SIGNALS

HONOR ROLL OF DONORS

ANNUALREPORT2001

PROTEOMICS:MAD COW DISEASE

REGULATORY BIOLOGY: AIDS

INFORMATICS:BALINT’S SYNDROME

SALK SIGNALSVOLUME 5 / NUMBER 1 SUMMER 2002

A P U B L I C A T I O N O F T H E S A L K I N S T I T U T E F O R B I O L O G I C A L S T U D I E S

I N S P I R E D B Y S A L K

Anna and Mario Scipione

The Salk Institute as a beneficiary of our trust was the resultof a two-part process. First, my wife and I came to under-stand the purpose and benefits of a Charitable RemainderTrust (CRT). Then we had the opportunity of selecting thebeneficiaries. We decided to each select an organizationdedicated to improving the basic quality of life. I chose theSalk Institute with surprisingly little effort.

Jonas Salk, as well as the Institute, have been recurringinterests for me. I recall asking lots of questions about get-ting my polio vaccine before entering school in Ohio. That iswhen I first remember hearing about Jonas Salk and howvaccines work. Later, during elementary school, our weeklyscience paper covered the Salk Institute and its distinctivebuildings. During my graduation year from college, I cameto San Diego for a job interview and my cousin took me tothe Salk Institute. We walked around to enjoy the buildingsand the view. I had forgotten it was here.

Around 1996, I read an interview in The San Diego Union-Tribune, where I learned much more about the workings ofthe Salk Institute and its funding. Until that point I had noidea how the Institute operated. A year or so later, we set upour CRT. The recent memory of the article and my highregard for the organization convinced me what my choiceshould be.

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Richard A. Murphy President and CEO

Kristin Bertell Vice President, Institute Relations

Dianne D. Day Vice President, Development

Warren Froelich Director of Communications

Ray Ramseyer Director of Gift Planning and Endowment

Shannon Rose Editor

Goss Keller Martínez Design

Suzanne Clancy Science Writer

Marc L. Lieberman Multimedia Manager

Kent Schnoecker Photographer

Carole C. Mayo Editorial Assistant

Salk Signals is published three times a year by the Salk InstituteP.O. Box 85800, San Diego, California 92186-5800

Mad Cow Disease page 8Roland P. Riek uses NMR to uncover proteinresponsible for mad cow disease.

AIDS page 14Katherine A. Jones wants to stop AIDS in its tracks.

Computational Biology page 16One of the hottest new areas of research is at theintersection of biology and computer science.

Balint’s Syndrome page 20Those with Balint’s syndrome see the worldin a fractured manner.

O N T H E C O V E R Salk Assistant Professor John H. Reynoldsas seen through a kaleidoscope

Cell Biology page 10Genome projects herald revolution in biology.

SIGNALSSALK SIGNALS

Proteomics page 4Learning how proteins work is key tounderstanding disease.

Annual Report 2001

D E P A R T M E N T S F E A T U R E S

VOLUME 5 / NUMBER 1 SUMMER 2002

A P U B L I C A T I O N O F T H E S A L K I N S T I T U T E F O R B I O L O G I C A L S T U D I E S

DURING THE PAST YEAR, theworld of biomedical sciencehas been altered foreverwith the solving of thehuman genome. We haveentered a new age of dis-covery, a post-genomic erain which scientists willprobe ever more deeply intothe unsolved mysteries ofbiology. The result will be abetter understanding of dis-ease leading to new med-ical treatments and cures.

This issue of Salk Signalsprovides a brief look at howSalk scientists will beexploiting post-genomicscience in the future. Wewill establish a newresearch group in chemicalbiology and proteomics,sciences aimed at under-standing the structure andinteractions of proteins andcreating new molecules toprobe protein function. Wewill focus efforts on stemcells, which are key to pro-viding new ways to regener-ate or replace diseasedtissues. Our regulatory biol-ogists will study how genes

are turned on and off innormal and diseased cells.And our computational andtheoretical biologists willuse computer simulationsto interpret data and toestablish hypotheses thatcan be tested in the labora-tory. These new researchinitiatives will require thehiring of a new generationof Salk scientists who willconduct independentresearch studies as well ascarry out collaborativeresearch with faculty in dif-ferent fields, which hasbeen a hallmark of theSalk’s success.

As part of this effort, theInstitute welcomed two newscientists this year. RolandP. Riek joined the Instituteas an assistant professor instructural biology anddirector of the new NMR(nuclear magnetic reso-nance) facility, which willhelp us determine thestructure and dynamics ofproteins and their interac-tions. Dr. Riek will useNMR spectroscopy to con-

tinue his studies of prionproteins, which are infec-tious and transmissible,and have been identified asthe cause of mad cow dis-ease and Creutzfeldt-Jakobdisease in humans. JanKarlseder also joined thefaculty during the past yearas an assistant professor inthe regulatory biology labo-ratory. Dr. Karlseder stud-ies cell replication,particularly the role andregulation of telomeres,which are located at theend of chromosomes. Oneof his goals is to understandthe molecular mechanismsthat result in telomereshortening, a naturalprocess that occurs withaging. Cells with criticallyshort telomeres enter aperiod of arrest calledsenescence, which isbelieved to be a potenttumor suppressive mechanism.

Also included in this edi-tion of Salk Signals is a spe-cial Annual Report sectionand our Honor Roll of

Donors. For fiscal year2001, more than 900 indi-viduals, families, corpora-tions, foundations andgroups donated more than$35 million to supportSalk’s activities. We areespecially grateful to theMarch of Dimes, which pro-vided the initial funding forthe Salk Institute and whichhas graciously supportedour scientific pursuitsthroughout the years.

I would also like to thankthe members of our Board ofTrustees for their guidance,support and financial back-ing. In addition to giving oftheir resources and talents,the trustees and many othersupporters have donatedtheir time to the Institute invarious capacities. We areindebted to all of you.

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One possibility relates to thesymphony metaphor; coher-ence may be missing in autisticindividuals. In other words,there is no conductor, andtherefore no reorganization.Each instrument continues toplay its own tune. Newapproaches to therapies mightfocus on restoring harmony.

Genes and Cancer

Genetic instability is a distin-guishing feature of cancer cells.Extra copies of certain growth-promoting genes, as well asbroken or rearranged chromo-somes accumulate in cancercells, while other genes — usually those that rein in growth— are missing. This genetic tur-moil fosters the aggressive andunchecked growth and divisionof cancer cells.

Recent work from SalkProfessor Geoffrey M. Wahl andhis group in the Gene ExpressionLaboratory points toward onecause of this instability. In arecent paper, published in theresearch journal Molecular Cell,the investigators show thatmutations in a gene called c-myccan create DNA damage. Theyalso show that over-stimulationof the c-myc gene can shutdown the mechanisms a cellnormally uses to monitor andcheck genetic damage.Specifically, c-myc can depressthe activity of a protein knownas p53, an important “guardian”of a cell’s genetic integrity.

Link between BreastCancer Drug andHeart Failure

The probable link between thebreast cancer drug Herceptinand cardiac failure, one of itscommon side effects, was iden-tified by a team led by AssociateProfessor Kuo-Fen Lee andreported in the May 1 issue ofthe journal Nature Medicine.

