation could be given of
the apparently disordered sequence of
nocturnal theatre with an audience of one"
crowd,
laughter
Men
turned
--- this
ideas in the
While he was on the ambulance train he kept a diary. You
might expect such a diary to contain harrowing
descriptions of the terrible things he saw, but most of the
entries are laconic. Here's one of the more exciting ones
"a.m. clean windows at Abbeville. p.m. several bombs on
Abbeville, one near the train which smashed windows
previously cleaned. Went to Dupont". His diary is
illustrated with maps and sketches, some in colour, but
there are no people at all in the sketches, only landscapes.
The only thing that seems to have moved him was the
celebrations of November 11th 1918, of which he says
"My curiosity goads me to wander for miles through
dense intoxicated crowds until I too am utterly sick with
the smell of spirits, the crushed flags, the glistering eyes
After the war he went up to
St John's College,
Cambridge. He chose a course called Moral Sciences,
which was a combination of mathematics, logic,
psychology, and philosophy. There were two reasons
for his choice. One was that he wanted to study
mathematical logic under Bertrand Russell, one of the
greatest mathematical logicians and philosophers of the
century, and I am sure that my father also admired
Russell for having been imprisoned on account of his
pacifistic opposition to the war. His other reason for
choosing Moral Sciences, even though he could not
stand philosophy, was his interest in psychology,
apparently kindled by that lecture about Freud's theory
of dreams. In general, he was disappointed by the very
limited scope of the Cambridge psychologists, but
there were a few people there interested in Freud's
ideas. One of these was W H R Rivers, who during the
war had treated the poets Siegfried Sassoon and
Wilfred Owen at the Craiglockhart psychiatric unit in
Edinburgh.
As soon as my father could manage it, he left
Cambridge for Vienna where Freud himself and other
leading psychiatric thinkers were to be found. At first
he may
have
seemed destined to become a
psychoanalyst, and himself was analysed as part of the
training; but he
became disillusioned
with
psychoanalysis: it was not rigorous enough, too
difficult to test scientifically. According to my mother
he would have made a lousy psychoanalyst anyway,
because he would have been too interested in his own
ideas to pay enough
attention to the ideas of his
patients.
Coming back from Vienna in 1924, my father made a
train journey, which turned out to be very significant in
hi s l ife . H e w as tra vel li ng w it h t w o y ou ng
Englishwomen he had met a couple of days before on a
mountain-climbing expedition.
One of the young
women, called Margaret Leathes, was one of the first
female medical students in this country. As she
reported much later, Lionel "became fascinated by the
anatomy book that I had with me and he decided to
enlarge the study of psychology, which he had been studying in
Vienna, by taking up medicine with psychiatry in view. I was
on my way to do my hospital work at the Royal Free Hospital
in London, having taken the first and second years in
Cambridge. Lionel did the first three years of medicine in one
year by juggling with his registration dates, and in the end I
qualified in medicine only three months before he did!
Meanwhile, he brought me an orchid in a Chianti bottle and
thereafter we had supper together almost nightly for the
duration of our respective student days". Fig 7 shows him
looking at her adoringly.
The Colchester Survey
In 1929, an influential Government report was published
drawing attention to a major problem of the time: there were
already over 100,000 mentally handicapped people being
looked after in public institutions, and the number receiving
this care had increased dramatically in the 21 years since the
previous survey. People must have been afraid that the number
of inmates of mental institutions was going to increase
indefinitely, and they had very little idea what the causes of
mental handicap were.
My father, appointed by the Medical Research Council to study
these problems, began the enormous project which was to
150 families
Average age of:
mother
father
573 normal babies
31.2
33.8
154 D.S. babies
37.3
39.4
at birth of:
Figure 8: 150 families.
occupy him for the next seven years. Every single one of the
1280 mentally retarded patients in the Royal Eastern
Counties Institution, Colchester was investigated with the
utmost care. They were given standard intelligence tests,
examined clinically for known diseases such as epilepsy,
and, most painstakingly of all, the family of every patient
was visited two or three times, either by my father or by his
assistant Miss Newlyn, to find out as much as possible about
the patient's parents, brothers and sisters, grandparents,
uncles and aunts, and so on. Things like their dates of birth
and death, miscarriages and stillbirths, and particularly any
diseases or other unusual medical conditions. The
investigators also c hecked many other sources of
information: educational records, hospital records, and so
on, with the utmost rigour throughout. At the end, all the
data were published in a book which even today is a model
of how to do such investigations.
The main conclusion was that most of the patients in the
institution were essentially normal, just not very bright.
On the average, the parents of these patients were also
less intelligent than the general population, but there is
no sharp dividing line between these patients, or their
parents, and the general population. It is just like stature.
Some people are much shorter than the average, and the
parents of those short people tend also to be shorter than
the average, but there is no sharp dividing line between
short people and those of "normal" hei g ht. At the same
time, there were a minority of patients whose mental
handicap was due to one of a number of well-defined
diseases. The parents of these patients were of normal
intelligence on average, but the disease may still have a
hereditary cause.
Down's syndrome
One of these well-defined diseases is the one we now
know as Down's syndrome (DS), though at that time it
was called mongolism. My father used to be very fond of
these particular patients, because of their sense of
humour, mischievousness, good temper, and love of
music. They are also noted for their obstinacy, and
perhaps this appealed to him too, as an echo of
something in his own character. It had been known for a
long time that Down's syndrome was more common
among the children of older parents, but nobody had
managed to sort out whether it was the age of the mother
or the age of the father that really mattered; or perhaps
some other factor such as how many previous children
they had had.
My father treated this puzzle a bit like some of the chess
problems he was so fond of. and managed to crack the
problem by a beautiful statistical argument. He made a
careful study of 150 families of Down's syndrome
patients : that is, 150 fathers, 150 mothers, and all their
children. In each family there is at least one child with
Down's syndrome. The data showed that on average the
mothers were older when they had the Down syndrome
babies than the normal ones. But the fathers were also
older (fig. 8). So which is the determining factor,
father's age or mother's age?
Let's test the hypothesis that the mother's age is the
determining factor, the father's age being irrelevant. We
can do this by considering a particular group of children,
those whose mothers at the time of birth were 37.3 years
old. If the hypothesis is true, that only the mother's age
matters, then the fathers of the Down's syndrome
children in our group would be just like the fathers of the
normal children in the group. In particular the fathers of
the DS children at the time of birth would be no older,
on average, than the fathers of the normal children. The
average age of the fathers of DS children born to 37.3 year
old mothers is 39.4 years; and the average age of the fathers
of all children born to 37.3 year old mothers is practically
the same, 39.5 years. So, for children born to 37.3-year-old
mothers there is no tendency of the fathers of the DS
children to be older than average. The hypothesis that only
the mother's age matters has passed the test.
We could try another test of this same hypothesis, that only
the mother's age matters. Let's consider another group of
children, the ones born to 31.2-year-old mothers. The
average age of the fathers of the normal children in this
group 33.8 years, and the average age of the fathers of all
the children in the group is also 33.8 years : it makes no
difference whether you include the fathers of DS children in
the average or not. So again, the father's age is irrelevant,
once you know the mother's age.
What about the alternative hypothesis, that the father's age
is the determining factor? You can do a similar calculation,
Figure 9: Constable's drawing of
Thorington Hall.
Figure 10: Thorington Hall.
but this time the numbers do not agree. This hypothesis
fails the test. So the conclusion is that the mother's age is
very important and the father's age is not a significant
factor. This fact is well-known now, but at the time it was
a big step forward, the first unequivocal piece of
knowledge about the origins of Down's syndrome.
Another event from this period is of particular interest
because of Alexandrina Peckover's bequest of her house to
the National Trust. In 1936 my father had the chance to
buy a big farmhouse dating back about 400 years, called
Thorington Hall. It was in the part of the Essex-Suffolk
border, near Dedham and Flatford, which was made
famous by the painter John Constable, and in fact
Constable made a drawing of this very house (Fig. 9). My
father had the house renovated and then presented it to The
National Trust, on condition that he could use it during his
lifetime, and all of us spent many happy summers there
over nearly three decades. Fig. 10 shows Thorington Hall
as it looked in one of those summers).
Canada and the War
The year 1938 when the Colchester survey came out, was
also the year of some even more important
German annexation of Austria in March 193'.
crisis in September and the infamous Kristallna.:7November. Then early in 1939 came the German
at
_
4
Czechoslovakia. It was a black time for almost _ mica
Eur o pe . In my fam ily , h o wever , we had a str o ke - my father received an invitation to a conferenzz
United States around Easter time, and he took :T.•
and us us three boys with him. We stayed in an ex po - in Philadelphia for three months and then at a lake in
where an old friend of my mother had a summer cottage.
Meanwhile my father had found a job as a doctor in a
psychiatric hospital in London, Ontario. He rented a house
there, number 1000 Wellington Street, and we were sitting
there on packing cases, waiting for some furniture to arrive,
when the news came that war had been declared. I still
remember the sound of Hitler's ranting voice on the radio,
one of the most frightening sounds I have ever heard. I was
10 years old at the time.
After about three years his job as a doctor in the psychiatric
hospital was upgraded by giving him the additional duties of
acting director of medical statistics for the province of
Ontario. A couple of years later he was made director of
psychiatric research for Ontario, while still continuing his
job at the hospital. One of his duties in this new post
involved sitting in his office in the provincial capital
Toronto answering letters, sometimes even having to answer
letters which he himself had written a few days earlier in
London Ontario. He made a big study, based on hospital
records of 1600 patients treated with the newly introduced
shock therapy, to find out whether this treatment really did
the patients any good. He concluded that the treatment had
little effect on schizophrenic patients but that it did help the
manic-depressives, though even here its effect seemed to be
to speed the recovery of patients who would have recovered
anyway than to cure patients who would not otherwise have
recovered. He also
retardation.
resumed his research into mental
In 1944 my mother, then aged 43, became pregnant again.
We three boys, then aged 11,13 and 15, were of course well
aware of the risk that a child born to a mother of this age
might have Down's syndrome, and there was great
excitement as the due date approached. A soon as my sister
Shirley came into the world, my father applied his diagnostic
expertise to her and announced, in his characteristically
cautious way "I don't think it's an imbecile". Indeed, very far
from being an imbecile, she is the only one of his four
children to have followed him into the medical profession :
she is now a clinical geneticist and co-author of a book about
the genetics of cancer.
Later that year, my father had another thing to be excited
about. He had been in contact with J B S Haldane, a scientist
he greatly admired, who was a professor at University
College London (England). The exciting news was that,
thanks to Haldane's advocacy, my father had been offered
an appointment as a professor at that college. So in the late
summer of 1945 we set sail for England, and he stayed at
University College for the next 20 years.
The Galton chair of Eugenics
Let me tell you a bit about the position my father took up.
It was not just an ordinary professorial position, but one
with a special title ; he was to be called "The Gallon
Professor of Eugenics", and the laboratory he was in
charge of was called the Galton Laboratory. Francis Galton
was a scientist, born in 1822, and lived in the Victorian
age, when science was confidently equated with progress.
Galton had the idea that the human race could be improved
by selective breeding, in roughly the same way that
farmers or racehorse owners breed animals, and he coined
the word "eugenics" to mean trying to do this. In 1869 he
published a book "Hereditary Genius" in which he
proposed that the State should encourage the most able
people --- by which I suspect he meant the people who
were most like himself --- to have large families, while the
less able might perhaps be encouraged to enter monasteries
and convents so that they would not propagate their kind.
Later on, he came to realize that it was not quite that easy,
if only because so little was known about how human
qualities were inherited, and he spent the rest of his life
trying to get a better understanding of this. Galton was a
pioneer in the use of statistical methods for this purpose.
When he died in 1911, Francis Galton left most of his
fairly substantial estate to University College London to
pay for a professor who would study this subject of
eugenics he had invented, that is to say the study of how
the human race might be improved by breeding.
During the time between Francis Galton's death and 1945
the idea of eugenics had gone far beyond the fairly beni gn
ideas of Galton himself and had taken on some extremely
controversial aspects. In the first two decades of this
century, 16 states of the USA passed laws permitting
compulsory sterilization of various types of criminals,
epileptics, the insane, and the severely mentally
handicapped inmates of state institutions. Later on several
European countries followed suit, the most notorious being
Nazi Germany. After the abominable behaviour of the
Nazi doctors was revealed at the Nuremberg trials, the
sterilization side of eugenics became much less
fashionable, but it did not die out entirely: only last
summer there was a scandal in Sweden when it was
revealed that, during the period 1935-1976 some 60,000
Swedish women had been sterilized against their will,
either because they were considered to be mentally
handicapped or because they were not Nordic types.
So you can see that in accepting a chair with the word
Eugenics in its title, my father was stepping into a potential
minefield. He dealt with the situation adroitly. Although
he was strongly opposed to such things as compulsory
sterilization, he concentrated not on the moral side but on
the scientific side: that is, on finding out, like Galton
before him, real facts about human heredity.
In his inaugural lecture,* he set out his attitude very
clearly, and gave an example based on his own research to
show how ill-founded were some of the ideas of the
eugenicists. For his example he took a disease called
phenylketonuria, or PKU for short, which he studied
closely in his Colchester days. This disease, caused by a
recessive gene, leads to severe mental handicap and was in
those days almost untreatable. Today it can be treated by
means of a special diet.
He used this disease as an example against the idea of
trying to improve the racial stock by sterilization of the
unfit. First of all, it is pointless to sterilize the actual
victims of the disease, since hardly any of them have
children anyway, and anyway 99% of the harmful genes in
existence at any given time are in the carriers, not the
victims. The only way to eliminate the harmful genes
would be to sterilize all the carriers, assuming of course
that they could all be identified. But this would require
sterilizing about 1% of the population. As my father put it,
"only a lunatic would advocate such a procedure to prevent
the occurrence of a handful of harmless imbeciles".
Within a few years he was also challenging the arguments
of the milder eugenicists, those who did not advocate
sterilization but maintained gloomily that because people
of lower IQ tended to have larger families, the number of
low-IQ people must be increasing, causing the average IQ
to fall. His favourite counter-argument was that if the
eugenicists' argument were really correct, then back in the
time of William the Conqueror everybody must have been
supreme geniuses. He also argued that in any case the
eugenists' argument proves nothing, since even though
people of moderately low intelligence may indeed be more
fertile than the average, peopl e of extremely low
intelligence are much less fertile than the average, so that
the differences in fertility tend to cancel one another out.
Working at the Galton laboratory
During the 20 years from 1945 to 1965 when my father
was in charge of the Galton Laboratory, it became a worldrenowned centre for the study of human genetics. People
came from all over the world to work with him. In
particular he was the first clinical geneticist, that is to say
*recently reprinted; see page 49.
he advised parents who already had one mentally
handicapped child what the chances were that if they
had another child the new one would also have the
same affliction.
My father was always on the look-out for easily-tested
characteristics that might be attributable to a single
gene. A few rather well-known examples of such
characteristics are colour-blindness, the blood groups
A, B, 0 and the disease haemophilia. Now, some
people have a lot of difficulty distinguishing different
musical notes. We say that these people are tone deaf.
He had the idea that if colour-blindness was on a gene,
maybe tone-deafness was also on a gene, and so he set
out to devise an objective test for tone-deafness. His
idea for doing this was to ask the person being tested to
distinguish two versions of the same tune, one where
the tune was correct but the harmonies were unusual,
and the other where the tune had also been changed.
This particular idea may not have been a big scientific
success, but it does illustrate what you might call his
sense of amusement, and also his love of music. He
never took up musical composition seriously, but here
is another composition of his is which is at the same
time a kind of puzzle. I have given it the title WAS IT
A RAT I SAW, a palindrome which spells the same
backwards as forwards. This piece is a musical
palindrome. If you reverse it by turning the musical
score upside down, you get exactly the same music
(Fig. 11).
WAS IT ,4 AT
iai mmummonormiii mlimiurrnaiiiiiiiwn
MINIM
a
U1111110111111111111Maill111111Milli
miLINN
, AVIDINM
MWIMINEWT11111111111111•11E0
t mli oi l ow i mp vi m
lilliiiiiiimitinrnillimiiirtraBiroshwir
q
,. s.
11111111
taaillilling
zimmlitulmildiminni
iltifilimsrial
u
n i s m m a i m o11111011111111111111WMIIIIIMM
t i m a m m e a a i s s i l a w a i m mIL,
litillitiliiiii
11111111111111111
111•11111111•Iiiitisilikili
MII
f
PAVS?Key 11 S Vti
Figure 11: A musical palindrome
Not just a geneticist
Coming back to the late 40's, although we were no
longer at war with Germany and Japan it was far from
being a peaceful time. International events like the
Berlin blockade of 1948-9, the Korean war starting in
1950, and the first thermonuclear explosion in 1951
gave some of us the feeling that human existence itself hung
by a thread. As a good pacifist, my father felt that he should
try to encourage people in the Soviet Union who felt
friendly towards us in the West, and in the late 40's he used
to spend a lot of time at the premises of an organization
called the Society for Cultural Relations with the USSR, with
its subsidiary the Anglo-Soviet Chess Circle. My mother
used to called it his "spiritual home". I don't think he
pursued this much beyond about 1950, though. It was about
then that Soviet genetics was hi-jacked by a man called
Lysenko who was badly misinformed about genetics, but
very well-informed about how to pull the Stalinist political
levers for his own ends, and most of the good Sovi et
geneticists ended up in prison, or worse.
In 1951 the international situation still looked very serious.
My father and some of his colleagues wrote a letter to the
medical weekly "The Lancet" which, crudely paraphrased,
said that a nuclear war would be a public health catastrophe
and therefore doctors had the ethical duty to try to prevent
war. The letter led to the formation of The Medical
Association for the Prevention of War, of which my father
was a founder member, and later chairtnan for more than 10
years, and my mother was the editor of their bulletin for a
similar period. The MAPW was part of the worldwide
protest movement which eventually led, in 1963, to the
signing of the treaty banning nuclear weapon tests in the
atmosphere. The stated aims of the MAPW included
studying the causes and results of war, and what they called
the psychological mechanisms by which people were
conditioned to accept war as a necessity. One of my father's
own contributions to these investigations was his booklet
"On the objective study of crowd behaviour", which
appeared in 1952.
During the last 10 years or so of his life he became interested
in a very fundamental problem: what is life? What is the
essential difference between the living matter in a plant or
animal or human from the non-living matter in a stone or a
piece of paper? And how did the first living matter come
about, in a world where until then there had been no life at
all? The idea had been around for some time that the
essential difference between living and non-living matter is
the ability of living matter to grow, to manufacture more of
itself. This raised the question, how does this self-replication
work; what is the mechanism, inside the living cell, a yeast
cell, for example, by which the cell reproduce s itself? My
father wanted to show that very simple structures could
replicate themselves. So that if at some time in the distant
past of our planet this structure had arisen by some chance
arrangement of non-living matter, it could have
automatically begun to grow, and life on Earth would have
begun!
So here was another puzzle for my father to work on, to
invent simple structures that could replicate themselves.
To help him think about it, he started making himself
wooden working models having a self-replicating
property. There is an illustration of this on page 4. It
comes from a paper he wrote jointly with my brother
Roger in 1957. The boat-like things rested on a flat rail,
and to make the model work he shook the whole thing
from side to side. So long as you started from the
position illustrated on the top line nothing much
happened, but if you connected two of the boats
together, as illustrated at the left of the second line, then
the shaking would cause others to link up, leading
eventually to the position on the last line. So the
structure consisting of two boats linked together has
replicated itself, given what he called the right "food" --in
this case, the food consisted of individual unlinked
"boats".
Around about this time the cell biologists were finding
out by extremely clever experiments how DNA actually
does replicate itself in living matter. It turned out that the
mechanism was different from the one with the boats.
The DNA molecule is rather like a zipper, and in its
normal state the two halves fit together, the zipper is
done up. But the wonderful thing is that if you put it in
the right kind of chemical soup and then unzip it, then
as the two halves come apart each of them will attach to
itself molecules from the soup so as to make the other
half of a new zipper.
I suspect that my father must have been very
disappointed that he had not been the one who hit on that
crucial idea of self-replication by zipper. For many
years he continued to make wooden self-replicating
mechanisms of ever-increasing complexity and
ingenuity. Some of them are preserved in the Science
Museum in London. He enjoyed making them and he
also enjoyed showing them to an admiring audience --perhaps some compensation for the much more
widespread admiration he would have attracted if he had
been the one who solved the problem of life itself by
thinking of the zipper mechanism.
This work may call for some posthumous admiration
too. It is thought that BSE and related diseases are
caused by a particular kind of big molecule called a
prion. Prions don't contain DNA, but even so they seem
to be able to reproduce themselves. What's more, their
chemical structure seems to be similar to the structure
my father came up with when he tried to think up a big
molecule that could reproduce itself using his
mechanism rather than the DNA zipper mechanism. So it
may be that his mechanism is the one prions use, and if
you hear one day that a cure for BSE has been
discovered it is conceivable that my father's ideas about
self-reproduction may have contributed to it.
