F R I D A Y ,
J U N E
6 ,
2 0 0 3
TODAY’S EVENTS
Linda Buck on olfaction
Linda B. Buck, a Howard Hughes
Medical Institute investigator at
the Fred Hutchinson Cancer
Research Center in Seattle, gives
the Friday lecture today (June 6).
Her talk, titled “Unraveling
Smell,” begins at 3:45 p.m. in
Caspary Auditorium.
Buck’s lab explores the mechanisms underlying smell, taste and
pheromone sensing in mammals.
Mammals can detect thousands of
different chemicals in the external
world. Most of these molecules
are perceived as having distinct
odors. Some are sensed as having
a particular taste, such as bitter or
sweet, or they act as pheromones,
stimulating programmed physiological or behavioral repertoires.
How do mammals sense such a
vast array of chemical structures?
In the olfactory system, hundreds
of odorant receptors are used in
combinatorial fashion to encode
the identities of thousands of
odorous chemicals. Studies from
Buck’s lab have revealed how
these combinatorial codes are
represented in the nose, olfactory
bulb and olfactory cortex to generate diverse odor perceptions.
Searching for receptors that recognize environmental chemicals
in the peripheral sense organs, her
group has identified distinct
multigene families encoding
receptors for odorants,
pheromones and bitter tastes, and
a single gene encoding a candidate sweet receptor.These
chemosensory receptor genes
have provided a large set of
molecular tools with which to
explore the mechanisms underlying perception and the neural circuitry of behavior.
news notes
THE NEWSLETTER FROM THE ROCKEFELLER UNIVERSITY’S OFFICE OF COMMUNICATIONS AND PUBLIC AFFAIRS
Keeping
telomerase
in check
Researchers identify
protein key to
chromosomal tug-of-war
Deep within some of your cells, on
the spindly tips of your chromosomes, a finely balanced game of
tug-of-war is underway. One team is
pulling outward, increasing the
length and lifetime of the genetic
rope of DNA, while the other team
stands in firm resistance, preventing
the chromosome ends — the telomeres — from growing too long.
Now, new research may explain just how this
locked battle arises. Reporting in the May 25
online version of Nature, Rockefeller
researchers Diego Loayza and Titia de Lange
demonstrate how a recently identified human
protein called hPot1 acts as an intermediary
between telomerase, the enzyme that extends
the telomeres, and the TRF1 protein complex,
which blocks the activity of telomerase.
“HPot1 may be the missing link in chromosome length maintenance,” says Loayza, the
postdoctoral fellow who executed the study.
“Cells made to produce a mutant copy of
hPot1 could no longer regulate the length of
their telomeres.”
Slow-burning telomeres
Normally, telomeres shrink like a burning
candlewick as cells divide and grow old.While
most cells grow old gracefully as their telom-
Connecting the dots. A recently
discovered telomere binding
protein, hPot1, may explain how
healthy cells keep their chromosomes from growing too long.
The merged image above shows
how hPot1 (stained red) binds to
the tips of telomeres (stained
green) in vivo.
eres steadily count down the rest of their lives,
others put up a fight. Germ or reproductive
cells and the rapidly dividing cells of the
immune system require a longer life and as a
result possess a special enzyme, called telomerase, that resists the telomere clock.
Discovered in the mid-1980s, telomerase
actively adds new DNA to the ends of telomeres in germ and immune cells, thereby
increasing the cells’ life span.
How bacteria-eating
viruses may make you sick
Buck received her undergraduate
degree from the University of
Washington in Seattle and her
Ph.D. from the University of
Texas Southwestern Medical
Center at Dallas and did postdoctoral research in neuroscience at
Columbia University.
Her honors include the Lewis S.
Rosenstiel Award for distinguished work in basic medical
research, the Louis Vuitton–Moet
Hennessy Science for Art Prize,
the R. H.Wright Award in olfactory research, the Unilever
Science Award, and the 2003
Gairdner Foundation
International Award. She is a
Fellow of the American
Association for the Advancement
of Science and a member of the
National Academy of Sciences.
Unfortunately, longer life is not always a good
thing. If the wrong cells start manufacturing
telomerase, they can become immortal — a
necessary step in the development of cancer.
Researchers believe that it may eventually be
possible to disarm cancer cells by turning off
their telomerase, but more basic research is
required. Scientists are still trying to understand how healthy germ and immune cells
continued on page 5
It’s not Streptococcus bacteria that are harmful,
researchers say, but the viruses they carry
A strep-infected child in a daycare center plays with a toy, puts
it in her mouth and crawls away.
Another child plays with the
same toy and comes down with
strep.
Nerve cell structure solved
Using X-ray crystallography and other techniques, Rockefeller scientists recently
produced this image of a 14-unit signaling molecule that plays an important role
in communication between nerve cells. Story on page 5.
It’s a scenario repeated several
million times each year in the
U.S. But while logic would dictate that the Streptococcus bacteria
left on the toy was the culprit in
transferring the disease from the
first child to the second, new
research suggests it may not be
that simple.
Rockefeller University
researchers have now shown that
in many cases it’s not the bacterium itself that spreads disease but
a virus that infects and destroys
bacteria. Called a bacteriophage,
this “bacteria-eating” virus causes
disease by transferring toxins and
other disease-causing genes
between bacteria.
The findings, reported in the July
issue of Infection and Immunity,
show for the first time that bacteriophage, or phage — previously
thought not to be infectious to
humans — may be a new target
for fighting certain infections.
