ON THE
DNA REVOLUTION
NEWS
A Hothouse of Molecular Biology
Green thumbs at a British lab helped cultivate the achievements of the
much-feted Watson and Crick and a slew of other luminaries. Can its
success be duplicated, or even sustained?
won their prizes in 1962. Sanger claimed
one in 1958 and a second in 1980; Klug garnered the prize in 1982; Milstein and his
student, Georges Köhler, in 1984; and
Walker in 1997. The most recent winners
are Brenner, Sulston, and Horvitz.
Can such stellar results continue? Big labs
that churn out lots of data already threaten the
lab’s preeminence. And the lab’s own exponential growth threatens to dilute the intense
interactions that have characterized the place.
But LMB’s current director, structural biologist Richard Henderson, feels confident it will
still provide fertile soil. As Perutz once wrote,
“Well-run laboratories can
foster [creativity in science].
But discoveries cannot be
planned; they pop up, like
Puck, in unexpected corners.”
Shortly after Sydney Brenner learned that often budgets. The fiefdoms that plague unihe and two former labmates had won the versity departments are absent. “All these
2002 Nobel Prize, he received this e-mail elements add up to a strong formula for dofrom a Chinese researcher: “I wish also to ing good science,” says LMB molecular biwin a Nobel Prize. Please tell me how to do ologist Matthew Freeman.
it.” The answer, Brenner announced at the
Although Watson and Crick are perhaps
award ceremony last December, is simple. the most famous, the list of 750 or so alum“First you must choose the right place … ni reads like a Fortune 500 of biology. Sciwith generous sponsors to support you.” In entists there essentially created the field of
addition, he urged, “choose excellent col- structural biology. Over the past 5 decades,
leagues.” For Brenner and
a dozen other Nobel laureates, the right place was
Cambridge, U.K., and the
right people were their
peers at one of the world’s
Roots in physics
first laboratories devoted
LMB had it origins in the
to molecular biology.
illustrious 19th century
What started about 55
Cavendish Laboratory, part of
years ago as a pilot prothe University of Cambridge.
gram in biophysics at the
Cavendish scientists excelled
University of Cambridge
in physics. J. J. Thomson
eventually became the Labdiscovered the electron there,
oratory of Molecular Bioland Ernest Rutherford
ogy (LMB), now home to
smashed the atom.
about 300 researchers and
In 1915, Bragg, working
alma mater to hundreds of
with his father at the
molecular biology’s most
Cavendish, became the
influential. Among the
youngest person to win a
dozen Nobelists the lab has
Nobel Prize. The father-son
spawned are James Watson
and Francis Crick, who co- Prized moment. Francis Crick, Maurice Wilkins, John Steinbeck (Nobel laureate in team’s success set the stage
discovered the structure of literature), James Watson, Max Perutz, and John Kendrew (left to right) all left Stock- for a new direction for the
lab: biophysics. They had
DNA there 50 years ago. holm with Nobel Prizes in hand.
figured out how to use x-ray
Watson has called LMB
“the most productive center for biology in the they invented key technologies such as crystallography to probe the inner nature of
history of science.”
DNA sequencing. And they have helped to crystals. In so doing, they created a window
The lab’s recipe for success dates back to elucidate some of the most fundamental into the molecular structure of biological
its early days, when leaders such as Max questions in biology: how genes carry the materials as well.
After World War II, Bragg was finally
Perutz had the luck and insight to pick the instructions for proteins, for instance, and
able to sneak biology through the lab’s back
best and the brightest (among them some how a single cell develops into an animal.
quite unorthodox choices) and secure them
One great mind begat another, as the lin- door. Knowing that the Medical Research
almost unlimited support, both financial and eage of Nobel laureates makes clear (see Council (MRC)—even then the United Kingcollegial. In the budding field of molecular graphic). Prize winner William Lawrence dom’s biggest research supporter—was keen
biology, “his operation became known as the Bragg, director of the physics lab where on melding physics and biology, he conplace to be,” says John Sulston, who shared LMB was conceived, brought in Max vinced it to create the MRC Unit for Relast year’s Nobel Prize in physiology or medi- Perutz, who in turn recruited John Kendrew search on the Molecular Structure of Biologicine with Brenner and H. Robert Horvitz.
and Crick. Crick attracted Watson and cal Systems in 1947. Its two members were
The lab welcomed researchers who wan- Brenner. Brenner’s protégés included Perutz, a chemist who wanted to try x-ray
crystallography on proteins, and his student,
dered across disciplines and then encouraged Sulston and Horvitz.