In 1964 my father received a prestigious award from America,
given by the Kennedy family in recognition of the mental
retardation of President John F Kennedy's sister Rosemary, and
presented by President Lyndon Johnson in person. But he did
not spend the money on himself the way that many people
would: buying a bigger house, a new car, or even a new suit.
Instead he used the money to help establish a research centre at
Harperbury Hospital near St Albans. So after his retirement
from University College in 1965 he didn't stop working, he just
transferred his place of work to this new Kennedy-Galton
Research Centre. He continued working there, close to the
mentally retarded hospital patients he liked so much to study,
until his death in May 1972.P
Acknowledgements
I am grateful to Richard Barnwell, George Fraser, Neil
Hamilton, Shirley Hodgson, Humphrey Hodgson, Anthony
Penrose, Joan Penrose, Martin Penrose, Alex Poteliakhoff and
Michael Smith for information, artifacts and helpful suggestions
used in the preparation of this talk.
Bibliography
C Gander, The Peckover and Penrose family tree, in leaflet
Peckovers of Wisbech published for the exhibition of the same
name, Wisbech 1980 (?)
H. Harris, Lionel Sharples Penrose 1989-1972 Biographical
Memoirs of Fellows of the Royal Society 19, 521-561 (1973)
D. J. Kevles, In the name of Eugenics. Harvard University
Press.
M Newman (formerly Mrs Margaret Penrose), The Peckovers
of Wisbech,address at the opening of the Peckover Exhibition in
Peckover House Wisbech on 14 July, 1980
M Newman, unpublished memoirs, circa 1988.
M. G. H. McReynolds, The Peckovers of Wisbech : a Quaker
banking family. Wisbech Society and Preservation Trust,
Wisbech (1994)
E. J. Penrose, Alexander, Baron Peckover of Wisbech printed
for private circulation by W Poyser, Wisbech, circa 1919.
L. S. Penrose, Psychoanalysis and chess, item 5/1 of the
Penrose archive, manuscripts room, University College London
library; diary, item 4/1 of the same; music manuscripts items
6/1 and 6/2 of the same; photographs item 8/2 of the same.
L. S. Penrose, The relative effects of paternal and maternal age
in mongolism, J. Genetics 27 219-224 (1933)
L . S. Penrose, Phenylketonuria : a problem in eugenics
(inaugural lecture delivered at University College on Jan 21 ,
1946) Lancet June 29 1946, pp 940-953.
Lionel Penrose as Galton Professor
E.B. Robson, Galton Professor Emeritus
As many of the people here today to celebrate this Centenary knew Lionel Penrose best as
Galton Professor at UCL, I shall speak mainly about his work in this context. If this seems a
shade parochial I will excuse myself in advance by reminding you that for his Presidential
Address at the Third International Congress of Human Genetics in Chicago, in 1966, at about the
time of his retirement, Penrose chose to speak on "The
English Tradition of Human Genetics". This was much
criticised at the time, but it reflected the man. He was
not a globe-trotter - he preferred to be in his own place, a
broken down armchair overlooking the traffic of Gower
Street, and it's about that place that I will speak.
Soon after my arrival at the Galton as a Ph.D. student
Penrose asked me to look at a manuscript which had just
arrived for the Annals. Before I had time to do more than
look at the first few pages Penrose became impatient and
came looking for me to ask what I thought of it. I
protested that I hadn't finished reading it. "Reading it?",
he said, "I never read the text, I don't care what they
think, I only look at the Tables." This made a big
impression on me, and when, in turn, I became Editor of
the Annals, I tried to remember that opinions are one
thing but that Tables have to add up.
This fascination with numbers was at the core of his
personality. It didn't seem to matter what they were
about, the incidence of Down Syndrome at different ages,
the way people vote and behave in crowds, or even the
frequency of different parts of speech in the plays of
Shakespeare. What we used to call "The AntiShakespeare Society" was one of his favourite leisure
pursuits. It combined the use of numbers in the unusual
context of literary criticism, with the unpopular view that
William Shakespeare didn't write the plays of
Shakespeare.
Expertise and iconoclasm were an
irresistible combination for him.
Penrose's scientific reputation was based on the
"Colchester Survey", a study of mental deficiency in the
area where he worked in the 1930s. A government report
in 1929 had drawn public attention to the problem when
it claimed that 300,000 people in England and Wales
could be certified as mentally deficient, but it was
recognised that the statistics were hard to interpret in
medical terms, since they were based on Poor Law
definitions regarding destitution. More scientific input
was clearly needed and the MRC supported Penrose in
his Survey of 1,280 patients and their relatives. The
result, as they say, is history, but it illustrates very well
my point about his reliance on numbers as almost exactly
hal f t he Re p or t w as d e vo te d t o a n Ap pe nd ix
summmarising the data, whilst the minimalist text
included no fewer than 62 Tables, at least one per page.
It is interesting to look back to Galton's work on the same
subject. In his book "Hereditary Genius" Galton also considers
the other extreme, and speaking of them he says:
"No doubt a certain proportion are idiotic owing to some
fortuitous cause which may interfere with the working of a
naturally good brain, much as a piece of dirt may cause a first
rate chronometer to keep worse time than an ordinary watch."
Using the genetical approach Penrose sorted out some of these
"bits of dirt", but his general conclusion was not unlike
Galton's, that the causes were multiple, and it was to sorting
out some of these causes that his future work was directed,
appropriately enough in the Chair endowed by Galton himself
in the University of London.
The previous Professors were Karl Pearson and R.A. Fisher,
both statisticians of distinction, and so when the Chair came to
be refilled after the War Penrose was a fitting choice. He was
the first medical graduate in the post and so he came to a
Department lacking any clinical facilities. As eugenics was not
part of the undergraduate curriculum the Department
functioned solely as a Research Unit, although Penrose himself
gave a weekly lecture. All the members of staff attended these
lectures each year, in order to make up some sort of critical
mass. JBS Haldane also attended - in his deck chair! Penrose
went to JBS' lectures, and this was characteristic of the very
great respect which the one felt for the other, although they
could not have been more different in personality. JBS'
interests in population genetics, especially in mutation rates and
heterozygous advantage were crucial to Penrose's very deep
perception of the range of his chosen subject. Penrose was
fortunate in gaining the support of the Rockefeller Foundation
from the beginning, and keeping it for 20 years. This
connection with the USA was important and brought many
Americans to the Galton in the succeeding years.
Penrose gave the appearance of being an archetypal Quaker,
quiet and unostentatious, and, unlike most Professors, not
seeming to insist on his own way. (Or indeed to revealing what
that way might be.) But somehow most of the staff found
themselves in number-generating exercises. The classical
approach of collecting pedigrees was continued by Dr Julia
Bell, as in the days of Karl Pearson, but Mary Karn found
herself collecting data on human birth weight. She was joined
in this study of quantitative inheritance by two young people,
Robson and Fraccaro. Sarah Holt, a mouse geneticist in the
days of Fisher, found herself taking fingerprints, and hence
counting dermal ridges.
biochemical individuality similarly left the Galton, first to the
London Hospital Medical College and then to King's College,
London, when Harris became Professor of Biochemistry there.
Penrose's first new appointment was, not unexpectedly, of a
mathematician. Cedric Smith always claims that he didn't
really know the nature of the job for which he was
interviewed. Be that as it may, he went on to collaborate
closely with Penrose on the theoretical side and to provide
solid support to generations of research fellows.
Penrose's satisfaction with these developments was clearly
expressed in his Chicago lecture:
In the Colchester Survey Penrose had written that "it is the
aim of modern research in human genetics to examine the
behaviour of individual genes (and) to determine the
topographical relationship of one gene to another", giving as
a reference his own paper in the Annals on the detection of
autosomal linkage using sib pairs. He saw clearly however
that morphological characters made poor test loci (even
though Ed Reed was working on the genetics of hair colour at
that time) and the most promising candidates were the blood
group loci. To restart serology at the Galton Penrose recruited
Sylvia Lawler. She joined the Lab after learning blood
grouping from Rob Race at the Lister Institute.
Typing families was a major activity in the 50's, especially
after the arrival of the super-energetic Jim Renvvick. Not only
English families, but data arrived from Ferrara and Sardinia
when Marcello Siniscalco made the first of his many visits.
After the initial success of Jan Mohr in detecting an autosomal
linkage group, Sylvia and Jim also met with success. It was in
these pre-computer days that we all depended so heavily on
the computations done by Sheila Maynard-Smith and
published in the familiar blue book - Smith, Penrose and
Smith, Mathematical Tables for Research Workers in Human
Genetics.
Penrose was also very sympathetic to biochemistry. Within a
year ofling's description of phenylketonia Penrose had
found a case at Colchester and investigated it experimentally
with the help of Krebs, and even then involved Gowland
Hopkins in attempts to devise a low phenylalanine diet. Harry
Harris arrived at UCL soon after Penrose, and after a brief
foray into sense perception with Hans Kalmus, he was
encouraged into the ambience of Charles Dent and metabolic
medicine, and the days of chromatography started in the Lab.
At first the studies were on known diseases such as cystinuria,
and here Ursula Mitrwoch's skills in microbiology were
deployed in developing the bioassay of amino acids.
The biochemical work moved more into the same area as the
serology when Oliver Smithies introduced starch gels and
showed that common individual differences could be detected
using electrophoresis. This was the start of the description of
polymorphic enzyme markers, and their use in linkage studies.
The work on red cell antigens slowed down and Sylvia's
interests took her into transplantation and hence to cancer
genetics at the Institute of Cancer Research. The work on
"the exact description of the hereditary polymorphisms, which
overrun the boundaries of antiquated ideas of racial groups,
help us to comprehend, rather than to deplore each other's
inborn peculiarities."
The extension of experimental techniques in cell culture and
the resultant description of the human chromosome
complement was perhaps the advance which gave Penrose the
most personal pleasure, as Down's Syndrome always
remained close to his heart. Joy Delhanty set up this
technique and still runs Cytogenetics at the Galton. Penrose's
"nose" for curious and informative cases of mental deficiency
was invaluable, but case material perhaps lacked, for Penrose,
the cherished aspect of generating numbers. But not for long.
By studying abortions a whole new dimension opened up,
interest in mutation revived and selection
during the
interuterine period could be investigated.
Using sex
chromosome abnormalities he reinvestigated finger ridge
count, and then embarked on even more esoteric analyses of
the general topology of dermal ridges.
In his retirement he set up a research Unit at Harperbury
Hospital called the Kennedy Galton Centre
for Mental
Defic ie ncy Re sear ch a n d Dia g n os i s. Ke n ned y in
acknowledgment of yet another American benefactor, the J.P.
Kennedy Foundation, but Galton? Penrose seemed not to be a
sentimental man, and many of the ideas of Galton did not
appeal to him, but perhaps, when it came to the point, he
couldn't give up being a "Galtonian".
To those of you here today the expression "The Galton
Laboratory" is a commonplace. It provokes no uncertainties
but in fact it is an illusion. There is no such place. Lionel
Penrose simply used it as a heading for his notepaper in order
to avoid giving his address as the Department of Eugenics!
Penrose was a dedicated opponent of Eugenics which he
regarded as an uninformed and dangerous policy of racial
purification and despite his general lack of interest in outward
forms, he devoted a great deal of energy to ridding the College
of the taint of Eugenics. He did not succeed in getting the
Chair renamed until 1963, because of legal difficulties over
the working of the Galton Bequest, but in 1954 the Annals of
Eugenics became the Annals of Human Genetics, and in 1965
the College changed the name of the Department. This really
symbolised the years in which Penrose influenced the most
fundamental change in our subject from an armchair discipline
of a semi-sociological nature, to a fully fledged laboratory
subject.
The origin of
trisomy in
humans
Terry Hassold
Department of Genetics, Case
Western Reserve University,
Cleveland OH 44106 USA
INTRODUCTION
Trisomy is the most commonly identified chromosome
abnormality in humans, occurring in at least 4% of all
clinically recognized pregnancies. The vast majority of
trisomic conceptuses spontaneously abort; indeed, trisomy
is the leading known cause of pregnancy loss, with no less
than 25% of miscarried fetuses having an additonal
chromosome. Occasionally, trisomic fetuses survive to
term, but these are typically associated with characteristic
genetic disorders, the most common of which is Down
syndrome.
Despite the incidence and obvious clinical importance of
trisomy, we still know relatively little about its origin, that
is, the mechanisms that cause chromosomes to non-disjoin
in meiosis in either the oocyte or sperm. However, this
situation is now changing, due to advances in molecular
and molecular cytogenetic technology. In the following
review, we summarize some of the recent developments,
particularly as they relate to our understanding of three
basic questions:
1) in which parental gamete and at what stage of meiosis
d oe s no n -d i sju nc ti o n o c c ur , a nd d o d i ffe r e r e nt
chromosomes behave similarly or dissimilarly with respect
to this process?
2) what is the relationship between parental age and
trisomy and, in particular, what do we know about the
basis of the association of increasing maternal age with
trisomy?
3) is there an association between aberrant genetic
recombination and meiotic non-disjunction in humans?
1. THE PARENT AND MEIOTIC
STAGE OF ORIGIN OF TRISOMY
The recent identification of multiple, highly polymorphic
DNA polymorphisms on all human chromosomes has
made the determination of parental origin of trisomy a
straightforward matter. In our laboratory and those of our
collaborators Patricia Jacobs, Stephanie Sherman and
Wendy Robinson, we have used this approach to study the
parent and meiotic stage of origin of over 1000 trisomic
fetuses or liveborns, with the results being summarized in
Table 1. The most extensively studied condition has been
trisomy 21, with over 700 informative cases. Maternal
errors predominate, accounting for about 90% of cases. Of
these, over 75% are compatible with meiosis I (MI)
nondisjunction, while for paternal trisomy the reverse is
true. A small proportion, approximately 5%, of cases are
apparently due to mitotic nondisjunction See table 1 overleaf
The other human trisomies that have been studied display
remarkable variability in origin. Nevertheless, the available
evidence suggests that – like trisomy 21 – errors at maternal
MI predominate for most trisomies.
2. THE PARENTAL AGE EFFECT
The association between increasing maternal age
and trisomy is one of the most important etiological factors
in human genetic disease. For trisomy 21, an exponential
increase in risk occurs in the mid-30s, and this risk is still
the most common reason for offering prenatal diagnosis to
older women. The association between maternal age and
other trisomies is not as well known, since most such fetuses
spontaneously abort. Nevertheless, the age effect extends to
these conditions as well. In fact, for women in their forties
the chance of having a conceptus trisomic for any
chromosome is probably at least one in five.
Despite the obvious clinical importance of the
maternal age effect, we still know little about its basis.
Several models have been proposed to account for the
effect. These include prenatally determined differences in
chiasma frequency among oocytes, leading to an age-related
increase in the frequency of univalents (the so-called
"production line hypothesis"); a declining oocyte pool with
age; diminishing ability to select against aneuploid oocytes
with age; and changes in the follicular environment, spindle
apparatus, or meiotic cell cycle in the ageing. However, it
remains unknown which, if any, of these models apply.
Indeed, until recently it has not been possible even to dispel]
the idea that the age-dependent increase in trisomy is due to
decreased likelihood of aborting a trisomic conception rather
than to an increase in trisomy frequency at conception.
Recently, molecular studies finally have put this
last, "relaxed selection", model of the maternal age effect to
rest. That is, the model predicts the presence of a maternal
age effect in trisomy, regardless of the parental origin of the
extra chromosome. However, studies of trisomy 21 and sex
chromosome trisomy indicate an age effect in cases of
maternal, but not paternal, origin. Furthermore, in trisomy
18 and trisomy 21 those cases consistent with a mitotic
origin show no association with increasing maternal age,
regardless of the parent of origin of the additional
chromosome. Thus, it seems likely that the maternal age
reflects the amount
of recombination that
Origin (in %)
occurred
Maternal
No. of
Paternal
mei o si s,
t hi s
Trisomy
Cases
Mitotic
I
II
approach makes it
2
18
28
54
13
6
possible to compare
7
14
17
26
57
the
15
34
15
76
9
meiotic
16
104
-100
recombination
that
I8
143
-33
56
11
21
724
3
5
67
22
2
occurred in normal
22
38
3
-94
3
versu s
tr is o my XXY
142
46
38
14
3
generating
meioses.
XXX
50
6
60
16
Several laboratories
have now used this
effect is restricted to cases involving maternal meiotic nonapproach to study recombination and nondisjunction and it
disjunction.
is now clear that most—if not all—human trisomies are
associated with alterations in recombination (Table 2).
However, there is less certainty about the relative importance
Most studies have focused on maternal meiosis I errors,
of advanced maternal age on errors at meiosis I and II. In
and have identified significant reductions in recombination
maternally derived sex chromosome trisomy, the increase in
in the nondisjunctional meioses. Unexpectedly, in studies
maternal age is limited to cases of maternal meiosis I origin.
of trisomy 21 of meiosis II origin, there appears to be an
Similarly, in trisomy 16, a condition thought to be entirely
excess of recombination, suggeting that -- at least for
maternal-age dependent, virtually all cases result from
trisomy 21 -- errors scored as arising at meiosis II may
maternal meiosis I non-disjunction.Thus, these studies
actually have their genesis at meiosis I.
implicate an age-related effect on maternal meiosis I, but not
meiosis H. However, in studies of trisomy 21 and trisomy 18
PERSPECTIVE AND FUTURE
there is no significant difference in mean maternal age in cases
STUDIES
of maternal meiosis I and maternal meiosis II origin, even
In the
past, research on human trisomy has
though both trisomies are known to be more common in older
women. This suggests that, for these chromosomes, increasing
focused on
characterizing the incidence and origin of
maternal age affects chromosome segregation at both
different trisomic conditions, and on evaluating the
divisions. Thus, it may be that the causes of maternal ageincidence of
trisomy in different types of clinically
related trisomy vary among chromosomes, with some
recognized pregnancies. These studies have provided
chromosomes being susceptible to meiosis I and meiosis II
valuable information on the occurrence of trisomy in our
non-disjunction with age, and others only to meiosis I nonspecies, but have provided little insight into the underlying
disjunction.
mechanisms responsible for non-disjunction. Recently,
Table 1- Summary of studies of the parent and meiotic/mitotic stage of origin of human u-isomies
RECOMBINATION AND NONDISJUNCTION
3.
In yeast and female Drosophila, the relationship
between errors of meiotic recombination and non-disjunction
is well established. In both, mutants which reduce meiotic
recombination invariably have increased frequencies of nondisjunction, indicating that a certain level of recombination is
necessary to ensure proper chromosome segregation. See table 2
overleaf.
Until recently, there were no data on the possible relationship
of aberrant recombination and non-disjunction in humans.
However, with the advent of DNA polymorphisms, it has
become possible to construct genetic maps of normal and
trisomy-generating meioses; since the length of a genetic map
this situation has begun to change, with more attention
being given to studying the basis of human non disjunction. This has resulted in the identification of an
important correlate of human trisomy, namely aberrant
genetic recombination. In future studies of recombination,
it will be important to determine if increased, as well as
decreased, recombination is associated with trisomy; if
aberrant recombination is important in the genesis of
trisomy for all, or only certain, chromosomes; and if the
suggested
association between maternal-age dependent
trisomy and aberrant recombination is real.
It a ls o wil l be i m p orta nt to a p ply ne w
technologies to study chromosome behavior in the cells of
origin of non-disjunction, i.e., sperm and egg cells. Recent
advances in
fluorescence in situ hybridization (FISH)
Table 2 – Summary of genetic map lengths -- trisomy-generating vs. normal meioses
Stage of origin
No. of
cases
Paternal I
39
13
52
XXX, XXY
15
16
18
21
Maternal I
73
181
98
63
47
382
172
146
72
129
91
39
XXX, XXY
18
21
Maternal LI
24
84
133
181
146
72
140
138
107
Trisomy
Map length (cM)
Normal
Trisomic
XXY
technology now make it possible
to s tud y t he s egre ga ti o n of
individual chromosomes and, by
combining this approach with
studies of human spindles, to
actually visualize the movement
of individual chromosomes
during cell division. Preliminary
studies using this approach to
st ud y hu ma n a nd m u rine
oogenesis are already underway
and should provide a powerful
approach to the analysis of
female non-disjunction.
Male non-disjunction is also now amenable to systematic analysis, since FISH can be used to rapidly screen for
aneuploidy in sperm. Using this approach, it will be interesting to correlate sperm aneuploidy levels with variation in speci fic
chromosome structures, such as centromeres and peri-telomeric sequences. The former are essential for normal chromosome
segregation and the latter are associated with high levels of recombination in the male; both are extremely variable in human s. By
combining standard molecular techniques with FISH, variants in chromosome structure can be identified and their effect on
chromosome segregation monitored by screening sperm for evidence of aneuploidy. This approach will be useful for studying
paternal non-disjunction, and may well lead to the identification of hereditary components to human trisomy.
this article appears in the Annals of Human Genetics. Koehler & Hassold. Vol 62 Part 2 November 1998.
e
A fuller version of
A review of this topic by Dr Hassold will appear in the Annals of Human Genetics.