“Controlling the phage may be as
continued on page 3
news notes
JUNE 6, 2003
Laboratory on the Biology of Addictive Diseases
Diagnosing addiction in five minutes or less
New test for drug and alcohol addiction gets straight to the point
A new survey can quickly test for
addiction to cocaine, heroin and
alcohol simply by asking about
the time in a person’s life when
he or she was drinking or using
these substances the most, according to a study by Rockefeller
University researchers.
Based on Rockefeller professor
Mary Jeanne Kreek’s decades of
research into how substance use
affects the brain, the survey gets
surprisingly accurate results by
asking just a handful of questions
on the patient’s history of drug
use. In fact, only three answers
influence the patient’s score: the
duration of the heaviest period of
use, the frequency of use during
that time, and the amount then
typically consumed at one sitting.
The new survey is called the
Kreek-McHugh-SchlugerKellogg (KMSK) scale. It consists
of six to eight questions about the
individual’s heaviest period of use
of four different substances: alcohol, tobacco, cocaine and heroin/opiates.
Scott Kellogg, a Rockefeller clinical psychologist who helped
develop the test, is the first author
of a study on its effectiveness
published recently in the journal
Drug and Alcohol Dependence. He
and his colleagues recruited 100
volunteers, both with and without
histories of substance abuse, and
administered both the KMSK and
the “gold standard” SCID-1 tests
to each of them.
The results showed that the
KMSK scale was very accurate at
predicting whether or not an
individual had been addicted to
either heroin/opiates or cocaine,
Kellogg said.The screen could
detect 100 percent of the heroin/opiate addicts, and 97 percent
of the cocaine addicts — results
that are at least as good as other
brief tests already in use. For alcohol, the KMSK scale could detect
90 percent of people who met
the formal diagnosis of alcohol
addiction. However, the alcohol
test was slightly more likely than
the other two to give a false positive result, meaning it sometimes
identified a person as an alcoholic
when the individual did not meet
the formal criteria.
(The higher rate of false positives
is probably related to the complexity of alcoholism, which
depends not only on exposure but
also on factors such as drug use,
other psychiatric disorders and
genetics.“And from a clinical perspective, having an occasional false
positive means that we have
uncovered individuals with histories of high levels of alcohol use
who did not experience major
negative consequences of their
drinking but are at risk of devel-
oping them,” Kellogg says.)
as heart disease,” he says.
The test’s beauty is in its simplicity. By asking only about a specific
time period, it focuses exclusively
on the period when exposure to
the substance was most likely to
contribute to long-term addiction.“In research animals, an
intense enough period of heavy
exposure to drugs or alcohol will
cause fundamental physiological
changes in the brain,” Kellogg
explains.“That’s why asking about
exposure is so important in trying
to gauge addiction.”
And, although developed as a
research tool, emergency rooms
and clinics may eventually use it
to test for addiction, Kellogg said,
because its novel approach could
spot a subset of addicted people
who might otherwise be missed.
Those individuals could then be
referred for a full evaluation
before a formal diagnosis is made.
The KMSK scale may prove helpful to other scientists who study
addiction, especially those who
focus on the link between exposure to drugs or alcohol and
dependence, Kellogg says. It may
also aid research on other diseases.
“It could be used in studies of
other conditions where drug or
alcohol use can be a factor, such
Kellogg and his colleagues are
planning to create similar tests for
barbiturates (sleeping pills), benzodiazepines (sedatives) and marijuana.“We’re especially interested
in developing a scale for marijuana, because we have less evidence
about how different levels of use
relate to addiction,” Kellogg says.
“We’re also interested to discover
whether a high or low score on
the KMSK scale can predict an
addicted individual’s response to
treatment.”
How bacteria-eating viruses may make you sick continued
important as controlling the bacteria,” says senior author Vincent A.
Fischetti, professor and head of the
Laboratory of Bacterial
Pathogenesis and Immunology.
“It’s possible that phage present in
the saliva of a child or another
individual can cause the conversion of an existing non-toxigenic
organism to a toxigenic one.We
always believed that phage were
not infectious to humans, but in a
sense, they are.”
Scientists classify certain bacteria
such as those causing scarlet fever,
diphtheria and E. coli O157 (a
source of food poisoning in contaminated meats) as toxigenic,
meaning that these microbes produce toxins — transported by
phage — that cause disease.
People can carry colonies of
bacteria, such as strep, without
being sick as long as the microbe
doesn’t carry a toxin-encoded
phage.
But, when a toxin-producing
phage moves to a nonvirulent
bacterium, it transfers a toxin
gene to the new organism.This
process, called lysogenic conversion, transforms the harmless
microbe into a virulent bug.
Scientists were not sure where the
bacteria picked up the phage until
two years ago when Thomas
Broudy, then a graduate student
in Fischetti’s lab, identified a factor in human saliva that causes
the phage to become active.
“Since phage and the bacterium
are out in the environment, it was
thought that the microbe picked
up the phage there,” says Fischetti.
“We now know that phage are
designed to do this in humans,
and not in the environment, by
taking advantage of a human factor called SPIF to allow the transfer process to occur efficiently.”
In the lab, Broudy added SPIF
(soluble phage inducing factor) to
lysogenic bacteria.The result:
SPIF mobilized the phage and the
bacteria disentegrated, or lysed.
Because the bacterium he was
studying, Group A strep, is only
found in the human throat,
Broudy deduced that the phage
was induced or activated there,
and not in the environment.
The question was, could a nontoxigenic organism that is found
in the oral cavity become toxigenic if you add a bacterium that
is carrying a toxin-encoded
phage?