them to interact closely. Even today, when inWhen then-director Perutz moved the lab physical chemist Kendrew. For the next 10
terdisciplinary work has become de rigueur, to its own building in 1962, Frederick years, Perutz and Kendrew raced to identify
LMB stands out for its cross-fertilization and Sanger and Aaron Klug came on board. the molecular makeup of two key blood procommunity spirit. Lab groups there remain Sanger brought in César Milstein and John teins, myoglobin and hemoglobin. They desmall and flexible, sharing equipment and Walker. Perutz, Kendrew, Crick, and Watson vised better ways of doing x-ray crystallogra-
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Crick continued debating
possible structures during almost daily lunches, walks,
MRC Unit for Research on the Molecular
teas, dinners, and even outStructure of Biological Systems
ings on the Cam River.
Max Perutz
1947
Only after Linus Pauling of
1939–2002
the California Institute of
Technology in Pasadena, seen
as the lab’s fiercest rival, came
up with an incorrect view of
John Kendrew
DNA did they get the go1946–1974
Francis Crick
ahead to continue their work.
1950–1977
With the help of one of Franklin’s prize x-ray diffraction images, they finally figured out
how the components of DNA
James Watson Sydney Brenner
fit together.
1951–1958
1957–1992
On 28 February 1953,
they began to build a papermetal model demonstrating
the pairing of the bases in
Laboratory of
this double helix. As the story
Fred Sanger
Molecular Biology
goes, at lunch that day in the
Aaron Klug
John Sulston Robert Horvitz
1962–1983
Eagle Pub, Crick couldn’t
1962–
1969–1992
1974–1978
contain his excitement, announcing, “We’ve found the
secret of life.”
John
Walker
César
Milstein
Nobel lineage. Many scientists at the Laboratory of
But beyond the Eagle,
1962–1983
1963–1995
Molecular Biology (orange) and its predecessor
their colleagues and the world
(green), have received honors at Stockholm and, over
didn’t take much notice. At
the decades, attracted new talent destined to win
Georges
Köhler
the time, “there was much
prizes. (Dates reflect years spent at the lab.)
more excitement about the
1974–1976
Slinky wire-frame spring
walking down the stairs,” rephy and faster ways of analyzing the reams of sessed with determining DNA’s structure. calls Michael Fuller, then a lab assistant and
data generated—harnessing the mathematics They assumed that the structure would re- now the lab’s special projects coordinator.
department’s primitive electronic digital com- veal how genetic information was passed Unraveling the mathematics of how this new
puter for their calculations.
from one generation to the next. Their first toy worked “seemed to excite [lab scientists]
Perutz recruited allies from diverse back- attempts were a flop, however, and Perutz a lot more than the DNA model itself.”
It took another decade for Crick and
grounds: Crick was a physicist, Watson a zo- instructed the pair to leave DNA to Rosalind
ologist, and Brenner a physician. Space was Franklin and Maurice Wilkins, who were others to work out some of the basic principles underlying gene
tight. Crick and Watson—and, later, Crick using x-ray crystalfunction, informaand Brenner—sat back to back in one office. lography to study
tion that gradually
“By 1956,” Perutz wrote, “the Unit had this molecule at
helped confirm his
grown so large, I spent my time scrounging King’s College in
boast. Watson left
for a little bench space in a butterfly museum London. Ostensibly
the lab for Harvard
here or the abandoned cyclotron room working on other
in 1958, where he
there.” Together—closely—they began to projects, Watson and
sought out the seturn biology on its ear.
crets of a different
nucleic acid, RNA.
Life’s secret
Brenner became
Watson and Crick shared a
Crick’s closest colcommon passion: to figure
laborator, working
out what genes were made of.
with bacterial virusCrick, like many of his cones, or phages, to vertemporaries, thought genes
ify Crick’s ideas. Towere proteins; Watson begether they helped
lieved they consisted of DNA.
crack the triplet naSoon after Watson arrived
ture of the DNA
in Cambridge in 1951, the Crowded spaces. When Max Perutz and
code and track the
brash young American—he his budding molecular biologists outgrew
path of information
was 23 at the time—convinced their space in the Cavendish lab (right),
from gene to proCrick that DNA was the stuff they moved into a hut behind this fatein. Molecular biolof genes, and they became ob- mous physics center (above).
