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THE SALKINSTITUTE FOR
BIOLOGICALSTUDIES10 | 09

Discovering Their Related Secrets,
Step by Step

ALSO IN THIS ISSUE» Institute Launches Vision Center» Symphony at Salk Raises $784K» Salk Establishes Presidential Chair

October 2009

Inside Salk

11
One on One with Tatyana Sharpee

3

EXECUTIVE MESSAGE

4NEWS BRIEFSIn Search of Excellence

NIH Designates Salk One ofSeven National Basic ResearchCenters Focused on Vision
President Bill Brody Appointed
to CIRM Board
Postdocs Honored with Glenn
Center Fellowships
Readership of Institute News
Increases Via Twitter andFacebook Pages

William R. Brody, M.D., Ph.D.
President
Marsha A. Chandler, Ph.D.
Executive Vice President

5-10

Rebecca Newman
Vice President,
Development and Communications

International Council meets in Spain.

11-21

INSTITUTE NEWSOne on One with…
Tatyana Sharpee

Scientist Vicki Lundblad
14 Salk
Shares Her Perspectives on
Nobel Prizes, Telomeres,and RisksService Awards Ceremony
15 Salk
Honors More Than 140 Staff
Members During Luncheon
Institute Launches New
16 Salk
Website for Polio Survivors
Biology Lab Remembers
17 Plant
Founding Scientist Chris LambC O V E R S T O RY

Spanish Gathering for
18 AInternational
Council

Genes and Cancer
Discovering their Related
Secrets, Step by Step

19 Discovery Roundup

22-23

Susan Trebach
Senior Director,
Communications
Mauricio Minotta
Director, Communications
Editor, Inside Salk

PHILANTHROPY

Longtime Donor Ruth Hamill
Bequeaths $250K to Institute
Institute Establishes Presidential
Chair to Honor Irwin M. Jacobs

Gina Kirchweger
Director,
Scientific Communications

Broadway Veteran
Bernadette Peters Dazzles
Symphony at Salk Audience

Sarah Loffler
Production Coordinator
Joe Belcovson and Kent Schnoeker
Photographers

CALENDAR

Inside Salk is printed
on recycled paper
Inside Salk is published by the
Salk Institute for Biological Studies.
We welcome your input. Please sendcomments to communications@salk.edu
or contact the Communications
department at 858.453.4100 x1226.

18

Back Cover

ON THE COVER

Illustration by Jamie Simon demonstrates a healthy cell morphing
into a cancer cell.

EXECUTIVE MESSAGE

In Search of Excellence

Dear Friends,
Scientific discovery requires uncommon minds – people
who understand rational scientific thinking but aren’t afraid to takerisks and bet on ideas often scorned by others as either unworthy or
unknowable. History demonstrates time and again that these rare creative
geniuses defy logic to uncover major discoveries that lead to new understanding of how organisms function in health and disease.
To continue the legacy of excellence that has defined the Salk
Institute, we are now searching for the next generation of scientificpioneers. I am particularly delighted to give you an early alert regarding
our latest faculty recruitment successes.
You will learn more about these exceptional scientists in the months
ahead. But as a brief preview, let me tell you about the three extremely
promising researchers we have just attracted to the Salk:
Sreekanth Chalasani, assistant professor in the Molecular Neurobiology
Lab. Chalasani’s research focuses on how the C. elegans worm’s nervous
system responds to changes in the environment, such as a sudden
lack of food. He hopes to learn more about how complex neural circuits
process information and guide behavior.
Bjorn Lillemeier, assistant professor in the Immunobiology Microbial Pathogenesis Lab. Lillemeier uses biophotonics technology – highresolution fluorescence microscopy – to study the organization of plasma
membranes and their contribution to membrane-associated signaltransduction in T-cells. T-cells, the most common type of lymphocytes,
attack virus infected cells, foreign cells, and cancer cells, but also play
an integral part in the regulation of the immune system’s activity. Adding
a new perspective on how T-cell responses are controlled during development and disease could identify new targets for the manipulation ofT-cell function.
Ye Zheng, assistant professor in the Immunobiology Microbial Pathogenesis Lab. Zheng studies how regulatory T-cells maintain immune
system tolerance to prevent autoimmune diseases. He hopes that abetter understanding of how these regulatory T-cells are generated andmaintained will lead to new therapeutic approaches in a wide range of
autoimmune diseases and tumor immunity.
The competition for top flight scientists is definitely global. That’s why
we are so pleased to welcome each of these gifted junior faculty members
over the next few months. Their research will both strengthen and diversify our efforts in Immunology, Neurobiology and Biophotonics – all key
directions for us.
The opportunity to recruit new faculty is especially gratifying, given
the current economic downturn. It is a tribute to the major gifts we havereceived in support of scientific discovery, in addition to the creative andcollaborative environment for which the Salk Institute is renowned.
The past few months have brought other positive news, including
the NIH designation of a National Eye Institute here at the Salk – theWilliam R. Brody“

To continue the legacy of excellence
that has defined the Salk Institute,
we are now searching for the next
generation of scientific pioneers.

”

only one in the San Diego area, directed by Professor Tom Albright.
Ours is one of just seven such U.S. centers focused exclusively
on basic vision research.
And the California Institute for Regenerative Medicine awarded
Salk researchers Juan Carlos Izpisúa Belmonte and Inder Verma
a $6.6 million grant to move ahead on exciting research to develop
stem cell-based treatments for some rare, incurable genetic diseases.
We could accomplish none of the above without your generous
philanthropic assistance, and I thank you for your steadfast supportof the Salk Institute and our mission to advance basic understandingof biology in health and disease.

William R. Brody, M.D., Ph.D.
Irwin M. Jacobs Presidential Chair

Inside Salk October 2009www.salk.edu

3NEWS BRIEFSNIH Designates Salk One of Seven National Basic
Research Centers Focused on Vision
A $3.8 million grant from the National Eye
Institute (NEI) of the National Institutes of Healthplaces the Salk Institute among one of seven
NEI-designated centers focused exclusively on thebasic research of vision, and is the first basic sciencefacility created by the NEI in nearly a decade.
The only one of its kind in the San Diego region,
the new Salk Institute Center for the Neurobiology
of Vision is a consortium of 15 investigators led byThomas Albright conducting research on the visualsystem. The five-year grant funds core facilities that
support each of the scientists' research projects.

The new vision center will take a broad approach tounderstanding the development and plasticity of thevisual system, the mechanisms of the neural processing of visual stimuli, and the link between visual
perception and behavior.
Understanding the mechanisms that process visual
inputs in the retina and the brain and how that affects
behavior provides a model system for better understanding the central nervous system. Such basic
studies can also one day contribute to the developmentof prosthetics that restores vision to the blind.

President Bill Brody Appointed
to CIRM Board

Postdocs Honored with
Glenn Center Fellowships

Lt. Gov. John Garamendi has NAMED
Salk President William R. Brody to serve on
the California Institute for Regenerative Medicine’s oversight board. Brody replaces Salk
Executive Vice President Marsha A. Chandler,
who served for the last two years.
“Dr. Brody is an accomplished scientist,
widely recognized among his peers as oneof the nation's forefront thinkers in biomedical engineering and healthcare policy,” said
Garamendi, who make five appointments tothe committee.
Brody, renowned for his achievements inbiomedical engineering, spent 12 years aspresident of Johns Hopkins University before
joining Salk.
CIRM was created as part of Proposition
71, the California Stem Cell Research andCures Initiative, which was approved by votersin 2004. Since then, the 29-member oversightcommittee has approved 295 grants worth$761 million, making CIRM the largest sourceof stem cell research funding in the world.

