Berkeley Science Review - Spring 2003

B E R K E L E YsciencereviewSpring 2003 Vol.3 no. 1

BERKELEYsciencereview

EDITOR–IN–CHIEF

Colin McCormick

MANAGING EDITOR

Jessica Palmer

COPY EDITOR

Kira O’Day

EDITORS

Delphine FarmerKira O’Day

Sherry Seethaler

ART DIRECTOR

Una Ren

ART

Jessica Palmer

WEBMASTER

Tony Le

SPECIAL THANKS

Marcia BarinagaJennifer Kahn

PRINTER

UC Press

©2003 Berkeley Science Review. No part of this publication may be reproduced, stored, or transmitted in any form without express permission of the publishers. Publishedwith financial assistance from the College of Letters and Science at UC Berkeley, the UC Berkeley Graduate Assembly, the Associated Students of the University of California,and the UC Berkeley College of Natural Resources. Berkeley Science Review is not an official publication of the University of California, Berkeley, or the ASUC. The content in thispublication does not necessarily reflect the views of the University or ASUC. Letters to the editor and story proposals are encouraged and should be e-mailed [email protected] or posted to Berkeley Science Review, 10 Eshleman Hall, Berkeley, CA 94720.Advertisers, contact [email protected] or visit http://sciencereview.berkeley.edu.

Dear Readers,

Berkeley is an amazing place for science. From the labs and offices on campus to the halls of theLawrence Berkeley National Lab, so much world-class research happens here that it takes yourbreath away. But even those of us who are full-time science graduate students see only a smallpart of it. For all the hours we put into our work, we often don’t have a clue about excitingdiscoveries happening across campus—or in the room next door.

Enter the BSR. When we were founded in 2000, our goal was to bring the best of Berkeleyscience to the campus public, in a clear, engaging way. Eran Karmon, one of our founders andour first Editor-in-Chief, particularly articulated this aim, and worked tirelessly to bring theidea of a popular science journal, dreamed up by a handful of graduate students, to a colorful,solid reality.

Tragically, Eran died this Spring. We all mourn his passing, and we will miss his energy anddedication. But we are proud to be carrying on his vision of an incisive, well-written journalabout Berkeley science. This, our fourth issue of the Berkeley Science Review, firmly establishes usas a twice-yearly, full-color publication, committed to bringing you the best of Cal science,science policy and science-related work. We are a magazine for the curious: from Karen Levy’supdates on lobster sniffing, to Dan Roche’s overview of Bay Area biotech, to Julie Walters’feature story on the discovery of extrasolar planets, the BSR has got it covered. Let us know howwe’re doing, at [email protected].

Like Eran, we are all interested in science writing and science communication. If that’s who youare too, let us know—we’re always looking for new editors, writers and layout staff. And ourefforts aren’t limited to the print magazine. All issues of the BSR are available online, atsciencereview.berkeley.edu. You’ll also find information there about our ongoing seminar series byprofessional science writers and journalists, sharing their thoughts on careers and opportunitiesin the world of science communication. Most recently we hosted Science correspondent MarciaBarinaga, and we’ll soon be hearing from the SF Chronicle’s science writer, Keay Davidson.

Science is about exploration, and science writing is about communication, two of the greatesthuman endeavors there are. Like I said, we are a magazine for the curious. So go ahead, turn thepage and learn something. The BSR: because Cal science is great.

Cheers,

Colin McCormick

We dedicate this issue to the memory of our cofounderand first Editor-in-Chief, Eran Karmon.

Features

BERKELEYsciencereview

Arteries revoltagainst a

sedentary lifestyle.

18 The Hapless Heart

By Sherry Seethaler

By Julie Walters

28 Strange New Worlds

The pull ofdistantplanets.

DepartmentsBSR Vol. 3 no. 1

38 The Maverick Scientist

Counterpoint

One of Berkeley’s mostcontroversial professorstakes on cancer.

Perspective40 In the Face of Uncertainty

Could trips abroad bedraining our blood banks?

Current Briefs

On the cover: An interior view of the center of theGammasphere detector. Designed to bemovable, Gammasphere left LawrenceBerkeley National Lab in the Fall of 2002for its current home at Argonne NationalLab in Illinois. Watch for a model of it inThe Hulk this Summer!(Photo courtesy of LBNL.)

Read about it on page 7.

New research points to apossible cure.

8 Hitting Malaria Where It Hurts

7 GammasphereHigh-tech toys lure The Hulkto Berkeley.

Clique-ish electrons give in topeer pressure.

10 Superconducting Vinaigrette

Tasty lobsters smell good too. 11 Get a Whiff of This

Understanding learning at thecellular level.

13 What Pavlov Didn’t Know

Profile16 Connie Chang-Hasnain

Tunable lasers comeback to Cal.

4 Labscope

Defining the Structure of Water

Sparrow Mutations

Sticky Toes

6 Biotech BeatHigh points in Bay Area biotech

The Back PagePygmy octopi swing both ways

Death by Liquefaction

15 Quanta (heard on campus)

Labscope

Professor Teresa Head-Gordon of the Department of Bioengineering is settling a debate over the planet’s most importantliquid: water. For 30 years, this little molecule has been the subject of much controversy, as researchers have tried to deter-mine just how structured liquid water can be. Now, Head-Gordon and her coworkers have measured the molecular structureof water, using X-ray diffraction techniques, computational methods, and theoretical analyses. In a typical X-ray diffractionexperiment, a sample of a pure material is bombarded with high-energy light, and the resulting pattern of scattered X-rays isanalyzed for structural information. Head-Gordon’s latest experiments—employing state-of-the-art equipment at the LawrenceBerkeley National Laboratory’s Advanced Light Source and an exacting theoretical analysis—have shown that liquid water atroom temperature is more ordered than previous experiments have suggested, resolving the long-standing controversy overthe structure of this ubiquitous fluid. The group’s work will help elucidate how water influences the folding and stability ofproteins. This is of particular interest to Head-Gordon, whose lab focuses on modeling the structure and folding of large,complex protein molecules. Learn more at www.lbl.gov/~thg.