To answer this question, Broudy,
first author of the new Infection
and Immunity paper, and Fischetti
took human pharyngeal cells cultured in a petri dish and added
toxigenic and non-toxigenic
strains of Group A strep.They
found that the phage indeed
jumped from the toxigenic strain,
causing the bacterial strain that
was not carrying the phage to
produce toxins.The Rockefeller
researchers later repeated the
experiment in the throat of a
mouse and obtained the same
results.
Broudy also isolated a toxin-car-
Deadly pinwheel. Several toxin-encoding phage attach themselves to a fragment of the cell wall of the bacterium
Streptococcus pyogenes. Researchers now believe these phage may cause non-toxic bacteria to become toxic.
rying phage and introduced it to
a mouse carrying a colony of
noninfectious strep bacteria.
The result: the noninfectious bacteria became toxigenic.“It makes
sense that the phage would want
to induce at a site where it would
potentially find its host,” says
Broudy.“The system is designed
so that when a phage-carrying
strep goes into the oral cavity, the
phage induces, where it is released
to infect any non-toxigenic bacteria that can potentially be
there.”
SCIENCE NEWS
Laboratory of Populations
Looking for light. Because of
their dependence on light as an
energy source (and their inability
to get up and move someplace
sunnier), plants must constantly
monitor the quality and quantity
of their light to control growth
and flowering. Nam-Hai Chua’s lab
has proposed that one mechanism
by which they accomplish this is
a phosphate-based protein called
PP7. By growing genetically
modified Arabidopsis seedlings
under several different wavelengths of light, Chua and his
colleagues determined that PP7
reacts to blue light to signal the
plant’s growth pathways.The
research was published in May in
The Plant Cell.
Diagramming dinner
Japanese Encephalitis, cloned.
Researchers studying viruses like
to make genetically identical
clones of their subjects in order
to learn how they infect cells and
replicate in real time. But until
now all attempts to clone the
Japanese Encephalitis Virus (JEV)
had failed. Charles Rice’s lab, in
conjunction with colleagues in
Korea, overcame the problems by
using bacterial artificial chromosome vectors (BACs) as templates
for JEV RNA transcription.Their
efforts led to the first JEV clone
that was both stable and highly
infectious in susceptible cells.The
technique could help lead to new
JEV vaccines. JEV is a close relative of the West Nile flavivirus
that emerged in New York in
1999 and is spreading across the
U.S.The study appears in the
June issue of the Journal of
Virology.
Sting operation. Next to bees,
yellow jackets cause more stings
in humans than any other insect.
When Te Piao King and his lab
tested individual components of
yellow jacket venom in mice,
they found that its toxicity
requires the synergistic action of
two components: a peptide called
mastoparan and a protein called
phospholipase A1.Together, the
components cause an inflammatory response at the site of injection. And one of them, mastoparan, may stimulate antibody
response.The research could lead
to new treatments for people
with allergies to yellow jackets.
The study was published in the
International Archives of Allergy and
Immunology.
Calling all T cells. It’s not that
cancer cells are fighting the
immune system and winning; it’s
that the immune system isn’t
even fighting back. A recent
study from Madhav Dhodapkar’s
lab shows that immune system T
cells taken from the bone marrow
of multiple myeloma patients
don’t attack cancer cells. But take
the T cells out, treat them with
specialized immune dendritic
cells, and suddenly the tables
turn, at least in in vitro experiments.The researchers say that
recruiting and bolstering the
body’s own immune system cells
in this fashion could represent an
exciting new way to halt or
reverse the progression of some
cancers.The study was published
in the Proceedings of the National
Academy of Sciences.
— Zach Veilleux
Predicting ecological patterns is easy — if you have a foodweb
Clichés notwithstanding, it’s not
so easy being a big fish in a small
pond.
greater than expected, and if so,
why is that? How rare should a
particular big, fierce animal be?
As humans, the size of our pond
— our ecological community —
is irrelevant as long as we have
supermarkets, where food by the
crateful magically appears on the
shelves. But for fish there is no
restocking; eat up the lake and
they starve.
“Ideally, we would like to create
communities in the lab,” he says.
“You can yank out one thing and
see how other species react.” In
fact, this sort of manipulation was
done at Tuesday Lake, where
researchers removed almost all the
fish in 1985 and replaced them
with an equal weight of a larger,
predatory fish, the largemouth
bass. Carpenter and colleagues
then collected foodweb, body
mass, and abundance data again in
1986.
Luckily, Rockefeller’s Joel Cohen is
looking out for the fish — big
and small. His research on the
ecosystem of a tiny lake in
Michigan has resulted in an intricate diagram of the who-eatswhom world of an aquatic community. It has also revealed some
surprises about previously documented relationships and ecological patterns.
Ever since Charles Darwin wrote
one of the first descriptions of a
foodweb in 1838, biologists have
been studying the patterns in
which animals eat one another.
Typically, a relatively small number of big animals eat a much
larger number of smaller animals,
both of which eat plants. For the
most part, though, studies of
species abundance and body size
have not been directly linked to
foodwebs.
Cohen and his co-authors,Tomas
Jonsson, a former postdoctoral
researcher in Cohen’s lab who is
now at the University of Skövde,
Sweden, and Stephen Carpenter,
of the University of Wisconsin,
used information collected from
A tangled web. The foodweb of Michigan’s Lake Tuesday. Each cluster of horizontal
bars represents a single species; the wider the bars, the greater the biomass, numerical abundance and body mass of that species.
Lake Tuesday in Michigan’s
Upper Peninsula in 1984.The
data included abundance and
body size information on the 56
different species found in the
upper layer of Lake Tuesday’s
water, including microscopic
plants called phytoplankton, small
animals called zooplankton and
several species of fish.