Preimplantation genetics of Down syndrome
Joy D. A. Delhanty
The Galton Laboratory, University College London, UK
In 1959, as I was about to graduate, Lejeune published his finding of an additional small chromosome as the cause of Down
syndrome, DS, (or mongolism, as it was then called). I found this very interesting and talked about it with my tutor, John
Maynard Smith. John wondered whether this discovery would prompt Lionel Penrose to take on a student to work in this
field. This turned out to be the case and so it was that I went to the Galton Laboratory to occupy the niche that Professor
Penrose had for so long reserved for someone to work on somatic chromosomes. The next few years were very exciting,
with new chromosomal syndromes described every few months. Among the reports was one by Polani and colleagues of a
DS child with 46 chromosomes, due to Robertsonian translocation. Professor Penrose had among his collection of families
one in which two sibs were affected with DS, born to a relatively young mother. When I cultured the skin fibrobasts it was
evident that both DS sibs had 46 chromosomes, with a DG type Robertsonian translocation, but the mother had 45
chromosomes, and the same translocation. This was the first example of this type of rearrangement in a parent causing
predisposition to DS in the offspring.
Today, most families of this type, and others at high risk of transmitting genetic disorders, can be helped to achieve a normal
family by means of prenatal diagnosis. Some, however, are unsuccessful, and together with those unable to contemplate
pregnancy termination, are requesting an alternative, such as genetic diagnosis before implantation.
Preimplantation genetic diagnosis (PGD) involves biopsy of the embryo 3 days after fertilisation in vitro following routine
superovulation procedures. The embryo by then consists of 6-10 cells of which 1-2 can safely be removed for molecular
diagnosis using the polymerase chain reaction (PCR), for monogenic disorders, or fluorescent in situ hybridisation (FISH) for
interphase chromosome analysis. We now routinely use FISH with X and Y chromosome specific probes to sex the embryo
in families with X-linked disorders. Data that we have accumulated since 1991 of the spare embryos from these PGD cycles
has shown that in 3 day-old human embryos chromosomal mosaicism is very common, affecting at least 30% of those
apparently normally developing. This could be one of the main factors affecting the success of IVF. Moreover, we have
shown that the most extreme form of mosaicism, where there appears to be completely uncontrolled division, is str ongly
patient related. In the last few years we have progressed to using FISH to detect chromosomally unbalanced products due to
parental translocation or gonadal mosaicism. The first couple came after 3 consecutive DS pregnancies, two of which were
terminated. Gonadal mosaicism in the mother was suspected, although this could not be proved somatically. In collaboration
with the IVF Unit at the Hammersmith hospital we carried out two cycles for PGD, using a dual colour FISH strategy to test
for chromosome 21. In the second cycle, two embryos were normal for the tested chromosome and transferred to the mother,
but with no ensuing pregnancy. Overall, four of the remaining 5 embryos were trisomic for 21, the fifth was tetraploid.
Similarly, 3 of 4 oocytes that remained unfertilised had additional copies of chromosome 21. The fact that in 2 oocytes
additional material was of chromatid origin suggested that the mechanism leading to such a hi gh frequency of chromosome 21
aneuploidy (7/11 eggs or embryos) involved precocious chromatid separation early in meiosis as proposed by Ros Angell.
The second couple came for PGD after 4 early miscarriages and the birth of a daughter with DS had led to the detection of a
maternal balanced reciprocal translocation, 46, XX, t (6;21). This couple also underwent 2 cycles of PGD; one embryo tested
normal for chromosome 21 by dual-colour FISH and was transferred, leading to a biochemical pregnancy. All ten of the
remaining embryos or oocytes were unbalanced for chromosome 21, the ma jority due to 3:1 disjunction at meiosis. This
provided the first opportunity to test directly the outcome of female meiosis in a reciprocal translocation carrier. So, alth ough
the very high level of unbalanced meiotic products in these couples meant that they did not achieve a normal pregnancy we at
least made progress in beginning to understand the reasons for this and the possible mechanisms involved.C-1;
The Fragile X Syndromes
Patricia A Jacobs
Wessex Regional Genetics Laboratory, Salisbury District Hospital,
UK
Among the many research interests of Lionel Penrose one
that ran as a constant thread through his scientific life was
the investigation of the causes, and especially the genetic
causes, of mental retardation. It is a great loss to all of us
that he died before the discovery of the trinucleotide repeat
diseases. This novel class of mutations, with no precedence
in any experimental organism, would surely have delighted
him; firstly because it explains some common types of
mental retardation as well as disease, such as Huntington's
and Myotonic Dystrophy, that have long puzzled human
geneticists, and secondly, because the underlying mutational
mechanism has revealed a new type of inheritance in which
the rules of Mendel do not apply. The trinucleotide repeat
mutations are an enigma for geneticists but I am sure that an
original thinker such as Lionel Penrose would have enjoyed
and been more that equal to the challenge.
The first trinucleotide repeat disease to be discovered was
the Martin-Bell, or Fragile X syndrome, an X-linked disease
associated with moderate levels of mental retardation. The
disease is caused by an expansion of a CGG motif in the
first exon of the FMR1 gene. The repeat is transcribed but
not translated and when more than 200 copies of the repeat
are present they are associated with methylation, repression
of the gene and absence of this protein product. The
absence of the FMRI protein leads to mental retardation.
More recently a second X-linked gene, situated distal to
FAIR', has been described. This gene, FMR2, also causes
mental retardation, although milder that the with FMR1
form, and again the retardation is associated with
expansion of a transcribed but not translated, trinucleotide
repeat, namely CCG, in exon 1 of the gene.
The trinucleotide repeat expansion of both FMR1 and
FMR2 appears to exist in three forms: normal, with repeat
numbers of up to 50, permutations with repeat numbers of
approximately 50 – 200, and full mutations with repeat
numbers over 200, the latter being associated with
transciptional silencing of the genes and mental
retardation. The mutational mechanisms underlying the
change from normal, to pre-mutation to full mutation are
not understood. However, the discovery that the mutation
is associated with a trinucleotide repeat expansion has
provided a tool with which to investigate the biology of
these genes.
We now know that the diseases are not as frequent as was
first thought: FRAXA mental retardation (associated with
the expansion of the FMRI gene) occurs in approximately
1/6,000 – 7,000 males, while FRAXE retardation
(associated with expansion of the FMR2 gene) is
extremely rare. We know that the change from pre- to full
mutaiton only occurs during female gametogensis and is
determined by the size of the premutation in the mother.
The mutational mechanism that underlies the change from
normal to premutation in the mother. The mutational
mechanism that underlies the change from normal to
premutation in not understood (nor has it ever been seen!)
but it must be complex and appears to depend on the
number of repeats, their haplotypic background and, in
FRAXA, the number and position of interspersed AGGs in
the trinucleotide repeat array.
Until recently the perceived wisdom was that premutations
were without phenotypic effect, as the FMR 1 protein
appeared normal in premutation carriers. However, two
recent pieces of evidence suggest that alleles in the
premutation range may have a phenotypic effect. The first
of these is the surprising observation that some 23% of
females with FRAXA premutations (but interestingly
enough not those with full mutations) have premature
ovarian failure, while the rate in the general population is
only 1%. Secondly, there is some evidence from our large
survey of boys with special educational needs of a
significant excess of boys with premutations and alleles in
the large "normal" size range by comparison with controls.
If this is substantiate, it suggests that such alleles may
contribute more to the etiology of mental retardation than
full FRAXA mutations and furthermore that the FMR1
gene may affect mental ability in at least two ways, as
well as having an important role in the maintenance of
ovarian function.
How Lionel Penrose would have loved such a puzzle. oa
50 years on - linkage
N.E. Morton
Human Genetics, University of Southampton, UK
When Penrose assumed the Ualton chair in 1945 genetic markers were virtually limited
to blood groups, methods to detect and estimate linkage were ingenious but inefficient, and no autosomal linkage had been
recognised in man. During his tenure the Galton Laboratory was the focus for linkage studies, and all the early successes with
major genes were made by investigators who worked or had trained there, including development of lods by Cedric Smith and
mapping of myotonic dystrophy by Jan Mohr, elliptocytosis by Sylvia Lawler, and nail-patella syndrome by Jim Renwick.
Curiously this primacy was not reflected in the biography of Penrose written by Harry Harris for the Royal Society, which does not
mention linkage. The independence that Penrose encouraged must have obscured the pivotal role he played in extending linkage
from half a dozen Galtonians in the Fifties to several thousand researchers today. The turning point was demonstration of two
clinically indistinguishable types of elliptocytosis, one due to mutation in protein band 4.1 closely linked to the Rhesus blood group,
the other caused by defects in unlinked spectrins. This example of the power of linkage opened the door to a science of medicine
based on causes rather than symptoms.
As reviewed by John Edwards, the unique contribution of Penrose to mapping was nonparametric analysis of affected sib pairs.
Introduced in 1935 to dispense with parental genotyping, it lay fallow until DNA technology provided a high density of
markers that could be used to map oligogenes underlying common diseases too complex for parametric analysis. This
development, not fully appreciated during the lifetime of Penrose or indeed for many years afterward, promises to dominate
human genetics for the next 50 years. In time linkage and allelic association, which depend not on physical assignment but on
the same genetic map, will have the database required for efficient localisation of disease genes, comparable to one of the
current multiplicity of sequence databases.
The papers presented here reflect the range of Penrose's mind, from the personal recollections of Cedric Smith to the next
generation of nonparametric methods used by Tony Monaco. Therefore this Penrose celebration is as much a glimpse into the
future as commemoration of an Augustan age when small was not only considered to be beautiful but proven to be effective,
when the Galton professorship was the senior chair in human genetics, when linkage had not yet reached its apogee, and when
alternatives to locate genes were (except for deletion mapping) inconceivable.ffi
Memories of
Lionel Penrose
Cedric Smith
University College London, UK
Someone has said, "in these days
we are privileged to sit side by side with the giants on
whose shoulders we stand". The giants who founded
mathematical genetics, especially human genetics,
were Fisher, Hogben, Haldane, Wright and Penrose. I
have not sat side by side with all of them, but I have been even
more lucky, in that they have all been personal friends.
In 1945 I was working with Friends Relief Service, packing
bales of secondhand clothing to go to the areas of Europe
devastated by the recent war. A friend said to me, "Lionel
Penrose is looking for a statistician". So I went to see him.
We chatted, and he asked me what was my occupation.
"Working for Friends Relief Service". Somehow I had the
impression that he knew what that was, and indeed, later on I
found that he had offered his country house for the use of
Friends Relief Service.
Then he said, "You must see
Professor Haldane."
I made an appointment to see Prof Haldane at 6 o'clock
one evening, and turned up, only to find his room empty
and locked. I was baffled, but then a door opened,
somebody emerged, and in response to my appeal, he
suggested trying another door. I found the great man in
a deck chair, surrounded by masses of algebra. "We
weren't expecting you till 6" he said, it then being 6.15,
"You know why you have come here. Prof Penrose
wants me to test you on your mathematics. He thinks
we might have a job for you, but I DON'T THINK SO.
Have you read my paper on (something or other)? "No." Have you read my paper on (something or
other)? - "No." Have you read my paper on (something
or other)? - "I'm sorry ." - "Don't be sorry. I didn't
think you would have done. Would you like to have
supper with me and my wife?" - "Yes please." End of
interview.
Weeks went by, month went by, nothing happened. So I
came up to London to see Prof Penrose. "Tell me, have
I got the job, or haven't IT'. - Yes, you've got the job.
I'll ring the College Secretary ........... He says that the letter
of appointment is just being written. When will you
start?" For some reason, I suggested july 23.
Weeks went by, months went by, nothing happened. I
applied for another job. Then a letter came from UCL
"You have been appointed as Assistant Lecturer from
october 1". So I rang Lionel Penrose, asking if I should
start on july 23 or october 1. "On july 23, of course." "But will I get paid ???" - "Yes."
So I walked into the Galton Lab on july 23, and the
Professor's Secretary, a charming northern Irish lady,
emerged, saying, "We've been expecting you for a long
time, Dr Smith." Then Lionel Penrose appeared and
asked, "Are you musical ?" - "I hope so. Why?" - "I
have here a record of 25 common tunes (such as
Clementine or God save the Queen). They are played
twice, once right and once wrong, and it for you to listen
and say which is which." Some of the mistakes were
obvious, some quite subtle.
But I made only one
mi st ake i n t he tes t . "T ha t s h o ws t hat n o t all
mathematicians are tune-deaf', said the prof, "now I
will introduce you to Dr Hans Kalmus." Hans produced
some liquid, asking me to say whether it smelt of lemon
or of almond. After trying, I had to confess that I was
not sure. "That's all right", said Hans, "That's where
most people hesitate. Now I will introduce you to Dr
Sadie Holt. She will take your finger-prints.
So I started work in the Galton Lab, almost 52 years
aczo, and I am still there. When I was a student, I
happened to come across some book by Haldane. I read
parts. found them fascinating, and thought that it could be
quite fun being a mathematical geneticist, following
Haldane, Fisher and Hogben as they together worked out the
theory in perfect harmony. Now I was starting a career as a
mathematical geneticist, not any conscious choice, but
simply because it happened to be the first academic job
which came my way.
However, I was soon to be rather disillusioned about my
vision of harmonious collaboration between Haldane, Fisher
and others. As in so many other fields, relations between the
real top experts were marked by considerable bickering and
snarling. However, Lionel Penrose was something of an
exeception. Memory is fallible, but I can not remember him
speaking an unkind word about any particular person (in
spite of disagreements with the opinions of particular
groups, such as the eugenicists.)
Once a year Lionel would take a party to Harperbury
Hospital, the home of a group of mentally retarded
individuals, partly to explain any genetic implications, and
to introduce us to several inhabitants. I got the impression
that he looked on each resident, not simply as a patient, or as
inferior, but as a fellow human being, to be treated with the
respect due to every person, and as a personal friend.
There was in UCL at the time a "Professors Dining Club",
which met at intervals to dine and hear a talk on some
academic subject. Some lecturers got together, and decided
to form a rival club, with professors being excluded. This
"Science Society" was an instant success, and still prospers.
But, a few years after its foundation, there was a proposal to
admit Penrose. The justification for this breach of the rules
was that "he was exceptional, in that everyone who knew
him liked him". And he was duly admitted.
I soon got to know Lionel and his wife quite well. They had
a large house, close to Golders Green Station, and I was
several times invited to supper there. Incidentally, they had
a device consisting of a round table, with a rotating disk in
the middle, on which food was placed, so that one could turn
it to bring whatever took one's fancy within reaching
distance.
Lionel also owned a large country house in the Constable
district in Suffolk, where he would go for week-ends and
holidays. This had a peculiarity that it consisted of two
par t s, j oi ned to ge t her phy s ical ly, bu t wi t h no
intercommunication. To get from one to the other one had
to come out of one door into the open air, and then go in by
the other, I understand that he left it to the National Trust.
Lionel was a man of many talents and interests. He came
from a distinguished family. His father was a leading
Quaker artist, and, in particular, painted 2 paintings which
used to be hung up in Friends House (just the other side of
Euston Road). One, "None shall make them afraid", shows
the invasion of a Quaker meeting in America by a band of
hostile Indians who relented and made friends with the
Quakers. The other, "The presence in the midst" depicts a
typical Quaker meeting. Unfortunately, one of these was
stolen some time ago, and the other removed for safety.
Lionel's brother Roland was one of Britain's leading artists.
Lionel himself had considerable artistic talent, and an
exhibition of some of his paintings is on display today.
this sense, AB was self-replicating. He made various
modifications of the basic idea, representing mutation and
linkage. However, very soon after that, Crick and Watson
published their model of DNA, with a hint as to how it
might succeed in replicating itself, and interest in the
Penrose model was lost. This seems to me to be a great
pity. Although the Penrose model had no biological
application, nevertheless it represented an ingenious
solution to the problem of constructing a self-replication
mechanism.
Lionel and Margaret were quite good chess players. As I
am no good at chess, I never actually played with them, but
reports are good. However, they were eclipsed by their sons
Oliver and his younger brother Jonathan, who was for
several years British chess champion.
Walking upstairs can be tiring. Lionel and his son Roger
succeeded in designing a staircase by means of which one
could descend from floor 3 to floor 2, from floor 2 to floor
1, from floor 1 to the ground floor, and then from the
ground floor back to floor 3, starting again, so that one
could get from one floor to another by walking downwards
all the way. It would have been convenient to have such a
staircase installed in Wolfson House. Alas, it was just an
illusion: one could draw such a staircase convincingly on
paper, but one could not make one in reality.
Lionel also was something of a musician. I once asked him
to harmonize a tune which was generated by a mathematical
rule, and he proceeded to do so, though remarking that it
was somewhat inferior to Beethoven.
Academically, although professionally he was a human
geneticist, he also was well versed in psychology,
psychiatry, medicine, biology, and statistics.
He had an ability to present ideas in a simple form. One
example of this was his "sib-pair test for linkage", discussed
elsewhere in this meeting. Unfortunately, this was not very
efficient, as it was first presented, as it combined together
data from highly informative families, less informative
ones, and those which were quite non-informative. Fisher
proposed instead "efficient scores" or "u-functions", which
seemed at first sight to be quite different. However, as
Lionel noticed, u-functions were no more than his sib-pair
test, but weighted to take into account the different amounts
of information provided by different types of mating. Both
Penrose's sib-pair test and Fisher's u-scores were
superseded by Newton Morton's introduction of z or "lod
scores", which have been in almost universal use since.
However, the break with the past is not quite as great as it
might seem, since both u -scores and lod-scores are
examples of the use of the logarithm of a likelihood ratio.
One long standing problem is how living creatures succeed
in replicating themselves. Could a machine be constructed
to do that? Some theoretical results seemed to show that it
would have to be a very complicated machine, containing
thousands of parts. But Lionel succeeded in making
one(modelled in wood) consisting of only 2 parts, say ! and
B, and operated by A the force of gravity. So long as only
separate parts A and B were present, they stayed separate.
But A and B could combine to make a compound, AB.
Introduce just one AB into a mass of separate As and Bs,
shake, and many more compounds AB would be formed. In
"Mankind MUST proceed to disarmament, or face
annihilation." These words (which I quote from memory)
are exceedingly strong: NOT that it would be rather a
good ideas to disarm, BUT that disarmament is essential if
the human race is to survive. I wonder how many present
know the source of this declaration - not guessing it, but
knowing it for certain?
If you have guessed the origin of these statements you
have probably thought of some pacifist or anti-nuclear
society, no doubt worthy in its own way, but one with no
responsibility for the direction of human affairs, and so
free to make extreme statements whenever it felt useful to
do so. Well, you would be rather far off the mark.. The
statement "mankind must proceed to disarmament, or face
annihilation" followed long and detailed deliberation and
was endorsed unanimously and signed by all governments
of the United Nations. Governments have responsibility
for the conduct of affairs throughout the world, and are
generally very cautious, which adds considerably to the
importance and relevance of such a statement.
One would expect such carefully considered and weighty
statements from such authorities to be well known
throughout the world. Instead, they seem to be known to
very few, and largely ignored by governments.
Why did they make such a strong statement? They say
"constant dripping wears away the hardest stone". There
is already a vast accumulation of devastating weapons,
bombs, chemical and biological agents. Accidents will
happen, no precautions ensuring total 100 per cent security
have been devised, so that, sooner or later, if nothing is
done, some disaster (such as nuclear war) is sure to
happen.
journal, "Medicine and War", and has important
international links.
What can be done to avert catastrophe? As a physician,
Lionel thought of war as a serious disease of society.
And a natural approach to curing a disease is to do
research on its causes in a careful, objective scientific
manner. Lionel suggested as an approach to preventing
war an objective academic study of its causes and nature
(following the meteorologist Lewis Fry Richardson, who
thought the same, but who was almost totally ignored).
He and his wife Margaret were the founding spirits of
the Medical Association for the Prevention of War,
which has such aims, and now produces an academic
Well, I hope that I have given you some idea of what kind
of man Lionel Penrose was. To me he is still the very
distinctive individuals, with his own likes, dislikes, virtues
and failings, who I know very well in person. But to
almost everyone present today, he must be principally a
name met with in books and papers, and mostly limited to
his work in human genetics. Regrettably, I can not bring
him back to life. But I hope to have given you some idea
of what he was like, as a human being, and not merely as a
distinguished scientist.
Penrose and sib-pairs
J. H. EDWARDS
e
John Edwards with
Shirley Hodgson
Department of Biochemistry, University of Oxford, UK.
Abstract
Penrose's sib-pair papers (1935, 1947, 1953a) are discussed in relation to recent
applications. His essential contribution that parental typing was an inefficient addition to sib -pair data for linkage detection
remains. Parents now have even less to offer with contemporary markers in the detection of linkage, although not the
enumeration of haplotypes. Attention is drawn to two little known papers by Penrose on multifactorial disease (1937, 1953b),
and it is suggested that this term should replace polygenic in relation to family analyses.