Temina Madon

Seen a familiar little bird poking about in the garbage cans on Sproul Plaza? Chances are it’s a house sparrow. NorthAmerican house sparrows, initially introduced from Europe in 1851, are a common sight in most urban areas. Historicallydocumented populations of house sparrows provide researchers with a great opportunity to tackle questions about evolu-tion within populations. Researchers at UC Berkeley’s Museum of Vertebrate Zoology are currently investigating sparrowevolution by isolating DNA from the feathers of 100-year-old museum specimens. The researchers then use computer-generated mutation models to predict, based on the sequence of the 100-year-old DNA, what sequences one would expectto find in present-day sparrow populations. They then compare the predicted sequences to DNA taken from present-dayhouse sparrows that live in the same location. In addition to answering basic questions about evolution, the research mayalso provide further insights into why the house sparrow has been such a successful colonizer. Learn more about theMuseum of Vertebrate Zoology at www.mip.berkeley.edu/mvz/.

Bill Monahan SPARROW MUTATIONS

BERKELEYs c i e n c e 4r e v i e w

DEFINING THE STRUCTURE OF WATER

“Death by liquefaction,” this caterpillar’s autopsy might conclude. A few days after eating from leaves peppered with baculovirusparticles, the caterpillar host develops a swollen, waxy appearance before finally collapsing into a puddle of goo. Baculoviruses, whichinfect only insects and other arthropods, can be seen through an ordinary light microscope, and are extremely environmentally hardy.Though the outcome is gruesome for the infected victims, baculoviruses are effective biocontrol agents. Susceptible insects includeagricultural pests such as the corn earworm, which is responsible for millions of dollars in agricultural losses each year. Researchersin the Volkman lab (Plant & Microbial Biology) are currently wading through the goo, studying baculovirus pathogenesis in severalspecies of caterpillars and mosquitoes. Learn more at www.mollie.berkeley.edu/~volkman.

Kira O’Day DEATH BY LIQUEFACTION

Ever wish you could run up the wall and across the ceiling like a gecko? If Berkeley professors Robert Full (Integrative Biology),Ronald Fearing (Electrical Engineering), and colleagues have their way, you might soon be able to. These researchers have finallydiscovered the sticky secrets of gecko toes and are working to develop adhesives based on the same principles. Geckos have500,000 tiny hairs on each foot, and at the end of each hair there are 100–1000 branches tipped with pads called spatulae. Thatworks out to a huge surface area of contact. Until recently, scientists didn’t know if gecko toes worked by relying on the surfacetension of the thin film of water that coats most surfaces or on van der Waals forces—weak attractions between molecules causedby electric polarizations. It turns out that geckos on special hydrophobic (water-repelling) surfaces boogie just as well as geckoson usual surfaces. Since geckos on hydrophobic surfaces could not rely on interactions with a “skin” of water, they must rely onvan der Waals forces. Using this knowledge, the researchers have developed materials with nanobumps—synthetic hair tips likethose on the geckos’ feet—that are super sticky too. Learn more at polypedal.berkeley.edu/.

Sherry Seethaler STICKY TOES

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Teresa Head-Gordon

Kira O’Day


BRIGHT SPOTS OF BAY AREA BIOTECHBiotech Beat

Richmond-based Sangamo BioSciences and Yale University have demon-strated that DNA-binding proteins called zinc finger proteins (ZFP) may beuseful in treating heart disease. Zinc finger proteins work by binding to aspecific DNA sequence and causing a nearby gene to become active, result-ing in the production of the protein encoded by that gene. Researchersused specially engineered ZFPs to cause more of a protein called VEGF A tobe produced. In mice, increasing the amount of VEGF A resulted in theappearance of new blood vessels, a process called angiogenesis. Accordingto Edward Lanphier, Sangamo’s president and chief executive officer, thedata provide “important evidence of the utility of our lead ZFP therapeuticprogram for treating coronary artery and peripheral arterial diseases.”

Gilead Sciences, located in Foster City, is the developer of the anti-HIVdrug tenofovir. Gilead Sciences will be supplying the drug to Family HealthInternational (Research Triangle Park, NC), which has been awarded a $6.5million grant by the Bill & Melinda Gates Foundation to study the safetyand efficacy of using tenofovir to prevent HIV infection. “It is imperativethat we not only strive to develop new drugs, but that we also considernew uses for existing ones, such as tenofovir, which has tremendous po-tential as a dual HIV treatment and prevention technology,” said Ward Cates,president of FHI”s Institute for Family Health. The study will evaluatetenofovir treatment as a method of reducing the risk of HIV infection insexually active adults who are regularly exposed to the virus. The drugworks by selectively blocking an enzyme involved in the replication of HIV.

Elan Pharmaceuticals (South San Francisco) and Biogen (Cambridge, MA)have reported promising clinical results for the drug natalizumab in thetreatment of patients with relapsing forms of multiple sclerosis (MS).Natalizumab is the first in a new class of drugs known as SAM (selectiveadhesion molecule) inhibitors. In MS, immune cells migrate through theblood-brain barrier into the brain, leading to inflammation and destruc-tion of the myelin sheath (the insulation for the nerves), and eventualnerve cell death. Adhesion molecules on the surface of the immune cellsplay an important role in the migration of these cells. Natalizumab bindsto a specific adhesion molecule on the immune cell, inhibiting immunecells from leaving the bloodstream and preventing them from migratinginto the brain or the inflamed gut tissue and worsening the disease condi-tion. The drug is currently in the Phase III stage of clinical trials.