Cohen’s analysis revealed that the
weight of the total living material
— the biomass — was about the
same no matter whether you
were looking at the biggest fish or
the smallest phytoplankon. In
other words, the total weight of
the few, heavy fish roughly
equaled the total weight of the
more numerous large zooplankton and the still more numerous
smaller zooplankton further down
the chain.This held true despite a
huge variation in body size and
abundance: the largest organism
was 12 billion times the size of
the smallest and outnumbered by
a factor of 10 billion.
When Cohen and his coauthors
graphed each species’s average
body mass against its numerical
abundance, the result was a nearly
straight diagonal line from the
rarest, heaviest species to the
commonest, lightest one. Many
data points, each representing one
species, are close to the fitted line;
a few are farther off the line.
“I’m interested in explaining the
deviations,” Cohen says. For
example, a species far above the
trend line is one with, on average,
a larger population than its average body size alone would predict.That leads to scientifically
testable questions:Why is the
species more abundant than
expected? Is the productivity of
the species on which it feeds
On analysis, Cohen and Jonsson
found that although species
changed between the two sampling years, ecological patterns
remained almost the same.“The
manipulation had remarkably little effect on the relationship
between biomass and abundance.
The natural history of the system
changed, but not the ecology. It
was as if you had a different cast
of characters acting out the same
play,” he says.
Indeed, Cohen’s basic research on
ecological communities has implications for his applied research on
Chagas disease in Latin America.
There a human household with
dogs, cats and chickens — and
bugs that transmit parasites
between them — may be viewed
as an ecological community with
its own foodweb. Understanding
such systems better could lead to
interventions that help reduce the
spread of the disease.
PEOPLE IN THE NEWS
Most of us are lucky if two dozen
people show up for our birthday
parties.When Rockefeller
Professor Emeritus E.G.D. Cohen
turned 80, his entire field turned
out to celebrate.The three-day
Statistical Mechanics Conference
held this May at Rutgers
University in New Jersey was in
honor of Cohen and his half-century of research on fluid dynamics. Rockefeller Professor Mitchell
Feigenbaum was a keynote speaker
at the conference.
In April, the National Academy
of Sciences announced the election of 72 new members in
recognition of their achievements
in original research. Among them
was Rockefeller University
Hospital Physician-in-Chief Barry
Coller. Fewer than 2,000 scientists
are active members of the N.A.S.;
31 are from Rockefeller.
Elaine Fuchs, who was recently
named Rockefeller’s Rebecca C.
Lancefield Professor, received an
honorary Doctor of Science
degree from Mount Sinai School
of Medicine at its convocation in
May.
The hydrogenosome, a cellular
organelle that generates energy in
certain one-celled organisms (circular structures pictured at right),
was a major find 30 years ago. Last
month it won its discoverer,
Rockefeller Professor Emeritus
Miklós Müller, a fellowship in the
American Academy of
Microbiology. Only 1,800 scientists
have been elected to the academy
in its entire 50-year history.
Thomas P. Sakmar, Acting President
Editor: Zach Veilleux
Cathy Yarbrough, Vice President for
Communications and Public Affairs
Art Director: John Haubrich
Suggestions for stories should be sent to newsno@rockefeller.edu,
interoffice Box 68 or by fax to (212) 327-7876.
Contributors: Joseph Bonner (dir. of communications),
Whitney Clavin, Lynn Love, Holly Teichholtz
News&Notes is published by the Office of Communications and Public
Affairs for faculty, students and staff of The Rockefeller University.
The Rockefeller University is an affirmative action/equal employment opportunity employer. | ©2003 The Rockefeller University
Forging ahead on stem cells
With federally approved human embryonic stem cell lines
limited, Rockefeller explores new research avenues
Creating new laboratory cultures
of human embryonic stem cells is
legal in this country. In practice,
however, few U.S. academic institutions have been advancing
human embryonic stem cell
(HESC) research since August
2001. At that time, President Bush
ordered that federal funds for
HESC research would be available only for studies using already
existing cell lines listed on a
National Institutes of Health
(NIH) Registry. The President
imposed a moratorium on federal
funding of research that would
establish or study “new” HESC
cultures.
The decision was disappointing to
scientists: time and experience
have proved that the registry lines
are inadequate in many ways and
provide the means for only a limited understanding of basic biological mechanisms.
Because scientific research is so
heavily supported by federal dollars, the task of creating parallel
tracks of exclusively privately
funded research is daunting for
academic institutions. Most simply
lack the experience and resources
to do it.
Rockefeller, however, is overcoming those obstacles by developing
pragmatic solutions to the legal
and administrative issues of establishing a privately funded HESC
research enterprise.
Acting President Thomas P.
Sakmar has led the way in developing these solutions. By making
privately funded HESC research
one of his priorities, he has
moved the university dramatically
ahead in the past year.With the
administrative and legal issues
now well managed, Rockefeller
scientists are poised to establish
new HESC cultures this year.
At a Rockefeller University
Council meeting earlier this year,
Sakmar, who is an M.D.,
explained his rationale:“Stem cells
represent a potential for advancing the practice of medicine and
revolutionizing the way we treat
disease.” But before realizing this
potential, scientists must delve
more deeply into the basic characteristics of human embryonic
stem cells.This research would
answer the question of how the
cell becomes an organism and
how specific body tissues arise.
The answers to these questions
could lead to exciting, diseasespecific therapies.
guarantee broad-ranging research
progress.Vice President for
Development Marnie Imhoff and
her staff are actively engaged in
securing private support.To date,
more than $3 million has been
raised for HESC studies.