Seven Salk postdocs have received
a total of $840,000 in research grants
through the Institute’s Glenn Center topursue a research topic central to aging
that involves at least two laboratories. They
will each receive $60,000 for two years tocover their salaries, benefits and equipment.
The Glenn Center for Aging Research wasestablished in January with a $5 million
gift from the Glenn Foundation for Medical
Research. Led by Andy Dillin, the Glenn
Center draws from nine of Salk’s leading
laboratories specializing in genetic analysis,
stem cell biology and metabolism research
to address the overarching goal of defining ahealthy lifespan, or healthspan, and answer
one of the most elusive questions in biology:
Is there a defined biological process of aging
that is universal to all organisms?
The new Glenn Center Fellows are: Laure
Crabbe, Toby Franks, Star Lee, Yair Pilpel,
Lei Wang, Jamie Whyte, Katja Lamia.

Thomas Albright

Liming Pei

In related news, researcher Liming Pei,
who works in Ron Evans’ lab, received afellowship from the Francis Family Foundation. As a 2009 Parker B. Francis Fellow,
Liming will receive $156,000 over three years
in support of his research, which focuses onembryonic development of the lung.
Originally from China, Pei graduated from
UCLA with a Ph.D. in Molecular and Cellular
Pathology in 2006 and joined the Evans labthat same year.

Traffic to Institute’s Website Increases Via Twitter and Facebook Pages
The Communications department has
dived into the social media sphere to increase
the number of people it reaches on the Web– leading to a 20 percent increase in traffic
originating from referring sites such as
Facebook and Twitter.
Since launching the social media pages
in the spring, the Salk Institute has gained a
combined fan base of more than 645 people

4 Inside Salk October 2009and organizations (and growing) that havevoluntarily signed up to follow news updates
and “tweets.”“By adopting social media as anothercomponent of our overall communications program, we have been able to reach a whole newaudience from around the world and provide
them regular news feeds from the Salk,” says
Communications Director Mauricio Minotta.
“This introduces the Institute to potential new

supporters and organizations that may beinterested in licensing the Salk’s technology.”
On average, the Institute’s website receives
about 200,000 unique page views per month.
Press releases on the Salk’s scientific discoveries and alerts on its symposiums are among theitems communicated through the social media
platforms. To view the pages, visit www.twitter.
com/salkinstitute and www.facebook.com/
salkinstitute.
www.salk.edu

NO
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V ESR BSRTI OE R
FSYGenes &

Cancer

Discovering Their Related Secrets,
Step by Step

Inside Salk October 2009www.salk.edu

5COVER STORY

Geoff Wahl will never forget the day in 1989
when he got a crazy idea for a new experiment. He had alreadybeen at home for some time when it hit him just before 9 p.m.
He rushed back to his lab at Salk that night hoping somebody
would be there. He was in luck. He found his postdoc, Yuxin Yin.
“This is what’s great about science. I told him, ‘I’ve got thiscrazy idea, but it’s a good crazy idea because it suggests anexperiment,’ ” Wahl says.
For more than a decade, Wahl’s lab had been working to understand the mechanisms behind genetic instability
and its link to cancer, and by this point theysuspected the p53 gene, which is now
known to be mutated in half of all humancancers, played a key role.
Wahl’s crazy idea came at a time
when his lab was studying an anti-proliferating compound. When administeredto cancer cells, most would die off, with the
exception of a few resistant ones that continued
to divide. But what if the drug was applied to noncancerous
cells with normal p53 genes?
As Wahl predicted, the cells stopped dividing completely,
which led him to test one final idea: replace the mutant p53
gene of a cancerous cell with one from a normal cell. To his
team’s relief, the cancer cells stopped dividing.
Published in 1992, the series of experiments was among
the first to demonstrate p53’s role in maintaining genomic
stability – leading many in the field to regard p53 as theGuardian of the Genome.
It is in fact at the genetic level where cancer begins. To be
precise, it is the mutation of specific types of genes that leads tothe development of the disease, which the National Cancer Institute (NCI) estimates will claim more than 562,000 lives thisyear (1,540 per day) in the United States. It also estimates thatnearly 1.5 million more will be diagnosed with cancer in 2009.
Mutations in our genes take place every day of our lives. The
simplest examples are DNA damage to skin cells caused by the
sun’s ultraviolet rays, or in the lining of our gut from toxins infood that we ingest, or in the lung as a consequence of smoking
cigarettes. Despite the common frequency of these biologicalevents, many of us may never develop cancer.
Why? Cells are equipped with mechanisms -- p53 chief
among them – that detect and either repair DNA damage orsignal the cell to self-destruct if the damage is too great.
“These genes are part of the normal growth process for human beings. This is how we have evolved,” says Reuben Shaw,
Hearst Endowment assistant professor in the Molecular and Cell
Biology Laboratory, who, like Wahl, is one of 30 faculty membersin the Salk Institute’s NCI-designated Cancer Center. “Every
species has evolved a mechanism to get rid of the cells that are
chronically exposed to something that could be bad for them.”

6 Inside Salk October 2009

But the machinery isn’t fool proof. For reasons not yet completely known, cells with DNA damage sometimes go unrepairedand continue to divide as mutant copies of their original self.
These mutant cells are prime candidates for cancer development in cases where the affected genes are normally designed toregulate cell growth (oncogenes) or cell death (tumor suppressor
genes, such as p53). In the unfortunate event a second or third
mutation occurs to multiple genes, cancer will always develop.
The process is expedited if an oncogene is mutated in combination with damage to p53 in the same cell, Shaw says.
“P53’s main function is to serve as a sensor for cells to makesure it is safe for them to reproduce their genetic dowry, or toprevent them from attempting to do so when conditions are suboptimal,” says Wahl. “If p53 function is lost because of damage
to its gene, then the cell has no ability to sense impending
dangers, which enables the cell to divide and leads to production
and perpetuation of mutations. This creates opportunities for
additional mutation to form, and that’s when things really startgoing haywire. The problem just compounds itself.”

Scientists were first clued into cancer’s genetic nature after
Salk’s Distinguished Professor and Nobel Laureate Renato
Dulbecco collaborated on a study that explained how oncogenecarrying tumor viruses interact with host cell chromosomes
to replicate themselves and induce cancer. The work led toDulbecco’s Nobel Prize in 1975 and revolutionized the way
scientists think of the disease.

www.salk.edu

COVER STORY“This is what’s great about science. ‘I’ve got thiscrazy idea, but it’s a good crazy idea because it
suggests an experiment.’– Geoff Wahl”

» WEB EXTRA
To hear Geoff Wahl discuss p53 further,
visit www.salk.edu/insidesalk/wahl

The discovery opened the door to new areas of cancer research, which has led to a deeper understanding of the disease
over the last three decades. Today, scientists can now identify
and quantify the steps that lead to cancer in the body. Thereis also growing evidence that chronic inflammation can also
induce cancer, especially in the liver and pancreas, the latterof which claimed the life of actor Patrick Swayze in September.
Interestingly, some of the rare cases in which patients inherit
defective copies of either oncogenes or tumor suppressors havehelped scientists zero in on genes that are involved in specifictypes of cancer in the rest of the population.
“The genes shared by members of a single family are 99
percent identical so you can pinpoint the key genetic difference between the family member who got cancer and the one
who didn’t,” Shaw explains. “Then you study the genes of a

» WEB EXTRA
To watch video of our interview with Nobel Laureate
Renato Dulbecco, visit www.salk.edu/insidesalk/dulbecco

Inside Salk October 2009

completely unrelated cancer patient and trace the mutationback to that same spot in their DNA and bingo, you’ve foundthe cancer-causing gene.”
There are approximately 22,000 genes in the humangenome. To date scientists have identified and decoded morethan 300 cancer-causing genes, which has enabled researchers
to match them up with the types of cancer they induce. Thisin turn has led to the development of drugs to counteract theactivity of these mutant genes.
Researchers at the Salk’s Cancer Center have identified anumber of them. Oncogenes FOS and MOS, which are mutatedin fibrosarcomas, and REL, which leads to lymphosarcomas,
were identified by Inder Verma, an American Cancer Society
professor in the Laboratory of Genetics.

www.salk.edu

7COVER STORY“In the long run what we hope is that if enough cancer
genomes are sequenced, commonalities will begin to
emerge for a particular cancer type so that they can be– TONY HUNTER
correlated with more effective treatment.