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Dan Roche

Current Briefs


Not many pieces of physicsequipment make their wayonto the big screen, but that’s

what’s in store for the Gammaspheredetector next summer. Director AngLee decided to use a model of thethree-meter spherical detector in hismovie The Hulk as the location offictional scientist Bruce Banner’sgamma-ray-induced transformationinto a green goliath. Originally locatedat the 88-inch cyclotron at LawrenceBerkeley National Laboratory (LBNL),Gammasphere was designed to studygamma rays—high-frequency electro-magnetic radiation—emitted fromrapidly rotating nuclei.

With a cost of $20 million,Gammasphere serves as an experimentalfacility for a diverse group of users.During its nine-year history, researchersfrom almost 100 institutions around theworld have used Gammasphere toproduce nearly 400 technical publica-tions and 30 PhD theses. It has beenparticularly helpful to researchers atinstitutions that couldn’t afford to dothis type of research on their own. SaysPaul Fallon, leader of the NuclearStructure group at LBNL, “Smalluniversity groups have really benefited.They come, do their experiment, andthen go home and analyze the data.”

To produce the rapidly rotating nucleistudied in Gammasphere, ions are

first accelerated to high energiesinside a cyclotron. Invented byBerkeley Nobel Laureate ErnestLawrence, a cyclotron uses electricand magnetic fields to acceleratecharged particles and ions. Uponreaching the edge of the cyclotron,the ions, which can be anything fromhydrogen to uranium, are traveling atclose to 10% of the speed of light andare diverted into Gammasphere. Atthe center of the detector the ionsstrike a thin foil target, where aboutone in 100,000 collides and fuses withanother nucleus. The high-energyrotating nucleus produced by thisfusion emits neutrons, protons, and aburst of up to 30 gamma rays, all withinnanoseconds of the initial collision.

Inside Gammasphere, 110 germaniumdetectors have been arranged in a 10-inch-radius sphere around a foil target.

Unlike the electrons in a metal, whichcan move freely, the electrons ingermanium, a semiconductor, normallyremain confined. However, if they aregiven a large enough energy kick, as isthe case when a gamma ray strikes thegermanium, they can escape. A typicalgamma ray will liberate close to onemillion electrons. During an experi-ment, an electric field is applied to thegermanium, causing the free electronsto move and produce an electriccurrent. Since thermal energy can alsoexcite the electrons, the germaniumdetectors must be kept at extremelylow temperatures. This is achieved withliquid nitrogen, which must be addedto the detectors twice a day.

The gamma-ray emission from rapidlyrotating nuclei can reveal clues aboutthe structure of nuclei. AugustoMacchiavelli of LBNL gives thefollowing analogy: “To learn aboutatomic structure, you excite theelectrons in an atom and see the visiblelight that is emitted. To study nuclearstructure, you excite the protons andneutrons, but since the energies aremuch larger, you see gamma rays.” Oneof the major areas of interest forGammasphere is so-called super-deformed nuclei. These football-shapedrotating nuclei formed in the target ofGammasphere are only barely heldtogether by nuclear forces. As theyreturn to their more spherical normalstates, the super-deformed nuclei emita pattern of gamma rays. They providean excellent testing ground fortheoretical models of the nucleus. “Bystudying nuclei at the extremes ofmass, spin, and energy, you isolate and

GAMMASPHEREPutting a new spinon physics

An outside view of the assembled Gammaspheredetector. Designed to be movable, Gammasphereleft LBNL in the Fall of 2002 for its current home atArgonne National Lab in Illinois. Watch for a modelof it in The Hulk this Summer!(Photo courtesy of LBNL.)

amplify aspects of nuclear physics,” saysFallon. Experimenters recentlyobserved super-deformed 108Cd nuclei,believed to be the most elongatednuclei yet detected. They hope to findeven more highly deformed nuclei,known as “hyper-deformed,” which arepredicted to exist.

Though built to study nuclear struc-ture, Gammasphere is a versatiledetector and has been used for a varietyof applications in particle physics andastrophysics. One experiment used theisotope 54Mn as a clock to probe theage of cosmic rays in our galaxy.Cosmic rays are extremely high-energyparticles (normally nuclei) that areproduced in space. Many questionsremain about their origins, including

their age. Using a procedure analogousto carbon dating, the age of Mnarriving at the Earth in the form ofcosmic rays can be determined bycomparing the amounts of 54Mn to theother, more stable Mn isotopes in thecosmic rays. However, an accurateknowledge of the radioactive lifetimeof 54Mn is necessary for this technique.In space, 54Mn can only decay through avery rare mechanism, and the decayrate is difficult to determine. UsingGammasphere to search for thedistinctive dual gamma-ray signature ofsuch a decay, the decay rate—and thusthe lifetime—of 54Mn in space has beendetermined, yielding an average age ofroughly 15 million years for the cosmicrays in our galaxy.

Alysia Marino

Want to know more?

www-gam.lbl.gov/


The Gammasphere assembly wasdesigned to move between severaldifferent facilities, though Fallonstresses that it is “movable, not portable.”The entire process of dismantling,shipping, and reassembling the detectortakes four months. In the Fall of 2002, itwas moved to Argonne National Labora-tory in Illinois. But don’t worry; you cancatch it in The Hulk next Summer.

HITTING MALARIA WHERE IT HURTSNew weapons against an old enemy

Malaria kills close to twomillion people each year, themajority of them infants and

children in the developing world.Although treatment for malaria iseffective in most cases, the rise ofdrug-resistant strains is leadingresearchers to search for new ways oftreating the disease. Michael Marletta,a professor in the departments ofChemistry and Molecular and CellBiology at UC Berkeley, has identifiednovel molecules that effectively blockan important step in malaria diseaseprogression. In the process, he and hisstudents have uncovered a uniquebiochemical pathway.

Malaria is caused by infection withparasites in the genus Plasmodium.