Herceptin targets a proteincalled Her2, which is found inexcess in some breast cancercells. The study shows that themouse version of Her2 (callederbB2) is needed for properheart cell function.

“It was possible thatHerceptin triggered cardiacmalfunction by a number ofmechanisms,” said Lee, “butnow it appears that the drug’sdirect action on Her2 is the culprit.” He added that it shouldbe possible to engineer newgenerations of drugs that wouldameliorate Herceptin’s deleteri-ous effects on heart function.

Investigators in Lee’s labora-tory made mice that wouldstop making erbB2 selectivelyin their heart tissue. In collabo-ration with researchers at theUniversity of California, theyshowed that hearts from themice displayed clear signs ofcardiomyopathy similar tothose observed in Herceptin-related cardiac dysfunction.

Almost all women takingHerceptin also receive or havereceived other anti-cancer

drugs, particularly anthracy-clines. Because concurrentHerceptin/anthracycline treat-ment increases cardiac dys-function in patients, Lee andhis colleagues examined theeffects of anthracyclines on themutant mice.

They found that heart cellsfrom the mice were much moresensitive to adriamycin, a com-monly used anthracycline, atdrug levels resembling those inpatients undergoing treatment.Although it appears thatHerceptin-related cardiomy-opathy is directly related to thedrug’s anti-cancer mechanism,it should be possible to designstrategies to counteract thedangerous side effect.

“If we could develop agentsthat can stimulate the heart, par-ticularly cardiomyocyte contrac-tility, then those might allow youto use Herceptin aggressivelywhile protecting the heart,” saidLee. Efforts in his laboratory arefocusing on this approach.

New View of BrainMay Shed Light onAutism

According to generallyaccepted neuroscience dogma,the brain works somewhat likean electronic bucket brigade,with incoming signals passedfrom one region to the next in alinear fashion.

This somewhat passive role ischallenged by a recent study led

by Salk Professor Terrence J.Sejnowski and his team in theComputational NeurobiologyLaboratory. Instead of thebucket brigade metaphor, thesescientists see the brain more asa symphony orchestra waitingto come into harmony with thelifting of a conductor's baton.

“Our data indicate the brain‘at rest’ is more like a sym-phony orchestra warming up— one hears a lot of discordantactivity,” said Sejnowski, referring to the study, whichappeared in the Jan. 25 issueof the journal Science.

“Then the conductor — orstimulus — appears on thescene and imposes synchrony.”

In the recent work, the inves-tigators applied a mathematicaltechnique called ICA(Independent ComponentAnalysis) that allowed them to examine each of more than13,000 experimental trials individually.

The result, a generation ofstrong waves as depicted onan electro encephalogram(EEG) recording, suggests a farmore dynamic view of thebrain’s activity.

It also opens new avenues toexplore certain brain dysfunc-tions, including schizophreniaand autism. Neuroscientistsknow that some important brainresponses are too small or miss-ing in autism. The new methodof analysis may help to explainthe underlying biological reasonsfor the altered responses.

F R O M T H E J O U R N A L S

Senyon Choe, a structural biologist,searches his mind for a metaphor to best

place the life sciences in a historical con-text: where we’ve been — the era of the

gene — and where we’re going — the era of the protein. He turns to music.

By analogy, Choe says, the gene is like amusical score, with all the notes andtimescales carefully charted for each

instrument. By extension, proteins — theproducts encoded by genes — are akin to

the violinist or piano player who carriesout the instructions set down by the score.

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Now, here’s where it getscomplex.

“There’s only onemusic score, but thereare many different ways

of playing the same music,” saysChoe, an associate professor at theSalk Institute. “Consider the way a lit-tle child plays and the way (Vladimir)Horowitz plays a Beethoven piece.

“So the complexity of protein func-tion and regulation is far greater thanthe complexity of genetic makeup.”

Consider the scope of the problem.Briefly, there are far more proteinsthan the approximate 30,000 genesidentified by the Human GenomeProject, perhaps 10 to 100 times asmany. To truly understand how theseproteins work together in concert, sci-entists must determine how ensemblesof proteins come together. Only then,will scientists truly understand howthe body functions and what goeswrong in disease.

This is the promise of proteomics,the technical expression for the studyof proteins and their interactions. If allworks, researchers like Choe envisiona new era in medicine, where drugsand other therapies can be customizedfor each individual patient. But don’tdiscard the tubes and bottles in yourmedicine cabinet just yet.

“We thought when we knew thegenome, we would know everything weneeded to know,” said Joseph P. Noel,professor of structural biology at Salk.“But we really were just scratching thesurface.”

If scientists have only scratched thesurface, what do they expect to findwhen they dig further?

To Noel and others interested in proteomics, the goal is to reveal howthe now cloistered world of cellularproteins perform their daily routines.They help us to digest food; provideenergy; carry oxygen in blood; fightinfection; and allow us to think, speak,

write sentences and paragraphs. “We’re talking about the cell as it

goes through a variety of processes,”said Noel, “how these proteins changeas the cell grows, divides, differenti-ates within tissues, ages and dies.

“We want to know how each compo-nent and each complex changes as afunction of all these events.”

Much of this work is being driven bytechnical advances that are allowingscientists to see proteins as neverbefore — from the minute grooves,ridges and pockets that make up theirthree-dimensional structures to theirinteractions with other proteins, nomatter how fleeting.

This list includes mass spectrome-try, which, by sorting and identifyingmolecules based on their mass, helpsscientists to identify proteins in func-tioning networks. Then, there’snuclear magnetic resonance (NMR),which produces clear images of proteinsas they merge, trigger intricate chemi-cal changes, and then part. Thesetechnologies, combined with geneticsand x-ray crystallography — whichproduces brief snapshots of proteins— are expected to generate far moreaccurate models of proteins at work.

With such sophisticated tech-niques, Noel hopes to gain a betterunderstanding of plant evolution to

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Senyon Choe Joseph P. Noel

find out how and why plants producethe 100,000 or more different proteinsduring their life cycles. Some of thesemolecules are harmful to humanswhen ingested; others provide valuablenutrients. And a few other proteins andmolecules hold the potential to curedisease, including heart disease andcancer.

So, aside from answering fundamen-tal questions about the chemistry ofplant proteins, Noel says this researchone day could yield crops that help pre-vent or treat life-threatening ailments.

“By enhancing food stuffs for theproduction of beneficial molecules wecan ingest easily and cheaply,” hesays, “we can produce somethingthat’s quite beneficial to mankind.”

Before plants like these can be engi-neered, Noel and others are working toidentify key protein networks respon-sible for health benefits. From these,he hopes to create dynamic models ofhow they perform the biological task inquestion. For the most part, these pro-tein-protein interactions are weak andfleeting.

“With traditional analytical tools,people have studied protein-proteininteractions that typically bindstrongly with each other,” said Noel.“That is, they come together and theyrarely, if ever, come apart — such as

an antigen-antibody interaction. Thoseare easy to study.

“But such interactions are rare, andthere’s a whole host of protein-proteininteractions that are relatively weakand highly regulated, which form anddissolve over time.