”

Work by Ronald M. Evans, professor
in the Gene Expression Laboratory, led
to the discovery of a family of nuclear
hormone receptors, a member of which –the estrogen receptor (ER) – is now known
to contribute to the development of breast
cancers when expressed at high levels.
Another nuclear hormone receptor, theretinoic acid receptor (RAR), plays a keyrole in promyelocytic leukemia when joined to the
product of a second gene.
“The fundamental progress in cancer researchover the last 30 years has been to identify specificgenes that cause cancer,” Dulbecco says. “Once thegenes responsible for cancer have been identified,
you can move forward to therapy.”
Founded in 1970 by Jonas Salk and designatedan NCI Center in 1973, the Salk Institute Cancer
Center is led by Tony Hunter, an American Cancer
Society professor in the Molecular and Cell Biology
Laboratory. His discovery of tyrosine phosphorylation, a key event in normal cell growth which candrive tumor cell proliferation when unregulated,
eventually led other scientists to develop a newgeneration of cancer drugs, including Gleevec– a leukemia drug whose developers received theLasker Prize for their work in October.
The Cancer Center is made up of three distinct
research programs: Metabolism and Cancer, Mouse
Models and Stem Cells, and Growth Control andGenomic Stability. Thirty of Salk’s 57 principal
investigators, 161 postdoctoral researchers, and70 graduate students are part of the Center, which
continues to make new breakthroughs with potential for new therapeutic strategies.
Like Wahl’s, some discoveries are born fromunorthodox ideas.

This year, Shaw published a study that demonstrated how he used rapamycin, an immunosuppressantdrug normally prescribed to prevent organ transplant
rejection, to drastically reduce tumors in lab mousemodels developed to mirror Peutz-Jeghers syndrome,a rare cancer of the colon in which patients inherit
a mutated copy of the LKB1 gene.
He got the idea after first linking LKB1, a tumor
suppressor also commonly mutated in lung cancer,
to AMPK, a protein involved with glucose production. Further studies by his team revealed that AMPK
regulates TOR, an oncogene that is highly expressedin cancer (its name is short for Target of Rapamycin).
Shaw then asked the question: Will rapamycin
work on LKB1-deficient tumors to block TOR activity?
He found out that it does. The massive tumors that
had developed in the mice’s colons drastically shrunkin size and were stabilized in the experiments.
“This is a wonderful example of being able to use
basic research and genetic modeling to treat humandisease,” Shaw says. “We basically put the micethrough a clinical trial and test them with different
doses of rapamycin.”
Current studies in Shaw’s lab are examining whether these same therapeutic approaches will work in amouse model they have developed for lung cancer.

» WEB EXTRA
To hear Reuben Shaw discuss his latest
experiments using compounds to treat
cancer, visit www.salk.edu/insidesalk/shaw

8 Inside Salk October 2009www.salk.edu

NO
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V ESR BSRTI OE RFSYOther strategies being tested in the Cancer Center seem born out
of science fiction, but show great promise. Clodagh O’Shea, assistantprofessor in the Molecular and Cell Biology Laboratory, and her teamhave developed a modified adenovirus, normally associated with upper
respiratory infections in humans, to undergo selective lytic replication in
p53-deficient cancer cells while leaving all other tissues intact.
Once introduced into the tumors, the virus multiplies and causes thecancer cells to implode – releasing thousands of viral offspring in theprocess to seek out more cancer cells. Initial clinical trials in the UnitedStates using an early version of the modified virus showed encouraging results when it was injected directly into the tumor. However, O’Shea
believes the latest modified virus will be highly effective.
“In an ideal world, it would be really amazing if we could inject it
systemically so it could spread throughout the body and find distant micro
metastases in places where we don’t even know the cancer has spread,”O’Shea says.
“However, the virus we work with is not a naturally blood-bourne virus,
so there are factors that can limit its activity. That’s why we are also turning to different serotypes/subgroups of virus that naturally infect different
tissues, such as the colon and the kidney.”
In order to really understand cancer, however, Dulbecco suggested in
a 1986 Science article that the human genome would first need to besequenced so that it could be compared to its cancer counterpart. Four
years later the Human Genome Project was initiated by an internationalgroup of scientists and completed in 2000.
“Now that it’s cheaper to sequence, it’s clear that cancer cells havehundreds of mutations, which makes it more difficult to know which genes
are important,” Hunter says. “But in the long run, what we hope is that
if enough cancer genomes are sequenced, commonalities will begin to
emerge for particular cancer types so that they can be correlated withmore effective treatments.”
Most of the cancer-therapy drugs available today work to counteract
the uncontrolled activity of oncogenes as a result of p53 mutation. But
more is being done to find treatments for the other 50 percent of cancers
where p53 is not damaged. In such cases, there are two proteins that are
working in conjunction to degrade or completely inactivate the p53 gene:
Mdmx2 and Mdmx.

“…we are also turning to different
serotypes/subgroups of virus that naturally
infect different tissues, such as the colon”and the kidney.

– Clodagh O’shea

Assistant Professor Clodagh O'Shea (right)
with UCSD graduate student Kristen Espantman

Inside Salk October 2009www.salk.edu

9COVER STORY“

The fundamental progress in cancer research overthe last 30 years has been to identify specific genesthat cause cancer. Once the genes responsible forcancer have been identified, you can move forward– RENALTO DULBECCO
to therapy.

”“These are proteins that are working like anti-tumor suppressors,” Wahl explains.
“When they bind to p53, the cell can no longer sense DNA damage or initiate thecell death program.”
His lab is now working on developing new compounds that impede Mdm2 andMdmx’s ability to bind to p53 and restore the gene’s normal protective function.
“It’s rare for academia to go into drug discovery experiments, but we felt it was
important for us to do so, and we also feel these compounds will be very valuable
research tools,” Wahl says.
The most recent studies at the Salk involve research of stem cell-like cells andtheir relationship to cancer. It’s a very new field that may provide more answers
and possibly new treatments in the future.
Teams of scientists in the Verma and Fred H. Gage labs, for example, are using amodel for glioblastoma, the deadliest and most common brain cancer in humans, touncover the nature of specific cancer cells that are capable of spawning new tumors.
“There is increasing evidence that there is a population of cells in most cancers
that have stem cell-like properties,” Hunter says. “It’s a field that’s in flux atthe moment because how these cells acquire these properties is unclear. There is aschool of thought that you have to target these tumor-initiating cells because if you
only kill off the rest of the tumor, then it doesn’t matter because they simply regrow.
“Chromatin reprogramming is a critical step in the genesis of stem cells and thisappears to be true of the stem cell-like cells in tumors,” Hunter says.
A recent finding from the Wahl and Juan Carlos Izpisúa Belmonte groups has
shed light on this idea. They found that p53 itself acts as a block to chromatin
reprogramming in somatic cells, suggesting that the lack of p53 in most tumors may
predispose cells in these tumors to undergo reprogramming and adopt stem-cell likefates. (See story on page 20.)
As a result, there is now a heightened interest in using new-generation inhibitorsthat will block chromatin reprogramming as new types of cancer therapy. The Evanslab is currently testing one novel inhibitor developed by his team on colitis-associated colon cancer in lab mouse models.
“The Salk Cancer Center has a history of significant contributions that have led toa deeper understanding and treatments for cancer,” Hunter says. “Over the next few
years, new findings hold the promise to lead to new types of cancer drugs, and to
alleviate the mortality and suffering from this terrible disease.”