The convention established by Penrose, both as author and Editor, of raw data being published alongside its analysis, which
later fell into disuse on grounds of sheer bulk, can now be remedied by the Internet, and has been for the largest set of sib-pair
data on diabetes. (Davies et al. 1994)This is essential if the contributions to the identity and location of alleles possibly relevant
to common disorders, none of which are likely to be more than suggestive in any single study, can be combined to assess
consistency and joint evidence. Attention is drawn to a third little known paper by Penrose of high relevance to the strategy of
familial investigations in multifactorial disorders. __
The full version of this talk is published in the Annals of Human Genetics:
J. H. Edwards. Penrose and Sib Pairs. Ann. Hum. Genet. (1998), 62, 365-377.
The original Penrose papers referred to here will appear in full text at:
http://www.gene.ucLac.uk/anhumgen/
References
Crow, T. J., 1991, A Note on "Survey of Cases of Familial Mental Illness" by L S Penrose, Eur Arch Psychiatry Clin
neurosci 240:314-324.
Davies, J. L., Kawaguchi, Y., Bennett, S. T., Copeman, J. B., Cordell, H. J., Pritchard, L. E., Reed, P. W., Gough, S.
C. L., Jenkins, S. C., Palmer, S. M., Balfour, K. M., Rowe, B. R., Farrell, M., A, H., Barnett, Bain, S. C., and Todd, J.
A., 1994, A Genome-wide search for human type 1 diabetes susceptibility genes, Nature 371:130-136.
Penrose,
L. S., 1935, The detection of autosomal linkage in data which consist of pairs of brothers and sisters of
...nspecified parentage., Ann. Eugen. 8:133,138.
Penrose,
L. S., 1937, Genetic Linkage in graded Human Characters, Ann. Human. Genet 10:*,*.
P enrose,
L. S., 1947, A further note on the sib-pair method*, Ann. Eugen. 13:120-124.
P enrose,
L. S., 1953a, The general purpose sib-pair linkage test, Ann. Eugen. 18:120,124.
Penrose,
L. S., 1953b, The Genetical Background to Common Diseases, Acta. Genet. 4:257-265.
Genetics of Autism
A P Monaco and The International Molecular Genetics of Autism Consortium
Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
Rapid progress has been made in the molecular genetic understanding of single -gene disorders during the last 15 years. The
positional cloning of genes responsible for monogenic inherited diseases is now relatively straightforward. A new challenge in
human genetics is to unravel the genetics of more complex, polygenic diseases which in many cases are relatively frequent in
the population. Using resources provided by the human genome project and advances in genetic technology and statistical
genetics, many groups are scanning the genome for genes that give rise to susceptibility to polygenic disorders. In my
laboratory, we have initiated genetic studies of four complex neurodevelopmental disorders of childhood, including autism,
specific language impairment, specific reading disability and attention deficit hyperactivity disorder.
Autism is characterized by impairments in reciprocal social interaction and communication, and restricted and stereotyped
patterns of interests and activities. Developmental difficulties are apparent before three years of age and there is evidence for
strong genetic influences most likely involving more than one sus ceptibility gene. Our consortium has collected affected
relative pair families with childhood autism using the ADI and ADOS diagnostic criteria. Blood samples for families are sent
to Oxford and DNA is extracted for genetic studies. A two -stage genome search for susceptibility loci in autism was
performed on a total of 99 families identified. Regions on six chromosomes were identified which generated a multipoint
maximum lod score (MLS) above 1. A region on chromosome 7q was the most significant with an MLS of 3.55 in the subset
of 56 UK affected sib-pair families, and an MIS of 2.53 in all families. These chromosome regions will be tested in
independent families for replication of the linkage results and family based association studies will be used to help narrow the
critical region containing the susceptibility gene(s).
Candidate genes in the critical region will be tested for etiologic mutations or variants which are potentially involved in
autism. __
Lionel Penrose
Shirley Hodgson
Guy's Hospital, London, UK
As Lionel's daughter, I probably had a different perspective of him from his professional
colleagues. I think Lionel owed his success to his gifted intellect combined with a delight,
enthusiasm and playfulness in his approach to life, tempered by a very deep sense of moral
values derived from his Quaker background. This was
combined with an unconventional nature which enabled
him to step outside the accepted beliefs on any subject,
almost as a matter of principle, and re-evaluate them in the
light of as much objective data as he could obtain. He
would never reject an idea because it was unpopular
(indeed unconventional ideas had a particular appeal for
him). This allowed him to be one of the very few people at
the time who disputed the ideas of the Eugenics movement,
and enabled him to develop novel and sometimes heretical
ideas on a wide variety of issues such as crowd behaviour,
proportional representation, chess, the authorship of
Shakespeare, and many genetic and statistical theories. For
instance, in challenging the currently accepted view that a
form of Icthyosis (Hystrix Gravior) was inherited as a Plinked trait (based on an East Anglian pedigree) Lionel
visited many different East Anglian churches and searched
their records, with characteristic tenacity, in order to
provide evidence that this genetic interpretation was based
on an incorrect pedigree.
He had a childlike energy and was constantly excited by
new ideas and followed them through with determination
and a sense of confidence in his views. This was a
development of his love for intellectual games and puzzles,
such that, as Roger (my brother) pointed out, there was no
real distinction for him between work and play. He also
had a deep antipathy to war and conflict, reflected in his
being a founder of the Medical Association for the
Prevention of War, and was committed to the proper care
and respect being given to all members of society,
including the intellectually disadvantaged, which
contributed to his vehement opposition to the aims of the
Eugenic movement.
Characteristically, he used strictly intellectual arguments to
counteract those of the proponents of the Eugenics ideas.
He had a breathtaking number of different skills, including
playing chess, music, painting, and making puzzles (using
a fretsaw in the garden). He used to teach me how to do the
puzzles at a tender age and then show off my abilities to
unsuspecting (adult) visitors, with impish glee. He once
tried an experiment on a pair of identical twins we knew
who were both unable to do the puzzles, then taught one of
the twins the secret whilst the other was outside, and then
was excited by the fact that the untaught twin could do the
puzzles on her return. He suggested that subliminal
communication between them was the explanation for this
result.
He was inherently very sociable, and had a lively sense of
humour, and our home was often full of fascinating people
and wonderful conversation, from which we all derived
much pleasure. He loved music and painting, and my own
appreciation of these must partly have derived from his
infectious enjoyment such as of a particular change of key in
a Mozart Aria, or the ability to capture the subtle shadows
cast by the leaves of a tree in a watercolour painting.
As a geneticist, I am continually being surprised by the
number of ideas in Human Genetics which were first
suggested by Lionel, often many years before they were
accepted, although his caution about accepting the
possibility that anticipation was a truly genetic phenomenon
rather than ascertainment bias was over-interpreted as
denying it. Many specific examples of his ideas will be
presented by others in this booklet, but I will mention one or
two he had which particularly caught my imagination. He
had a fascination with dermatoglyphics, perhaps because
they were not a popular preoccupation, and because he
fancied that they provided a method by which inherited
characteristics could be quantified. I have a memorable
recollection of him designing and "combing" an imaginary
spherical dog, which enabled him to explore the topology of
whorls and loops. I was also intrigued by his interpretation
of his discovery of an inverse correlation between the total
dermal ridge count and the number of sex chromosomes.
This effect was greater for an extra X chromosome than for
a Y, by a factor of about 3 (in proportion to their relative
sizes), suggesting that the effect on ridge count could be due
to an osmotic effect of increased chromatin volume rather
than the effect of specific genes. Such an effect can also be
demonstrated in plants, and is reflected in the oedema of
extracellular tissues seen in individuals with Turner's
Epiloia
Sue Povey
MRC Human Biochemical Genetics Unit, University College London,
U K.
One of the diseases which Lionel Penrose found in his
Colchester survey was "Epiloia" now more usually known as
Tuberous Sclerosis (TS). Although this disease can cause
problems in many organs of the body, the main features are
skin rashes, seizures (particularly infantile spasms) and
mental handicap. Many of the affected children show severe
behavioural disturbance including autism.
Syndrome. He himself expressed this idea as being heretical at
the time, but possibly containing "the germ of an idea".
Another interesting observation he made was that
measurements of the atd angle on the palm of the hand, which
is increased in individuals with Downs' syndrome, in the
mothers of such individuals, showed an average deviation in
the mean value from normal. A mathematical analysis of this
demonstrated that the difference from the mean was greater in
the mothers of two affected children than of one, leading him
to deduce that one tenth of mothers of one child with Downs',
and half of the mothers of two affected children, could
themselves be mosaic for Downs' syndrome.
On a more personal note, one of the characteristics Lionel
certainly had was an unconventional nature, which sometimes
led to difficulties - for instance the porter at the Lodge of the
Whittington Hospital where I was working, said he was "very
concerned that a Very Strange gentleman had called for me
and claimed that he was collecting me to take me to the Royal
Society Soiree - a likely story!"
Unconventionality is fine so long as it can be harnessed by a
powerful intellect and used to develop original ideas, as in his
case!
Lionel never did discuss his experiences in the war, where he
played a role in the Quaker Red Cross. The only story he ever
told me about it was that he cured a soldier of a month's
constipation by giving him an aspirin, and telling him it was a
wonder cure! His other experiences at that time must have had
a great effect on him, and contributed to his abhorrence of
war. I still have two paintings he did at that time which depict
a desperately bleak landscape.
Lionel was indeed a remarkable father to have, and was
supported and encouraged at even the most difficult times by
Mar garet, my mother. He was challenging, enthusiastic and
original, although not always able to express his personal
emotions. A very hard act to follow. The daughter of a
colleague once asked him, when he was playing with kites
with her, whether he was a professional kite flyer. Perhaps she
was right to suppose that he wasle
Shirley Hodgson with
Sue Povey
Penrose established from his studies in Colchester that the
disease is inherited in an autosomal dominant manner, that some
cases are familial but that many arise as new mutations, and that
even within a family the range of severity can be enormous. He
postulated either that unlinked modifying genes affected the
severity, or that possibly variation in the "normal" allele could
be responsible. From the frequency of Epiloia in the Institution,
coupled with the estimate of the prevalence of severe mental
handicap in the population, he estimated a mutation rate of about
1 in 40,000 (1,2).
Have we made any progress in the problem since 1936? Two
genes, TSC1 on 9q34 and TSC2 on 16p13 have been identified.
Mutation in either of these can cause TS, with some evidenc e
that disease caused by mutations in TSC2 may be more severe
and are particularly common in severe sporadic cases of TS.
The majority of the characteristic lesions seen in this disease,
benign hamartomas, appear to be monoclonal in origin and show
loss of heterozygosity suggesting that these genes function as
tumour suppressors. Each hamartoma presumably arises as a
result of a "second hit" on a cell already carrying a germline
mutation. Not surprisingly, population surveys find that the
disease is more prevalent than previously reported, at least 1 in
12,000 new-borns being affected. In addition to having a
valuable (albeit labour-intensive) molecular diagnostic tool, and
having provided occupation for sophisticated biochemists in the
attempt to elucidate previously unknown signalling pathways,
we are now in a position to investigate the extreme variability of
severity which intrigued Penrose. This is also of great concern
to families in which this disease occurs. Two significant
advances have been made. One is the recognition of the major
role of germline mosaicism, rather than true non-penetrance,
in the birth of a second affected child to apparently healthy
parents. The other is the fact that true non-penetrance,
defined as transmission through an obli g ate heterozygote
with no clinical signs, has not been demonstrated, since the
only well-documented case turns out to be the result of two
independent mutations in the same family. However, there
remains an enormous amount of intra-family variation.
Whether this is entirely explained by the random and
unpredictable nature of the "second hits" or whether as
Penrose suggested, there are modifying genes or dominance
effects is currently under investigation, both by observations
in human families and by breeding experiments in
"knockout" mice. Some of the new data presented in this
talk will appear in reference 3. Reference 4 is a recent
review DO
.
References
1. Gunther, M and Penrose, L. S. "The Genetics of Epiloia"
(1935). J. Genet. 31, 413-430.
2. Penrose, L. S. "Autosomal mutation and modification in
man with special reference to mental defect" (1936). Ann.
Eug. 7, 1-16.
3. Young, J. M., Burley, M. W., Jeremiah, S. J., Jeganathan,
D., Ekong, R. Osborne, J. P. & Povey, S. (1998). A
mutation screen of the TSC1 gene reveals 26 protein
truncating mutations and I splice site mutation in a panel of
79 tuberous sclerosis patients (1998). Ann. Hum. Genet. 62,
202-215.
4. Young, J. M., & Povey, S. (1998). The Genetic Basis of
Tuberous Sclerosis. Molecular Medicine Today, 4 (7),
313-9.
Thanks for Moomin
Marco Fraccaro
University of Pavia, Italy.
Dear Professor,
(I
never came to address you by your first name nor even to think of you as Lionel, although you signed the
letters you wrote to me after I left the Galton with your first name). The reasons for which I have been and still am
grateful to you are so numerous that I can't possibly list them all.
What you gave me in 1954 and later on was not so much in terms of direct teaching or immediate instruction
(although 1 would have never been able to write my first paper in English without your help), but it was your way of
dealing with facts and fancies that left a profound impression on me.
The subtle (and sometimes less subtle) art of making fun of whom you didn't approve was eagerly absorbed by a
young man coming from a country where vendetta rather than irony, is the weapon for both attack and defence.
Your influence extended to apparently minor incidents such as the hint that perhaps it would be better to take the
News Chronicle rather than the Times. To a young anglophile (my idea of English was then based on P.G.
Woodehouse) The Times was believed to be essential reading.
You opened the Chronicle at the appropriate page and showed me the comic strip about the Moomin family. "It
comes from Scandinavia and is very good". I took your advice and that was my first introduction to Scandinavia.
More had to come of that in a short while. I was at the Gallon when Jan Arvid Book came from Uppsala to see
you. He came from the Statens Rasbiologiska Institut, a name that sounded somewhat sinister. But you told me
that it was directed by a man called Gunnar Dahlberg who was "very good" and the first to react to the latent and
less latent racialist sympathies of some
Swedish circles. Dahlberg had published a
book which was translated into English
and published in 1942 with the title Race,
Reason and Rubbish, which expressed your
liberal views very clearly. You told me that
Dahlberg was ill and that J.A. BOOk was to
succeed him. That was all for the time
being. After a while I got a letter from
BOOk o ffering me a job a s "assistant
director" at the State Institute for Race
SMIRK .SER; NI
NTE PIT T DE
Biology and Human Genetics. I understood that BOOk had asked your advice and that you had recommended me
for the job, but typically you never stated that openly. I arrived in Uppsala on January, 8th 1956 when the
temperature was minus 12 degrees Celsius an d that was the second introduction to Scandinavia which you gave
me.
I soon found out that the Moomin (Mumin in Swedes) strip was a regular feature of a local paper, so I continued
my acquaintance with that marvellous family. In Uppsala I came to know more about the Moomins and their
inventor, a Finland Swede called Tove Jansson. There were books by her and a long series of collected strips
which I still treasure.
The contacts soon extended beyond the Moomins and I married a Swedish girl wh o knew everything about them.
Our first son was baptized in the Uppsala Cathedral and named Plinio Yngve Penrose. You made for him with
your own hands one of those extraordinary animal puzzles which your son Roger showed during the meeting.
I wanted to tell you this on the One Hundredth anniversary of your birth. But, above all 1 wanted to thank you for
Moomin.
Yo u r s eve r,
Marco Fraccaro
PS For those who have never seen Moomin I reproduce here (above) one strip from a story you especially liked. It
was centered on a dispute between a zoologist and a botanist as to whether a strange thing was an animal or a plant.
The entire Moomin family stare at them from the left.e
Penrose in Canada
Peggy Thompson
Hospital for Sick Children, Toronto, Canada.
It is a special privilege to attend this symposium honouring Lionel
Penrose on the hundredth anniversary of his birth, and to talk about the
Canadian phase of his notable career. Reports of his contributions,
such as Harry Harris's biographical memoir for the Royal Society (1)
and the account in Daniel Kevles' book, In the Name of Eugenics (2),
emphasize his pre-Canadian and post-Canadian periods and say little
about his years in Canada, But Penrose was 41 when he and his wife
Margaret and their three sons came to Canada in 1939 for what was to
be a six-year stay, and their daughter was born in Canada. The early
to mid-forties are a productive and eventful time in almost anyone's life
story,showthatduringthoseyearshecontinuedtomake
significant contributions to human genetics and that his
initiatives in Canada are still having consequences today.
Lionel and Margaret Penrose were no strangers to Canada.
Margaret had lived there for several years when her father,
physiologist John Beresford Leathers, was a professor at
the University of Toronto, and she had many old friends
there. The family settled in London, a city about 120 miles
south-west of Toronto, where Penrose was based at the
London Psychiatric Hospital, a facility of the Ontario
Department of Health. They sent their sons to local
schools, and when their daughter was born her brothers
chose to name her Shirley after their favorite girls name in
those schools. They made many friends in the local
University of Western Ontario, among whom they
established a reputation for originality and hospitality that
has persisted to this day.
Penrose's first position in the London Psychiatric Hospital
was as a Senior Assistant Physician (temporary), but he
soon won recognition for his research and statistical skills
as well as for his clinical knowledge. The next year he was
named Acting Director, and two years later Director, of the
Medical Statistics Branch of the Ministry of Health, and he
also became Director of Psychiatric Research for the
Ministry. These appointments indicate the direction of his
interests, but they do no measure his accomplishments or
show why in 1953 he was to be lauded by Haldane as the
world's leading human geneticist. Just what, then, was he
doing during those Canadian years?
Of course, he had regular medical duties; among other
clinical activities, he was the first person to diagnose
phenylketionuria in Canada. He also became responsible
for visits to related institutions to assess their services and
report on them to the Ministry. These reports are
interesting to read, as they often deal with topics quite
remote from psychiatry or genetics. For example, on one
report he strongly criticized the lack of a garage to house
the hospital bus in winter weather. Though such an activity
may seem a waste of his abilities, it demonstrates the
compassion and concern he always showed for the patients
in his care.
Penrose's forty or so publications during the Canadian
years appeared in a variety of British, American and
Canadian journals. The topics ranged from very broad and
philosophical (mental disease and natural selection; future
possibilities in human genetics) to specific and practical
(results of shock therapy; matrix intelligence tests).
Reflecting his clinical work, the emphasis is on mental
illness rather than on mental defect as in his earlier papers.
A common feature of all Penrose's family studies, in
sparsely settled Ontario as well as in England, is the large
number of cases he was able to collect for each analysis.
A letter written to Haldane in 1944, kindly sent to me by Dr.
Krishna Dronamraju, reveals Penrose's scientific activities
during his Canadian years. Perhaps the most striking
information in the letter is that by that time, he was already
searching for a way to examine the chromosomes in the "the
cells of grossly abnormal individuals". He mentions to
Haldane "the method of Crustchov", who had earlier
developed a way of culturing lymphocytes on slides, and his
hope of eventually setting aside "a small corner of the
Galton" for these studies. (By that time he was hoping that
the Calton Professorship would materialize but was not
assured of it). In the letter he also describes his large,
ongoing study of age of consent and sex in familial mental
illness, commenting that "there is so much to talk about in
this data that it almost requires a book." He predicts
(correctly) that this work will probably not appear in the
American Journal of Psychiatry because "it has no appeal to
any psychiatrists who are influential",. He goes on to
describe his studies of filial and fraternal correlations,
including the effect of assortative mating. He also reports
his research on diabetes mellitus, which was published with
the diabetologist E. M. Watson the following year.
When Penrose became Director of the Medical Statistics
Branch of the Ontario Ministry of Health, he had to make
weekly trips to Toronto to the central offices of the Ministry
in Queen's Park. (Apparently on these visits he sometimes
had to write himself letters in response to ones he had sent in
wearing one of his other hats.) About this time he began to
cross the park to the Department of Zoology at the
University of Toronto for scientific discussions with Dr.
Norma Ford (later Norma Ford Walker). Dr. Ford,
originally an entomologist, had come to human genetics
through her assistance to physicians at The Hospital for Sick
Children who were looking for ways to control the parasitic
fly Wohlfahrtia vigil, a threat to sleeping babies. Access to
Sick Kids, then as now, opened a treasure trove of genetic
disorders. Dr. Ford had few if any colleagues who shared
her interests, and welcomed the opportunity to consult with
Dr. Penrose about such matters as Down
Syndrome,
dermatoglyphics, and multiple births.
In those years Penrose became a familiar figure in the
Department of Zoology. This was during my own time as a
graduate student under Dr. Ford's supervision. I did not
meet Penrose personally then and I do not recollect hearing
him give a seminar in the Department, though the archive
says he did. I first met him and his family personally during
the International Congress of Genetics in Montreal in 1958,
when he and his son Roger demonstrated their famous
models of automatic mechanical self-replication. My valued
status as a family friend did not develop until much later.
But I am sure that much of what Dr. Ford taught us came
directly from her conferences with Dr. Penrose, always
passed on to her graduate students as absolute gospel. I
see her as having received the equivalent of a postdoc
from this association, and feel entitled to claim Dr.
Penrose as a member of my own academic pedigree,
though as a second-degree forebear rather than a firstdegree one.