“As a general theme, the real goal ofthe next decade will be to understandthe nature of these weak interactions,with the aid of advanced technology.”

For his part, Senyon Choebelieves “protein chips”— the counterparts to themuch-publicized “genechips” — will help scien-

tists to better identify proteins, theirfunctions and what goes awry to causedisease.

Choe is a member of the nationalJoint Center for Structural Genomics,which has as its goal to determine thethree-dimensional structures of up to2,000 proteins, using “high-through-put technology” that includes roboticsand massive computational resources.

As part of this effort, he is workingwith scientists at University ofCalifornia, San Diego, Stanford andthe Scripps Research Institute tobuild a chip of about a dozen proteinsthat mimics the activity of TGF-betareceptors, a class of proteins that is

essential for a wide variety of func-tions. These include cell growth anddifferentiation, tissue repair and boneformation, immune response andtumor formation, and programmedcell death.

“We’d like to use this small set ofproteins as a ruler, so to speak, to mirror how this receptor works in thebody,” said Choe. “It can be used as atool to determine developmentalstages, how signals are transmittedfrom cell to cell. We can also use thischip to assess the status of disease,including cancer, so we can test theeffectiveness of a particular anti-cancerdrug on tumor growth.”

Such discoveries offer just a glimpseinto what’s possible.

Choe returns to the music metaphor.“It’s like we’ve just discovered the

entire score of an old Beethoven pianoconcerto,” he says. “To play it, we callupon the components, those individualproteins. With proteomics, we’re goingto learn how to understand who thoseplayers are and then how they cometogether to play it.

“With that knowledge, we can gain abetter understanding of life itself. Andthen we’ll get the individualized medi-cine we’re seeking. It will happen. Ihave no doubt. It’s not hype. But it willtake time.” –By Warren Froelich

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To truly understand how these proteins work together in concert,

scientists must then determine how ensembles of proteins come

together. Only then, will scientists truly understand how the body

functions, and what goes wrong in disease.

It’s like no other infectious agent.Unlike bacteria, viruses or anyother known pathogen, thisstrange particle has no geneticmaterial. It’s pure protein.

During the past couple of years,however, this entity called a prion hasgained international notoriety foranother reason: it’s been implicated asthe culprit responsible for bovinespongiform encephalopathy (BSE),commonly called mad cow disease.

Though thousands of cattle inEngland and other parts of Europehave been destroyed to help preventthe spread of this neurodegenerativedisease, health officials and othersworry about the potential impact onthe hundreds of thousands of humanswho consumed infected beef over thepast decade.

“It’s in our interests to move as fastas we can to find out more about prionproteins,” said Roland P. Riek, astructural biologist who joined theSalk Institute last year from the Swiss

Federal Institute of Technology inZurich, Switzerland.

“But it’s fundamental science, andit’s going to take a huge amount of timeto find anything that might lead to adrug or anything like that,” he added.

To find weapons against this publichealth menace, Riek has enlisted thesupport of sophisticated nuclear mag-netic resonance (NMR) instruments toget a better view of its structure and,potentially, how it causes infection inthe brain. Just as astronomers tuneinto radio waves emitted by objects inouter space, NMR works by tuninginto the radio waves emitted by atomswithin materials.

“I think the important thing with

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Assistant Professor R O L A N D P . R I E K , director of the NMR facility at Salk, studies protein structures, particularly the events that occur when proteins misfold.

Roland P. Riek (right) relies

on the Salk’s new NMR

facility, funded by The

Kohlberg Foundation, Inc.;

the Fannie E. Rippel

Foundation; and the

H. N. & Frances C. Berger

Foundation.

MadCowF I N D I N G W E A P O N S A G A I N S T D I S E A S E

NMR is that we are able to get a betterglimpse of protein-protein interactions,”said Riek, who directs Salk’s new NMRfacility, “and we are able to work insolutions in environments that are phys-iologically similar to living systems.”

The term prion (for proteinaceousinfectious particle) was first coined in1982 by University of California, SanFrancisco scientist Stanley Prusiner. Itwas also Prusiner who proposed theheretical notion that prions cause avariety of brain disorders, includingCreutzfeldt-Jakob disease in humans,when a benign form of the protein —typically found at the surface of normalcells — becomes distorted. This abnor-mal prion protein, he said, then bindswith other normal proteins, which thenbecome distorted, producing a chainreaction that ultimately results in thewidespread death of brain cells.

Using NMR facilities in Zurich, in1996 Riek and colleagues unveiledthe first three-dimensional view of anormal prion particle. The ratherunusual protein consists of two dis-tinctly different segments of approxi-mately equal size: half appearing as asphere-like object, the other half form-ing a long, flexible tail.

From the structure, Riek and otherscientists are gaining early clues intonormal prion protein activity, and whatmight happen when the protein turnsinfectious.

Among other things, Riek has foundsmall structural differences acrossseveral species. Such insights mightprovide critical information aboutwhether prions from one species, suchas cows, can infect another species,including humans.

To continue this work, Riek will

rely on a new NMR instrumenthoused at the Salk Institute. The cen-terpiece of the instrument is a largecore magnet that generates an align-ment of nuclear magnets called spins,which then are manipulated by radiowaves.

Riek will be collaborating with Salkscientists investigating a variety ofstructures important for understand-ing myriad ailments, including AIDS,mental disorders and cancer.

“San Diego is an incredible centerfor NMR work,” said Riek. “At Salk,we’re coming together real fast withseveral collaborations already.

“This synergy of activity should giveus information about binding inter-faces, about structural details, andabout enzymes that could result in therational design of new drugs. That’sthe goal.”–By Warren Froelich

CellTo

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Professor Walter Eckhart may present acalm and cool veneer, but words like“exciting, challenging, unparalleled”pepper his speech about the new era

of post-genomic discovery.“It’s a particularly exciting time to

be working in biology and to see how allthis basic knowledge is able to be applied

to important human problems,” saidEckhart, a professor in the Molecular and

Cell Biology Laboratory and director ofthe National Cancer Institute-designatedCancer Center at the Salk Institute, one

of only eight in the country.

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The completion of manygenomes, including themuch-heralded HumanGenome Project, hascracked open the door to

new realms of discovery in basic biol-ogy, and researchers like Eckhart arepushing it ever wider with their con-siderable intellect and new technolo-gies. If human beings have only twiceas many genes as a worm, then whatdistinguishes humanity?

“It’s a revolution in biology,” saidFred H. Gage, a professor in theLaboratory of Genetics and an experton stem cells. “And one that will haveprofound effects on how we do science,as well as on how we think abouthuman health and disease.”

PAINT ING A COMPLETE P ICTURE

“We are getting quite a lot of informa-tion about the components of cells, forexample the genes and the machinerythat make up proteins, and the compo-nents of how cells communicate,” saidEckhart.

“But that is only a partial picture ofhow cells work. Cells are more than justa mixture of their components. If youput all of the components in a bag andshook them up, you wouldn’t get a cell.”

So what would paint a more com-plete picture — one that would lead toan understanding of the “importanthuman problems” of disease?

Learning how these componentswork together to create a functioningwhole, explained Eckhart.