Juan Carlos Izpisúa Belmonte

10

Inside Salk October 2009

Fred H. Gage

Inder Vermawww.salk.edu

INSTITUTE NEWSOne on One with…

Tatyana
Sharpee

Assistant professor Tatyana Sharpee is among

innovative research early in their careers with thethe newest faculty members at the Institute. Since

potential for making significant contributions tojoining Salk in 2007, she has been recognized withbiological research. An authority on information

several prestigious research awards, including thetheory, Sharpee’s team uses a statistical method

Alfred P. Sloan Research Fellowship, the McKnight

she developed to decipher how the brain codes andScholar Award and named a Searle Scholar – honors

processes information from natural visual stimuli.

that are reserved for scientists who have demonstrated

Inside Salk October 2009(continued on next page)www.salk.edu

11NEWS BRIEFS

I understand you first studied the properties of electrons.
What influenced you to turn your attention to neurons?
The theoretical ideas are similar even though the physical systems arevery different. And the closest application between statistical physics
and information theory is neuroscience. When I was a little girl, I wanted
to be a doctor. But I also greatly admired my grandfather, who was amathematician/physicist. Working in theoretical and computational
biology, in particular neuroscience, provides a way to be connected tothe two fields. After completing a thesis in theoretical physics, I joined
the Sloan-Swartz program during my postdoctoral studies that provides
biology training to physicists.

What fascinates you about the brain?
It’s remarkably efficient. For example, my desktop computer uses 60
watts of power and some estimate that the brain uses just 12 watts. Yet
the brain is very good at doing analog computations that are very hardmathematical problems such as forming a map of surrounding events
that come in through our visual system. So for example, your eyes move
three times per second and each time you have a pinhole presentationand yet that’s not what we perceive. We perceive a whole continuous
field. The algorithms for doing this do not exist, except in the brain andwe have yet to find out what they are.

You developed a method for analyzing the brain cells’
response to natural visual stimuli. What type of stimuli
do you use in your experiments and how is it different fromstandard practice?
We use a collection of scenes that I took while walking through thewoods with a video camera. The reason for using such natural stimuli isthat they elicit good responses from high-level neurons whose job is tointegrate incoming visual information. When such neurons are presented
with simplified stimuli devoid of objects, they respond poorly, sometimes
not at all. Our hope is that, although we do not know before the experiments which combination of visual features will drive a particular neuron,by taking scenes from the visual world there will be some features ofinterest to any visual neuron. A collaborative project with Salk professor
John Reynolds' laboratory was recently funded by NEI to both develop
new statistical methods and use them to analyze responses of high-levelvisual neurons.

So if you only take measurements from just one neuron ata time, how do you know what part of the scene caused it
to fire? How do you know it wasn’t a shape, or a color thattrigged the response?
That’s why people were shying away from using natural scenes: they areso complex that when you get a spike, you didn’t know what actuallytriggered it. Although you can’t make a determination from just one“

Disorders of the nervous system are devastating.

Understanding details of communication with”spikes is a pre-requisite for developing better cures.

12

Inside Salk October 2009www.salk.edu

Does your work focus solely on visual stimuli?
We also use auditory stimuli to learn more about the auditory cortex,
which is not as well known or studied as the primary visual cortex.
Auditory studies in some ways are more complicated, and some argue
that primary auditory cortex is more equivalent to high-level visualneurons than to the primary visual cortex. We know that a given neuron
will prefer a certain frequency in the tone or maybe it’ll have a sweep
up frequency or a sweep down frequency, but that’s about it. But
through the auditory experiments, we learn about a different brain area
and as theorists we try to make parallels between different senses, suchas vision or audition, and search for overarching principles.

“

INSTITUTE NEWSframe, it actually becomes possible when you analyze responses from10,000 different images, taking into consideration which combinationof features produced spikes and which did not. Together with mypostdoctoral advisors, we worked to develop an algorithm that can dothis correctly regardless of which frames were presented. It is very
important with natural stimuli because they are often poorly controlled.
To illustrate the main idea of the methods let’s say an image contains
three elements, and the next image contains these elements in different
positions or perhaps even different elements. Then as you do your analysis, you start to see, a-ha, this one caused a spike, and this one didn’t
when the elements were moved apart. So you start getting statistics ofthe most likely feature that is associated with a neuron’s response.
Using advanced statistical techniques, we can create templates forneuron activity from natural visual stimuli.

from a classic Soviet film “woman is a human being too.” So I think thegovernment tried to promote participation of women. But there’s theofficial language and then there’s reality. I wasn’t always comfortablebased on the peer pressure, but I think at least at the early stages of
their careers women participation was encouraged.

Was there anyone in particular who encouraged you to get
into science?
Yeah, there were lots of people. I had a very good physics teacher inhigh school, Anatoliy Israilevich Shapiro, who had interesting techniques
for teaching students. For example, he would provide very small blank
sheets of paper, just several square inches, and give us problems tosolve. He thought that having to express ones thoughts on the small
sheets promoted creativity when you really had to think about what
to write in such a small space. And a problem could be, for example:“Write 10 ways to speed up the drying process of a wet umbrella.” He
always emphasized that it was better to solve one problem 10 different
ways than to solve 10 problems the same way. My family also influenced
me. My grandfather and grandmother are mathematicians and myparents are physicists, so even though I thought I had a choice, inreality I didn’t. I was gently steered into this field.

You work in a field that’s dominated by men. Do you everI’m also attracted to differentfeel the need to encourage other women to consider
a career in computational neurobiology?

theoretical models and theoretical
I recently gave a presentation for Women Scientists in Action at theWhat does your lab hope to learn by these typesof experiments?
questions. One of those is
One goal is to learn how signals are integrated in the visual cortex toallow us to perceive objects and shapes. I’m also attracted to theoretical questions of optimization of information transfer in networks. Thereis an emerging viewpoint that the primary function of many biologicalnetworks, either within a cell or between cells, as in neural networks,
is the transfer and processing of information. So for example, throughphosphorylation a given protein can integrate multiple inputs into asingle output that is a graded function of the combination of inputs.
At least mathematically, this operation is very much analogous to theintegration of signals in the nervous system where a given neuron would
sum its synaptic inputs, and produce a spike if the result of integration
exceeds a certain threshold. In our recent work (currently in press), we
have described how networks of such graded nodes can be set up toconvey the maximal amount of information. Assuming the network is
optimal, our theoretical analysis also provides a way to infer the strengthof interactions with unmeasured parts of the network. This is importantbecause only rarely do we have measurements on a complete circuit in
the nervous system. We are looking forward to seeing how these ideas
will fare against experimental data.

optimization of informationtransfer in networks.

”

You grew up in the Soviet Union. Where were you in youracademic life during the dissolution period? And was acareer in science encouraged for women during that time?
That was around 1992, so I was graduating from high school. The
official policy of the Soviet Union was equality for all, to quote a slogan

Inside Salk October 2009

Rueben H. Fleet Science Center where I spoke to the girls there, butthey are so little. I haven’t talked to fifth and sixth graders in like 20
years (laughs). So I was trying to tell them about all of the advantagesof being a scientist, but I am afraid that my presentation could havebeen way out of their interests. But it was a learning experience for me
as well, so maybe next time I’ll be able to connect better with the girls.