The story of Penrose in Canada would not be complete
without mention of phenylketonuria, even though his
famous paper on the subject, the Galton Inaugural Lecture
entitle Phenylketonuria: A Problem in Eugenics (3), was
not published until 1946. Recently I heard Dr. Charles
Scriver of McGill speak on the topic, Phenylketonuria is
not Boring. In his talk he drew attention to the many
fundamental genetic concepts mentioned in this seminal
paper. The discussion is wide-ranging and touches on
many topics still highly relevant in medical genetics more
than fifty years later, including eugenics and natural
selection; the presence of many rare recessive disabilities
in man, "and doubtless many more lie awaiting
detection"; parental consanguinity; clinical heterogeneity
both within and between families; heterozygote
advantage; and the possibility of altering the course of
PKU and other metabolic diseases by deliberate alteration
of body metabolism.
Since these concepts must have been gestating in
Penrose's mind during the Canadian years as well as
earlier and later, I feel entitled to include this 1946 paper
in his Canadian contributions.
When Penrose was awarded the Galton Chair in 1945, his
appointment was hailed by the local London newspaper,
the London Free Press, in a "local boy makes good" style,
an indication of how closely connected to the local scene
the Penroses had become. The Galton chair marked the
end of his working years in Canada, but years later, in
1991 a whole new segment of the story opened.
In that year, a report entitled Survey of Cases of familial
Mental Illness, submitted in 1945 by Penros e to the
Division of Psychiatric Research, Ontario Department of
Health, was published in The European Archives of
Psychiatry and Clinical Neuroscience (4). The report
summarized their findings of a survey of the diagnoses
and onset ages in a large number of cases of familial
mental illness covering the period 1926-1944. It had been
located by Dr. T. J. Crow of the Clinical Research Centre
in Harrow, and is accompanied by a brief paper of
comments by Dr. Crow, emphasizing the chief findings
(5).
When Dr. Anne Bassett came to Toronto in the early
nineties as a psychiatrist at the University of Toronto and
the Queen Street Mental Health Centre, she decided to try
to find the work on which the 1945 report was based. Her
search was long and initially frustrating. The basic data
admitted to a psychiatric hospital, while the other was a coded
list with no names but with details of diagnosis, age of onset,
family data, relationship to the affected relatives and so on.
Fitting the two lists together was a very large job, since the
numbers were huge. 7339 individuals from 3,109 families, or
about 10 percent of the total population of the Ontario mental
hospitals. Once the matching had been complete, it was
possible to go to the original hospital charts themselves, but
because of its age and fra gility the material could not be
photocopied or scanned and had to be transcribed by hand.
Now that the data are usable, though not without some
limitations, they are being used in schizophrenia research to
explore such topics as positive and negative symptoms,
reproductive fitness, anticipation, and the association of
paternal transmission and anticipation. The work is ongoin g
(6-10).
This brief account of Penrose's Canadian years ma y help to
fill the gap in the historical record left by his six years'
absence from the English scene. I hope it will show that
during that time Penrose led a very active professional life.
that his influence on human genetics through Norma Ford
Walker, her students, and their students in turn has been
significant and lasting, and that his studies of familial mental
illness still have much to teach his successors.e
Acknowledgments.
The author thanks Dr. Joe Berg and Dr. Cyril Greeenland for
their invaluable contributions of personal and archival
information, which includes letters by the late Margaret
Penrose Newman to Dr. Greenland at the Archives of the
Ontario Mental Health Centre in Toronto; Dr. Hubert Soltan of
the University of Western Ontario, London, editor of the book
Medical Genetics in Canada and author of its chapter on
Penrose (11); Dr. Anne Bassett for her enthusiastic
cooperation in this project; and Dr. Krishna Dronamraju for
making available the 1944 Penrose-Haldane Letter, a historical
treasure.
References
1. Harris H (1974) Lionel Sharples Penrose (1898-1972). J
Med Genet 11:1-24.
2. Kevles DJ (1985) In the Name of Eugenics. Alfred A. Knopf,
New York
3. Penrose LS (1946) Phenylketonuria: A Problem in Eugenics.
Lancet 1: 950-953
4. Penrose LS (1991) Survey of cases of familial mental
illness. Eur Arch Psychiatry Clin Neurosci 240: 315-324
5. Crow TJ (1991) A Note on "Survey of Cases of Familial
Mental Illness" by L.S. Penrose. Eur Arch Psychiatry Clin
Neurosci 240:314-3158.
6. Bassett AS, Collins EJ, Nuttall SF, Honer WG (1993)
Positive and negative symptoms in families with schizophrenia.
Schizophr Res 11:9-19
Continuedd
7. Bassett AS, Honer WG (1994) Evidence for anticipation
in schizophrenia. Am J Hum Genet 54:864-870
8. Bassett AS, Bury A, Hodgkinson KA, Honer WG (1996)
Reproductive fitness in familial schizophrenia. Schizophr
Res 21:151-160
9. Bassett AS, Husted J (1997) Anticipation or
ascertainment bias in schizophrenia? Penrose's
familial mental illness sample. Am J Hum Genet 60:630637
10. Husted J, Scutt LE, Bassett AS (1998) Paternal
transmission and anticipation in schizophrenia. Am J Med
Genet 81, in press
11. Soltan HC (1992) Lionel Penrose. In Medical Genetics
in Canada, H C Soltan, ed, pp 36-39. The University of
Western Ontario Regional Medical Genetics Centre,
London, Ontario.
The Galton Laboratory
1952-53.
Barton Childs
Johns Hopkins University, USA
In what follows I shall be
guided by the observations
of Ford Maddox Ford
who, in a memoir, recognised
the fragility of the memory
for facts, but its accuracy and
precision as to impressions. So I shall be recounting my
impressions of a year in the life of the Galton Laboratory
47 years ago.
In 1951 I was a pediatrician in charge of children's
outpatients at Johns Hopkins. I was deeply impressed by
our inadequacy when faced by infants and children
pitifully handicapped by congenital malformations, and so
looked for guidance in understanding the origins of these
anomalies. A look at the literature revealed genetic
causes for some, but a wider search exposed a ferment in
the field of Human Genetics. Beadle's one gene — one
enzyme connection had surfaced, and we in Pediatrics at
Hopkins were aware of Avery' views on DNA because
Maclyn McCarty (of Avery, Macleod and McCarty) had
been a resident in pediatrics at Hopkins just a few years
before. And then I discovered the Annals of Eugenics
where I saw articles by Harry Harris on Cystinuria.
Accordingly I wrote to Professor Penrose asking if I
might sit at his feet for a year. Months passed. I began to
think of other possibilities, but at last a letter came. In the
meantime I had found enthusiastic support from the
Commonwealth Fund.
I turned up at The Galton one day in early July, 1952.
The only living soul there was Mrs Jackson, Professor
Penrose's efficient and kindly secretary. She said that
everyone was away on a "long vac" and business would
be resumed in September. In the meantime she showed
me the library which was on the floor below, in the
department of Biostatistics, presided over, she said with
an air of gravity, by Professor Pearson. The name meant
nothing to me until I began to discover why the place I
had come to was called The Galton Laboratory for
National Eugenics, of which Karl Pearson, the father of
the Chairman of Biostatistics, had been the final director.
I spent 10 days or so in that library discovering Galton,
Pearson, Fisher and others including Archibald Garrod.
So the days passed happily enough. Then one morning,
as I read, the door opened to admit a man with a huge
smile. He pronounced himself to be Harry Harris and
offered to show me around.
In those days the Galton occupied the third floor of the
building just on your left as you enter The University
College grounds from Gower Street. The rooms were on
both sides of a long hall running north and south. At the
north end was Harry's lab which we saw first. He was
then engaged in a family study of Cystinuria using paper
chromatography. Large squares of filter paper were
made into cylinders held together by paper clips and
dipped into jars of various sizes and shapes, at the bottom
of which were the solvents. After incubation the papers
were removed, dried and stained with ninhydrin, and
there were the spots. All very high tech. Equally
advanced was a home made paper electrophoresis device
which separated serum proteins into more or less discrete
blobs. I was duly impressed, and after a few days of
reading of Harry's papers, I asked if I might work with
him. We decided on a family study of the urinary
excretion of pigment after eating beetroot, a study that
taught me more about the nature of research than about
anthocyanins in the urine. London was still under the
cloud of war; tumble-down buildings, unpainted and still
under the constraints of rationing.
The Cast of Characters at the Galton 195253.
Harry also showed me the room where I was to sit. It
was a large room at the opposite end of the hall, well lit
by skylights and windows and equipped with four tables,
one of which was mine. For a time I was alone in my
corner, but then Hans Kalmus turned up. Kalmus was, I
believe, a greatly underrated geneticist, if for no other
reason than he was willing to tackle unpopular problems.
He had worked on the genetics of taste with Harris and
the year I was there he collected secretions from auxiliary
sebaceous glands in families. Later he studied the genetics of
perfect pitch and, characteristically, papers published in the
90's on the same subject failed to mention his work. He wrote
several books that showed his originality of thought, his
knowledge was enormous, and he was always happy to share
it. The first thing he said to me was that he had been refused a
U.S. visa on the grounds that he was a "suspect" person, and
wouldn't I be more comfortable in another room? All with
much laughter and throu ghout the year he would look
significantly at me and mutter "suspect person" and then
laugh. Being the only American there I was the butt of a
certain amount of anti-Americanism which, althou gh always
teasing and good natured, forced me, a life long democrat.
into defending a Republican administration I didn't vote for or
like.
Before long another roommate turned up. Sheila Maynard
Smith was a charming young woman whose husband John,
had recently joined J.B.S. Haldane, Sheila worked with a
calculator, the computer of the time. I think she had an
electrified machine, others worked with something that had to
be cranked by hand. The fourth table was occupied by
Marcello Siniscalco recently arrived from Naples with strong
recommendations, but very little English. He was as ebullient
then as now, and, tapping into the Italian network in London
he soon found the best restaurants in the neighbourhood. He
also eked out his living by giving reports to the homeland on
the BBC radio.
Next to our room was that of Sylvia Lawler whose interest
was in blood grouping. It may be that the 1950's were the
heyday of the blood grouping game. There was much newly
evoked interest in human genetics and who but the blood
groupers could provide leadership. Sylvia was very kind in
other ways too, inviting my wife and me to her house where
we met among others, Rob Race and Ruth Sanger whom we
found to be attractive, interesting people.
Beyond Sylvia was Ursula Mittwoch who was a pioneer in
cytogenetics. With characteristic insight, the Professor had set
her to looking at the chromosomes of patients with Down's
syndrome, then known as Mongolism. Her slides, as anyone
who knew her knew they would be, were beautiful. Next was
Mr Mundy, the Department Mr Fixit, a man of many talents
who dealt with the diversity of personalities with a tact worthy
of the diplomatic service. He was also an amateur of
photography, and I have on my wall a facade of the main
college building, the work, I think of Wilkins. Bette Robson
was a charming vivacious red haired young woman, the only
g=raduate student, last years students, Ed Reed and Bob Krooth
having gone on to Oxford. I was very grateful to Bette who
was kind and helpful to me in sorting out the personalities and
in showing me how to get on in general. Marcell() should
have taken his leads from Bette instead of Harry Harris, for
reasons which will emerge.
Rooms on the West side of the third floor were mostly
devoted to Professor Penrose's research enterprises. Across
from Harris' lab was Sara Holt who pursued the professor's
interest, and her own, in dermatoglyphics. I spent several
days with her, measuring angles and counting ridges and
concluding that the action in human genetics was, and would
be. elsewhere. Miss Karn and Helen Lang-Brown were two
more of the professor's agents and no two were ever less
alike. Where Miss Kam was small and retiring, hardly ever
seen, Miss Lang-Brown was more in evidence, rather
formidable and a great talker. Miss Karn worked on
Professor Penrose's massive study of the genetics of birth
weight, while Lang-Brown was a general helper. Marcello
Siniscalco, finding his way around, asked Harry Harris
`Who is she?' pointing to Lang-Brown. 'That's Miss
Sweetie Pie.' Was the reply, and so Marcello addressed her
until she put him straight.
The Professor's room was like everyone else's. He was the
least self important of men. He knew his worth but was
beyond flattery. He worked a good deal at his desk, and
having brought some data on congenital hypothyroidism
with me, I sometimes wanted his advice. Mrs Jackson
would tell me when to try and I would knock, usually
receiving a gruff, unpromising greeting. I soon learned to
ignore these signs and to plunge right to my request. Soon
he would become more interested in the possibilities and it
might be no easy job to break off. He was unfailingly
helpful. I wrote two papers while at the Galton, depending
heavily in both on Professor Penrose's help, but he declined
to append his name to either, although he published one in
the Annals of Eugenics, of which he was editor. One reason
for terminating sessions with the Professor was that he
smoked a pipe containing a favourite tobacco which when lit
emitted a smoke that nearly everyone found noxious.
Marcello, however, liked it, and asked Harry Harris if he
knew what it was called. 'Rubbish' said Harry, so Marcello
amused the Professor by asking where he bought his
'rubbish'.
Like every else Professor Penrose was kind enough to ask
my wife and me to his house in Golders Green. Once, in
late November around our Thanksgiving time when he
might have imagined that we were thinking of home, he
asked us to come to help eat a large turkey sent him by a
friend in the States, in fact a professor at Hopkins. On
another occasion, a party for everyone at The Galton, I
observed J.B.S. Haldane putting lighted matches in his
mouth and trying to persuade Shirley Penrose then 7 or 8
years old, to do the same. She was resolute in declining to
try.
Mrs Jackson, the Professor's secretary was unfailingly
cheerful, efficient and sympathetic. Only once did we see
her down. In February of 1953 there was a classical London
Fog (the last I think). All traffic stopped, the fog was as
dense in the deep tube as on the surface and upon awakening
in the morning one found a ring of black soot around one's
nares. As it happened, Mrs Jackson had had a room painted
in her house the day before the fog, which because the paint
was still wet, blackened the surface of the walls of the room.
We all saw her point. It was time for us to be sympathetic. I
think Cedric Smith was on that side of the hall too. He was
an imposing presence, ever ready to talk and to teach, and as
nice a man then, as he is now.
Downstairs, on the first floor was Professor Hans Gruneberg:
being precise, pedantic, German to the marrow, fascinating in
the extent of his knowledge and in the relish with which he
displayed it. In one of his lectures he cited medicine as a
branch of genetics. I thought it lese-majesty then, but now I
see the point was more subtle than I knew. But Grunie
wasn't perfect. When I asked him what he saw in cell or
tissue culture, he replied, without hesitation that it was a
lunatic idea. With him that year was Tony Searle, whose
company we often enjoyed at tea in the afternoon. In another
building were the Haldanes, J.B.S. himself and Helen
Spurway, his wife. Spurway, as she was generally called,
was a tall, lean woman with a voice that guaranteed that she
did not go unheard. J.B.S. was his inimitable self, not a bit
unhappy that his behaviour generated 'Haldane stories'. But
in his lectures and comments at seminars his extraordinary
mind was in evidence. Always inventive, always penetrating
and often funny too, he held everyone's attention, not
because of his reputation, but because of the originality of his
thoughts. This is, as I remember them, the case of characters.
Educational Opportunities:
For people like me there was time for data analysis and for
messing about in Harris' lab, as well as time for reading, and
for courses, all of which were of absorbing interest. I read
widely and started my own genetics library at Lewis'
bookstore in Gower Street and at Foyle's in Charing Cross
Road. The reading was, in part, supplementary to the
courses. The first of these was a series of lectures by
Professor Penrose on human genetics, lectures that were
always initiated by 'Ladies and Gentlemen', never mind that
there were only 3 or 4 people in the room, none a woman.
Looking back at my notes I see an emphasis on mathematical
rigor which today might have been driven out by molecular
biology. But conceptually, Penrose was always ahead of his
time. Among other things he understood that the idea that all
disease had a genetic dimension was more than a platitude
because every gene would turn out to exert a biochemical
effect.
So all diseases would be a consequence of
biochemical differences. He also saw clearl y the
relationship of disease to evolution and natural selection. I
didn't know at the time what a privilege it was to be his
student.
Other courses included statistics, taught in part by Florence
Nightingale David, and statistical genetics taught by Cedric
Smith, Mouse Genetics by Hans Gruneberg and Population
Biology by Haldane. Marcello and I also profited by a
laboratory experience in Drosophila genetics presided over
by Spurway, with J.B.S. Haldane as her assistant. She took
this distinction seriously, ordering him about and called not
Jack or dear, but Haldane. We did the classical experiments
to demonstrate segregation, independent assortment and so
on. I have always been inept in the laboratory and so was
inclined to remove the cotton plugs in the bottles of flies at
inopportune times.
Of course, this was a signal for
whomever could, to take wing and escape, leaving the lame,
the halt, and the blind at the bottom of the bottle. Now,
since the point of the experiment was to compare counts of
the able bodied flies with those of the disabled, my ratios
were always biased on the side of the latter, which Haldane
always tried to explain by invoking segregation distortion or
by other more arcane reasoning, but never by stupidity on
the part of the experimenter. Another course of note was a
series of lectures on immunogenetics taught by Race,
Sanger and others at the Lister Institute. No doubt it is hard
today to imagine the prominence of blood group biology 50
years ago, but the Lister stood out as the home of advanced
thinking in immunogenetics.
The Day at The Galton
Business began at around 9.30am, usually with coffee. I
recall remarkably little social or other interference with
work during the day. Lunch was informal, consumed in
someone's room and accompanied by talk, usually of
science. Occasionally we would go out to one of
Marcello's restaurants; I recall with special fondness, La
Colombina. Tea was at 4.00, usually accompanied by what
I called cookies, the English called biscuits, and any
quartermaster might have called 'hard tack'. Tea time was
a time for consultation.
I recall waiting until tea to ask
questions and argument might become lively. It was also a
time to meet visitors. Ruggiero Ceppelini visited for
several weeks and L.C. Dunn and Theodosium Dobzhansky
turned up seeking advice in setting up their Institute for
Human Variation at Columbia in New York. Other more
local, heroes visited too. I recall C.D. Darlington and R.A.
Fisher. One had the sense that The Galton enjoyed a certain
"hub" status.
The Ideas of The Galton
There were three themes that pervaded The Galton;
biochemical, developmental and populational. It was a
time when it was still possible to be a generalist and
Penrose was authoritative in all three. After all it was he
who created the organisation to explore these three
avenues.
complex interaction between the product of the genes of the
mother, those of the foetus and experiences of the
environment. Others profited by being included in his work.
Bette Robson was working on the birthweight of the babies of
first cousins whilst I was there.
1. Biochemical:
In the 1940's Penrose had worked with Quastel to study
phenylketonuria. Indeed it was they who gave it that name.
He knew of Garrod and inborn errors, but unlike others he
appreciated also Garrod's idea of chemical individuality,
and he articulated in the 1940's his belief that all gene
action would be shown to be biochemical. Today's reader
will hardly be able to imagine a time when that represented
a profound insight. He also brought Harris to The Galton
and supported his rise to dominate the field of human
biochemical genetics.
3. Populational
2. Developmental:
Much of Penrose's work was in development. His
Colchester study on the classification of mental retardation,
his work on Mongolism and on the genetics of birthweight
all contributed to our understanding of developmental
variation. After leaving The Galton he became interested in
chromosomal aberrations, but while there he supported
Ursula Mittwoch's study of the chromosomes of mongols.
Penrose was instrumental in changing mongolism to
Down's Syndrome, saying that Down described the
condition and anyway they weren't Mongolians, they were
British! And in his work on the genetics of birthweight, he
showed that a baby's weight at birth was a result of a
Conclusion:
Professor Penrose took an evolutionary view of everything he
did. For example, in the birthweight study he showed that
optimum birthweight is around 8.0 pounds while the average
is 7.5 pounds. This was a surprise because one would expect
those values to coincide.
He was also interested in linkage and devised a sib pair
method that was a precursor of that which is used today. It
was characteristic of him to have ideas that were in advance of
the technical means of testing them.
The opportunity at The Galton Laboratory in the early 1950's
was unique. The breadth and depth of the Galtonians' grasp of
genetics and human biology, and the lack of structure that
all o wed a s tud e nt ( li ke me) t ime f or read i ng and
contemplation, provided the wherewithal to go on in whatever
direction seemed compatible with temperament and interests.
Those were leisurely days, but leisure did not mean waster, it
might mean thoughtful. I was conscious of great privilege in
participating in life at The Galton. Am I an old fool in
wishing there could be more such opportunities today? I hope
not.FT
Roger Penrose (left) with Rod Smith
from the Science Museum
demonstrating how some of Lionel
Penrose' original models work.
Lionel Penrose As
Scientist And
Mentor:
' hiN14 Recollections
And Lifelong
Legacies
G R Fraser MD
Department of Clinical Genetics, Oxford Radcliffe
Hospital, Oxford, UK.
In composing this title, I thought long and hard how to
summarize my relationship with a man who has
profoundly influenced not only my professional career but
also my entire outlook throughout life. Other attributes
which had run through my mind were Lionel Penrose as a
man, as a teacher, as a humanitarian, and as a friend. It is a
great pleasure to have this opportunity to join in a tribute to
Lionel, to acknowledge my personal debt to him, and to
express my gratitude for the privilege of having known
him.
He was a man, take him for all in all,
I shall not look upon his like again.