For example, the mechanics of mito-sis (the process by which the bodyproduces new cells) have beenobserved and studied for decades, butscientists don’t know much about themolecular means by which chromo-somes (which contain genetic mater-ial) are duplicated and partitioned intodaughter cells in an accurate way.

“Understanding this process better istremendously important for grasping

the complexities of diseases such ascancer,” said Eckhart, “where there isgenetic instability and a lot of chromoso-mal rearrangements and changes. Andthe recent accumulation of informationabout genes and how they function willhelp us to comprehend this process, aswell as many other cellular processes.”

Now that DNA microarrays, or genechips, allow researchers to examine theactivities and relationships of largegroups of genes, they can determineevolutionary connections between sim-ple organisms and more complex ones.

“We can study the relationship ofgenes from one organism to anothermuch more easily as a result of thevarious genome projects — theviruses, the fruit fly, bacteria and soon,” said Eckhart. “We are beginningto see that by understanding the devel-opment and structure of simple organ-isms, we can understand them incomplicated organisms. So we studyfruit flies and other simple organismsto get an idea of how similar processeswork in complex organisms, such aschickens, mice and humans.”

Such knowledge could lead to morerapid and precise diagnosis of disease,determination of who might be moresusceptible to certain diseases, andthe development of novel therapies.

As the new era moves forward,Eckhart envisions several specific

Fred H. Gage Walter Eckhart

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overarching goals: understandingembryonic development, how the func-tions of the body are coordinated andstem cell biology.

UNDERSTAND ING STEM CELLS

According to Gage, the HumanGenome Project has changed the wayresearchers look at stem cells — cellsthat have the ability to divide and giverise to specialized mature cells for allorgans of the body, such as the liver,brain and blood.

“Because the human genome isavailable, we can use that knowledgeto determine what genes are unique forembryonic versus adult stem cells,”said Gage, leaning forward over hisdesk to emphasize his point.

“We can also identify genes that areunique to stem cells versus more dif-ferentiated cells, such as liver cells orneurons. In addition, we can deter-mine the difference between normaland diseased cells.”

What Gage anticipates will keephim and his colleagues “busy for along period of time into the future” ishow to obtain the most primitiveembryonic stem cell lines (those thatcan give rise to most tissues), how lin-eage restricted stem cells (more spe-cialized stem cells that give rise tocells with a specific function) can shiftand how organs take shape.

Creating new embryonic stem celllines through what is popularly knownas “therapeutic cloning,” or as Gageprefers to call it, “nuclear transfer,”could lead to tailoring stem cells forthe individual to avoid tissue rejec-tion. In nuclear transfer, the nucleus isremoved from an unfertilized egg, andDNA from an adult cell is insertedinto this egg. When the “new” egggrows into a few hundred cells, stemcells can be harvested that wouldmatch the adult donor’s genome.

“Nuclear transfer — understandingwhat is called the reprogramming ofthe genome so we can take cells andteach them how to become more prim-itive, to again recapitulate the embry-onic stem cell lineage — is a veryexciting issue,” said Gage. His mindleaps ahead to a future that involvesdiscovering if a stem cell can convertfrom one lineage to another. Can stemcells targeted to become blood cells orliver cells turn into muscle or braintissue?

“There is a tremendous amount ofinformation that needs to be gatherednow,” Gage emphasized, before mov-ing on to discuss his next anticipatedventure — organogenesis.

“It is one thing to say you have astem cell that can make all these differ-ent individual cells. It is another to saythat you can take a stem cell and make

a heart, liver or any other organ. Andthat is what organogenesis is all about.”

A brain, for instance, is not com-posed of one type of stem cell, butmyriad stem cell lines — a mixturefrom blood, nerves, muscle. To createan organ as complex as the brain orthe heart, scientists have to look at theinteraction of all the different stemcell lineages and how they coordinatein time and space to give rise to afunctioning organ.

“For a basic scientist, that is justexciting. How does that happen? Andof course, the practical implicationsare tremendous. There is the possibil-ity that we could reconstruct an organin a dish that can be used for trans-plantation,” said Gage.

“It sounds a little bit out of therealm of science fiction, but I don’tthink it is impossible.”

Indeed, these kinds of questions are those that researchers at the SalkInstitute thrive on answering. “This is basic research,” said Gage. “Thesekinds of questions have important biological significance, but also have important practical implicationsas well.”

As for Eckhart, he always keeps inmind “that even though we are havingfun doing this, what is important isthat we are trying to alleviate humansuffering.” –By Shannon Rose

As one cell divides to form two, its genetic material is first

duplicated, then evenly separated into the two new cells.

Mistakes in this process can lead to cancers or birth defects.

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“And that this phosphorylation is arequirement before anything can hap-pen to start the whole process of acti-vation and replication.”

She and her team hope that a furtherunderstanding of this crucial step forreplication of the HIV-1 virus will lead to new treatments and therapiesto block the Tat/cyclinT1/cdk9 partnership.

Cutting-edge technology at theInstitute may help in her quest. Shehopes to utilize the newly installednuclear magnetic resonance (NMR)instrument to determine the structureof the cyclin T1/cdk9 complex.

“Once we can physically see thestructural interactions we will have abetter sense of how easy or difficult itmay be to disrupt the recruitment ofthis complex by Tat,” said Jones.

“It clearly is a kinase that is widelyused by the cell for regulation of many,many different genes — if not for allgenes. So clearly, blocking all of theactivity of the complex with a drugwould not be ideal, but there is a win-dow where an inhibitor could beadministered at levels below that ofharming its normal necessary func-tions.” –By Shannon Rose

Tat (transactivating tran-scription factor) is likethe engine of a train —without it, HIV-1 goesnowhere, which is exactly

where biochemist Katherine A. Joneswants it to go. Jones, a Salk Instituteprofessor in the Regulatory BiologyLaboratory, has been studying the elu-sive machinations of the protein Tatfor 18 years, since her postdoctoraldays at the University of California,Berkeley, and the start of her career atthe Salk Institute in 1986. And withan estimated 40 million people world-wide living with HIV or AIDS at theend of 2001, she is not about to stopanytime soon.

“AIDS is a major, major problem inthe world today,” said Jones. The U.S.Census Bureau estimates that by2010, the average life expectancy willbe reduced by 40 years in Zimbaweand Botswana, and in South Africa by30 years.

“This is horrifying — the resultingpopulation will be unlike anythingwe’ve ever seen before,” said Jones.“We hope our work here at the SalkInstitute will help to stop these typesof statistics in their tracks.”

Tat is essential for replication of theHIV-1 virus, which depends upon theproteins and machinery found in normal cells to duplicate itself. Oncethe virus has managed to replicate, itconverts the host normal cell into amachine that spits out more and more copies of the virus, which arethen released and find other cells toinfect.

Jones and her team found that Tat,the first protein the virus makes onceit infects a cell, binds with a proteincomplex already present in a normalcell — cyclin T1, identified by Jonesduring her tenure at Salk, and its part-ner, cdk9, a kinase. A kinase is a pro-tein that adds a phosphate to otherproteins in a cell in a process calledphosphorylation.

Evidently, Tat serves as the engine,pulling the box cars, cyclin T1 andcdk9, to a different location in the hostcell where the process of replicationcan begin. The lab is homing in onexactly how Tat moves the complexand thus turns it into a lethal combi-nation.