You’ve received several prestigious fellowships in the lastyear. How will you use the funds to expand your research?
At the genetic level, we know the code in DNA is universal whether it’s afly, a mouse or a human, and that’s a great success of molecular biology.
In neuroscience, we don’t even know exactly what the code is, other than
the spikes are important. For example, we don’t know to what extent the
precise timing of individual spikes matters, and the answer might turnout to be different for neurons in different systems or species. So oneof the grants is meant to help my lab search for universal symbols inneurotransmission, comparing the structure of neural code in visual orauditory neurons in mammals, birds, and/or flies.

What would finding these universal codes tell us?
Disorders of the nervous system are devastating. Unfortunately, thecures that are available are rather blunt or nonexistent, and often do
not take into account the fine scale organization of the nervous system.
Understanding details of communication with spikes is a pre-requisite
for developing better cures.

www.salk.edu

13

INSTITUTE NEWS“

It’s hard to sleep at night, when you

have a sense of the magnitude of the
discoveries unfolding.

– Vicki Lundblad”

Salk Scientist Vicki Lundblad Shares Her Perspectives on Nobel Prizes,
Telomeres, and Risks
When Salk Non-Resident Fellow Elizabeth Blackburn,
Carol Greider and Jack Szostak receive the Nobel Prize in Medicine
in early December, Salk Professor Vicki Lundblad will have an insider’sview. As Szostak’s invited guest at the Stockholm ceremony, she will celebrate with the winners that the field of telomere biology is receiving thisgrand international recognition.
Lundblad, a professor in Salk’s Molecular and Cell Biology Laboratory,
was a postdoctoral fellow in Szostak’s lab at Harvard, where she made afundamental discovery about the role of the enzyme telomerase in cellproliferation. Lundblad recalls it was a tremendously heady time, to bepresent at the start of a new area of study. As a young scientist, “it’s hardto sleep at night, when you have a sense of the magnitude of the discoveries unfolding.”
Lundblad was caught up in a pure basic science problem – how theends of chromosomes are maintained. It was also an era of strong U.S.
commitment to such basic research. “For Jack to get the funding heneeded and for me to get a postdoctoral fellowship, it was simple, it justwasn’t an issue.”
When Blackburn (a professor at UC San Francisco), Greider (then aBlackburn grad student) and Szostak pursued their theories about telomerase working with a ciliated pond organism and baker’s yeast – “nobody
had a clue” that these findings would have serious implications for humancancer and the aging process, Lundblad said. Ironically, she pointed
out, “in today’s NIH environment, with the focus on immediate medical
relevance, it is not clear this research would have been funded.” She
added: “that’s why support by private philanthropy for basic research
is so crucial.”

14

Inside Salk October 2009

Beyond the issue of ongoing support for basic science, Lundblad says
this award-winning work had another key element deserving mention: thescientists were going against the scholarly tide in performing their early
telomerase experiments. Remembering her first taste of that scientificcreativity and its results, she said: “It is a phenomenal place to be, when
you know you are heading in the right direction, and everyone else islooking elsewhere.” But going against conventional wisdom requires afree-wheeling environment.
“I came to the Salk exactly because of its support for that environment” of intellectual risk-taking, Lundblad said. Of course, taking suchrisks means dealing with failure, and Lundblad laughs: “I’ve had some
spectacular failures.” But such failures are hugely instructive – and “ifyou aren’t failing occasionally, then perhaps you aren’t taking enoughrisks.”
Today, both Lundblad and colleague Jan Karlseder, an associate
professor also in the Molecular and Cell Biology Laboratory at Salk,
continue to aggressively probe the mysteries of telomeres, working withyeast, worms and human cells to unlock the next big question in telomere
biology: how are these natural chromosome termini protected against thecell’s tendencies to get rid of DNA ends?
And Lundblad reports that, decades after the first pivotal insightsthat resulted in this year’s Nobel Prize in Medicine, excitement about
telomere research in Salk laboratories is extremely high. Enmeshed inwhat one scientific colleague calls “venture science,” Lundblad andKarlseder are both caught up in the challenge of the research and “stilllosing sleep at night.”

www.salk.edu

INSTITUTE NEWSSalk Service Awards Ceremony Honors More Than
140 Staff Members During Luncheon
Event to Become Annual Tradition at the Institute
The Institute hosted its first everSalk Service Awards Ceremony in honor of morethan 140 staff members who had achieved
between 10 and 45 years of employment. The
Sept. 9 luncheon took place at the Institutewhere President Bill Brody, Academic Council
Chair Greg Lemke and Master of Ceremonies
Walter Eckhart thanked those in attendance
for their hard work over the years.
“Our strength is the dedicated service of allof you,” Brody said. “You are the reason why
Salk is so successful.”
Lemke spoke about non-academic departments at the Institute and gave examples of

Inside Salk October 2009

how each contributed to research before saying: “It takes more than the cadre of scientists
to reach the level of our success. It takes thework of a broader group of people who are
represented here today.”
After the luncheon each of those being
honored were called by name and invited tothe stage where they were photographed withBrody and Lemke. The Hypotheticals, a
singing group composed of Salk employees
and scientists, provided comical entertainment
with spoofs of television show tunes from thedecade in which each group of honorees
began their employment at Salk.

The ceremony, which will be an annual
event moving forward, concluded near theInstitute’s Theodore Gildred Court, where
Executive Vice President Marsha Chandler
unveiled a series of red bricks that had beenengraved with the names of those who had
achieved 25 years or more of service.
“This is a new tradition to honor thoseof you who have served the majority of yourcareers at Salk,” Chandler said. “The names
engraved on these bricks represent a truly
special group. They are members of the Salk
family who have shown steadfast dedication
to your work and to the Salk Institute, andfor that we thank you.”www.salk.edu

15

INSTITUTE NEWS

Shedding Light on the Latest Ravagesof Polio in America:
Salk Institute Launches Website
for Polio Survivors
The Salk has launched PolioToday.org– a resource for polio survivors intended to raiseawareness of the crippling post-polio syndrome(PPS), a serious neuromuscular condition
that can strike an estimated 40-50 percent ofpeople decades after they were first infectedwith poliovirus.
The World Health Organization estimates
there are about 10-20 million polio survivors
worldwide. Characterized by extreme fatigue
and renewed weakness or paralysis in thelimbs, PPS is often misdiagnosed because its
symptoms resemble other crippling neurodegenerative diseases. The severity of paralysis
during the original polio infection (decades
earlier) does not seem to play in role in whether
or when PPS strikes, and the syndrome istypically gradual in onset.
“I have had patients who had very mildcases of polio, or don’t even remember having
had polio when they were young, end up with
post-polio syndrome,” says Dr. Jacquelin Perry,renowned orthopedic surgeon and world authority on gait analysis who treats PPS patients at
Rancho Los Amigos National Rehabilitation
Center in Downey, California.
PPS mimics other debilitating diseases,
and because there is no single diagnostic test
to confirm it, it is considered a disease of
exclusion – meaning it requires specialized
testing by well-trained physicians who ruleout all other possibilities to achieve a proper
diagnosis. That diagnostic complexity andconfusion, coupled with the fact that the U.S.
polio survivor population is now elderly (orclose to it), has relegated the PPS community
to relative obscurity.
“People suffering from PPS seem to exist in
the shadows, far from broad public awarenessof the disease and its terrible manifestations,”
says Susan Trebach, Salk Institute SeniorCommunications Director. “Our goals are to