From Hamlet by William Shakespeare
My education as a geneticist began as an undergraduate
during my pre-clinical medical studies, when I took Part II
of the Natural Science Tripos in Cambridge in genetics,
spending a year from 1952 to 1953 with Professor R A
Fisher, Lionel's predecessor in the Galton Chair. Fortified
by this experience in Cambridge, and having subsequently
completed the four years of clinical studies required for a
medical qualification, I decided to do a PhD.
I duly arrived at the Galton Laboratory as an MRC supported PhD student in October 1957 and thoroughly
enjoyed two years of the most stimulating and the most
intellectual academic environment which I have ever
known. There is a general consensus of opinion about
Lionel's laissez-faire attitude as head of the department; I
found this to be a great advantage. In this connection,
Sylvia Lawler, a long-time associate of the Galton
Laboratory, is quoted as follows in Daniel J Kevles'
informative book In the Name of Eugenics: Genetics and
the Uses of Human Heredity (Alfred A Knopf Inc, 1985), a
book in which Lionel plays a substantial role.
"Anyone who managed to get a PhD in the Galton
Laboratory had to have a streak of originality. There was
no spoon-feeding. Penrose would take people in, shut them
in a room and let them get on with it."
In my own experience, this was indeed so. Thus, one of my
most vivid memories of my time as a PhD student dates
from April 1959 when, after 18 months of my
scholarship, I told Lionel that I would not be staying for
a third year since I had found a job in Oxford. He said
that he was sorry to see me go and that it was a pity that I
had not prepared a PhD thesis. "But, Professor," I said,
"1 am writing a thesis and you shall have it before I
leave in October." Lionel was not in the least taken
aback by this unexpected revelation; he merely wanted to
know what the topic of the thesis was. I told him the
topic and said that the thesis was the fruit of a
collaboration with two physicians across the road at
University College Hospital, Dr M E Morgans and Dr W
R Trotter, in a study of the Pendred syndrome of
deafness with goitre.
I duly left my thesis (Deafness with goitre (syndrome of
Pendred) and some related aspects of thyroid disease)
with Lionel in October 1959; some months later I
telephoned from Oxford and suggested diffidently that
perhaps something might happen.
"Ah yes, the thesis. Perhaps you could come to tea some
time next week. Charles Dent (a metabolic physician at
University College Hospital over the road) can be the
external examiner. I shall telephone to tell you which day
he will be free." The three of us duly had tea and a
pleasant conversation about neutral themes in Lionel's
room at the Galton Laboratory. Lionel then declared the
formalities to have been observed. While he gave no
indication that he had read it from cover to cover, I did
hear much later from a reliable source that he thought
highly of the thesis.
Later a much extended version of these studies was
published in the Annals of Human Genetics, edited by
Lionel at the time—Fraser, G R: Association of
congenital deafness with goitre (syndrome of Pendred).
A study of 207 families. Annals of Human Genetics, 28:
201-249, 1965.
Recently (1997-8), Reardon, Trembath, and their
collaborators identified the gene responsible for the
Pendred syndrome and localized it to chromosome 7831
(Gausden, E, Coyle, B, Armour, J A I.., Coffey R,
Grossman, A, Fraser, G R, Winter, R M, Pembrey, M
E,Kendall-Taylor, P. Stephens, D, Luxon, L M, Phelps, P
D, Reardon, W and Trembath, R: Pendred syndrome:
evidence for genetic homogeneity and further refinement
of linkage. Journal of Medical Genetics, 34: 126-129,
1997.). They reported their findings in another session at
this very meeting, postulating that the normal gene acts
in the control of iodide and chloride transport across the
cell membrane. Homozygosity for mutant forms would
then lead to the thyroid defect and, by affecting ion
transport in the cochlea during embryonic life, to the
congenital hearing defect which together characterize the
Pendred syndrome.
the Prevention of Nuclear War, an organization which won the
Nobel Peace Prize in 1985.
Despite these advances in the study of the Pendred
syndrome, there remains much much more to be discovered
in long searching by future generations even about this very
tiny subject. Indeed, in this, as in all other fields of scientific
endeavour, past discoveries will provide future generations
with ever expanding areas of uncertainty within which to
pursue their voyages of discovery. And future generations
will continue to be guided in their searches by the precepts
and examples of their ancestors. To adapt a phrase attributed
to Isaac Newton, the reason that future generations will see
further is that they will be standing on the shoulders of
giants, into whose illustrious company Lionel has been
received.
Lionel considered war to be like a disease, useless and
harmful. Thus, in a later letter to the Lancet (Lancet (i): 415,
1951), the following answer was given to those who had
disagreed with the first letter on the grounds that problems of
peace and war are political and are not suitable subjects for a
medical journal.
Lionel was well aware of the importance of preserving
detailed archives of family studies and insisted on doing so
with respect to the data collected in the Galton Laboratory,
whether presented as a PhD thesis or submitted to the Annals
of Human Genetics for publication. It was for this reason that
I had scrupulously kept my records regarding the 207
families which I had studied, so that I was able to pass them
on more than three decades later to Drs Reardon and
Trembath and to their collaborators.
Lionel was brought up in a Quaker household and his aversion
to war was already developed during his childhood. when he
wrote a little poem: We are under one king/Let our flag be
peace/Let us take our swords off/And let the bloodshed cease.
During the first world war, he served in the Friends'
Ambulance Train of the British Red Cross in France.
Incidentally, Dr Reardon is the only person in the world,
apart from the typist and myself, to have read this thesis from
cover to cover, more than three decades after it was written.
He has kindly written a historical note in which the thesis is
summarized (Reardon, W P: Historical note: Dr George
Fraser. Journal of Audiological Medicine, 6: 185-9, 1997.).
The mention of Dr W R Trotter in connection with the
Pendred syndrome brings to mind the multi-faceted diversity
of Lionel's intellectual interests in that in 1952. in his role as
a psychologist, he published a little book called On the
Objective Study of Crowd Behaviour (H K Lewis, London),
based to a substantial extent on the book Instincts of the Herd
in. Peace and War (Fisher Unwin, London), written in 1920
by Wilfred Trotter, the father of my collaborator.
Lionel had a keen appreciation of the ridiculous and a subtle
sense of humour. As one example among many, 1 quote a
remark which has always remained at the forefront of my
mind because the sentiment is so frequently of relevance in
situations in which we find ourselves as scientists. "1 wish"
he said, "that our colleagues when they are talking nonsense
had a secret sign to let their fellow-scientists know whether
they themselves know that they are talking nonsense."
Lionel was one of the signatories of a letter to the Lancet in
1951 (Lancet (i): 170, 1951), which was instrumental in
promoting the Medical Association for the Prevention of
War. He later played a leading part in its administration,
being chairman for ten years. I believe that this association
was one of the precursors of the International Physicians for
Doctors have a social responsibility as well as a personal one
to their patients; they have an ethical tradition and an
international allegiance. War is a symptom of mental ill
health. Its results include wounds and disease. Doctors are,
therefore, properly concerned in preventing it. An "epidemic
of trauma" requires prophylactic treatment as much as any
other epidemic.
Subsequently, having completed a period of training in
psychiatry in Vienna, he returned to England in order to study
for a medical qualification followed by a thesis for the MD
degree on a patient with schizophrenia. The germinal scientific
achievement of his early career was undoubtedly the
remarkable Colchester Survey of Mental Defect which he
began in 1931 at the age of 33 years, as his initiation in human
and medical genetics (Penrose, L S: A Clinical and Genetic
Study of 1280 Cases of Mental Defect (The 'Colchester'
Survey). Medical Research Council Special Report Series, His
Majesty's Stationer), Office, London, 1938.).
During the seven years between 1931 and 1938, by
painstaking clinical and genetical studies of these 1280 cases
and their relatives, including, for example, 6629 sibs, he was
able to make a substantial beginning on the dissection of the
legally defined entity of mental deficiency whose aetiological
heterogeneity had hardly been explored previously, into its
clinical, genetical, and biological components.
Every one who knew Lionel is aware of the fact that he always
derived great pleasure from working with persons with the
Down syndrome and from playing with them. I was able to
witness this affinity and the harmony of the relationship
between Lionel and these persons at first hand when I
accompanied him on his visits to Harperbury Hospital, a large
mental hospital near St Albans where he later set up the
Kennedy-Galton Centre after retiring from the Galton Chair in
1965. The persons with the Down syndrome greeted him
happily when he entered the ward and a festive atmosphere
reigned during his visit. Lionel was attracted and charmed by
the good-tempered disposition of these individuals, their
liveliness, and their frequent liking for music which was one of
his own abiding interests.
In a memoir of Lionel (Harris, H: Lionel Sharples Penrose
1898-1972. Biographical Memoirs of Fellows of the Royal
Society: 19, 521-61, 1973.), Harry Harris, his successor in the
Galton Chair, quotes a passage from Lionel's 1933 book
Mental Defect (Sidgwick and Jackson, London), pointing out
that that his prose was usually much more cautious and
restrained: "-The term "foetalism" could well be applied to the
condition and this would be a more characteristic name than
"mongolism". The peculiar temperament of affected persons,
their secret source of joy, may be akin to the sort of happiness
which the foetus might be supposed to experience in its
blissful intrauterine surroundings.".
As far as Lionel was concerned there was no question that
persons affected with the Down syndrome were each to be
regarded as human beings in their own right. I never had the
opportunity, and I have never met any one who did have the
opportunity, to speak with him about developments in the area
of prenatal diagnosis and subsequent avoidance of births of
children with the Down syndrome, developments which were
beginning on a small scale at the time of his death.
I know that he was in favour of genetical counselling in
general. I am sure that he would understand our present
dilemmas in this area, and those of our patients, very well. In
my own work involving counselling and investigation of
several thousand families containing members with deafness,
blindness, cancer, and other conditions, I hope that I have
followed his approach when dealing with problems connected
with hereditary disease. His innate gentleness and kindness
were always to the fore, and he listened with sympathy and
understanding to the worries and anxieties of the members of
the families with whom he was associated in an advisory role.
The r e i s a very e nl i gh te ne d se c t i on o n the t o pic of
transabdominal amniocentesis at the very end of the
commentary to the fourth (new revised) edition of his classic
The Biology of Mental Defect (Sidgwick and Jackson,
London), the successor volume of Mental Defect, published in
1972, the year of his death; the commentary was actually
added in that year. The final words are—From the point of
view of prevention in selected individual cases, this procedure
(ie, amniocentesis) may occasionally be of great benefit. One
of its greatest values is the aid it provides in allaying maternal
anxiety in cases where there is a risk and a normal result is
given by the test. It is not to be supposed, however, that it will
act as a method of purifying the human stock of abnormal
genes and aberrant chromosomes, as might be hoped by
eugenical enthusiasts.
Towards the end of the book itself, before the commentary,
Lionel wrote, in discussing controversies which were current
even outside the framework of the Nazi New Order in
Europe, in connection with proposals for the "euthanasia" of
low-grade defectives:
The object of medical science in civilized communities is to
keep people alive. This principle has no exceptions and it
applies also to low-grade defectives of all kinds ........Not only
are these low-grade defectives harmless, they are not
responsible for their own condition; they can be happy and
they can stimulate human feelings and parental love. By all
canons of civilized society, they have a right to demand care
and comfort even if they are unable to give adequate returns.
The ability of a community to make satisfactory provision for
its defectives is an index of its own health and progressive
development; the desire for their euthanasia is a sign of
involution and decay of human standards.
Lionel made many important contributions to the study of
the Down syndrome in the fields of statistics, cytogenetics
and dermatoglyphics. He is well known, for example, for
showing that the birth incidence of the Down syndrome
increases with maternal age, by using refined statistical
methods for teasing out, or disentangling, the separate
effects of the strongly correlated variables of maternal and
paternal age and birth rank.
It is of interest to note that Lionel thought as early as the
thirties of the possibility that it might eventually prove
possible to treat phenylketonuria by administering a
phenylalanine-restricted diet. He tried some simple diets
without success and consulted F Gowland Hopkins at
Cambridge about the possibility of constructing a
nutritionally adequate phenylalanine-restricted diet. At that
time, such an enterprise seemed impracticably expensive,
but Lionel lived to sec his visionary idea successfully put
into practice by others many years later.
Lionel was well aware of the social, as well as of the
scientific and medical, significance of his work on mental
subnormality. The closing words of his 1933 book Mental
Defect (Sidgwick and Jackson, London) read as follows:
Since mental deficiency is not a clinical or biological entity,
but only a legal concept useful for social and administrative
purposes, the problems concerning the subject have both a
social and political as well as a scientific and medical
significance. From the scientific point of view, these
problems can be coped with systematically after sorting out
the different types of individuals to be found legally
classified as mentally defective. But the problems have also
to be tackled from the social point of view. We have to
remember that there will always be, in any human society,
brilliant people and simpletons, and what to do with the
simpletons will always remain a social problem. This is a
question which civilization has to face. A society which is
ideally conducted will have to make arrangements so that
the simpletons can find a useful purpose in their existence.
might be a unit dominant character in some families.
I always kept in touch with Lionel after leaving the Galton
Laboratory in 1959, and throughout my life I have regarded
him as a friend. The major part of my subsequently published
contributions to our profession was to be based on the ideas
which I had acquired from him by diffusion or osmosis. The
methodology of two of my contributions is modelled on the
Colchester Survey in that I attempted to apply the same
techniques to childhood blindness and to childhood deafness
or, rather, severe visual handicaps and severe hearing losses
in childhood, in two books to the first of which Lionel was
kind enough to write a preface.
It has astonished me throughout my work in this field that
neither Lionel nor any of the several investigators who had
conducted equally extensive genetical studies of breast cancer
previously, stumbled on at least one family showing the
extraordinary aggregation of breast cancer among its members
with which we have become so familiar since attention was
drawn to this phenomenon, twenty-five years and more ago.
Fraser, G R and Friedmann, A 1: The Causes of Blindness in
Childhood. A Study of 776 Children with Severe Visual
Handicaps (with preface by L S Penrose). pp 245: Johns
Hopkins University Press, Baltimore and London, 1967.
Fra se r, G R: The C auses of Profo und Deafness in
Childhood. A Study of 3,535 Individuals with Severe Hearing
Loss Present at Birth or of Childhood Onset (with foreword
by V A McKusick). pp 410: Johns Hopkins University Press,
Baltimore and London, 1976.
Recently, for the past eight years, I have been engaged in
running a clinic for familial cancer, the number of families
referred rising from 32 in 1990 to 566 in 1997, a total of
2337 in all. Such families now represent over a third of all
referrals to the Depai orient of Clinical Genetics.
Of course, I found that Lionel had visited this field. In an
essay published in 1934, which won the Buckston Browne
Prize of the Harveian Society (The Influence of Heredity on
Disease, H K Lewis, London, 1934.), he speculated on the
possibility that carcinoma of the stomach might be a unit
dominant character in some families. This speculation was
based on his knowledge of the description by Warthin of a
cancer family in the early years of this century ( Warthin, A S:
Heredity with reference to carcinoma. Archives of Internal
Medicine, 12: 546-55, 1913.). This family was later to
become the prototype of the Lynch cancer family syndrome,
after extensive follow-up studies including later generations
(Lynch, A T and Kush, A: Cancer family 'G' revisited:
1895-1970. Cancer, 27: 1303-11, 1971.).
In 1948, Lionel published a genetical study of 519 cases of
breast cancer (Penrose, L S, Mackenzie H J, and Kam, M N:
A genetical study of human mammary cancer. Annals of
Eugenics, 14: 234-66, 1948.). He found one brother affected
with breast cancer in his series, and he wrote that even the
presence of this single case of a disease so rare in males must
be regarded as very exceptional in so few families. While
Lionel knew of the family described by Broca in the 19th
century in which ten women in four generations had had
breast cancer (Broca P P, Traite des Tumeurs P Asselin,
Paris, 1866.), he did not go so far as to speculate, as in the
case of cancer of the stomach, that carcinoma of the breast
Lionel had many skills with his hands which he put to good
scientific use, as in making his fascinating series of wooden
self-replicating machines. To take another example, he gave
me a photograph of a large family tree which he had
constructed using pieces of string in ingenious representations
of complex relationships. I gave this photograph to colleagues
in Paris in 1971, and it contributed to the development of the
Paris pedigree-drawing programme which is the ancestor of
some of the programmes which are in use today.
I had the good fortune to be asked to translate Professor Benno
Muller-Hill's book about the collaborative role of many
academics, specifically in the fields of human genetics,
anthropology, and psychiatry, in the abominations perpetrated
in the name of totally misplaced ideas about racial inferiority
and superiority, marking the period of the domination of
Germany by Hitler.
Murderous Science: Elimination by Scientific selection of
Jews, Gypsies, and Others Germany 1933-1945. Oxford
University Press, 1988 (paperback edition with corrections
and additions, Cold Spring Harbor Laboratory Press, 1998), a
translation by G R
Fraser of Muller-Hill, B: TOdliche
Wissenschaft: Die Aussonderung von Juden, Zigeunern and
Geisteskranken 1933-1945. Rowohlt Taschenbuch Verlag
GmBH, Reinbek bei Hamburg, 1984.
I never had the opportunity of discussing with Lionel his
views on these excesses of the Nazi New Order in Europe, but
on turning to the marvellous inaugural lecture which he gave
in January 1946 after he had taken up the Galton chair in
1945, entitled Phenylketonuria: a problem in eugenics
(Lancet (i): 949-53, 1946), I find that he wrote of this
condition:
To eliminate the gene from the racial stock would involve
sterilizing 1 per cent of the normal population, if carriers
could be identified. Only a lunatic would advocate such a
procedure to prevent the occurrence of a handful of harmless
imbeciles.
Precisely such lunatic ideas are extensively reported in
Professor book, emanating from members of the
German academic establishment intent on underpinning the
aberrant biological ideologies which Hitler, Hirnmler, and
their accomplices put into practice within the framework of
their implementation of the Nazi New Order, thus discrediting
the very word 'eugenics' and covering it with opprobrium.
And later in his inaugural lecture, having stated that no cases
of phenylketonuria had been found among Jews or negroes,
Lionel wrote: A sterilisation programme to control
phenylketonuria confined to the so-called Aryans would
hardly have appealed to the recently overthrown government
of Germany. So much wisdom condensed in a single
sentence—the infallible mark of a truly great man. And he
wrote this at a time when very little was known of the excesses
of the Nazi New Order in Europe.
I end this series of quotations by reproducing extracts from the
last section, entitled Positive Eugenics, of the fourth (new
revised) edition of his classic The Biology of Mental Defect
(Sidgwick and Jackson, London), published in 1972, the year
of his death.
It has been one intention throughout this book, to explore the
broad problems of eugenics and to show that they cannot be
solved until the mode of action of natural selection on the
human race is much more fully understood than it is at
present. It may be relatively easy to point to genes which
appear altogether bad; for example, those which make their
possessors victims of epiloia or of Huntington's chorea. Even
these may not be unfavourable in all circumstances. Carriers
of "bad" genes may sometimes have compensating
advantages .......
The position is quite different when we try to identify "good"
genes. The human types which are accepted by eugenists as
desirable can be specified to some extent
Nothing is known,
however, about the actual genes which might form the basis of
such qualities ...
That evolution in civilized man was subject to a great variety of
social agencies, which did not apply to animals and plants
was clearly understood by Galton (Hereditary Genius,
Macmillan, London, 1869). Subsequently, Pearson (The Scope
and Importance to the State of the Science of National
Eugenics, Eugenics Laboratory Lecture Series, London, 1909)
after examining the same problems, asserted that civilization,
by allowing the unfit to survive, was suspending the process of
natural selection. It can be argued that the function of
eugenics is to compensate for the biological errors of social
life. This aim seems to underestimate the potentialities of
biological adaptation. The human species is very variable and
variation within the species is favourable for long-term
survival; Fisher (The Genetical Theory of Natural Selection.
Clarendon Press, Oxford, 1930) called this variance the
"energy" of the species. Given sufficient energy, the human
race should be able, even without the aid of eugenics, to adapt
itself biologically to civilized life without risking extinction.
The opposite view is to call every heritable deviation from a
theoretical optimal type, undesirable load (Muller, H J: Our
load of mutations. A review of some aspects of genetical
variation. American Journal of Human Genetics, 2: 1 1 176, 1950.) .........
It is abundantly clear that, in the present state of knowledge
concerning human genetics, the prospects of positive
eugenics, in the sense hoped for by Galion, are extremely
narrow. Advances are continually being made in genetical
science and in knowledge of the relationship of genetical
constitution to environmental stresses. Notwithstanding,
even when the scientific knowledge of human heredity
eventually becomes as complete as that of some
experimental animals and plants, the utmost caution will be
required in its application. The central problem, of what
types of human beings are required, involves an insight into
the future which at present we do not possess. The ultimate
aim will have to be to compromise between the maximal
vigour of the phenotypic population and its maximum
potentialities for the future.
Against this background, the study of mental defect will
continue to hold an extremely important place in the fields
of medicine, psychology and genetics. The idiot, in earlier
times alternately despised as an outcast or venerated, now is
seen as an integral part of the human race in its struggle for
evolution and survival, unwittingly yielding information of
the greatest value in the progressive understanding of the
biological structure of the whole group. High-grade and
borderline mental defect are phenomena which have come
into prominence only since human life has become
urbanized and industrialized. Civilized communities must
learn to tolerate, to absorb and to employ the scholastically
retarded and to pay more attention to their welfare.