Plasmodium parasites are carried byfemale Anopheles mosquitoes. When ahuman is bitten by an Anopheles

mosquito, the malarial parasites in themosquito’s saliva enter the bloodstreamand travel to the liver, where theyreproduce in the liver cells. Eventually,these cells burst, releasing parasitesthat subsequently infect red blood cellsand degrade hemoglobin, the iron-containing protein that carries oxygenthroughout the body. The resulting ironand oxygen deficiencies lead to anemia,chills, and fever. The most severecomplication comes from the blockage

of cerebral blood vessels by infectedcells, which cuts off oxygen to thebrain and causes death in two to threedays. When the Plasmodium-rich bloodof a malaria victim is drawn by anothermosquito, the parasitic life cycle iscomplete, and the disease is spread.

Most treatments for malaria arethought to target the hemoglobin-degradation pathway of Plasmodium.Hemoglobin is comprised of theprotein globin and four molecules ofheme, an iron-containing molecule that isthe site of oxygen transport. Plasmodium

parasites cleave hemoglobin to separateheme from globin. The globin is thenfurther degraded into amino acids thatare used by the parasite for its own

Current Briefs

proteins. What happens to heme is amore complex story. Free heme istoxic to cells due to the high reactivityof the iron. For that reason, humanbodies bury heme deep withinhemoglobin, where it can only reactwith oxygen. Yet Plasmodium areregularly exposed to toxic heme. Thequestion that the Marletta lab is tryingto answer is how the parasite can dothis and survive.

Research in the lab suggests that aprotein expressed by Plasmodium,

histidine-rich protein 2 (HRP-2),binds to free heme and prevents itfrom damaging the organism. HRP-2binds multiple molecules of heme andcoordinates the formation ofhemozoin, the final nontoxic heme-containing protein. According toMarletta, targeting HRP-2 is a goodway to attack Plasmodium. “The pathwayis unique to the parasite and it isessential. We can look at ways to targetthe parasite while not interfering withhuman heme metabolism.”

Eric Schneider, a graduate student inthe Marletta lab, collaborated with thelaboratory of Jonathan Ellman in thedepartment of Chemistry to search forcompounds that inhibit heme detoxifi-cation by HRP-2. Using as a startingpoint an antimalarial drug that hadtoxic side effects, the researchers madechemical modifications and tested theability of HRP-2 to bind heme. Todetermine heme binding to HRP-2, theresearchers used a spectrophotometricassay that took advantage of the factthat heme bound to HRP-2 absorbedlight differently from free heme. By

adding various chemicals to a mixtureof HRP-2 and heme, and tracking thelevel of light absorbance, Schneider andhis colleagues were able to identifyinhibitory molecules. These inhibitorswere then tested for their ability to killPlasmodium in vitro. The lab found thatchemicals that blocked heme binding toHRP-2 also killed the parasite. Impor-tantly, the drugs worked as well withdrug-resistant strains as with non-resistant strains. Taken together, theexperiments offer a possible target fornew antimalarial drugs.

The exact mechanism of action of theidentified drugs is still unknown. Thedrugs could bind HRP-2 and prevent itfrom binding heme, bind heme directly,or form a three-way complex thatprevents HRP-2 from forminghemozoin. Marletta and others involvedin the project, including graduatestudents Henry Chang and Hans

Carlson and postdocs Jacquin Niles andElizabeth Boon, are working to piecetogether the biochemical puzzle. Theirdata reveal a molecule with an unprec-edented heme-binding efficiency. HRP-2can bind 15 molecules of heme;hemoglobin, twice the size of HRP-2,only binds four. The structural changesthat HRP-2 undergoes to accomplishthis feat are similarly unique. In theabsence of heme, the HRP-2 moleculesare randomly structured. In the presenceof heme, each HRP-2 molecule becomesstructured and binds to another moleculeof HRP-2, forming a two-moleculecomplex, or dimer. Among the questionsthat the Marletta lab is trying to answeris how HRP-2 structurally alters itself toallow such a high level of heme binding,and how this restructuring allows for theformation of dimers.

For Marletta, fighting malaria andunderstanding the biochemistry ofPlasmodium are the dual goals of theproject. “Usually we start with aninteresting biochemical question, andfind an application to human health. Inthe case of malaria, we did the opposite.We wanted to find drugs that couldtarget the disease, and we stumbled intoa complex biochemical story.”

Infected red blood cells bursting open and releas-ing Plasmodium parasites.(Photo courtesy of Michael Marletta.)

Adam Schindler

Want to know more?

Interference with Heme Binding toHistidine-Rich Protein-2 as an An-timalarial Strategy. Clara YH Choiet al., Chemistry & Biology Vol. 9,pages 881–889.

www.cchem.berke ley.edu/~mmargrp/


Physicists at UC Berkeleyworking with so-called “hightemperature” superconductors

have mapped out a radically new pictureof the behavior of electrons in solids—abehavior that appears to resemble that ofan oil-and-vinegar salad dressing. Thiselectron vinaigrette may be a keyingredient in understanding a field thatBerkeley physicist Joe Orenstein hasdescribed as lingering in the stomach “likean indigestible dinner at a roadside café.”

Fifteen years and some 100,000scientific papers after the discovery ofhigh-temperature superconductors,most of their predicted applications,such as loss-free transmission ofelectrical power and magneticallylevitated trains, have yet to materialize.Instead, these materials have issued onechallenge after another to physicists’most successful theories of the quan-tum-mechanical behavior of electronsin solids. Now, JC (Seamus) Davis andhis collaborators in the Physics Depart-ment have used a technique calledscanning tunneling microscopy (STM)to take pictures of the electrons insuperconductors with resolution betterthan the size of a single atom. Thepictures reveal regions of two distincttypes of electronic behavior, or“phases,” which separate themselvesfrom each other like the regions of oiland vinegar in a salad dressing.

SUPERCONDUCTING VINAIGRETTEPhysicists find disorderwhere they least expect it

A “gap map” showing the width of the gap inthe spectrum of available electron energies, fortwo differently grown samples of BSCCO. Thefield of view is 560 Å by 560 Å. (Image copy-right Nature Publishing Group, 2001.)