16

Inside Salk October 2009heighten awareness and understanding of
PPS, encourage people to seek proper diagnosis
and treatment, and facilitate the growth of
online communities of polio survivors aroundthe world.”
PolioToday.org features video testimonials
from polio survivors who share recollectionsof their personal battles with polio when they
were young, their more recent diagnosis andmanagement of PPS, and how they are copingwith their condition. There is an expert opinion
video page featuring several clips by UCLA
Neurologist Dr. Susan Perlman, a PPS
specialist who explains the cause of PPS
and provides relevant information.
“Polio survivors have searched for a way toactively connect to one another for years,” says
polio survivor Gladys Swensrud from San Diego,
California. “This exciting Salk Institute site,
PolioToday.org, offers not only a forum for the
distribution of important polio and post-polio
related information, but it also creates a muchneeded link for polio survivors worldwide toconnect with one another using modern social
networking capabilities.”
Rick Van Der Linden, a polio survivor from
Hemet, California adds:“The best part of the site is that it’s beendeveloped just for us. It allows us to communicate with and learn from one another. It’s
the best thing going on the Web for the polio
survivor community.”“

Since going live in August, with no mainstream public announcement of any kind,
the Community section of the site is alreadyattracting attention as polio survivors, somefrom as far away as Australia, have signed up
to participate in various discussions that havebeen posted. Under the Emotional Stress and
PPS discussion topic, for example, members
describe the ways they control the anxiety anddepression associated with PPS.
“It is amazing to see people openly discuss
their deepest health concerns related to PPS
as well as how they found us in the first place,”says Mauricio Minotta, the Salk Communications Director leading the website project.
“It is especially gratifying to receive
comments, either on Twitter or YouTube, frompeople who tell us how much they appreciate
this new internet resource,” Minotta says.
The Resources page provides users with agrowing list of polio survivor groups around thecountry and PPS and polio-related literaturefrom other organizations such as Post-Polio
Health International, the World Health Organization and Rotary International Polio Eradication.
Most of the activity on PolioToday.org to datehas been generated through connections madeon Twitter, YouTube and Facebook.

The best part of the site is that it’s been developed

just for us. It allows us to communicate with andlearn from one another.

”www.salk.edu

INSTITUTE NEWS

Plant Biology Lab Remembers
Founding Scientist Chris Lamb
The scientific community was saddened thissummer when Chris Lamb, the founding scientist and directorof the Salk Institute’s Plant Biology Laboratory, died suddenly
at age 59 in Norwich, England.
A world-renowned researcher who pioneered studies in
the molecular mechanisms that underlie how plants defend
themselves against pathogens, Lamb was recruited by former
Salk President Frederic de Hoffmann from Oxford in 1983 toestablish what would become an extraordinary Plant Biology
program at the Institute.
In an interview last year for an Inside Salk cover story (Oct.
’08 issue) in celebration of the Plant Biology Laboratory’s 25th
anniversary, Lamb recalled his thoughts in deciding to take deHoffmann up on the offer to establish a lab at the Salk.
“This seemed a fantastic, if somewhat risky, opportunity,”
Lamb said. “Fantastic because of Salk’s great prestige andreputation in biomedicine and neurobiology. Risky, but exciting,because I would be starting something from ground zero.”Lamb left Oxford and headed for La Jolla, where he spent thenext 15 years conducting some of the groundbreaking work that
led him to become one of the most respected leaders in plantbiology research.
“Chris had a good sense of the big picture,” said Joanne
Chory, professor and director of Salk’s Plant Biology Lab, who
was recruited to the Institute by Lamb in 1988. “He was
focused and analytical, and always knew how to move things
forward.
“Lamb had a real sense of the beauty of plant biology,” shesaid. “Beyond his superb science, he will be remembered as thefounding faculty member of the Salk program and as an international voice for the discipline.”
Lamb returned to England in 1998 to lead the John Innes
Centre, one of the world's leading institutions of plant research.
He promoted a culture of excellence there, and was recently
named a Fellow of the Royal Society in recognition of his scientific achievements.

Chris Lamb“

Lamb had a real sense of the beautyof plant biology…Beyond his superb
science, he will be remembered as
the founding faculty member of the
Salk program and as an international”

voice for the discipline.
– Joanne Chory

In 2000 Lamb returned to Salk for a visit, saying he’dcome back to California “for a dose of optimism.” Chory said
he remained very fond of the Salk and spoke of how it had
influenced him.
Likewise, Lamb influenced the San Diego research landscape. Today, there are 16 Plant Biology principal investigators
across the mesa (Salk, UCSD and Scripps), seven of whom aremembers of the National Academy of Sciences.
“Chris’ legacy in La Jolla is not just his own science, but thescientists he identified and mentored who have made La Jolla
one of the top places for plant science in the world,” Chory said.
“We are deeply saddened by this loss.”
From left: Joseph P. Noel, Chris Lamb, Jeffrey A. Long, Detlef Weigel, Joanne Chory, James Umen,
Joseph R. Ecker at the 25th Anniversary Celebration of Salk's Plant Biology Lab last October.

Inside Salk October 2009www.salk.edu

17

INSTITUTE NEWSA Spanish Gathering
for International Council
More than 31 members of Salk’s
International Council gathered in Barcelona thisspring for three days of scientific presentations
and activities designed to update them on themost recent developments at the Institute.
Some of Salk’s leading scientists provided
overviews of their promising discoveries in stem
cell research and advancements in studies related
to metabolism, cancer and therapeutics forchronic disease.
Highlights from some of the group’s activities
included a tour of the charming medieval town ofSitges, a Gaudi architectural tour and an elegant
dinner and flamenco show hosted by the Spanish
government.
The Salk’s International Council is made up ofbusiness executives who serve as ambassadors of
the Institute in an effort to help raise the Institute’s
profile around the world as they share Salk’s latest
discoveries with their circle of influence.
To learn more about the Salk Institute International Council, contact Allyson Collins, director ofDevelopment Administration, at 858-4100 x2005
or e-mail: acollins@salk.edu.

At left: Hotel Casa Fuster, site of the meeting.
From left: Sukuma Jayananda, Frederik Paulsen, Ellen Schwickart,
Sukum Nawapan, Stephanie Still and Carl-Otto Still.

18

Inside Salk October 2009www.salk.edu

INSTITUTE NEWS

Discovery Roundup
Site for Alcohol’s Action in the
Brain Discovered
Alcohol’s inebriating effects may be familiar to
many, but the molecular details of its impact on brain activity remaina mystery. A new study by researchers at the Salk Institute provides abetter understanding how alcohol alters the way brain cells work.
Their findings reveal an alcohol trigger site located physicallywithin an ion channel protein; their results could lead to the development of novel treatments for alcoholism, drug addiction, and epilepsy.
Paul Slesinger and his team now show that alcohols directly interact
with a specific nook contained within a channel protein. This ionchannel plays a key role in several brain functions associated withdrugs of abuse and seizures.
Previous research by Slesinger and his group focused on the neuralfunction of these ion channels, called GIRK channels. GIRK channels
open up during periods of chemical communication between neurons
and dampen the signal, creating the equivalent of a short circuit.
Having the location of a physical alcohol-binding site importantfor GIRK channel activation could point to new strategies for treating
related brain diseases. Using this protein structure, it may be possible
to develop a drug that antagonizes the actions of alcohol for thetreatment of alcohol dependence.

X-ray crystallography revealed a binding site for alcohol in an ion channel.

Alternatively, “If we could find a novel drug that fits the alcoholbinding site and then activate GIRK channels, this would dampen
overall neuronal excitability in the brain and perhaps provide a newtool for treating epilepsy,” says Slesinger.