Subcultural mentality must inevitably result from normal
genetical variation and the genes carried by the fertile
scholastically retarded may be just as valuable to the human
race, in the long run, as those carried by people of high
intellectual capacity.
Lionel was distinguished in many roles. As a humanitarian
he was preoccupied by social and economic injustice and
hardship, and by the futility of war. As a scientist and a
teacher, a quotation from Osler provides a fitting encomium
with which to conclude this talk.
The great possession of any University is its great names. It
is not the pride, pomp and circumstance of an institution
which bring honour, nor its wealth, nor the number of its
schools, nor the students who throng its halls, but the men
who have trodden in its service the thorny road through toil,
even through hate, to the serene abode of fame, climbing
like stars to their appointed heights.
From Aequanimitas by Sir William Osler
From Eugenics to Human
Genetics
Ursula Mittwoch
Queen Mary & Westfield College, University of London, UK
The Penrose Centenary gave me
the opportunity to substantiate
the following remarks that I
expressed in my Inaugural
lecture (Mittwoch 1986):
"Lionel Penrose was Gallon Professor of
Eugenics from 1945-62 and of Human Genetics from
1962-65. The change in title did not entail any change in
the direction of his research. Throughout his working life
Penrose devoted his outstanding intellect to the
application of objective criteria for the study of physical
and mental characteristics that distinguish different human
beings. Such differences were totally divorced from value
judgements; and the notion that the human race could be
improved by selective breeding he regarded as both
ethically and scientifically unsound. By discarding the
rubbish that had accumulated in some areas if human
genetics, and by collecting data based on unbiased
ascertainment, Penrose was able to lay firm foundations
on which the science of human genetics could be built and
has since been able to flourish."
My first piece of evidence comes from a seemingly
unlikely source, the Journal of the Association of
Scientific Workers. The AScW was a trade union, which
included several prominent scientists among its members.
Penrose (1951) contributed an article entitled "Eugenics"
to the journal. It began by informing its readers that the
term "eugenics" was first used by Francis Galton to
denote the science of improvement of stock, particularly
human stock. Whereas Galion initiated the scientific
study of human heredity, on a less scientific level, eugenic
societies sprang up "like mushrooms" during the first
decades of the 20 th century. The dual aim of the eugenists
was to check the fertility of the socially unfit, and to
encourage the fertility of the intelligent by financial
inducements. Penrose opposed both aims. Negative
eugenics was largely futile because the seriously
handicapped are likely to be infertile, and positive
eugenics is invalidated because "we do not know what the
perfect human being is like; it is not sufficient to assume
that the perfect human being is exactly like ourselves".
In March 1965, Penrose gave a lunch-hour lecture at
University College London entitled "From Eugenics to
Human Genetics", which summarized the puzzling history
of the word "eugenics" as an intended academic subject and
its eventual replacement.
Galton had left a legacy to
establish a chair in eugenics.
As interpreted by the
university authorities, the duties of the Galton Professor
were "to further the knowledge of National Eugenics, that is
the agencies under social control that may improve or impair
the racial faculties of future generations either physically or
mentally". Although an anti-eugenist, Penrose accepted the
Galton chair, fortified by the knowled ge that his
predecessor, R.A. Fisher, had paid no attention at all to these
instructions (Penrose, 1965).
Work carried out in the Galton Laboratory prior to
Penrose's appointment did not support such eugenist views
as the existence of a special criminal type, or the
deterioration of the race as a result of greater fertility of the
lower social classes.
Indeed, the stature of school children
was shown to have steadily increased over a very long time.
Penrose considered that characters such as stature and
intelligence are affected by environmental conditions, while
their genetic components tend to be stabilized by the
principle of genetic equilibrium, resulting from decreased
fitness of extreme phenotypes.
Penrose thought that one of the main aims of
human genetics was to understand the relationship between
groups of genes, i.e. linkage; and he promoted the study of
statistical analysis for its detection (Smith, 1953), as well as
that of blood groups with a view to providing markers. The
first published autosomal linkage, between the genes for
Lutheran and Lewis (secretor), was by a "Galton pupil" Jan
Mohr (1951), to be followed by Sylvia Lawler (1953) for Rh
and ellyptocytosis, and by Renwick and Lawler (1955) for
ABO and the nail-patella syndrome.
Another line of investigation was to discover the
origin of fetal malformations, and a highlight was the
discovery of triploidy in a spontaneously aborted fetus
(Penrose & Delhanty, 1961). The advent of chromosome
studies helped to make human genetics into a truly
experimental science, and in 1962 Penrose succeeded in
discarding the word "Eugenics" from the Galton chair and
substituting "Human Genetics".
In his retirement,
heading the Kennedy-Galton
Centre,
Penrose
continued
with the study
of
dermatoglyphics, much of which was previously carried out
by Sarah Holt (see Holt, 1968). The patterns of dermal
ridges are genetically determined, and their analysis can be
quantified. Since the configurations are laid down at about
10 weeks of fetal life (Penrose & Ohara, 1973), they provide
a quantitative variable that remains constant throughout an
individual's life.
A triradius may be defined as the point where three lines
of parallel lines meet (Fig. 1). Three patterns of finger
prints are distinguished: arch, loop and whorl (Fig. 2).
The patterns of the ridges are converted into a quantitative
measure by counting the number of ridges from the centre
of the pattern to the centre of the triradius.
approved.
The exacting standards which he laid down have
enabled human genetics to develop into a rigorous
scientific discipline. To continue his legacy will require
constant effort to generate data against which new
hypotheses can be checked.0
An arch has no triradius,
and its ridge count is zero.
A loop has one triradius
and a whorl has two. The
total ridge count (TRC)
equals the sum of the ridge
counts on the ten fingers.
the 21' century. Lionel Penrose would surely have
Penrose
Fig.1 Diagrammatic
representation of a triradius.
studied
TRCs
(1967)
a
b
in
individuals with different sex chromosome constitutions
and illustrated his results in the graph shown in Fig. 3. It
is evident that there is an inverse relationship between
numbers of sex chromosomes and mean TRC, and that
the effect of the X chromosome is greater than that of the
Y chromosome. The mean TRC of XY males is 145.0,
and that of XX females 127.2. The graph is based on the
assumption that, starting from a theoretical TRC of 187
ridges, an X chromosome reduces the TRC by 30 ridges,
and a Y chromosome by 12 ridges. It is evident that in
males, there is a very close correspondence between
expected and observed means, while the correspondence
for females, although less good, is still in the correct
ranking order.
Fig.2. Prints showing the three ridge
patterns of the fingers; (a) arch; (b) loop;
(c) whorl. The straight lines
superimposes in (b) and (c) connect the
centre of the configuration to the centre
of the relevant triradius; the ridge count is
obtained from the number of ridges
crossed. Only the larger count in (c)
e
XY1
x
The mean TRC of patients with Turner's
syndrome is not only the highest, but, as pointed out by
Penrose, it is exaggeratedly high. In view of the recent
findings of Pat Jacobs and colleagues (Skuse et al. 1997)
of different responses to various psychological tests by
Turner patients with a paternal or a maternal X
chromosome, the question arises whether the two groups
differ in their TRC, which could suggest a developmental
difference going back at least to the second trimester of
fetal life.
Si nce fi ner - pri n t p at te r n s ar e n o w b e i ng
computerized, dermatoglyphics is moving straight into
;0.-‘1%;
X X >C"r /
.
• x x
x x Y•
•XXXX
X X X X.".1'
50
100
150
200
Obser 4 ,eed rri .uan T R C.
contributes to the
"total" ridge count.
Fig.3. Mean TRC values for different sex-chromosome
constitutions compared with expected (E) values, assuming that
E – 187 - 30 (X) - 12 (Y). (Data from Penrose, 1967).
REFERENCES
HOLT, S.B. (1968) The Genetics of Dermal Ridges. Springfield, Illinois: Thomas.
LAWLER, S.D. (1954) Family studies showing linkage between elliptocytosis and the Rhesus blood group system. Proc. 9'h Int.
Cong. Genet. (Bellagio, 1953), 1199-1201.
MITTWOCH, U. (1986). Males, females and hermaphrodites. Ann. hum. Genet. 50, 103-121.
MOHR, J. (1951). Estimation of linkage between the Lutheran and the Lewis blood groups. Acta path. Microbiol. Scand. 29, 339334.
PENROSE, L.S. (1951). Eugenics. Scientific Worker 5, 7-8.
PENROSE, L.S. (1965). From eugenics to human genetics. Penrose papers 77/2, University College London.
PENROSE, L.S. (1967) Finger-print patterns and the sex chromosomes. Lancet 1, 298-300.
PENROSE, L.S. (1969) Dermatoglyphics. Sci. Am. 221 (6), 72-84.
PENROSE, L.S. & DELHANTY, J.D.A. (1961). Triploid cell cultures from a macerated foetus. Lancet 1, 1261-1262.
PENROSE, L.S. & OHARA, P.T. (1973) The development of epidermal ridges. J. med. Genet. 10, 201-208.
RENWICK, J.H. and LAWLER, S.D. (1955) Linkage between the ABO nail-patella loci. Ann. hum. Genet. 19, 312-331.
SMITH, C.A.B. 1953) The detection of linkage in human genetics. J. Roy. stat. Soc. _B 15, 153 -192.
SKUSE, D.H., JAMES, RS., BISHOP, D.V.M., COPPIN, B., DALTON, P., AAMODT-LEEPER. G., BACARESEHAMILTON, M., CRESWELL, C., McGURK, R. & JACOBS, P.A. (1997). Evidence from Turner's syndrome of an imprinted
X-linked locus affecting cognitive function. Nature 387. 705-708.
Lionel Penrose touched the lives of many people during his interesting life.
As well as the talks that were given on the two days of the Symposium,
outlined above, many more people came from all over the world to join in this
celebration. In the second half of this report some of those people have put
down their thoughts and memories in writing.
Reminiscences of Orlando Jack Miller about Lionel
Penrose and the Galton Laboratory.
Orlando Jack Miller
I arrived at the Gallon Laboratory in September, 1958, an obstetrician whose interest in infertility had led me to propose
to Professor Penrose that I study the genetics of Turner syndrome and Klinefelter syndrome. I didn't realize that he had
already started such a study, with Mac Ridler searching for patients with aberrant sex chromatin patterns. Knowing nothing
about training opportunities in human genetics, I had spoken to Lee Buxton, my obs -gyn professor at Yale, who had come
from Columbia. Lee said he would ask his next-door neighbor about this. His advice: "The Galton Laboratory is the best
place to go for such training." How lucky for me that his next-door neighbor was L.C. Dunn!
The training experience was much like that six years earlier, as
described by Barton Childs (except the fly course was now taught by
John Maynard Smith), and provided total immersion in diverse aspects of
genetics. Lionel also insisted that we take the two-semester biochemistry
course: he could see where genetics was headed, and wanted his trainees
prepared. An additional feature I found stimulating was the seminar
series.Iremembermanyofthese,includingonesonself-incompatibilty
in plants (important to an obstetrician!), human blood groups (Rob Race), selection and evolution in fly population cages
(Dobzhansky), somatic cell genetics (Pontecorvo), and 21-trisomy in mongolism (Lejeune). There was a steady stream of
visitors, including former Galtonians, e.g., Marcello Siniscalco, David Y.Y. Hsia, Jean Frezal, Jim Renwick, and Jan
Mohr. The Galton was a good place to meet the movers and shakers in genetics.
Lionel had to cope with a large cohort of trainees while I was at the Galton: Park Gerald, Stan Wright, Ned Boyer, and
Alick Beam during the first year, A.M.O. Veale and Bob Sokal during the addition al six months I stayed on to continue
studies with Lionel on Klinefelter syndrome and its variants. George Fraser and Eric Blank were advanced degree students
during that time, so we also learned a good deal about Pendred's syndrome and Apert's syndrome. G enes for both of these
have been cloned in the past year or two, but those early studies laid the groundwork. We also learned a good bit about
maple syrup urine disease from Professor Charles Dent and his Canadian visitor, Charles Scriver.
Lionel and I traveled fairly often to Harperbury Hospital to study some of the patients with Down syndrome but
especially to examine patients Mac Ridler had found to have a sex chromosome abnormality. We also visited other
institutions so I could identify, by their clinical features, men with Klinefelter syndrome, especially those with variant
phenotypes. The patients liked Lionel, who showed an interest in them and treated them well - usually. He enjoyed talking
with them, and the time tended to slip by unnoticed. Once, when Sandy and I were visiting London some years after our
return to the States, Lionel drove us to Harperbury to see the Kennedy-Galton Centre, which meant so much to him. We
walked over to see the man with both Klinefelter syndrome and Down syndrome whom we had reported in Lancet in
April, 1959, the first example of double aneuploidy in man. He turned to me and said: "I remember you. You're the doctor
from over the sea. I've always wanted to go over the sea." Then he turned to Lionel and said: "Whenever you come, I miss
my dinner!", and Lionel said: "He's absolutely right."
e
Robert Sokal, Distinguished Professor Emeritus
Department of Ecology and Evolution, State University of New York, USA
Lionel Penrose was an inspiring presence whose many sided knowledge never failed to amaze the fellows in the department
that year.
I must have been a great disappointment to him. He had hoped to convert me to some aspect of human genetics, but I had
come to further my knowledge of biometry and pursued that goal determinedly. Then, midway through the year, Peter
Sneath and I got together to lay the foundations for numerical taxonomy, and that took care of the rest of the academic year.
Little did Professor Penrose or I guess that starting around 1980, I would turn to work on aspects of human variation and
genetics virtually full time. My wife and I have warm memories of Professor and Mrs. Penrose, whose hospitality we
enjoyed on more than one occasion. __
Remembrances of Professor Penrose and
The Galton, 1961-62.
James E. Bowman, MD, Professor Emeritus
Departments of Pathology, Medicine; Committees on Genetics, African and African American Studies,
and The College; Senior Scholar, Maclean Center for Clinical Medical Ethics, The University of Chicago,
USA.
My interest in Human Genetics began while I was in Iran on a Medical Education Program. I was involved in human
population genetics studies with no previous training in genetics and managed to write quite a few papers. Professor
Louis K. Diamond from Harvard visited Iran in 1960 and learned of my work. I had by then decided to return home to
the United States, and Diamond suggested that I should study Human Genetics before my return and offered to
recommend me to Professor Penrose. He also supported a Special Research Fellowship from NTH. Diamond informed
me that there was no place comparable to The Galton, and that he had previously recommended Park Gerald. Park Gerald
returned to Harvard with raves about his Galton experience and particularly, Professor Pe nrose (herein after referred to as
the Professor). My wife, Barbara, and five-year-old daughter, Valerie and I arrived and were immediately made
comfortable by the Professor, his family, and his faculty.
I occupied the famous large room with Sheila Maynard Smith, Hans Kalmus, and Tony Lee. I was constantly cold as
Kalmus would arrive and throw up the windows in the coldest weather. Fortunately, I arrived early about 8:00 AM so
that I was warm for awhile. The lady who brought tea soon learned to bring an ext ra large pot of hot water so that I could
dilute my tea--horrors, I never used milk!
My wife and I rapidly learned a new language, English-English. We learned how to pronounce Buckingham and
Tottenham, by not pronouncing each syllable. We began to substitu te lift for elevator and flat for apartment. Even so,
there are APARTMENTS, not FLATS across from my London Hotel, the Gloucester. I suppose this is evidence of
American contamination.
What most impressed me about the Professor was that he was quite unassu ming and shy. He was most gracious, had a
marvelous laugh, and when interrupted for a question or two appeared to have nothing else to do but listen and reply in
his singular polite manner. Helen Lange Brown did guard his privacy, but the Professor apparently was unaware that she
was so protective of his time. I still have notes on his
lectures, which I treasure.
I accompanied the Professor on many occasions to
Harperbury Hospital and on a trip to the Kennedy-Galton
Centre on a subsequent trip to Great Britain. It is an
experience that I will forever remember. I never saw so
many individuals (I will not call them patients) with
Down Syndrome since.
The persons with Down
Syndrome who do remarkably well. I have often
wondered how the individuals at Harperbury would have
fared if they had family contact with someone like the
Professor on a daily basis.
One day the Professor was particularly exited and happy.
He had just been informed that the had been awarded a
Fellowship in the Royal College of Physicians. He was
ecstatic. Here was the most distin g uished Human
Geneticist in the world exited about a FRCP, when he
was already FRS. I later learned that the Professor felt
that he had finally been recognized by his fellow
physicians. I attended the lecture that he gave before the
Royal College of Physicians.
As an uninformed American I also wondered why the
Professor never wore his MA gown instead of his
doctoral gown at University official functions. I then
learned that the MA (Oxon) degree was highly cherished,
more so than the MD degree.
My wife and I had many pleasant gatherings at the
Penrose household. The professor and Margaret were
most relaxed catered to our every whim and paid
particular attention to our daughter, which immediately
endeared us to them. Their children were in and out of
the room and always appeared to be busy. It was
wonderful meeting them again in London and
particularly the presentations and personal recollections
of their father.
Naturally, I have tried to read all of the Professor's many
contributions, even though most of them were not in my
area of investigation. Interestingly, one of his books, An
Objective Study of Crowd Behaviour has been most
useful to me in observing the dynamics of committee
meetings. I may also have taken unfair advantage of
some of my colleagues who did not know that invariably
three individuals with the same view could control a
committee of twenty.
Barbara and I were pleased that the Professor took time
out of his busy schedule when he was president of the
Sixth International Congress of Human Genetics in
Chicago to have dinner with us. His daughter Shirley
Hodgson also was our guest when she visited the United
States. To my wife and I she was still a child, though she
was not.
We were most anxious about her travelling
alone to the West Coast by bus, if I correctly recall.
As I mentioned a the Galton dinner, one of my highest
accolades is to the Galton faculty. He most certainly knew
how to chose colleagues, as have subsequent Galton
Professors. I particularly loved Helen Lang Brown. She was
feared by many; however. I soon learned that behind that firm
exterior was a heart of gold. Our family spent many a pleasant
time at her home, and we particularly enjoyed her sister who
had a most interesting career in the Foreign Service.
I spent considerable time with Hans Kalmus learning about the
intricacies of Colour Vision. I also assisted him in dig ging
considerable amounts of earwax from students in the College.
Kalmus's interests were so diverse that one could never predict
his next scientific foray.
He and his wife were also
magnificent hosts.
I also took John Maynard Smith's famous fly course where he
was an outstanding lecturer. I am not all certain the flies
appreciated me, but perhaps they did, for I accidentally gave
many of them their freedom. Unfortunately, I may have
missed discovering several aggressive mutants. I have all of
John's books on evolution and have devotedly followed his
remarkable career. His wife Sheila traded many stories in The
Room, and she was most helpful by guiding me through the
intricacies of statistical genetics, particularly in the paper that
we wrote together. I enjoyed her most useful treatise. John
and Sheila were also wonderful hosts.
Joy Delhanty meticulously introduced me to the mysteries of
chromosomes. It was an exciting period in those early days
and the Professor was particularly fascinated with the potential
of this new tool in human genetics. He would have been
intrigued by the progress since in this field.
C.A.B. Smith's course was most useful to me. He wa s also
quite gracious and accommodating even with questions that
must have seemed most elementary. I have his two volume
Biomathematics classic and I constantly refer to it. Professor
Smith is also an honest vegetarian. He passed my vegetarian
test with flying colours. His shoes were not made of leather.
Sarah Holt introduced me to dermatoglyphics, which had
always been obscure to me. I was even easily able to write a
chapter on dermatoglyphics in one of my books twenty-eight
years later because of Sarah Holt's excellent tutelage.
I admired Ursula Mittwoch's cytogenetics techniques. I have
never met anyone before or since who is as meticulous as
Ursula is. She also has a wonderful dry humour. I recall one
of her papers in The Scientist, Sex Under the Microscope. We
also wrote a paper together. Ursula and her husband Bernard
were also magnificent hosts. Bernard tried in vain to introduce
me to Cricket at Lord's, but I was a hopeless American. The
games lasted too long, but I was intrigued by the tea breaks.
I had many interesting conversations with the late Professor
Nigel Barnicot about my field of interest, human
population genetics. He and his wife were most gracious.
Professor Gruneberg's mouse genetics course that was
given with Professor M. Deol was fascinating. Their
meticulous dissections and specimens along with the
work of Ms Gill Truslove would be the envy of any
anatomist.
Tony Lee spoiled me. I, perhaps, judge too harshly the
artwork of journals. I thoroughly enjoyed watching him
improve on and redo the artwork of The Annals of Human
Genetics.
Mary Karn and Julia Bell were ageless. Julia Bell was a
walking encyclopaedia, and Mary Karn amazed me with
her ability to do sums in seconds.
Yes, Professor Penrose and The Galton will always be
with me. I am now writing another book for Johns
Hopkins University Press entitled, Eugenics Never Died.
I think of the Professor in each chapter and constantly ask
myself, "Would Professor Penrose approve?"