W. Lawrence Bragg
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ON THE
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DNA REVOLUTION
ogy was gathering steam, and Perutz’s crew
was stoking its engines.
and Crick but also Perutz and Kendrew that
they had won Nobel Prizes, the latter pair
for chemistry. The reputation of the lab
A very good year
soared. By the late 1960s, American post1962 was a vintage year for LMB. By then, docs “were the engines that powered the
Kendrew and Perutz had gotten their first lab,” says John White, one of those postreal look at the structures of myoglobin and docs, who is now at the University of Wishemoglobin. Kendrew’s student Hugh Hux- consin, Madison. White calls the group “Jim
ley of University College London had begun Watson wannabees.” They were a stark conhis groundbreaking work demonstrating that trast to their British colleagues, who liked to
sliding filaments powered muscle contrac- solve problems at tea instead of at the lab
tion. And Watson and Crick’s model had in- bench. The synergy worked well.
spired a slew of work on the gene-to-protein
One transatlantic transplant from the Salk
transition and the replication of DNA.
Institute for Biological Studies in California
That was also the year that Perutz’s crew was actually a Brit: Sulston. He was one of
left the Cavendish and set up their own shop: the first dozens of young scientists who
the official Laboratowould eventually come to
ry of Molecular Biwork with Brenner on his
ology. They moved
fondly named “worm projinto a new six-story
ect.” In 1974, Horvitz
building on the outmade the trip from Harskirts of town. Gone
vard for the same reason.
were the buttoned-up
What lured them was
lab coats, required
Brenner’s goal of using the
attire at the Cavennematode to help figure
dish. “Things beout how genes affect develcame much freer,
opment. “Most people
lighter,” says Fuller.
thought it was rather a
Per Perutz’s order,
joke,” Sulston recalls.
there were no doors,
True to the lab’s tradino locked cabinets—
tion, Sulston wasn’t given
no secrets among
much space, not even a
scientists.
desk. As far as Brenner
Sanger, whose
was concerned, “desks enwork at the Universicouraged time-wasting,”
ty of Cambridge on Breaking through. John Kendrew stands says Sulston. Perched at a
insulin had earned over a model of the structure of myo- lab bench, Sulston began
him a Nobel in 1958, globin, the first protein structure to be the painstaking task of
helped open the solved and the beginning of a new era in watching the cells of the
doors on the new lab. protein science.
nematode embryo multiply
Klug came, too, atunder a microscope and
tracted to LMB’s shiny new space and col- then drawing what he saw. “When [Horvitz]
leagues interested in the structure and func- came and found me looking through the
tion of proteins.
microscope, he didn’t think it was very sciChampagne corks flew that fall when entific,” Sulston recalls. Before long, “he
telegrams arrived telling not just Watson started doing it with me.”
Together, they tracked
how individual cells divide
and specialize to make the
adult worm. They noticed that
cells that had fulfilled their
functions sometimes died, a
phenomenon they dubbed
programmed cell death. By
working out the genetics of
this process, Sulston and
Horvitz opened up a new
field in cell biology, earning
the 2002 Nobel.
One floor away, Klug was
chasing after the structure of
Dynamic duo. César Milstein (left) and his student Georges viruses. The new imaging
Köhler developed a method for making monoclonal antibodies, method he and his colleagues
now used all over the world.
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Multitalented. While working on virus structures (modeled in photo), Aaron Klug developed new crystallographic methods.
tron micrographs to work out threedimensional structures, earned Klug a Nobel in 1982. But he, too, was drawn to the
unfinished business of RNA and DNA.
Klug and his colleagues eventually worked
out the structures of transfer RNA, which
shuttles amino acids to where they can be
added to the nascent protein. In addition,
Klug determined the structure of RNAs that
act as enzymes to cut up yet other RNA; he
also helped show how DNA is packaged as
a chromosome (see p. 282).
Quiet tenacity
Sanger and some of his protégés were as
quiet and unassuming as Watson, Brenner,
and Crick were outspoken. Sanger “was
not known to be spouting ideas at a 100
miles per hour like Francis Crick or Sidney Brenner,” says Alan Coulson, a nematode biologist who began his career as a
technician for Sanger in the 1960s. Like
Perutz and Kendrew before him, however,
Sanger had tenacity. He spent day after
day for years trying to devise a way to sequence DNA. Sanger eventually figured
out a relatively efficient way to label the
different bases and decipher their order,
winning his second Nobel in 1980.
For several soon-to-be laureates, including Walker and Milstein, Sanger was just the
“right” person. At first, to check the accuracy
of the sequencing, Walker determined the
amino acid sequence of those proteins encoded by the genes that Sanger was deciphering.