Sakmar, working with a university
task force he organized this year,
has implemented a three-pronged
strategy for HESC research —
science, infrastructure and funding
— that is already aiding efforts in
basic research.
Several laboratories on campus
have a primary interest in stem
cells. Among them are Ali
Brivanlou’s Laboratory of
Molecular Vertebrate Embryology,
Peter Mombaerts’s Laboratory of
Developmental Biology and
Neurogenetics, and Markus
Stoffel’s Laboratory of Metabolic
Diseases. Of these, two laboratories, Brivanlou’s and Stoffel’s, now
are studying human embryonic
stem cells, using NIH Registry
lines.
Associate Vice President Amy
Wilkerson led an administrative
group that surveyed Rockefeller
labs in September 2002 to identify scientists studying the basic
biology and clinical application of
human embryonic stem cells. One
of these labs has since been renovated, using private funds, to create a space for HESC research
that is separate from areas where
federally funded research is carried out. In addition, the Office
of Finance has established separate
accounting procedures that are
used to track this privately-supported work. All these arrangements assure that President Bush’s
mandate will be carefully
observed.
An embryologist, Brivanlou investigates the development of organisms from their earliest stages of
life.The early embryo, called a
blastocyst, contains about 150
cells that, when isolated properly,
can be studied for their abilities to
generate all tissue types in the
body (see illustration, below).
Brivanlou believes that learning
the molecular basis for this developmental process potentially will
allow scientists to create stem-like
cells from any body cell.
The university has hosted two
notable meetings in the past year
to gather and share information
about HESC research. An
October 1, 2002, conference,
attended by 60 administrators
from 16 major universities and
other institutions in the U.S.,
focused on the best practices for
setting up privately funded
research with human embryonic
stem cells.
Stoffel, a clinical investigator,
focuses on diabetes. In his
research on the function of pancreatic beta-cells, the insulinsecreting cells in the pancreas, he
and his colleagues have developed
a system for deriving new insulinproducing pancreatic islet cells
from embryonic stem cells in
mice. Could the same result be
achieved with human adult or
embryonic stem cells? If so, the
“new” laboratory-generated
insulin-producing cells could be
used to replace those pancreatic
cells destroyed in juvenile-onset
diabetes.
On November 13, 2002,
Rockefeller’s Brivanlou, with the
co-sponsorship of the New York
Academy of Sciences, brought to
campus several of North
America’s premier molecular vertebrate embryologists.The meeting resulted in a May 9 Science
Perspective article that proposed
scientific standards for studying
human embryonic stem cells and
expanded the argument for establishing HESC lines in addition to
Rockefeller’s HESC research initiative eventually will benefit from
federal government funding. For
the immediate future, however,
private funds are necessary to
Of mice and cells. A colony of human embryonic cells grows in a medium of mouse
embryonic fibroblasts. Many researchers are eager to study new human embryonic
stem cell lines that can be grown in human rather than mice media.
those in the NIH Registry. In the
same issue of Science, Editor-inChief Donald Kennedy urged the
magazine’s readership to consider
the consequences conservative
politics might have on the usually
robust U.S. research field.
Rockefeller officials also have
begun to work with fertility clinics to obtain donations from
patients who want to contribute
embryos in excess of clinical need
to stem cell research.Through the
Office of the General Counsel,
Rockefeller has collected published opinions on how such
donations should be handled, and
has explored the plans of other
institutions getting ready for
HESC research. As a result,
Rockefeller now has a set of rigorous ethical and legal terms that
it uses in working with reproductive health clinics to document its
relationship with the clinics and
with their patients who choose to
become donors.
Finally, to further encourage
HESC research, the university is
considering the launch of a new
journal of stem cell biology
through the Rockefeller
University Press. Press executive
director Michael Held commissioned a feasibility study by a for-
mer president and publisher of
Nature that will be completed this
month.“We want to take this
very compelling idea and ensure a
viable publication with a significant scientific and educational
contribution and lifespan,” says
Held. If it goes forward, the publication would be the first new
journal launched by the RU Press
in almost 50 years.
It’s all starting to come together.
“Now that we have coordinated
the administrative, financial and
scientific aspects of non-federally
funded human embryonic stem
cell research at Rockefeller, we
will be able to establish new cell
lines that will transform current
scientific understanding,” Sakmar
says.“We are joining an international effort in moving scientific
and clinical knowledge forward in
the 21st century, and continue
our leadership role in human
embryonic stem cell research in
the U.S.”
For Brivanlou, the scientific freedom is crucial to his future goals
in research. Brivanlou is ready to
create new HESC lines, and in so
doing, to create a new yardstick
by which he can more consistently measure them.
— Lynn Love
Potential
Stem Cells
Blastocyst
Blastocyst
Blastocyst
Pin Point
Pin Point
M A G N I F I C AT I O N
1x
1
10
M A G N I F I C AT I O N
100
1000
10x
Potential in a tiny package. A human blastocyst, or five-day embryo,
is merely a speck to the unassisted eye, just 0.1 millimeter in diameter
or about the same size as a pin point. But shown under progressively
1
10
M A G N I F I C AT I O N
100
1000
100x
1
10
M A G N I F I C AT I O N
100
1000
greater magnification (above, left to right), the roughly 150 undifferentiated cells within the blastocyst can be clearly seen. At this time, only
a handful of these cells are known to be stem cells, which have the
1000x
1
10
100
1000
ability to grow into any specialized cell in the human body and may
someday prove useful in a number of disease-specific therapies. The
remaining embryonic cells have yet to be fully explored.