“We are looking at the idea that Tatmay be changing how the complexphosphorylates,” explained Jones.

AIDSProfessor K A T H E R I N E A . J O N E S studies agene that is essential for HIV-1 to replicateand cause AIDS.

S T O P P I N G I N I T S T R A C K S

Data DataData

C O M P U T A T I O N A L B I O L O G Y : W H E R E B I O L O G Y A N DC O M P U T E R S C I E N C E I N T E R S E C T

The scene unfolding on Salk scientistThomas M. Bartol’s computer makes onefeel like an astronaut hurtling through a rainbow-hued asteroid storm. Odd formsand shapes whiz, whirl and occasionally

collide. But it’s not a futuristic flight simulator that has Bartol’s attention.

It’s a laboratory-generated simulation of anerve cell “firing” and passing a message

to another cell — an event that transpires ahundred million billion times a day in the

brain as we go about the business of living.The complexity of the human brain is

staggering. A pinch of brain tissue the sizeof a grain of rice contains approximately a

million cells, and each one of those can“talk” to 10 thousand other cells.

16 S I G N A L S / S U M M E R 2 0 0 2

18 S I G N A L S / S U M M E R 2 0 0 2

Bartol explains how he and his col-leagues used a model to help settleone dispute about how neurons com-municate with a particular muscle thatmoves the jaw.

“The connections between neuronsand the muscles they innervate arecalled synapses,” he said. “All psy-choactive drugs — both prescriptiondrugs like Prozac and illicit or recre-ational drugs — act on synapses. Sounderstanding synapses is essential tounderstanding brain function.”

On one side of the gap between anerve and a muscle, the neurons con-tain many tiny vesicles, little sacks ofmolecules called neurotransmitters.When a neuron fires, it releases thesetransmitters into the gap between itand the muscle cell.

On Bartol’s screen, the transmittersresemble snowflakes, confetti — orasteroids, depending on the speed ofthe movie. Ultimately, they reach themuscle, where they dock with anotherspecialized molecule called a receptor.

“After the receptor has bound twomolecules of transmitter, the receptor

DataDataData

Thomas M. Bartol Terrence J. Sejnowski

““

And each firing event hasmany components,” saidBartol, ticking off on hisfingers the individualmolecular motions that

add up to a single firing. “It’s prettyamazing that it ever happens correctly.”

Of course sometimes nerve cells,also called neurons, don’t work cor-rectly. Understanding how neuronsconduct their business is essential tobuilding a complete picture of condi-tions such as Alzheimer’s, Parkinson’s,depression and schizophrenia. Buthow do neuroscientists decide whereto start probing questions of brainfunction?

ORGAN IZ ING DATA THROUGHMODEL ING

“There are just too many potentialexperiments; there are millions ofexperiments one could do,” saidProfessor Terrence J. Sejnowski,director of the ComputationalNeurobiology Laboratory. “Ultimately,one must do experiments, but modelslike Tom’s simulator can give you agood idea of where you want to focus.”

The field of computational biology isa rapidly expanding one due in part tothe need for investigators to organizeand analyze the torrent of data gener-ated by large-scale efforts such as theHuman Genome Project. One branchof computational biology, usuallycalled bioinformatics, seeks to developefficient and helpful ways to catalogand compare data, be it sequences ofgenes, lists of proteins, or shapes ofcells. Sejnowski refers to this branchas the “white pages” of biology.

“We’re trying to compile a ‘yellowpages,’ a functional directory based onwho does what,” he said. “In order todo that we need to develop computa-tional models and test them withexperiments in living cells. Theresults of those tests help us to refinethe models. And so on.”

S I G N A L S / S U M M E R 2 0 0 2 19

changes shape — and we see it turncolor,” explained Bartol. “The shapechange is what permits electrical cur-rent to flow through the muscle celland the muscle to contract.”

For many years, scientists hadobserved that responses on the muscleend were not uniform across thesynapse. More receptors were acti-vated in some areas than in otherareas.

Many had puzzled over the reasonsfor this and carried out large numbersof experiments, none successful. Mostwere designed to test the theory thatmore transmitter was released at cer-tain sites, thereby reaching the musclemore strongly on the opposing side ofthe gap.

“If you were looking at a river bankand found heaps of leaves accumulat-ing at certain locations,” said Bartol,“in the simplest case, you might thinkthere were a large number of treesshedding on the opposite bank.

“But it’s also possible that someunderlying terrain or currents mightbe causing the pile-ups.”

Bartol and his colleagues were ableto apply their model to show that thetopography of the synapse couldindeed account for the differences inreceptor activation, even when thenumber of transmitter moleculesreleased was the same at each location.

“Hundreds of experiments had beendone to address the issue, but withoutresolution,” he said. “We hope in thefuture to be able to save experimental-ists a lot of time by using models torule out certain theories or pointtoward more likely ones.”

UNRAVEL ING HOW NEURONSWORK TOGETHER

Computational biologists also plan toscale up their modeling capabilities toexamine large networks of synapses orneurons. This effort will be needed tounderstand the intricate and coordi-nated processes that underlie complexbrain functions such as learning,memory and perception. Investigatorson the Salk’s vision research team relyon modeling to help them unravel howhundreds of thousands of individual

neurons work together to perceive theworld. This work may lead to a newunderstanding of mental disorderssuch as schizophrenia, as well asvisual prosthetic devices that couldrestore sight to those blinded bystroke.

And, ideally, investigators wish tounderstand the many other types ofcells in the body, which could lead tonew treatments for cancer, heart dis-ease and a host of immune disorderssuch as arthritis.

“Building models requires not onlybiologists, but mathematicians, physi-cists and computer programmers aswell,” said Sejnowski, who was trainedas a theoretical physicist at Princeton.

“One of the hottest new areas ofresearch is computational biology, atthe intersection between computer science and biology. The next genera-tion of students who will be doingexperiments that involve looking at theentire genome and proteome will needto be as adept with using computermodels as they are with carrying outexperiments.” –By Suzanne Clancy

Computer-generated models of “messenger” molecules traveling from nerve to muscle.

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For most of us, gazingthrough a kaleidoscope orglancing in a fun housemirror is an amusing diver-sion. But suppose you were

forced to view the world permanentlyin a disorganized or distorted fashion?

Such is the plight of those affectedby perceptual disorders. Individualswith Balint's syndrome, for example,look out at the world around them inthe fractured manner produced bykaleidoscopes. Those suffering fromvisual prosopagnosia cannot distin-guish one person's face from another’s.

“These conditions are extremelydebilitating, as you can imagine,” saidSalk Assistant Professor John H.Reynolds, the newest faculty recruit inthe Systems Neurobiology Laboratory.

“They make it pretty much impossibleto function normally.”

And like more common perceptualdisorders such as dyslexia, the prob-lems appear to lie not in the eyes, butin the brains of these individuals —particularly in how their brainsprocess visual information.

“We really know very little abouthow objects are represented in thebrain,” said Reynolds. Since joiningthe Salk Institute in 2000, Reynoldsand his growing laboratory have beensetting up tests designed to probeideas about how the human brain rec-ognizes objects and focuses attention.They hope that understanding the mol-ecular and cellular bases of thesebrain functions will aid the design oftherapies for perceptual disorders.