They began with the DNA of bacterial viruses but later moved on to the mitochondria,
where Walker found the enzyme that became
the focus of his career, ATP synthase.
In keeping with the bare-bones bureauc-
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Well covered. Nematode biology became so popular that LMB researchers were each assigned to
study just a small part of the organism.
Milstein also sought out Sanger’s leadership, collaborating with him while a Cambridge Ph.D. student. Later, when political
unrest forced him to leave his native Argentina, he joined Sanger at LMB. Even
more unassuming than his mentor, he didn’t
strike his colleagues as Nobel material.
LMB researcher K. J. Patel likens Milstein
to the seemingly bumbling—yet effective—
TV detective Columbo. Sometimes Milstein
could be seen out in a nearby field pacing,
tape recorder in hand. He’d walk through the
halls distracted and oblivious. “But he was
really quite a deep thinker,” says Klug.
When Milstein joined LMB, Sanger suggested that he focus on antibodies instead of
enzymes. It turned out to be sage advice.
With Köhler, Milstein eventually developed
a way to make unlimited amounts of monoclonal antibodies, a uniform set of proteins
that all home in on the same target, paving
the way for a Nobel Prize in physiology or
medicine in 1984.
DNA REVOLUTION
Right place, right people
A British newspaper once
described LMB as a Nobel
factory. But Klug takes issue
with that characterization:
“It’s more like a plantation,
where you plant the seed.”
The fertilizer came in many
forms—money, equipment,
collegiality, to name a few.
For about a decade following World War II, MRC’s science budget grew about 17%
annually. “Anything could be
done. There were no limits,”
says Hugh Pelham, an LMB
cell biologist. And to get those
funds, all the researchers had
to do was ask. After 30 years New generation. Laboratory of Molecular Biology director
with MRC, Walker boasts, “To Richard Henderson (center) hopes his young researchers will
this day, I have only ever writ- follow in their forerunners’ footsteps.
ten one grant.” The support
has been consistent, although modest at ease. Klug still maintains a lab, although he’s
times; there was no money for wood-paneled officially retired.
offices or elegant oak desks, for example.
The tight space only intensified the caMoney flowed even without clear “re- maraderie. Rubin recalls being assigned the
sults.” Perutz, for instance, spent decades lab bench between the pH meter and the
before his hemoglobin work panned out. balance—about a meter wide. Individual ofSimilarly, the worm researchers were far fices, even for the top scientists, were out of
from prolific during the project’s first 10 the question until more space was recently
years. Even in today’s “publish or perish” added. “I think [crowding] was a good
climate, that attitude still prevails: “It’s not thing,” says Brenner. Similarly, the lack of
whether you have published a lot of papers, alternative dining options—then and now—
it’s more whether you have done some fun- meant that everyone ate together, and condamental work,” says LMB bioinformaticist versations and critiques were free-flowing.
Sarah Teichmann.
Ultimately, it was the people who made
When LMB researchers needed a new the place. “The LMB was able to conceninstrument, Perutz made sure technicians trate in one place very exceptional scienand engineers were there to build it, a model tists,” says Pollard. Today, some of that talhe learned at the Cavendish. “We were inter- ent would probably not make the first cut
ested in topics that stretched the tech- for a university position, given the apparent
niques,” says Walker, explaining how the lab discrepancy between the scientist’s experideveloped technologies such as x-ray crys- ence and the job description. Sulston, for intallography, DNA sequencing, and confocal stance, was a chemist working on the orimicroscopes.
gins of life when he came to study the
That left researchers free to concentrate worm. “Max [Perutz] had this uncanny abilon their work. “Your time was almost entire- ity to see something special, not necessarily
ly devoted to research,” says
Thomas Pollard, a cell biologist at Yale University and
LMB alum. Even senior scientists worked at the
bench—a tradition that continues today and goes far to
explain the lab’s vitality, says
Gerald Rubin of the Howard
Hughes Medical Institute in
Chevy Chase, Maryland,
who did his graduate work at
LMB. Perutz spent 90% of
his working time at the
bench until his death last
year, focusing most recently Creative energy. Milstein, Klug, Walker, and Sanger each pushed
on neurodegenerative dis- molecular biology in a new direction with their achievements.
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racy of the place, Walker never needed to
write a proposal about this new research direction. At the time, MRC relied on the lab
chiefs to decide how to spend the money it
allotted to the lab; they, in turn, trusted their
colleagues to come up with good projects.