A superconductor is a material,normally a metal, which loses allresistance to the flow of electriccurrents when cooled below a “critical”temperature (Tc). For an ordinarysuperconductor such as lead, Tc isaround -270°C, just a few degrees aboveabsolute zero. The high-temperaturesuperconductors derive their namefrom their comparatively warm Tc’s,which can be higher than -196°C, thetemperature of liquid nitrogen.Cooling an ordinary superconductorbelow Tc requires costly liquid helium,while liquid nitrogen is proverbially“cheaper than beer.” The high-temperature

superconductors’ best-kept and mosttechnologically tempting secret is whytheir Tc’s are so warm.

In Davis’ experiments, a tiny sample of thesuperconductor BSCCO (Bi2Sr2CaCu2O8)is kept colder than its Tc of -194°C inan evacuated chamber deep inside theSTM apparatus. The bulk of themachine cools the sample and isolates itfrom vibrations, allowing a tiny,needle-like tip to scan back and forthacross the sample’s surface, taking overforty measurements per nanometer.

Quantum mechanics makes only certainenergies available to electrons in solids.It also allows that, under certainconditions, these electrons can form ahighly-organized, superconducting“quantum fluid” that conducts electricalcurrents without any resistance at all.The change from non-superconductingto superconducting behavior changes thespectrum of allowed energies, mostnotably by changing the width of a gapin this spectrum. Davis’ STM measuresthe spectrum of the possible energiesavailable to electrons at each point in thesample. Among the informationproduced is a map of the width of thegap at various positions in the sample.

The surprising result of Davis’ measure-ments is that the data show a clumpinginto regions of distinct gap widths.According to former UCB graduatestudent and coauthor Dr. Kristine Lang,this clumping indicates that electrons inthe superconductor “segregate” them-

Current Briefs


selves into two different phases, ortypes of behavior. Some parts of Davis’sample are certainly superconducting.Other parts less than two nanometersaway suggestively resemble the elec-trons’ behavior at temperatures aboveTc, i.e., when the electrons are nothighly organized and can conductelectricity only with resistance.

According to Dung-Hai Lee of UCBerkeley, Davis’ experiments may revealBSCCO as one of the only knownsystems, and the first known supercon-ductor, in which inhomogeneityspontaneously arises in an otherwisehomogeneous material. The coexistenceof superconducting and non-supercon-ducting regions had previously appeared

Chris Weber

Want to know more?

Microscopic electronic inhomogeneity in the high-Tc superconductorBi2Sr2CaCu2O8+x. SH Pan et al., Nature Vol. 413, pages 282–285.

www.ccmr.cornell.edu/~jcdavis/

only in “granular” materials—thosecomposed of discrete grains of supercon-ductor pressed together. The disorderwhere the grains meet is enormous.Davis’ materials also contain disorder, butonly to a very small degree. Why theelectrons form two different phases, andwhy the phases separate themselves intonanometer-sized patches, remainmysteries. But these new mysteries mayhelp in solving high-temperaturesuperconductivity’s longest-standing

unsolved problems: Why are the criticaltemperatures so high? And what do theelectrons do when they’re not busysuperconducting? Hopefully, Davis’pictures of the electrons’ oil-and-vinegarbehavior will clarify the natures of boththe oil and the vinegar, and thus makehigh-temperature superconductivity a bitmore palatable.

GET A WHIFF OF THISThe ups and downs of lobster sniffing

When the funk bandParliament becamefamous in the 1970s with

its hit “Up for the Downstroke,” theymight well have been describing the waythat lobsters smell. According to arecent study by UC Berkeley’s MimiKoehl (Intergrative Biology) and others,spiny lobsters “sniff ” the aromas in theirsurroundings with every downstroke oftheir antennules.

Koehl explains that lobster “noses,” morescientifically known as olfactory anten-nules, are the “busy little appendages atthe front of their heads.” Like our ownnostrils, lobsters’ smelling appendages arecovered with hairs. But unlike humannose hairs, which serve only to filter out

dirt and other unwanted particles, thesmall hairs that cover lobster antennulescontain hundreds of chemosensoryneurons that communicate directly withthe central nervous system. By flickingtheir antennules, lobsters can sample themolecules in their fluid surroundings.

The details of the lobsters’ funkymolecular sampling technique are beinginvestigated by Koehl and her diversegroup of collaborators from StanfordUniversity, Bowling Green StateUniversity, and University of Colorado.Using flumes, plumes, lasers, andmechanical lobsters, the researchersrecently described how lobsters detectthe molecules in their environment withquick downward strokes of their

antennules. The study, published inScience, provides insight into how manydifferent kinds of organisms detectchemicals, and may have some usefulapplications for humans.

To study where and when the lobsterantennules capture molecules of anodor plume, the researchers set up anexperimental flume apparatus atStanford’s Environmental FluidMechanics Lab that mimicked theturbulent water flow normally encoun-tered by lobsters in their habitats.When lobsters flick their antennules,they essentially sample just a thin sliceof the water in their environment. Inorder to approximate this slice, theteam shined a sheet of laser light acrossthe plane of the flume, and thenreleased a plume of fluorescent dye,which allowed them to visualize themovement of the molecules.


Current Briefs

Want to know more?

Lobster Sniffing: AntennuleDesign and Hydrodynamic Fil-tering of Information in anOdor Plume. MAR Koehl etal., Science Vol. 294, pages1948–1951.

ib.berkeley.edu/labs/koehl

Karen Levy

These structures are used in smelling,feeding, breathing, and moving, and allinteract with fluid.

In her research on the physics ofhow organisms interact with theirenvironments, Koehl has studiedmoths, lobsters, kelp, sea anemones,flying frogs, sea slug larvae, sea fans(soft coral), sponges, and otherorganisms—whatever critter seemsappropriate for the question at hand.“My question wasn’t ‘how dolobsters smell?’” she explained. “Myquestion was, ‘what are the basicprinciples of how the structure of anarray of hairs affects its performancein molecular capture?’”