Gillian Ingall
In 1966 the 3rd International Congress of Human Genetics opened in Chicago. This was the time of the Civil Rights
movement and accompnaying unrest in cities and campuses all over the U.S. I was working with Dr. Robin Banneranm in
Buffalo, New York, and this was my first introduction to the big names in genetics. Having trained as a medical social worker
in England I knew of Dr. Penrose, and his was a familiar face among so many new ones.
The Congress opened with a warm welcome to the large number of International delgates. This was followed by a stern
warning from the Chairman to all participants NOT to venture out on the campus alone, but only in groups, even in
daylight.
This was too much for Dr Penrose. He stood up and stated that he had no intention of giving up his evening walk with his
wife, which he had taken all over the world, with no problems.
I believe most of us admired his spirit, but complied with the Chairman's directive. Whether Dr and Mrs Penrose defied
this warning, I do not know. We did not hear that anything untoward happened to them during that week, and I have a
feeling that he took his walks as usual.el
Reminiscences of the
Galton Laboratory and
Lionel Penrose 1957-1958
Arno G. Motulsky, M.D., D.Sc.
University of Washington, Seattle, Washington, USA
In 1956 I was an assistant
professor of medicine at
th e U n iver si ty of
Washington in Seattle
and worked in the
hematology division. I
had become interested in
human genetics though my work with the hereditary
hemoglobinopathies and inherited hemolytic anemias.
As an undergraduate, I had studied general and
drosophila genetics with Poulsen at Yale University and
later, during my residency training, had attended lectures
on human genetics by Strandskov at the University of
Chicago. Curt Stern's textbook on human genetics
became the bible for further knowledge and reference.
After giving some lectures on medical genetics to the
medical students in Seattle, the professor of medicine
(Robert Williams) at my institution was farsighted in
encouraging me to devote all my efforts to this field and
to set up a division of medical genetics. In preparation, I
travelled around the United States and Europe to visit
various units that were carrying out research in medical
genetics. After these trips it became clear that the Galton
Laboratory under Lionel Penrose in London was the
premier place to study human genetics. Here one was
exposed to the right questions and learned the appropriate
methodology towards their solutions. I felt also quite
deficient in statistical genetics that became acute when I
tried to understand articles in the Annals of Eugenics
(later the Annals of Human Genetics). Studying statistical
and formal genetics with masters such as Lionel Penrose
and C.A.B. Smith seemed the appropriate way of making
up for my deficiencies. My wife Gretel and my three
children aged 9, 5 and 2 arrived in London in the early fall
of 1957. We had arranged for what turned out to be an
inadequate and dismal apartment. Lionel Penrose and his
family graciously offered that we stay at their country
home for awhile until we found suitable accommodations.
However, we were lucky to find an appropriate apartment
in Edgware where we could move in immediately. I
therefore could start my work immediately.
The Prof took me around, gave me a desk and showed me the
various memorabilia relating to Galton. Having discovered a
wild mouse (peromyscus) model of the human red cell
disease (hereditary spherocytosis) I had become interested in
using such animals as a possible way of treating hereditary
anemias by marrow trans plantation. (Later, David
Steinmuller and I successfully treated these mice by this
route.) Having been impressed by Medawar and his group's
fundamental contributions to transplantation, I had contacted
him requesting to spend some time in his lab while largely
working with Penrose at the Galton lab.
The two units
however were very different, even though located in the same
institution, so that interaction with both Medawar and
Penrose did not work out. I therefore spent all my time at the
Galion lab.
Life there was quite different from working in Seattle.
The
starting hour of 10:30am seemed very civilized. Miss
Langdon-Brown (Penrose's secretary) was helpful in
providing for the daily logistics. Intellectual life was very
different for someone used to the task-driven atmosphere of
an American medical school. One could spend one's time
reading, studying, writing, talking, arguing and soaking up
the intellectual atmosphere of human genetics. The
building's inside temperature in winter became quite cold
and we sometimes wore an overcoat when working at the
desk. I attended lectures of Smith and Penrose on statistical
and human genetics respectively and studied their books and
articles. Lunch in the refectory and afternoon tea a t the
Galton Lab provided welcome chances to discuss science
with Penrose and other colleagues. Haldane was just about
to leave for India after my arrival but I saw him a few times
in the Commons room. Hans Gruneberg was a world expert
on mouse genetics. His medical background made him very
much aware that certain mouse mutations could be models
for human disease. Hans Kalmus was the human biologist
par excellence who had wide interests and a broad outlook on
biology, evolution and genetics. Our discussions on the
genetics of human color vision made a lasting impression and
led to my initiating an ongoing program on the molecular
genetics and phenotypic expression of colorvision many
years later. Ursula Mittwoch was interested in development
and cytology. Sylvia Lawler was the remaining member of
the imunogenetic group that earlier had included Race and
Sanger. Harry Harris had left the Galton to set up his own
unit at the London Hospital but often came to talk shop. His
interests in biochemical genetics were close to mine and the
combination of his approaches together with the quantitative
outlook of Penrose influenced me greatly.
Ms. Lang-Brown protected Penrose fiercely.
Yet, there were
occasions to talk things over with him. In those days, he
was greatly interested in the self-replicating wooden
models which he liked to demonstrate to us. To a medic
like me, their relevance to genetics were farfetched but
they demonstrated Penrose's far ranging and unusually
creative mind. Human linkage studies could not be done
because we lacked markers but the theoretical
background such as Penrose's sib pair technique had
already been developed. 1957-1958 was prior to the
discovery of the chromosome abnormality of Down and
other syndromes but research on this condition was
carried out by Penrose. I recall a home visit with a
family worker to see an affected child.
The University College library provided an interesting
find. In browsing its shelves I came across a small book
written in 1815 by Joseph Adams which established the
writer as a major founder of the field of medical
genetics. His work had been entirely ignored and his
book never had been taken out of the library by anyone.
The book was based on Adam's medical experience and
wide reading and established the basic observational
facts of medical genetics such as the differences between
familial and inherited diseases, inbreeding, and the role
of new mutations.
After nine months in London in 1958, I returned to
Seattle and the division of Medical Genetics became
fully established. Stanley Gartler joined the faculty. In
addition to research done in a variety of areas, various
young doctors and scientists from the USA and from
Europe came for training in medical genetics. George
Fraser, who had obtained his Ph.D. with Penrose during
my days, joined us as a faculty member for a few years.
One of our postdoctoral fellows (Joseph Goldstein) won
a Noble Prize in 1985 for his work on cholesterol
metabolism which followed earlier studies on familial
aggregation of hyperlipidemia and coronary heart
disease in Seattle. The division grew and now under the
chairmanship of George Stamatoyannopoulos has 40
faculty members with many of these having their
primary appointments in different departments of the
university.
While officially on emeritus status, I continue actively in
research, teaching, editorial and clinical work in medical
genetics. My career has been deeply affected by my stay
at the Galton Laboratory and I owe Lionel Penrose and
his colleagues a tremendous gratitude for allowing me to
benefit greatly from the Galton atmosphere.M
The Penrose Club
Ann Gath
Founder President of the Penrose Club
Medical Academics specialising in the psychiatry of
mental retardation have long looked to the memory of
Lionel Penrose, as an inspiration. Ours has been the
Cinderella branch of psychiatry itself long considered
by many other specialities as the Cinderella of all
Medicine. We had all be en brought up on the
Colchester survey as we had started our own modest
ventures enquiring into the nature of the deficits, the
underlying causes and social consequences of mental
retardation as well as the phenomenology of the brain
and functional disorders of patients with intellectual
limitations. When struggling with our colleagues, to
find funds for threatened departments, for registrars to
be allowed to work with us or for slots in which to
teach students, a group of us decided that we should
form a club to boost morale by sharing and discussing
research issues. Since several of us had been greatly
encouraged years ago by Lionel Penrose himself taking a
personal and searching interest in our own work, it was
decided to call the society after him who, at that time
was the only person to hold a fellowship of our College
as well as Fellowship of the Royal Society.
The club has been going for just over five years. It is
very definitely not a forum for established research
workers or well funded units to show off their wares, but
has been an occasion when young researchers do feel
welcome to tell us about their ideas and sometimes their
problems. The older ones are continually learning anew.
There is a named lecture, again after Penrose, and so far
the speakers have all worked with him. There is also a
tradition of getting together for a friendly meal. Near the
start, we met at Colchester and went on to drink wine at
Torrington hall, where the Penrose family lived. Before
the Millenium, we shall be there again.
L.S. Penrose and J.B.S.
Haldane
Krishna R. Dronamraju
Foundation for Genetic Research, Houston, USA
The friendship between L.S. Penrose and J.B.S. Haldane
spanned at least three decades, from the 1930s until 1964
when Haldane died. My comments and recollections
pertain to the period 1957-64, when I was closely
associated with J.B.S. Haldane during the last years of his
life in India. During my very first meeting with Haldane
in the fall of 1957, he mentioned Penrose while he was
showing me around his personal library at the Indian
Statistical Institute in Calcutta. One of the journals, the
Annals of Human Genetics, was edited by Penrose at that
time. I do not remember Haldane's exact words but I recall
that he spoke of Penrose with much cordiality and personal
affection. Later I came to know of their long friendship
and collaboration at the Galton laboratory. Haldane was a
member of the editorial board as well as a frequent
contributor to the Annals of Human Genetics.
In his Presidential Address to the Third International
Congress of Human Genetics at Chicago in 1966, Penrose
spoke of Haldane as follows: "I also, in particular, can
represent the traditions of human genetical researches
established by J.B.S. Haldane, who was my colleague
during the greater part of my time at University College
and to whose work I shall pay tribute in this paper....
During the last forty years, emphasis on mathematics in the
English school of human genetics was inevitable because
both Fisher and Haldane were specially attracted to the
subject on account of its formal ramifications."
(Penrose 1967). It was typical of Penrose that, while
paying tribute to both Haldane and Fisher he was too
modest to mention his own pioneering work on the
estimation of human mutation rates as well as several
other aspects of human genetics.
Human Mutation Rate
Although Haldane gave his first estimate of the human
mutation rate for haemophilia in a brief statement in his
book The Cause of Evolution (1932), the appropriate
date for priority in this respect was shared by Haldane
(1935) and Gunther and
Penrose (1935). Haldane
(1932, p.32) wrote: "... the rates of production by
mutation (for haemophilia) and elimination by natural
selection must about balance, and the probability of
mutation of the normal gene works out at about 10-5 per
life-cycle." However, Haldane later discussed the
matter of priority for the first estimates of a human
mutation rate, in a letter to James F. Crow, dated
September 22, 1961. The following is an excerpt from
that letter (reproduced in Dronamraju, 1987):
"I gave my first estimate of the mutation rate for
haemophilia in a book called 'The causes of evolution',
published in 1932.... I did not state how I got the figure.
But it was of course by the indirect method. About that
time I was working out the equilibria in a needlessly
cumbrous way in the Proceedings of the Cambridge
Philosophical Society.
Whether a bare statement
without adequate explanation should be regarded as
constituting priority, I do not know__ Still the fact
may be of interest. Penrose and I later published a joint
letter in 'Nature' a little before my paper on haemophilia
and Gunther and Penrose's on epiloia (Penrose and
Haldane 1935). Here at least we explained how we got
our results. And perhaps this would be the best starting
point in a historical account."
working at the Ontario Hospital in London, Ontario,
Canada. In a letter dated 10 September 1944, (see also
page 29). Penrose expressed hope that he would be
returning to England soon, possibly succeeding R.A.
Fisher to the Galton professorship.* He also expressed
strong interest in initiating human cytogenetic analysis
(along the Russian lines) at the Galton. It is obvious that
Penrose was soliciting Haldane's support in his attempt
to return to England, preferably as the new Galton
Professor at University College, London.
Recollections of Prof. Penrose
Although I knew Penrose for only a few years
of his long career, I came to appreciate his kindness and
helpful disposition toward his colleagues and students.
In 1961, while I was spending a year at Glasgow
University, Penrose invited me to give a seminar a the
Galton Laboratory on the "Y-linkage of hairy pinnae"
which was part of my doctoral research under Haldane.
It was my first introduction to several members of the
Galton staff including C.A.B. Smith, Hans Kalmus,
Sarah Holt, Mary Karn, Ursula Mittwoch, and Sheila
Maynard Smith. At the same time, I also met some
others who were not at the Galton then but were closely
related to the Galton group; a former associate of
Haldane, John Maynard Smith (in the Zoology
Department at University College London), Elizabeth
Robson (with Harry Harris at King's College), and a
student of Penrose, J.H. Renwick (then at Glasgow
University). I was also introduced to several visiting
American geneticists such as James Bowman from the
University of Chicago. I am happy to recall that many
of these members of the wider Galton family have
remained my life-long friends.
In t he followi ng y e ar (in 1962), at the
suggestion of Haldane, Penrose invited me to spend a
few months at the Galton laboratory to learn human
cytogenetic techniques and other aspects of human
genetics to broaden my knowledge and experience.
Although space was extr emely limited, Penrose
extended much kindness and advice which was most
helpful when I was beginning my career in human
genetic research. I had also an occasion in
1961 to
spend a weekend with the Penroses in Golders Green
and enjoyed their very kind hospitality. I recall
especially being shown the DNA models which greatly
interested Penrose.
Haldane-Penrose correspondence
Recently I came across some
war-time
correspondence between Penrose and Haldane, which
isnow a part of the UCL archives. Penrose was then
Haldane in India
During Haldane's last years in India, Penrose
and Haldane maintained close ties. In several letters,
Haldane kept Penrose informed of the research activities
of his group in India, mostly the work of Mrs. Haldane
(Helen Spurway), myself, S.D. Jayakar and Ajit K. Ray.
Penrose's last letter to Haldane was dated 11 November
1964, less than three weeks before Haldane's death on 1
December. It was concerned with offering hospitality to
another associate of Haldane, anthropologist Ajit K.
Ray, just as he helped me three years earlier. In the
same letter, Penrose thanked Haldane for copies of
Haldane's books, The Causes of Evolution, New Paths
in Genetics, and the French version of Heredity and
Politics.
References:
DRONAMRAJU, K.R. (1987). On some aspects of the
life and work of John Burdon Sanderson HALDANE,
F.R.S., in India. Notes Rec. R. Soc. Lond. 41, 211-237.
GUNTHER, M. and PENROSE, L.S. (1935). The
genetics of epiloia. J. Genet. 31, 413-430.
HALDANE, J.B.S. (1932). The Causes of Evolution.
London, Longmans, Green and Co. p. 32
PENROSE, L.S. (1967). Presidential Address – The
influence of the English tradition in human genetics. In
Proc. 3rd Intl. Cong. Hum. Genet, Plenary Sessions and
Symposia, (eds. J.F. Crow and J.V. Neel), pp. 13-25.
Baltimore: Johns Hopkins Press.
PENROSE, L.S. and HALDANE, J.B.S.
Mutation rates in man. Nature 135, 907-908.
(1935).
*please see the Web for further information, following
links from:
http://www.gene.ucl.ac.uk/anhumgen/
Some publications you might not know about:
• T.J.Crow. "A Note on "Survey of Cases of Familial Mental Illness" (1991). Eur. Arch. Psychiatr y. Clin. Neurosci,
240: 314-324.
Sir Cyril Clarke, KBE, MD, FRCP, FRS, President of the Royal College of Physicians of London, "Lionel
Penrose: some aspects of his life and work" (1974). J. Roy. Coll. Phycns Lond. Vol. 8 No. 3.
L. S. Penrose. "Phenylketonuria - a problem in eugenics." (1998). Ann. Hum. Genet. 62, 193-202. Inaugural Lecture
delivered at University College on 21 Jan. 1946 and reprinted with permission from The Lancet, 29 June 1946, pp.
949-953.
Acknowledgements
We thank University College London, The Clinical Genetics Society and The Genetical Society for
their financial support, the Science museum for the loan of the puzzles and everyone who gave
generous donations on the day.
Dian Donnai (left and Peter Farndon (centre) of the Clinical Genetics
Society talking to Gill Truslove (right).
...
and finally
This booklet was produced by Sue Povey and Marina Press. If you require further information you can contact us at:
MRC Human Biochemical Genetics Unit
University College London
Wolfson House
4 Stephenson Way
London NW1 2HE
UK
Tel: +44 (0)171 380 7410
Fax: +44 (0)171 387 3496
Email: sue@galton.ucl.ac.uk
marina@galton.ucl.ac.uk
The Centre for
UCILI luman Genetics
For information on the Centre for Human Genetics at UCL, please see our website at:
http://www.gene.ucl.ac.uldchg,
The Gallery
Some of the other faces at this successful and memorable day!
Joe Berg
Ruth Sanger
(Left to right) Ms Van den Bosch,
Jean Frezal, Jenny Van den Bosch
Bette Robson and Kurt Hirschhorn
(Left to right). Jean Frezal, Shirley Hodgson,
Sue Povey, Marina Press.
Malcolm Ferguson-Smith
(Left to right) Jenny
Parrin gton , Kurt and
Rochelle Hirschhorn
David Watt and Joe Berg
Jan Mohr
Renate Laxova
Richard Doll
Ed Reed
(Left to right) Sue Malcolm, Matthew
Darlison, Bernadette Modell
Joan Faulkner
Mike Ridler
Participants
Dr
A nge la
Bernard
Lucy
Alick
J o se ph
Sam
Shomi
J ame s
Patricia
Car o li ne
Mari Wyn
Cyril
Barton
Cyril
Lady
Clar e
Ge r ald
Sally
John
Howard
Ma tt he w
John
Mary
Clar e
J oy
Nick
Richard
Dian
Krishna
Yvonne
John
Louise
Kathleen
Peter
J oa n
Malc o lm
Patricia
Mar gare t
Mar c o
Ge o r ge
Jean
Mark
Ann
Godfrey
Pao la
A nge la
Shau n
Lynn
Ag ne s
Darren
J ane
Sue
Rod ney
Hilary
Terry
Kurt
Rochelle
Humphrey
Al -Jad e r
Apessos
Baruch
Baruch
Bearn
Berg
Berry
Bhattacharya
Bo w ma n
Boyd
Brown
Burley
Cha p ma n
Childs
Clarke
Clarke
Co n n
Cor ne y
Cottrell
Crolla
Cuckle
Darlison
Darlow
Davis
Davison
Delhanty
Dennis
Doll
Donnai
Dromanraju
Edwards
Edwards
Eunson
Evans
Farndon
Faulkner
Ferguson-Smith
Finch
Fox
Fracc ar o
Fraser
Frezal
Gardiner
Gat h
Gillett
Giunti
Go uge
Grave s t oc k
Gree n hal g h
Greer
Griffin
Halliday
Hamilton
Harris
Harris
Hassold
Hirschhorn
Hirschhorn
Hodgson
Julian
Shirley
A nn a
Ernest
David
Frances
Maij
Ann
Gillian
A
Pat
Mar gare t
Dharini
Ste ve
Re n at o
Sue
Chris
Sheila
John
D
M
Cat hy
Jack
Dorothy
Ursula
Michelle
Be r nad et te
Jan
Tony
Newton
Mrs
Arno
Patricia
Vicky
Ruth
Finbar
Keith
Nicholas
J e n ny
Mar c u s
Va ne ss a
Oliver
Kate
Jonathan
Roger
Rebecca
Sue
Marina
DJ
Martin
J ame s
J une
Edward
Michelle
Michael A
C
Derek
Bette
Hodgson
Hodgson
Hodgson
Hook
Hopkinson
Howard
Hulten
Hunt
Ingall
Jacks o n
Jacobs
Jame s
Jeganathan
Jo ne s
Lam
L ax ova
Malc o lm
Ma th ew
Maynard-Smith
Maynard-Smith
Mc Hale
Mc Hale
Mc Ma h on
Miller
Miller
M ittwoch
M ocre
Modell
Mohr
M o nac o
Morton
Motulsky
Motulsky
Munroe
Murd ay
Newbury-Ecob
O'Cal la g ha n
Parker
Parkinson
Parrington
Pem brey
Penrose
Penrose
Penr o se
Penrose
Penrose
Penrose
Pov ey
Press
Price
Quay
Ran ce
Rat h b o ne
Reed
Rees
Ridler
Roberts
Robson
Penrose: Pioneer in Human Genetics 57
A
Ruth
Letten
Julie
Chris
Liz
Mrs
Marcello
Hea the r
Ced ric
Mic hae l
Deb or a h
Susie
Vicky
Sand r a
Dallas
Mary
Peg gy
Patricia
Gillian
Peter
Ms
Jen ny
Heather
David
Dag an
Ruth
David
Ma gal i
Robin
Nick
Jane t
Philip
Doris
Maria
Teresa
Sag gar - Ma li k
San ger
Saug s tad
Sharp
Sheridan
Sh oe n ber g
Siniscalco
Siniscalco
Skirton
Smith
Smith
Stalker
Ste war t
Stinton
Strautnieks
Swallow
Swee ne y
Thompson
Ti p pet
Truslove
Turnpenny
van d e n B o sc h
van d e n B o sc h
Ward
Wa t t
Wells
W heel er
Whitehouse
Williamson
Winter
W o od
Young
Zack
Zallen
Zenzes
Penrose: Pioneer in Human Genetics 58