Regulating ions, linking nerves
Photographs of brain molecule show hub-and-spoke
structure critical to learning and memory
They were off by two.
tein made of 12 subunits.”
Scientists had been working on
the assumption that a tiny structure in nerve cells known as the
Calcium/Calmodulin-dependent
kinase II (CaMKII) contained 12
protein subunits. But Rockefeller
University graduate fellow André
Hoelz, whose image of the structure illustrated the cover of
Molecular Cell in May, showed the
Scientists believe that stable connections between nerve cells are
important for forming networks,
and these networks in turn are
important for memory, learning
and other higher cognitive functions. CaMKII plays a pivotal role
in forming these stable connections by sensing calcium ions that
flow from the gap between nerve
munication is achieved by oscillating calcium signals, such as when
the heart beats,” says Hoelz.
“With a big assembly such as this,
you have by default a high local
concentration of kinases.You just
wait for the signal and you go,
rather than having to recruit
kinases where they are needed,”
explains Hoelz, who collaborated
on this project with adjunct faculty member Angus Nairn and thesis advisor John Kuriyan. (When
Kuriyan moved to the University
of California, Berkeley, Hoelz
stayed and continued his research
in the labs of Professors Thomas
P. Sakmar and Günter Blobel.)
Hoelz’s research hit a roadblock
when a previously published lowresolution electron microscopic
reconstruction of the protein suggested it was too large and flexible to crystallize.
Learning on a curve. This angular view of the hub-and-spoke model of
Calcium/Calmodulin-dependent kinase II shows the 14 kinases (indicated by gray and
green lobes) packed tightly against a central hub. Structures inside two of the kinase
domains indicate the machinery that inhibits kinase activity, preventing “autophosphorylation,” the process by which chemical phosphate groups bond to one another.
actual number of subunits is 14.
cells into the receiving neuron.
“This is really a big surprise,” says
Hoelz.“In any scientific paper
about Calcium/Calmodulindependent kinase II the introduction begins with two sentences:
the first says that it’s important for
learning and memory, and the second says it is a dodecamer, a pro-
But because the duration of these
calcium signals is in the millisecond range, CaMKII must respond
extremely quickly to catch and
decode the signal.“This property
is important not only in the brain
but also in other cells throughout
the body where intercellular com-
“I decided to split the problem
into two pieces: the auto-inhibited kinase domain and the core
structure,” he says. Because “kinase
domains all look the same,” Hoelz
was able to use this information
along with X-ray crystallography
to fashion a hub-and-spoke
model in which 14 kinase
domains are packed tightly against
each other and the hub, in an
alternating up-and-down pattern.
With this structure, believed to be
the most complex of hundreds of
protein kinases in animal cells, scientists will be able to conduct
more detailed tests into the workings of nerve cells.
—Joseph Bonner
Record number of Ph.D.s
to be awarded June 12
Last June, 30 graduate students
received doctoral degrees from
Rockefeller, the most ever.This
year the number climbs again —
to 34.That’s the most degrees
conferred in one year since the
graduate program began in 1955.
This year’s Convocation will be
special also because an honorary
degree will be presented to
Rockefeller President Emeritus
Torsten Wiesel, who has remained
active on campus as well as internationally in promoting science
and human rights.Wiesel, the
Vincent and Brooke Astor
Professor at Rockefeller since he
joined the university in 1983,
shared the Nobel Prize in
medicine in 1981 for studies of
how visual information is transmitted from the retina to the
brain. During his six-year tenure
as president Wiesel established 30
new laboratories and six interdisciplinary research centers and
raised nearly $200 million in private gifts.
The June 27 issue of News&Notes
will contain excerpts of the presenters’ introductions of their
graduates at Convocation, along
with photos and other articles.
For more information or for tickets to Convocation, call Meridith
Egyes at 327-8072.
Convocation 2003 | Thursday, June 12, 2003 | Schedule of Events
2:30 Academic Processional from Weiss Lobby to
Caspary Auditorium
3:00 Convocation, Caspary Auditorium
5:30 Reception, Peggy Rockefeller Plaza
Keeping telomerase in check continued
keep their telomerase in check.
Bridging the gap
Loayza and de Lange focused on
the tips of telomeres, the region
where the tug-of-war takes place.
Here, telomerase grabs hold of
the very edge of the chromosome
— a single-stranded thread where
the DNA no longer forms a double helix — and elongates it. A
little farther in, on the doublestranded DNA, a large protein
complex called TRF1 sits in
opposition, preventing telomerase
from making the telomeres too
long.
Nobody knew how these two
teams communicate across the
single-stranded gap lying between
them. Scientists had attempted to
locate proteins that specifically
bind to this stretch of DNA, but
they kept coming up short.
The Rockefeller researchers
began their search for this missing
link with a single-stranded telomere binding protein called hPot1
(for “Protector Of Telomeres”),
originally discovered two years
ago by Nobel laureate Thomas
Cech, a professor at University of
Colorado, and his colleagues.
To study the association of hPot1
and other proteins on telomeres,
they developed a specialized
chromatin immunoprecipitation
(ChIP) assay.Typically, ChIP
experiments allow researchers to
identify proteins that bind to
DNA in living cells, or in vivo; in
this case, the ChIP technique was
modified to strictly examine
telomere binding proteins.
By combining this technique
with the inhibition of another
telomere-binding protein called
TRF2 — which results in a drop
in the amount of single-stranded
telomeric DNA — the
researchers were able to show that
hPot1 binds to the very tips of
telomeres in vivo, making it the
first known human protein to do
so (see image, page 1).