Why Some Tumors Don’t Respond to Radiation and Chemotherapy
A tightly controlled system of checks
and balances ensures that a powerful tumor
suppressor called p53 keeps a tight lid on
unchecked cell growth but doesn’t wreak havoc
in healthy cells. In their latest study, scientists
at the Salk Institute suggest just how finely
tuned the system is and how little it takes to
tip the balance.
When unprovoked, at least two negative
regulators—the related proteins Mdm2 andMdmx—prevent p53 from unleashing its power
to kill. But just slightly increasing the amount ofavailable Mdmx, which grips p53 and renders it
inactive, the Salk researchers discovered, mademice remarkably resistant to the harmful effects

Inside Salk October 2009of radiation but very susceptible to the development of oncogene-induced lymphomas.
“Our experiments emphasize how subtle andprecarious the balance is,” says postdoctoral
researcher and first author Yunyuan V. Wang.
“A slight shift of balance and the mice survive
the equivalent of Chernobyl but are in big
trouble when an oncogene is activated.”
Their findings could explain why some tumors
don’t respond to radiation or chemotherapy, andprovide novel routes for the development of new
anti-cancer therapies.
As a powerful tumor suppressor, p53 turns
on genes that either halt cell division to allow
time for repair of damaged DNA or, when all

rescue attempts prove futile, to prevent cells withgenetic defects from dividing, as this would fuelthe development of cancer. Consequently, before
any tumor cell can start proliferating willfully, itneeds to escape from p53’s iron fist.
“One way or another, p53 function is compromised in all cancers. Either p53 itself is mutatedor there is a problem with one of the proteins that
regulate p53’s activity,” says the study’s leader
Geoffrey M. Wahl, a professor in the Gene Expression Laboratory. “Our hope is that we can develop
small molecule drugs that will activate p53 in
those tumors where it is still functional but inactivated by one of its negative regulators.”

www.salk.edu

19

INSN
T IETWU ST EB RN IEEWF S

Discovery Roundup
Tumor suppressor
pulls double shift
as reprogramming
watchdog
A collaborative study by researchersat the Salk Institute uncovered that the tumor
suppressor p53, which made its name as“guardian of the genome,” not only stops cells
that could become cancerous in their tracks
but also controls somatic cell reprogramming.
Although scientists have learned how to
reprogram adult human cells such as skin cells
into so-called induced pluripotent stem cells(iPSCs), the reprogramming efficiency is still
woefully low. The Salk study, published in theAug. 9 advance online edition of Nature, gives
new insight into why only a few cells out ofmany can be persuaded to turn back the clock.
“Although we have been able to reprogram
specialized cells for a while now, there had been
nothing known about the control mechanismsthat prevent it from happening spontaneously
in the body and why it has been so hard tochange their fate in a Petri dish,” says
Juan-Carlos Izpisúa Belmonte, a professor in
the Gene Expression Laboratory, who worked
closely with Geoffrey M. Wahl, also a professor
in the Gene Expression Laboratory.
Their findings bring iPSCs technology a
step closer to fulfilling its promise as sourceof patient-specific stem cells but also force
scientists to rethink the development of cancer.
“There’s been a decade-old idea that cancer
arises through the de-differentiation of fullycommitted and specialized cells but eventually
it was discarded in favor of the currently
fashionable cancer stem cell theory,” says
Wahl. “Now that we know that p53 prevents
de-differentiation, I believe it is time toreconsider the possibility that reprogramming
plays a role in the development of cancer
since virtually all cancer cells lose p53
function in one way or another.”

Growth Factor Keeps Brain Development on Track
Salk scientists report that Fgf10, a member of the fibroblast growth
factor (Ffg) family of morphogens, lets brain stem cells know when it’s time to get towork, ensuring they hit their first developmental milestone at the right moment.
Their findings not only add new insights into brain development and a novel function
for Fgfs, but also reveal a possible mechanism for the selective expansion of specificbrain areas over the course of evolution, such as the greatly increased size of the frontal
lobe in humans.
During embryonic brain development, stem cells in charge of building the cortex—
the largest brain structure and seat of most higher cognitive functions—pass through aseries of tightly regulated stages: from omnipotent stem cell to cortical progenitors cells
capable of producing neurons.
“The timing of each of these transitions has critical implications for brain development, since minor changes in the proportion of progenitors exhibiting one or theother division mode at early stages will result in substantial changes in the number ofneurons and the size of the cortex,” says Dennis O’Leary, a professor in the Molecular
Neurobiology Laboratory, who led the study.
Early in corticogenesis, stem cell-like progenitor cells known as neuroepithelial cells
undergo symmetric cell division, producing two identical progenitors to expand the poolof neuroepithelial cells. Later on, they differentiate into more mature progenitor cells
referred to as radial glia, which then divide asymmetrically to produce a pair of unlike
daughter cells: one radial glia to maintain the pool of progenitor cells and a corticalneuron or a basal progenitor. The latter will migrate outward and then produce neurons
to establish the superficial layers of the cortex.
But little is known about the mechanisms that mediate the critical transition periodthat bridges the early expansion phase of neuroepithelial cells and the later neurogenic
phase, which produces all the neurons that will eventually form the six layers of
the cortex.
“These findings demonstrate a direct mechanism employed during normal development to regulate brain size,” says O'Leary. “These findings also have potential implications for how cortical areas have evolved. Selectively expanding the progenitor pool by
Fgf10 regulation of the timingof radial glia differentiation
could account for the selective
expansion of the frontal cortex,
which has been greatly expanded
in humans and is thought tobe important for evolving what
are considered typically humantraits.”Without Fgf10 (right), neuronal stem cells failto differentiate on time. As a result, they keep
multiplying and generate a bigger pool of radial
glia (shown in red).

20

Inside Salk October 2009www.salk.edu

INSTITUTE NEWS

Nicotinic Receptor
May Help Trigger
Alzheimer’s Disease“Jumping Genes” Create Diversity
in Human Brain Cells
Rather than sticking to a single DNA script, human brain cells
harbor astonishing genomic variability, according to Salk scientists.
The findings could help explain brain development and individuality,
as well as lead to a better understanding of neurological disease.
The team, led by Fred H. Gage, aprofessor in the Salk’s Laboratory of
Genetics, found that human brain cells
contain an unexpected number of socalled mobile elements—extraordinary
pieces of DNA that insert extra copies ofthemselves throughout the genome using
a “copy and paste” mechanism.
“This is a potential mechanism to create the neural diversity that makes each
person unique,” says Gage. “The brain
has 100 billion neurons with 100 trillion
connections, but mobile pieces of DNA
could give individual neurons a slightly
different capacity from each other.”In earlier work, Gage had alreadyshown that mobile pieces of DNA known
as LINE-1 elements (short for Long interspersed element 1) randomly add extra

Inside Salk October 2009

copies to the genome of mouse brain
cells. But whether or not the same process, colloquially referred to as “jumping,” held true for neurons in humanbrains had been a matter of some debate.
When postdoctoral researcher and firstauthor Nicole Coufal measured matchedsamples (brain versus other body tissues)
from numerous individuals, she foundthat some brain samples had as many as
100 extra copies per cell.
“This was proof that these elements
really are jumping in neurons,” explains
Coufal. Strikingly, it also means that not
all cells are created equal—humans aretrue chimeras since the DNA in theirbrain cells is different from the DNA in
the rest of their cells.