The results of this basic research mayalso have an applied use. The Office ofNaval Research, which partially fundedthe study, believes that understandingthe biomechanics of lobster antennuleflicking might help them develop“olfactory robots” that could samplemine sites or other underwater areasof chemical contamination that arerisky for human scuba divers. Accord-ing to Koehl, “They hope to learn fromwhat we learn from real animals whoare very successful at finding odors inmarine environments.”

They had only one problem. “Wecouldn’t convince a real lobster to flickits antennule in exactly the same planeover and over again enough times to get alarge enough sample size,” said Koehl.Instead, they created a mechanical lobsterand modeled its antennule movementsafter that of a spiny lobster, using theactual antennule sheath from a lobsterspecimen—complete with hairs andchemo-receptors—for the experiment.

Their findings showed that a lobstermust flick its antennules very quickly inorder for water to pass through thearray of small hairs and reach thechemoreceptor cells. The antennulesonly reach the critical speed required totake a new water sample on the rapiddownstroke of the antennule, whichlasts approximately 100 milliseconds.During the slower upstroke return ofthe antennule, the water sample isretained between the chemosensoryhairs until the next downstroke. Thus,with each flick of an antennule thelobster “sniffs” its environment.

Plumes of molecules are often thoughtof as amorphous clouds dissipating intotheir fluid surroundings, but at finerscales the molecules swirl around infilaments like milk in a coffee mug.Koehl’s research demonstrates thatlobster antennules can in fact capturethe fine details of this pattern by“sniffing,” or taking discrete watersamples in space and time, on the fastdownstroke. But does this fine-scaleinformation help them find food? Avoidpredators? Find mates? Do they use itat all or do they just average theinformation over time? The lastquestion, at least, will be the subject ofa future collaborative study already inprogress with a team of neuroscientists.

These aromatic findings help elucidatethe mechanics of a structure seenrepeatedly in nature. According toKoehl, “If you look across the animalkingdom you see that many kinds oforganisms have appendages with rowsof tiny hairs on them that catchmolecules from the surrounding fluid.”


Antennule in action: a mechanical lobster attached to an actual lobster antennule sheath “sniffs”a fluorescent plume. (Photo courtesy of MAR Koehl, JR Koseff, MB Wiley, and G Wang.)

Neurobiologists have knownfor decades that cells in thebrain learn in a fashion that

is analogous to the behaviorallearning of animals. In fact, thegrowth and change of synapticconnections in the brain is strikinglysimilar to Pavlovian conditioning, inwhich a reaction to one stimulus,such as food, can become trans-ferred to another, such as the soundof a bell ringing. Now researchers inYang Dan’s lab in the department ofMolecular and Cell Biology at UCBerkeley are discovering just how farthis analogy extends—and howcritically it depends on timing—when many and more natural stimuliare presented to the brain.

Classical conditioning is a well-knownform of behavioral learning. Russianphysiologist Ivan Pavlov outlined therules of classical conditioning in his 1926monograph, Conditioned Reflexes, whichsummarized several decades of work.Pavlov began his physiological studies onthe control of digestion in dogs (workfor which he won the Nobel Prize in1904), but soon discovered that thesalivary reflex could be triggered byother, seemingly innocuous stimuli, suchas the ticking of a metronome or a lighttouch, when repeatedly presented withfood. Pavlov found that the developmentof these conditioned reflexes dependedon the precise timing of the presenta-

tion. In particular, if theconditioned stimulus (thesound) preceded the uncondi-tioned stimulus (food), thesalivary response evoked bythe sound was strengthened,but if the food came first, theresponse to the sound alonewas weakened, or entirelyfailed to develop. Thisphenomenon, now calledPavlovian or classical condi-tioning, has been studiedintensively for the pastcentury, but the underlyingbrain mechanisms are farfrom clear.

In recent decades, a cellularanalogy to classical condition-ing has been discovered in thesynaptic connections of thebrain. Investigations fromboth Bert Sakmann’s lab (atthe Max Planck Institute inHeidelberg, Germany) andMu-ming Poo’s lab (now here at UCBerkeley) found that the timing ofelectrical activity, called spikes, in apair of neurons controls the synapticstrength between them. If a presynapticneuron A fires before the postsynapticneuron B, the synapse between them isstrengthened, while if the postsynapticneuron fires first, the synapse isweakened. Because these synapticchanges can persist for hours or even

days, this phenomenon is called “long-term synaptic plasticity.” Poo andSakmann were among the first toemphasize the importance of precisespike timing, consistent with the earliertheoretical predictions of Donald Hebband Gunther Stent. This timing rule hasbeen dubbed “spike-timing-dependentsynaptic plasticity,” and it has fascinatedboth experimental and theoreticalneuroscientists for two reasons. First, it

1) A photomicrograph of neurons in a brain slice of the vi-sual cortex. Presynaptic cells are labeled A, while the postsyn-aptic cell recorded from is labeled B. If the presynaptic cellsA fire before the postsynaptic cell B, the synaptic responsegets larger. If the postsynaptic cell fires first, the responsegets smaller.

2) A frame from a movie. The two circles indicate which partof the movie is directly observed by the two cells A and B.(Photo courtesy of Rob Froemke.)

How patterns of activity alter the circuitry of the brain

WHAT PAVLOV DIDN’T KNOW


seems that the overwhelming majority ofcells in the brain obey a similar rule formodifying their synaptic strength; andsecond, it suggests that understandingcomplex modifications of braincircuitry can be reduced to theinteraction of just two spikes, one ineach neuron that forms the synapse.