Thus, Sanger merely asked a few questions
before saying, “ ‘Why don’t you get on with
it?’ ” Walker recalls.
At the outset, the project did not garner
much support. “Quite a number said I was a
fool and that I was going to wreck my career,” says Walker. Instead, he shared the
1997 Nobel for determining the structure of
ATP synthase. He then went on to figure out
how this key membrane protein works.
ON THE
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DNA REVOLUTION
academic ability, and to home in on that,”
says Fuller. “There’s a history of people
with no qualifications who are now senior.”
Past as prologue
At the end of April, hundreds of former LMB
researchers will converge on Cambridge to
celebrate the 50th anniversary of Watson and
Crick’s DNA paper. They include numerous
Nobel laureates whose prizewinning research
came after their time at LMB, as well as
prominent department heads, institute directors, and journal editors. There is no doubt in
their minds that LMB is unique. “I don’t
think if you had put the same people in a U.S.
institution that they would have done as
well,” says Rubin.
But can it continue to be so special?
Thirty years ago, “the f ield was much
smaller. It was the place for U.S. postdocs to
go, and the best went,” Rubin explains.
“Now there are many good places.” Although funds still flow relatively freely, paperwork, regulations, and other constraints
have crept in, Henderson notes. And while
he and his colleagues pride themselves on
their small labs, which range in size from 1
to 10 people, they worry that they will fall
behind. “There’s so much more you can do
with more manpower,” says Pelham.
considerations are also gaining prominence. For instance,
25 years ago MRC
didn’t bother to patent
Milstein’s technique
for making monoclonal antibodies, now a
fundamental tool in
many industries. The
same was true of
Sanger’s sequencing
technology. Today,
patenting is encouraged, says Henderson,
and several compaBiological incubator. Hundreds of budding molecular biologists got nies, such as Celltech,
are associated with
their start at the Laboratory of Molecular Biology, opened in 1962.
the lab.
Klug and Henderson suspect that the
To keep pace with the burgeoning scientists and staff—about 400, more than place is good for at least a couple of more
twice the number 30 years ago—the build- Nobels. Even today, with universities,
ing has doubled in size every decade since medical foundations, and other organiza1962. A new building is in the works. Says tions working to create hotbeds of scienKlug, “I am worried that we will get too tific creativity, LMB still earns strong kubig and lose the ethos on which the lab has dos. Says Yale’s Joan Steitz: “There have
been very good research institutions that
been built.”
LMB now relies on a glossy annual re- have tried to capture the flavor and spirit,
port rather than word of mouth to publi- but they haven’t got it.”
–ELIZABETH PENNISI
cize its accomplishments. Commercial
NEWS
DNA’s Cast of Thousands
Watson and Crick’s discovery revealed much, suggested more, but left
many details unanswered. Ever since, researchers have been discovering
the proteins that unlock DNA and the genetic code
When James Watson and Francis Crick
elucidated the structure of DNA, they discovered an elegantly simple molecule.
With cardboard cutouts, metal, and wire,
they showed how DNA’s two chains wound
around each other, with the paired bases
inside, one full rotation every 10 bases.
Their model immediately suggested how
DNA copied itself and enabled genetic
information to flow from one generation
to the next. They boasted that they had
found the “secret of life”—essentially, biology’s master molecule that controlled
the fate of the cell and, consequently, of
the organism.
Fifty years of research since then has
shown that, despite its precision design, this
molecule can’t dance without a team of choreographers. Like a puppet, DNA comes
alive only when numerous proteins pull its
“strings.” At the time of their discovery,
Watson and Crick had only the haziest of
ideas about how this double helix interacted
282
with proteins. But rebuilt today, Watson and
Crick’s bare-bones model would be draped
with proteins that kink and curl, repair, and
otherwise animate DNA.
DNA ascendant
The age of DNA began well before Crick
and Watson were born. In the 1860s,
Friedrich Miescher, a Swiss working in
Tübingen, Germany, isolated a strange,
phosphorus-rich material from the cell nucleus. Within decades, it was clear that this
peculiar substance—later identified as nucleic acids—was fundamental to the cell’s
chemistry. Somehow.
Throughout the early part of the 20th
century, biochemists argued about DNA’s
role. Some postulated that it was the stuff of
genes; others insisted that proteins carried
Naked DNA. Watson and Crick’s first model of
DNA didn’t begin to reveal the complex set of
proteins the molecule needs to do its job.
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