KaleidoscopicEyesAssistant Professor J O H N H . R E Y N O L D S is working

to understand visual perception. His work couldprovide insight into such disorders as schizophrenia,

attention deficit disorder and autism.

L O O K I N G T H R O U G H

Reynolds finds modeling — usingmathematics or computers to simulatethe brain’s workings — to be especiallyimportant to his research progress.

“My own taste has tended towardsimple models that give you alterna-tives that can be tested in straightfor-ward experiments,” he said. Using thisapproach, his team recently uncovereda basic mechanism that appears togovern how we focus attention at thelevel of individual brain cells.

It turns out that when we pay atten-tion to a particular location in space,our brains can detect things that wouldotherwise be invisible. That is, a spot inthe lower right corner of a page mightbe too dim for us to notice if we areconcentrating on the upper left corner.But once we turn our attention to the

lower right, the spot becomes visible. “Many competing theories existed

about this phenomenon,” saidReynolds. “Earlier work had pointedto the importance of precise timing.With our collaborators at the NationalInstitutes of Health, we were able toshow that when an animal focusesattention on an area, the brain cellsresponsible for that area become syn-chronized. They begin to fire in uni-son, and this makes the signal theysend stand out, like coordinated clap-ping in a stadium.”

Reynolds and his group hope thatthis new understanding may leadtoward ways to cope with disorderssuch as autism and attention deficit dis-order, which are characterized by prob-lems with focusing or shifting attention.

But, in order to gain a more com-plete understanding of the brain,researchers will need to learn howcells in many brain areas worktogether. The presence of a leadingteam of computational biologistswas a key factor in attractingReynolds to take a position at theSalk Institute.

“Terry [Sejnowski] was definitelya draw,” he said. “His lab can buildmodels that are biophysically realis-tic, involving different cell types,different patterns of connections.

“Modeling doesn’t necessarilygive you the truth,” he added. “Butit can help you eliminate ideas youmight have thought were true, so wecan avoid wasting our time on deadends.” –By Suzanne Clancy

S I G N A L S / S U M M E R 2 0 0 2 21

Thanks to Frederick B. Rentschler

Everyone associated with Salk owes a tremendous debt of gratitude to Frederick B.Rentschler for his many years of service and dedication to the Institute. Rentschlerwill step down as chair to become co-vice chair. Rentschler brought to the Salkextensive leadership experience from the corporate world, having served as the former president and chief executive officer of the Beatrice Companies, as well asexecutive vice president of BCI Holdings Corporation. He was a captain in the U.S.Marine Corps in the 60s and served as deputy director of the White House FellowsProgram in the 70s.

Rentschler joined Salk’s board of trustees in 1988 and became chairman of theboard in November 1995. During his tenure as chair, the Institute completed a25,000-square-foot specialized research facility. Rentschler also created an endowed

chair for young and promising scientists at the Institute. Perhaps most importantly, he presided overthe planning for the Institute’s future success, which reviewed how Salk got to where it is today andwhat the Institute needs to build for tomorrow’s challenges.

When asked to assume everyday leadership of the Institute in 1999, Rentschler became Salk’schief executive officer, serving until October 2000. Few have contributed so much of their time, talentand resources. For all three, the Salk Institute is deeply grateful.

New Chairman

Jerry Kohlberg, a longtimesupporter and member of theSalk Institute Board of Trustees,was named chairman of theboard, effective April 16, 2002.Kohlberg replaces Frederick B.Rentschler, who served as chairfor six-and-one-half years and willbecome co-vice chair of the boardwith Marc Stern (see below).

Since joining the Salk boardin 1997, Kohlberg has been akey advisor in the governanceof the Institute. In 1999, he waschairman of the presidentialsearch committee and, in addi-tion, he launched a challengecampaign, providing endow-ment money that was matchedby the other trustees.

Kohlberg brings to the positionof chair a vast range of leadershipexperience. Long known as oneof the nation's investment andfinancial leaders, Kohlberg wasfrom 1976 to 1987 the seniorfounding partner of the investmentfirm Kohlberg Kravis Roberts &Co. (KKR), as well as foundingpartner with his son of Kohlbergand Company. Before foundingKKR, he was a senior partner andmember of the executive commit-tee at Bear, Stearns & Company.In addition to the Salk board,Kohlberg is an emeritus mem-ber of the Board of Managersof Swarthmore College.

He and his wife, Nancy, areactive in a number of philan-thropic activities, including environmental causes and

22 S I G N A L S / S U M M E R 2 0 0 2

S A L K N E W S campaign finance reform, persuading the House, Senate,and President of the UnitedStates to institute new lawsrestricting the amount of “softmoney” that can be contributedto candidates running for office.

Appointments

Two new trustees wereappointed to the Salk boardduring its New York meeting inApril. They are:● Howard H. Newman, vicechairman and partner of NewYork-based Warburg PincusLLC, a partner-owned invest-ment firm with holdings in morethan 180 companies in Northand South America, Asia andEurope.

Newman has been employedin several roles by WarburgPincus since 1984, includingmanaging director, vice presidentand associate. From 1974 to1983, he held various positionswith Morgan Stanley & Co., Inc.

He serves as a director forseveral public companies,including ADVO, Inc.; DimeBancorp, Inc.; EncoreAcquisition Company; SpinnakerExploration, Inc.; Cox InsuranceHoldings, Plc.; EEX Corporation;and Newfield ExplorationCompany. He also is vice chair-man of the Yale Alumni Fund.

Newman earned bachelor’sand master's degrees in eco-nomics from Yale and a Ph.D. inbusiness-economics fromHarvard University. He also wasa Marshall Scholar in economicsresearch at Cambridge University.

Frederick B. Rentschler

Jerry Kohlberg

Howard H. Newman

S I G N A L S / S U M M E R 2 0 0 2 23

● Darlene Marcos Shiley,Darlene Marcos Shiley, a well-known San Diego philanthropist.

Many San Diego organiza-tions are the beneficiaries ofthe time and support providedby Shiley and her husband,Donald. These include theShiley Eye Center at UCSD, theShiley Sports and HealthCenter at Scripps Clinic, andthe Shiley Theater at theUniversity of San Diego (USD),in addition to KPBS-TV, the OldGlobe Theater, and grants tothe Salk Institute and UCSD forAlzheimer’s research. TheShileys have endowed scholar-

New Salk Logo Unveiled

The identity initiative that will become part of the strategic communi-cations plan for the upcoming capital campaign was approved bythe Salk Institute Board of Trustees during its New York meeting inApril. Both words and graphics, created by the Scott ThornleyGroup of Toronto, Canada, are designed to help Salk delineate coremessages that will establish in the public’s mind the importance ofthe Institute’s research and mission.

The initiative was undertaken with the guidance of the Institute’smarketing and communications committee, consisting of represen-tatives from faculty, staff and leadership.

“Where Cures Begin,” the Institute’s public message, conveys thatthe treatments, devices and cures known to medicine — today andin the future — have their origins in the kind of basic research doneby our scientists. It’s a message we want the public to readily recog-nize and understand as inherent to the Salk Institute.