These studies emphasized the impor-tance of precise timing of neural activityas a critical determinant of brainfunction. But how do these rules,behavioral and synaptic, operate undermore “natural” conditions of stimulationoutside of the controlled lab environ-ment? What happens at the behaviorallevel when multiple, conflicting stimuliare presented at different times? Theseminal studies of Konrad Lorenz and BFSkinner showed that the first occurrenceof a particular stimulus was the mostimportant in developing or modifying aconditioned behavioral reflex, and thatthis could result in so-called “imprint-ing.” At the synaptic level, neurons areusually quite active, displaying complexpatterns of spiking activity in response tonatural stimulation. What happens to asynapse under such a barrage of spikes?One possibility is that a given spike pairis just as effective as any other for

Robert C. Froemke

Want to know more?

Spike-timing-dependent syn-aptic modification induced bynatural spike trains. Robert CFroemke and Yang Dan,Nature Vol. 416, pages433–438.

impulse.berkeley.edu

changing the synaptic strength. Analternative is that the first spike pair in aseries is the most important, withdiminishing returns from subsequentspikes, by analogy with the developmentof imprinting in animals.

My colleagues and I in Yang Dan’s labset out to answer this question, inorder to quantify how patterns of spikeactivity change synaptic strength. Wefirst reproduced the results of Poo andSakmann for pairs of spikes in brainslices of the visual cortex. We used anelectrode to directly measure thestrength of synaptic input from a smallpopulation of presynaptic cells A ontothe postsynaptic cell B. We then askedhow more complex patterns of activitywould control synaptic modification.By increasing the number of spikes(from two to three, to four, and finallyup to about a dozen), we incrementallyconstructed a mathematical model oflong-term synaptic plasticity. Finally,we compared the model to the activitypatterns recorded in the intact brain,visually stimulated with a movie. Ourmodel successfully predicted theoverall change in synaptic strength.One important finding was that thefirst pair of spikes are in fact dominant

in determining both the sign andmagnitude of synaptic modification. Asin behavioral imprinting, the first eventis most important in determining theoverall change in response (whilefunctioning, however, on a vastlydifferent time scale—tens of millisecondsinstead of minutes to days). We haveused this modified spike timing-basedlearning rule to predict the effects ofcomplex activity patterns in the brain, asrecently published in the journal Nature.Our lab continues to study the conse-quences of this interesting learning ruleon visual perception.

Current Briefs


Got a great story?Write for the Review.Submission guidelines are at sciencereview.berkeley.edu

“[At the meeting, I said] if the Americans would be willing to collaborate, I’d be happyto change the name to JACK: Japan-American Collaboration on Kamiokande.”

Masatoshi Koshiba, U. of Tokyo,(Comments on the early days of the experiment now known as Super-KamiokaNDE.)winner of the 2002 Nobel Prize in Physics; at the Segre Memorial Lecture,Nov. 19, 2002

“Sometimes science educators are in awe of the scientists out there building wisdom for futuregenerations of children and so forth. . . . Scientists view science educators often slightly naively,but sort of like, ‘Oh well, surely you must have this educational fix that you can pull out of yourtoolkit and just widget this a bit so you can have a good curriculum.’”

Michael RanneyGraduate School of EducationUC BerkeleyNovember 25, 2002

Quanta (heard on campus)


“Satan is using this theory of evolution, for which there is no tangible evidence, tolead lots of folks to Hell.”

Kent Hovind, founder of Creation Science Evangelism MinistryNovember 21, 2002

then joined the faculty at StanfordUniversity, returning to Cal in 1996.

Taking the existing technology to thenext level, Chang-Hasnain experimentedwith tuning VCSELs on the fly, usingmicroelectrical mechanical systems(MEMS) to raise or lower the laser’shovering disk, thus changing the lengthof the resonating cavity. [For a relatedarticle on MEMS research at Cal, see “MicroMachines” in the BSR Volume 2, number 2.]As the cavity length alters slightly, thewavelength of emitted light also changes.By making small changes in the voltageapplied to electrodes in a MEMS device,a single laser becomes capable ofoperating at 50, 100, or 1,000 differentwavelengths. Equally impressive is thatthe MEMS device can initiate thismechanical change within a few micro-seconds. Chang-Hasnain points out that

Dr. Connie Chang-Hasnain, aUC Berkeley Electrical Engi-neering professor and

founder of the laser manufacturerBANDWIDTH9, Inc., has longworked to advance the optical net-working industry. The head of theOptoelectronics Research Group inCory Hall, Chang-Hasnain investigatesthe applications of semiconductorlasers to high-speed communication.In all likelihood, her micromechanicaltunable lasers will someday change theway we ping, email, ftp, and chat.

Chang-Hasnain focuses on streamliningthe optical transmission of information.When you sit down at a computer withInternet access, you rarely think abouthow the information travels or whatimpediments may lie in its way. Fortransmission across the globe, data istypically broken up into small unitscalled packets. These packets travelalong a tortuous path, starting downoptical fibers as light, passing throughintermediate routing points, and endingalong electrical wires as they reach theirdestination. With present technology,this journey is often slow and inefficient.The Optoelectronics Research Group isworking to make the process 1,000times faster by eliminating the variousroadblocks that a digital signal faces.

Chang-Hasnain began her opticalnetwork research on tunable Vertical

Cavity Surface Emitting Lasers(VCSELs). These lasers are etched ontoa chip of semiconducting material, likethat used in computer microprocessors.A VCSEL looks like a sandwich, with aresonant cavity formed between thechip’s mirrored surface and a small,cantilevered reflective disk. The cavityemits small bursts of monochromaticlight, with the length of the cavitydetermining the light’s wavelength.Precisely controlling wavelength isimportant in data transmission since itallows engineers to multiplex severaldifferent signals down a single fiber,without any overlap. However, currentlaser technology is still limited because aseparate laser is required for eachdifferent wavelength of transmission orchannel. “It’s like needing 200 sizes ofclothes,” explains Chang-Hasnain. “Youneed a huge amount of inventory.”