For close to a decade, pharmaceuticalresearchers have been in hot pursuit of compounds to activate a key nicotine receptor thatplays a role in cognitive processes. Triggering
it, they hope, might prevent or even reverse thedevastation wrought by Alzheimer’s disease.
A new study from the Salk Institute, however,suggests that when the receptor, alpha-7,
encounters beta amyloid, the toxic protein foundin the disease’s hallmark plaques, the two may
actually go rogue. In combination, alpha-7 andbeta amyloid appear to exacerbate Alzheimer’s
symptoms, while eliminating alpha-7 seems tonullify beta amyloid’s harmful effects.
These findings, reported recently in The Journal of Neuroscience, may shed new light on theprocesses leading to Alzheimer’s and could haveimportant implications for researchers seeking
to combat the disease.
Intrigued by earlier studies showing thatbeta amyloid seemed particularly drawn tothe alpha-7 nicotinic receptors, researchers in
the lab of Stephen F. Heinemann, in the Salk
Molecular Neurobiology Laboratory, sought
to determine whether the alpha-7 receptors
actually modulate the effects of beta amyloid
in Alzheimer’s disease.
Hypothesizing that the alpha-7 nicotinic
receptors mediate beta amyloid effects in
Alzheimer’s disease, Heinemann’s team crossed
mice engineered to lack the gene for alpha-7
with a mouse model for Alzheimer’s disease,which had been genetically engineered tooverexpress amyloid precursor protein (APP),an antecedent to beta amyloid. They then put
the offspring through a series of memory tests.
Surprisingly, those with both mutations—toomuch APP and no gene for alpha-7—performed
as well as normal mice. The Alzheimer’s mice,
however, which had the alpha-7 gene and also
overexpressed APP, did poorly on the tests.
Pathology studies revealed the presence ofcomparable amounts of plaques in the brainsof both types of mice, but in those lacking thealpha-7 gene, they appeared to have no effect.
Similar disparities were evident in measurementsof the synaptic function underlying learningand memory.
www.salk.edu

21

P HN IELWA SN TBHRRI OE PF S
YLongtime Donor Ruth Hamill Bequeaths$250K to Institute
When she wasn’t taking her daily two-mile walk near her homeor meeting with friends from her sewing club, you might catch Ruth Hamill
playing a game of tennis or volunteering with Meals on Wheels. But when she
received invitations to the Salk Institute over the years, she wouldn’t pass up
the chance to hear presentations on scientific research, yet another one of her
longtime interests.
“I invited her to come hear a scientist speak at one of Salk’s events in the
1990s because I knew she was interested in biomedical issues and research ingeneral,” said Ruth’s friend and attorney for nearly 20 years Richard Muscio,
who previously served on Salk’s Planned Giving Advisory Committee.
“After that first meeting, she just fell in love with the place,” he said. “Ruthloved hearing new ideas. She was just fascinated by the depth and breadth ofknowledge and the creativity of Salk’s researchers.”
The science of cognition was of particular interest to Ruth, more so after
her husband, King, developed Alzheimer’s disease and passed away in 2006.
The couple supported Salk research as members of the President’s Club andeventually decided to include the Institute in their estate plan, which resulted
in a $250,800 unrestricted contribution when Ruth passed away in March.
Ruth is survived by her two sons, Rick and Dean, who are very supportiveof their parents’ philanthropic endeavors, Muscio said.

“

Ruth loved hearing new ideas. She was justfascinated by the depth and breadth of knowledge
and the creativity of Salk’s researchers.

King and Ruth Hamill

22

Inside Salk October 2009”

Institute Establishes
Presidential Chair to
Honor Irwin M. Jacobs
The Salk Institute has establishedthe Irwin M. Jacobs Presidential Chair
based on an endowment from Qualcomm
and its employees. The Chair commemorates Jacobs’ decision to step down aschairman of Qualcomm’s Board of Directors
and recognizes his ongoing dedicatedleadership of the Salk Institute’s Boardof Trustees.
The Presidential Chair will be Salk’s
largest endowment of its kind and will provide $4 million to the Institute when fully
funded. The inaugural chair-holder will be
the Salk President, William R. Brody.
“Endowing a chair that will help ensure
superb leadership at the Salk seemeda very fitting way to honor Irwin,” said
Paul E. Jacobs, chairman and CEO of
Qualcomm. “His legacy is linked to theattraction and development of the world’s
finest executive talent, and his instincts arealways to motivate, encourage and promote
groundbreaking research.”“Irwin Jacobs’ exemplary leadership of
the Salk Board has been critical to enhancing the Institute’s international renown,”
said Salk Executive Vice President Marsha
Chandler. “This Presidential Chair is theperfect recognition of Irwin’s inspiring guidance and commitment to the Salk’s future.”
Irwin Jacobs and his Qualcomm cofounders redefined how the world thinksof telecommunications and information
technology. More than 20 years after its
start, Qualcomm is a leading innovator ofadvanced wireless technologies, products
and services.
“We are pleased and proud to play arole in the ongoing excellence of the Salk
Institute,” said Paul Jacobs. “Salk discoveries are transforming our understandingof human health, and this is an outstanding way to support one of Irwin’s major
passions.”

www.salk.edu

PHILANTHROPY

Nearly 700 people gathered for an exceptional eveningthat raised $784K for basic research.

Broadway Veteran Bernadette Peters Dazzles Symphony at Salk Audience
Even a torrential morning rainstorm
failed to dampen excitement for the 14th annual
Symphony at Salk concert held Aug. 22 at theInstitute’s cliff-top courtyard overlooking the
Pacific Ocean. Mother Nature was quickly upstaged by a spectacular evening of music thatcombined the talents of multi-award winning
performer Bernadette Peters and the San Diego
Symphony led by returning guest conductor
Thomas Wilkins.
Nearly 700 people gathered at the Instituteto enjoy an exceptional evening of dining andentertainment at the sold-out fundraiser thatraised more than $784,000 — a new record —to benefit the Salk’s groundbreaking researchand its community outreach programs.

Peters dazzled the audience with her amazing vocal range that ensured every song wasdelivered to ultimate effect. She performed aneclectic mix of selections that showcased herversatility whether she was strutting through the
Broadway belter “Ain’t Nothing Like a Dame,”heating things up with “Fever,” or singing the
sweet and poignant ballad “Shenandoah.”Peters easily connected with the audience
between songs, delighting them with playful
conversation and racy banter that kept theshow at a lively pace until her exhilarating
finale, which included a haunting rendition of“I Honestly Love You” and “Some Other Time.”
Her show was preceded by a rousing performance by the San Diego Symphony under

the skillful direction of Maestro Wilkins playing
selections by Franz von Suppe, Gabriel Faure
and a stirring rendition of Johann Strauss Jr.’s“Emperor Waltzes.”
A champagne reception kicked off the festivities as guests mingled in the eucalyptus grove
and bid on several unique items offered at theevent’s first-ever silent auction. Prior to the startof the concert, they also enjoyed a delectable
meal prepared by critically acclaimed awardwinning chef and owner of Pamplemousse Grille
Jeffrey Strauss, who catered the event for thesecond year in a row.

» WEB EXTRATo see more images from this event, visit
www.salk.edu/insidesalk/symphony09

Inside Salk October 2009www.salk.edu

23

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PERMIT NO. 611
SAN DIEGO, CA

Telephone: 858.453.4100
Fax: 858.552.8285
www.salk.edu

There are many ways to support the Salk. For information on how you can help, please email giving @ salk.edu or call 858.550.0472

Salk Calendar
NOVEMBER 2009
1 Breathing & Sleep Symposium
5– 6 Transitional Mechanisms of
Early Lymphocyte Development
Symposium

11 Stem Cell Meeting on the Mesa 200917–18 4th Annual Peptide Therapeutics
Symposium

JANUARY 2010
13–15 Salk and Fondation Ipsen Symposium
on Biological Complexity: Sensory
Systems: Smell, Taste, Touch,
Hearing, and Vision

FEBRUARY 2010
4 Renato Dulbecco Nobel Lecture
11 Stem Cells and Cancer Symposium
18 Leslie Orgel Memorial Lecture

For additional information on these andother Salk events, contact the Development
Department at 858.453.4100 x1658

A group of high school students spent eight weeks at the Salk
where they worked with scientists on various experiments aspart of the Summer Internship Program.