The logo is a simple and stylized version of our original LouisKahn-designed architecture, which over the years has receivedinternational acclaim from architects and others. We’ll be using thisnew mark on Institute stationery, cards, invitations, publications andother related material.

ships and fellowships at severalinstitutions.

Shiley also has served on theboard of ScrippsHealth, is alongtime member of the USD

Board of Trustees, and hasbeen active with the UCSDBoard of Overseers and theKPBS Community AdvisoryBoard. She was elected to theDowntown Project AreaCommittee and appointed bythe mayor to the Commissionfor Arts and Culture.

A former television promo-tion/public relations director,she is the recipient of manyhonors and awards, includingthe San Diego Press ClubCommunity Activist-Headlinerof the Year, KPBS Woman ofthe Year and DevelopmentVolunteer of the Year byNational Society of FundRaising Executives (NSFRE).She is also co-winner, withDonald Shiley, of the UCSDDistinguished Service Medal,1998 Human Unity Award fromthe National Conference forCommunity and Justice,Philanthropists of the Year byNSFRE and the USDPresidents Award.

AWARDS/HONORS

Sydney Brenner was namedthe co-recipient of the 2002March of Dimes Prize inDevelopmental Biology. Theprize is awarded each year tooutstanding scientists whohave made exceptional findingsin the field of birth defects pre-vention. Brenner was honoredfor his “tremendously influential”body of work that has helped

revolutionize and open up newfields of study in molecular biol-ogy and genetics. Brenner alsowas named the first recipient ofthe Dan David Prize, an interna-tional prize awarded to peopleor institutions whose innovativeand interdisciplinary work hasan impact on one of three timeperiods. He was awarded thishonor for his impact on thefuture.

Joseph R. Ecker was nameda co-recipient of KumboScience International Award.He was cited for his leadershipin completing the sequence forthe first plant genome,Arabidopsis.

Fred H. Gage was named the co-recipient of the 2001Award for Medical Research in Alzheimer’s Disease. Gagewas honored for “pioneeringachievements” that have led toa new understanding of thedevelopment of nerve tissue inadults and the potential use ofneural stem cells to reverse theeffects of neurodegenerativediseases, such as Alzheimer’s.Gage also was named the Viand John Adler Professor in theLaboratory of Genetics andwas elected to the Institute ofMedicine, a branch of theNational Academy of Sciences.

Darlene Marcos Shiley

24 S I G N A L S / S U M M E R 2 0 0 2

SALK NEWS

Stephen F. Heinemann waselected to the Institute ofMedicine, a branch of theNational Academy of Sciences.

Tony Hunter received the KeioMedical Sciences Prize for hisfundamental research into themolecular basis for cellulargrowth and cell cycle regulation.The award is given each year toa researcher or researchers“whose achievement is creativeand distinguished, and has con-tributed to the advancement oflife sciences related to medi-cine.” Hunter also was invited topresent a talk during the NobelJubilee Symposium. To beinvited to speak on such anoccasion is a special honor,reflecting the high esteem inwhich Hunter is held by hispeers.

Jan Karlseder has beennamed a V Foundation Scholar,awarded by The V Foundationfor Cancer Research. The VFoundation, founded by ESPNand former college basketballcoach Jim Valvano, is a chari-table organization dedicated tosaving lives by helping to find acure for cancer. More specifi-cally, The V Foundation seeksout promising young scientistsfrom the finest research facili-ties across the country whoneed early developmental, criti-cal-stage grant support.

John H. Reynolds was nameda McKnight NeuroscienceScholar, given to young neuro-scientists in the early stages of their research careers.Reynolds also was awardedthe Fred Rentschler Chair,which supports young facultymembers establishing theirlabs at the Institute. And hewas selected to receive anAlfred P. Sloan ResearchFellowship.

Charles F. Stevens wasnamed The Vincent J. CoatesChair, given to supportresearch in “molecular neurobi-ology aimed at elucidating thechemistry of the brain.”

An endowed lecture at Salkhas been created in the nameof Marguerite Vogt. Vogt,who turned 89 years of age,was named among 33 “R&DStars to Watch” in theDecember 2001/January 2002Industry Week magazine.

Detlef Weigel received theCharles Albert Shull Awardfrom the American Society ofPlant Biologists. The prize isgiven in odd-numbered yearsto outstanding investigators inthe field of plant physiologyresiding in North Americaunder the age of 40.

John Henry FelixHonored

A dinner honoring retiringboard member John HenryFelix was held at the Sky Clubin the MetLife Building in NewYork City during the April boardmeeting. A trustee of theInstitute since 1989, JohnHenry served in various capaci-ties at the Institute, providingleadership and guidance aschairman emeritus, vice chair-man and chairman of the exec-utive committee, and chairmanof the development committee. He continues in a leadershipcapacity for the Salk InstituteInternational Council.

John Henry Felix

International Council

More than 40 attended theannual Salk InstituteInternational Council Meeting,held in May at the SalkInstitute. The distinguishedInternational Council members,leaders in their respectiveendeavors, attended seminarsby Salk faculty, toured the SalkInstitute laboratories andenjoyed the hospitality ofPresident and CEO Richard A.Murphy and his wife Elaine.Among others, DistinguishedProfessor Francis H.C. Crick,Professors Fred H. Gage andInder M. Verma spoke on con-sciousness, stem cells and diabetes, respectively. Nobellaureate and DistinguishedProfessor Renato Dulbecco,along with Professor SuzanneBourgeois, updated the councilon advances in cancer.

The council has played a keyrole in attracting private sup-port to the Institute since itsformation 25 years ago. Themembers, who represent awide range of interests, includ-ing business, law and the arts,have been highly successful inraising awareness of theInstitute’s work throughout theworld.

DEVELOPMENT NEWS

Renato Dulbecco — in addi-tion to several others previouslyassociated with Salk, includingDavid Baltimore and RobertHolley.

The sale and housing of FrancisH.C. Crick’s scientific papers inLondon and La Jolla garneredinternational attention in theLondon Daily Telegraph, LondonTimes and The San DiegoUnion-Tribune, among others.

The deciphering of the genomeof the puffer fish Fugu rubripesby an international researchteam brought recognition toSydney Brenner, who morethan a decade ago argued forsequencing this species’genome. Stories about theresults were carried in The NewYork Times, CNN and ScienceNews, among others.

Fred H. Gage’s discoveryabout neurogenesis in the adulthuman brain was highlighted inthe November 2 issue ofScience in an article about“Neuroscience: Unraveling andRepairing the Human Brain.”The article said that Gage’sfindings “remodeled a signifi-cant portion of the foundationof neuroscience. In fact, manyneuroscientists considered thediscovery of neurogenesis inadult humans to be the discov-ery of the decade, and perhapsbeyond.”

Suggestions that the lack ofnew brain cell growth mighttrigger depression, which

SALK IN THE NEWS

A front-page feature in theNovember 10 issue of The SanDiego Union-Tribune discussedreasons why many considerSan Diego a powerhouse in theneurosciences. Salk scientistsquoted or mentioned in thearticle included Fred H. Gage,Stephen F. Heinemann,Francis H.C. Crick, RogerGuillemin, Charles F.Stevens and Terrence J.Sejnowski. Gage andHeinemann were recentlyelected to the Institute ofMedicine, which was noted inthe Oct. 16 issue of the SanDiego Daily Transcript.