Next came an unexpected twist:
when the scientists deleted
hPot1’s ability to clutch DNA,
they observed that it still attached
to telomeres. How? The answer,
they discovered, is that hPot1 also
binds to the TRF1 protein complex. Bound to single-stranded
telomeric tips on one side and
TRF1 on the other, hPot1 was
clearly in the middle of the tugof-war.
In another experiment, when the
researchers engineered human
cells to produce a nonfunctional
version of hPot1, they observed
extra-long telomeres — indicating that hPot1 plays an essential
role in maintaining the length of
telomeres.
Finally, the scientists asked how
hPot1 fits into the “proteincounting” model of telomere
length. According to this theory,
TRF1 binds along the double
helix of telomeres and acts as a
measuring device to assess telomere length: the longer the telomeres, the more TRF1 that can
accumulate on the DNA.This
information was thought to be
relayed to telomerase but, again,
nobody knew how. By demonstrating that the amount of TRF1
bound to the telomeres dictated
the amount of hPot1 bound,
Loayza and de Lange were able to
conclude that hPot1 transmits
information about the length of
telomeres to telomerase. In other
words, hPot1 indeed appears to
be the mystery referee in charge
of keeping telomerase in check.
Unraveling the loop
Yet more questions remain. For
example, how precisely does
hPot1 “talk” to the telomerase?
The Rockefeller researchers propose that the loop at the tips of
telomeres, first discovered by de
Lange and Jack Griffith in 1999,
may be the key. According to
their theory, telomerase cannot
physically access the DNA while
the single-stranded tip is intertwined with DNA in a loop.The
new findings suggest that hPot1’s
intermediary role may boil down
to regulating the opening and
closing of this loop.
“HPot1 may be one of the key
components we were looking for,
but more experiments are needed,” says Loayza.“Other proteins
yet to be identified may be
involved.”
Given the ongoing efforts to
develop telomerase as a potential
target in the cancer clinic, a complete understanding of how
telomerase is regulated could
eventually be extremely helpful in
developing second generation
therapies.
— Whitney Clavin
calendar
WWW.ROCKEFELLER.EDU/CALENDAR.HTML
JUNE NINTH THROUGH JUNE TWENTY-FOURTH
Friday Lectures and
Thesis Presentations
These events are held in Caspary
Auditorium at 3:45 p.m. (unless
otherwise noted) and preceded by
tea at 3:15 in Abby Aldrich Rockefeller Lounge. All are welcome.
F R I D AY, J U N E 6
Unraveling Smell. Linda Buck,
Fred Hutchinson Cancer Research
Center and Howard Hughes
Medical Institute.
Scientific Events
M O N D AY, J U N E 9
Modeling Mucosal HIV
Transmission: Mechanisms and
Microbicides. Robin Shattock, St.
George’s Hospital Medcial School,
London. ADARC Seminar. Sixth
Floor Conference Room, ADARC,
455 First Ave. 12 P.M.
T U E S D AY, J U N E 1 0
Ion Channel Macromolecular
Signaling Complexes: Implications for Heart Failure and
Arrhythmogenesis. Steven Marx,
Columbia University. Pharmacology
Seminar. E-415 WMCCU, 1300 York
Ave. Contact Lissett Checo,
746-6250. 3:45 P.M. coffee, 4 P.M.
lecture.
W E D N E S D AY, J U N E 1 1
Modeling Tumors of the PNS
and CNS in the Mouse. Luis
Parada, Center for Developmental
Biology, University of Texas Southwestern Medical Center. MSKCC
President’s Research Seminar. Auditorium, Rockefeller Research Laboratories, MSKCC, 430 East 67th St.
4 p.m. tea, 4:30 p.m. lecture.
T H U R S D AY, J U N E 1 2
Design and Evolution of
Functional Miniature Proteins.
Alanna Schepartz,Yale University.
Biochemistry Lecture. E-115
WMCCU, 1300 York Ave. Contact
Esther Breslow, 746-6428. 11:45 A.M.
refreshments, 12 P.M. lecture.
W E D N E S D AY, J U N E 1 8
Working from Home and on the
Road: Access Files, E-mail and
Campus Resources Remotely.
Brown bag lunch seminar followed
by Q&A. ISS Summer Seminar
Series. 301 Weiss. Contact Antonia
Martinez, 327-7524. Open to RU
community and guests. 12:30 P.M.
Gene Therapy: Ups and Downs.
Inder Verma, American Cancer Society Professor of Molecular Biology,
Salk Institute for Biological Studies.
MSKCC President’s Research Seminar. Auditorium, Rockefeller
Research Laboratories, MSKCC, 430
East 67th St. 4 P.M. tea, 4:30 P.M.
lecture.
F R I D AY, J U N E 2 0
Telomerase Function In Vivo.
Christopher Counter, Duke University Medical Center. Cell Biology
Seminar. 116 Rockefeller Research
Laboratories, MSKCC, 430 East 67th
St. Open to RU/WMCCU/NYPH/
MSKCC community and guests.
11:30 A.M. tea, 12 P.M. lecture.
M O N D AY, J U N E 2 3
Maintaining Axon Positioning in
the Nervous System of C. elegans.
Oliver Hobert, Columbia University.
Student- and Postdoc-sponsored
Seminar Series. 301 Weiss. Contact
Jenni Peterson, 327-8368. 12 P.M.
lecture, 1 P.M. pizza luncheon.
Frequency and Function of HIVspecific T cells in Patients with
Immunologic Restriction of Viral
Replication. Mark Connors,
National Institute of Allergy and
Infectious Diseases, NIH. ADARC
Seminar. Sixth Floor Conference
Room, ADARC, 455 First Ave.
12 P.M.
T H U R S D AY, J U N E 1 9
Annual Blood Drive. 17th Floor,
Weiss Research Building. Contact
Amy Sullivan, 327-8379. 9 A.M. –
3:30 P.M.
T U E S D AY, J U N E 2 4
Trapping Regulatory Elements.
Melissa Rogers, University of
Medicine and Dentistry of New Jersey/New Jersey Medical School.
Pharmacology Seminar.Weill Auditorium,WMCCU, 1300 York Ave.
Contact Lissett Checo, 746-6250.
3:45 P.M. coffee, 4 P.M. lecture.
F R I D AY, J U N E 2 0
Tri-institutional Noon Recitals.
Jennifer Aylmer, soprano.
Caspary Auditorium. Open to RU/
WMCCU/NYPH/MSKCC community and guests. 12 P.M.
W E D N E S D AY, J U N E 2 5
The Arts and Other Events
F R I D AY, J U N E 6
Tri-institutional Noon Recitals.
Claude Frank, piano, and Andy
Simionescu, violin. Performing
Beethoven: piano and piano/violin
sonatas.Caspary Auditorium. Open to
RU/WMCCU/NYPH/MSKCC
community and guests. 12 P.M.
New University Services from
Library, IT and Telecommunications. IT, Library and Telecom staff
present RU’s new on-line training
site, extension-to-cellular service and
TripSaver document delivery service.
Seminar and demonstration. ISS
Summer Seminar Series.Weiss
Café/Lobby. Contact Antonia Martinez, 327-7524. 12 P.M.
F R I D AY, J U N E 2 7
F R I D AY, J U N E 1 3
Tri-institutional Noon Recitals.
Ruth Laredo, piano. Performing
works of Chopin, Scriabin, De Falla,
and Schumann. Caspary Auditorium.
Open to RU/WMCCU/NYPH/
MSKCC community and guests.
12 P.M.
Tri-institutional Noon Recitals.
Daedalus String Quartet. Closing
concert of the 17th season. Caspary
Auditorium. Open to RU/
WMCCU/NYPH/MSKCC community and guests. 12 P.M.
Reliving the double helix discovery
D
I
A
February 28, 1953, has gone
down in history as the day when
scientists James Watson and
Francis Crick, after two years of
painstaking work, solved the
structure of DNA. But as with
much of scientific discovery, the
foundation laid by scientists who
preceded them helped Watson
and Crick attain their “eureka
moment.” More than a few of
those early scientists were connected with Rockefeller.
PERMIT NO. 7619
NEW YORK, NY
P
US POSTAGE
F I R S T- C L A S S
New York Public Library exhibit showcases Rockefeller’s contributions to DNA science
Address Service Requested
Box 68, 1230 York Avenue, New York, NY 10021
The Rockefeller University
news notes
The Science, Industry and
Business Library branch of the
New York Public Library has
been celebrating the work of all
who contributed to the identification of DNA since the 50-year
anniversary of the discovery in
February.Their exhibit, Seeking
the Secret of Life:The DNA Story in
New York, borrows heavily from
the Rockefeller Achive Center in
Sleepy Hollow, New York.
“There was a great deal of early
discovery done right here in New
York and Long Island at
Rockefeller, Columbia and Cold
Spring Harbor, as well as at institutions funded by the Rockefeller
Foundation,” says Darwin
Stapleton, executive director of
the Archive Center.
The DNA story at Rockefeller
dates back to the early days of the
20th century, when the
Rockefeller Institute for Medical
Research, as it was then known,
was a place where the cell was
being studied intensively.The
nucleus — and nucleic acids —
fundamental to cellular genesis
particularly captured the attention
of early Rockefeller researchers
such as chemist P.A.T. Levene,
who joined the Institute in 1905.
Levene believed DNA was a large
polymer made of four nucleotides
bound by chemical linkages. He
proposed what came to be
known as the tetranucleotide
hypothesis, which implied that
proteins, and not DNA, carry
hereditary information.
In 1944, Rockefeller researchers
Oswald Avery, Colin MacLeod
and Maclyn McCarty, attempting
to understand the mechanism by
which pneumonia causes disease,
unexpectedly found that DNA
has the capacity to change bacteria from an innocuous to a virulent state, a process Avery called
the “transforming principle.”
These experiments allowed the
researchers to come to the unexpected and controversial conclusion that it is not protein but
DNA which carries hereditary
information.The findings of
Avery and his group linked
genetic information to DNA for
the first time.
From the 1930s into the 1950s,
The Rockefeller Foundation pro-
DNA signature. Rockefeller Professor Emeritus Maclyn McCarty, whose research in
the 1940s contributed to the discovery of DNA, gives his autograph alongside James
Watson at the February opening of the New York Public Library exhibit “Seeking the
Secret of Life: The DNA Story in New York.”
pelled DNA research forward by
its global support of molecular
biology. It was with Rockefeller
Foundation funding that Stanford
University, for example, acquired
one of the country’s first electron
microscopes. James Watson
recently said that if the Foundation had not been involved early
on, the entire enterprise of discovering the DNA structure
could have taken an additional 10
years.
Using Avery’s demonstration as a
point of departure, and drawing
on research in several
Foundation-funded labs in the
U.S. and England that were using
X-ray crystallography to reveal
the structure of large molecules,
Watson and Crick teamed up in
1951 to begin their pursuit of
DNA’s structure. From their base
at the Cavendish Laboratories at
Cambridge University; they published their cataclysmic findings
in the April 25, 1953, issue of
Nature.
The NYPL exhibit is on display
until late August.The library is
located at 188 Madison Avenue,
at 34th Street.