Ursula Bellugi’s studies onWilliams Syndrome, the oft-puzzling genetic disorder, werefeatured in Scientific AmericanFrontiers with Alan Alda. ThePBS broadcast aired nation-wide Wednesday, November14 and Sunday, November 18.Bellugi has been searching forthe underlying neurobiologicalbasis for this disorder, whichleaves language, facial recogni-tion and social skills remarkablywell-preserved, in contrast tosevere inadequacy in othercognitive aptitudes.

An article in the December 4issue of the Los Angeles Timesmagazine on the Nobel Prizehighlighted Salk’s three currentNobelists — Francis H.C.Crick, Roger Guillemin and

S I G N A L S / S U M M E R 2 0 0 2 25

sprung from Gage’s research,were highlighted in an article inthe National Post in Toronto.Other research conducted byGage and Henriette vanPraag, showing that runningcould spur growth of new braincells, was covered in theNovember 25 issue of TheChicago Tribune.

The continuing saga of theaging brain and how exercisemight stimulate the growth ofnew neurons, research con-ducted by Gage’s lab, was fea-tured in an article carried by theLos Angeles Times Syndicateand in separate items inNewsday and the Air ForceTimes. Gage’s most recentstudy offering proof that newlyborn cells in the adult brain func-tion just like any of their neigh-bors was reported in The SanDiego Union-Tribune, ScientificAmerican, Wired, Reuter’sHealthcare, Investor’s BusinessDaily and the La Jolla Light.

The debate over the merits andethics of stem cell researchresulted in a series of articles inthe December 18 science sec-tion of The New York Times. Inone article, Fred H. Gage — apioneer in the field of neuronalstem cells — mentioned thatthe brain generates an esti-mated 2,000 new neurons aday, running the gamut fromplace and face recognition tosense of smell. Inder M.Verma was featured in the

Sydney Brenner

Ronald M. Evans

Charles F. Stevens

26 S I G N A L S / S U M M E R 2 0 0 2

SALK NEWS

December issue of ScientificAmerican. Verma was quotedas saying “there will be a ‘hueand cry’ for the federal govern-ment to fund studies of newlygenerated stem cells if animalstudies using the currentlyavailable stem cell lines showpromise.” Another controversyover congressional bills thatwould ban all human cloning,including therapeutic cloning,was discussed by Verma in anop-ed article in the April 19issue of The San Diego Union-Tribune. Inder spelled out thedifferences between reproduc-tive cloning and therapeuticcloning, saying that no scientistwas in favor of the former, butthat most all scientists and sci-entific organizations hadendorsed therapeutic cloning.

Studies by Ronald M. Evansshowing a link between VitaminA and learning were carriednationally over ABC affiliates inseveral major cities throughoutthe country.

Another study, showing therelationship between runningand brain function, was also car-ried on ABC affiliates. Henriettevan Pragg was featured inthese latter presentations.

And an article on the frontpage of the October 10 issueof the La Jolla Village News,featuring research by CarroleeBarlow, discussed how runningmay help slow the progressionof neurodegenerative disorders.

A feature on the many factorsthat control memory, publishedin the November issue of theSouthwest Airlines Spirit maga-zine, quoted Charles F.Stevens about the value of for-getfulness, simply because ourbrains can’t store everythingwe’ve learned throughout ourlives. One estimate tells us alifetime’s worth of memoriesamounts to roughly 500 timesthe information stored in theLibrary of Congress.

From France, a profile onLeslie E. Orgel appeared inthe October issue of Science etVie, and a history of Nobelistswho contributed to cell biologybreakthroughs, reported in theOctober issue of La RechercheMedicale, included a segmenton Francis H. C. Crick.

The Chicago Tribune askedTerrence J. Sejnowski aboutnew research suggesting thatnear-death images and otherhallucinations involving geo-metric patterns are really there— on the inside of the brain.Peter Thomas, one of theUniversity of Chicago scientistswho conducted the work,involving mathematical modelsof the internal circuitry of thebrain’s visual system, has sincejoined Sejnowski’s lab at Salk.

Other scientists in Sejnowski’slab also have received recentmedia recognition. ScottMakeig, a senior scientist andlead author of a paper thatappeared in the January 24issue of Science, reported thatthe brain works in a far moredynamic fashion than previ-

ously thought. The results areopening new avenues toexplore certain brain dysfunc-tions, including schizophreniaand autism.

A computational model ofhovering behavior, developedby postdoc Martina Wicklein,was the subject of a feature inthe February 5 issue of TheSan Diego Union-Tribune.Wicklein is developing modelsof the visual system of hawk-moths who, like hummingbirds, hover in front of flowerswhile imbibing nectar. Asidefrom acquiring a basic under-standing of this behavior, suchknowledge might be used oneday by engineers to helpimprove highway safety, warn-ing drivers of a potential crashor for “smart cruise-controlsystems.”

Salk Nobelist RenatoDulbecco’s contributions tothe betterment of city life in SanDiego were mentioned bycolumnist Neil Morgan in theJanuary 23 issue of The SanDiego Union-Tribune. Morgannoted that Dulbecco is the onlylaureate known to have trainedfive other Nobel Prize winners.

Sydney Brenner was profiledin the March 18 cover story ofThe Scientist that featured aseries of articles by friends andcolleagues to commemoratehis 75th birthday. Called “oneof the most inventive and influ-ential scientists of his genera-tion,” Brenner’s life in science

was sketched out by suchluminaries as Paul Berg,Roger Brent, JonathanHodgkin, Horace Judson,Jonathan Karn, Chris Tanand Philip Tobias, in additionto Salk’s Francis H.C. Crickand Leslie E. Orgel. An articlein the same issue of TheScientist discussed the Fugugenome project and its rele-vance to understanding thehuman genome. Fugu, the formal name for pufferfish,offers a compact version of the human genome, packingessentially the same informa-tion into one-eighth the DNA.The idea to use Fugu DNAsequences to probe the humangenome came from Brenner.

The probable link between thebreast cancer drug Herceptinand cardiac failure, one of itscommon side effects, wasidentified by a team led byKuo-Fen Lee and reported inthe April 30 issue of the journalNature Medicine. The resultsmay also explain why a com-mon combination drug regimenincluding Herceptin is particu-larly toxic.

Studies in Joanne Chory’s labsuggesting a future with geneti-cally engineered grass thatstayed short, reducing mowingtime, was featured in an articlecarried over the NewhouseNews Service and the TorontoSunday Star.

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Symphony at Salk

Enjoy an evening of enchant-ment and music at the annualSymphony at Salk: AConcert Under the Stars.Reserve your seat early for this stunning event, to be heldthis year Saturday, August 24.The musical program will beperformed by the San DiegoSymphony, with baritone Kevin Deas and soprano Indira Mahajan. Preconcerttours and box suppers will be available. For reservationsor further information contact us at(858) 453-4100, ext. 1200.