Chang-Hasnain’s career in optoelec-tronic networking started whileearning a BS in Electrical Engineeringat UC Davis. Sometime during herthird year there, she “fell in love withelectromagnetism.” From E&M, it wasa natural progression to the fast-growing field of lasers. She specializedin low-power semiconductor diodelasers (like those used in CD players),earning a PhD from UC Berkeley in1987 and working at Bell Communica-tion Research (now known asTelcordia) from 1987 to 1992. She

Sheyna Gifford

CONNIE CHANG-HASNAINCommunication at thespeed of light

Profile


Professor Connie Chang-Hasnain’s tunableVCSELs may someday change the way we usethe Internet. (Photo courtesy of Karen Levy.)


this creates “a laser where one size fitsall: you tune, you dial, and you lock onto [the wavelength].”

Tunable lasers give packets of datamore flexibility, since many differentdata channels can fit into the sameoptical fiber, all controlled by the samelaser. Even better, if you need a newchannel, you just tune your laser to anew frequency. Before this tunablelaser development, packets could beslowed down by heavy traffic on thefew existing channels. Says Chang-Hasnain, imagine “getting stuck behinda huge truck driving at 25 mph all theway to LA. Now we have 100 lanes,which is fantastic.”

In 1997, Chang-Hasnain foundedBANDWITH9 to manufacture andmarket these tunable lasers. Someresearchers who have engineeredbreakthrough devices and started theirown companies become lost forever toacademia. However, returning toBerkeley in 2000 seemed a naturalchoice for Chang-Hasnain. “Research iswhat excites me—research andteaching,” she explains. Chang-Hasnaincredits contact with students here at Calas being integral to developing newtwists and turns on old technology. “Ateaching environment is the best placefor you to do research. We’re sur-rounded by extremely intelligentstudents who are always excited to learnnew things. These two years have beenreally, really exciting.”

Today, Chang-Hasnain is cofounding anew Berkeley-based research center,which will focus on creating a new classof optoelectronic materials based onnanotechnology. Over the last fewyears, she has been collaborating with

her students to develop fully opticalswitching. Currently, when packets ofdata reach a junction the light signal isconverted into electrical pulses, routedto its proper destination, and finallyconverted back to light to be sentfurther down the line. This conversionprocess is slow and has a negativeimpact on data integrity. The Optoelec-tronics Research Group is trying todevelop new semiconductor opticalswitching devices to replace theseelectrical switches, so that packetsremain in optical form through theirentire journey. Chang-Hasnain explainsthat with existing electronic switching,packets wait around like passengers atGrand Central Station before transfer-ring to a new channel. However, “opticalswitching would mean that each

passenger would switch by themselves. Itcuts out the need for a Grand Central.”

With semiconductor processingcapacity doubling every 18 months andthe potential for seamless opticalswitching just around the corner, itappears that computer users every-where will soon be networking evenfaster. Eventually, only the speed of lightwill limit the speed of informationtransmission. So remember: for moreinformation—better, faster, and ondemand—stay tuned.

Want to know more?

photonics.eecs.berkeley.edu/cch/

Americans have never had so many fat-relateddecisions to make at the grocery store. Food on theshelves comes in no-fat, low-fat, and reduced-fat

varieties. Yet despite this abundance of light options, Americansare getting heavier. According to the Surgeon General’s 2001Report on Overweight and Obesity, more than 60% of adults inthe United States are overweight, while close to 30% of the USpopulation is considered obese. In a troubling wrinkle for the nextgeneration, children and adolescents are now the fastest-grow-ing overweight group in the United States.

Widespread obesity has hefty consequences. Weight-relatedillnesses cost the US medical system over $100 billion annu-ally, even more than smoking. The Surgeon General estimatesthat these illnesses, which include heart disease, certain can-cers, and complications of gallbladder disease and diabetes,claim about 300,000 lives per year in the United States. Obe-sity can double or triple a person’s risk for heart disease, andaccording to the most recent statistics from the World HealthOrganization, heart disease, once limited to the affluent West,is now the leading cause of death in the world. In the year

Evolution didn’t prepare yourarteries for the modern world

Sherry Seethaler

THE HAPLESS HEARTFeature


Illustrated by Jessica Palmer

2000, cardiovascular diseases killed 17 million people world-wide, more than cancer and more than all infectious andparasitic diseases combined.

The statistics certainly imply that “fatness” causes or contributesto heart disease. But does it? If it does, then by what mechanism?To answer these questions, it is important to understand the work-ings of fat in the body, as well as how heart disease develops. Asheart disease has become an epidemic, our understanding of ithas moved forward by leaps and bounds. Recent research hascompletely changed the way we think about this complicatedcondition as well as the role of fat in the heart-disease epidemic.For more than half a century, UC Berkeley has been at the fore-front of this research.

The Skinny on Fat

To begin at the beginning, what is fat? Fats are found naturallyin both plants and animals and come in several varieties. Fatsare long chains of atoms, mostly carbon and hydrogen. Most ofthe fats in animal products are saturated, meaning that there areno double chemical bonds between any of the carbon atoms.Plant oils usually consist mainly of fats that have one or moredouble carbon bonds and are known respectively as mono- orpoly-unsaturated. The double bonds cause a kink in the carbonchain, making it harder for the chains to pack together. As aresult, unsaturated fats, like olive oil, tend to be liquid at roomtemperature, while saturated fats, like butter, are generally solids.

Two more compounds that tend to be lumped into discussionsof fat are triglycerides and cholesterol. Triglycerides are a formof stored fat in the body. They consist of three chains of fat


Trans-fatty acids

In some products, such as margarine, peanut butter, cookies, and crackers, unsaturated fats are artificiallysaturated to improve texture, in a process called hydrogenation. This replaces the double bond between thecarbon atoms with a single bond. The structure of the resulting fat tends to be different from the saturated fatsusually found in nature. These so-called trans-fatty acids may increase the risk of heart disease more than natu-rally occurring fats. Like saturated fats, they increase levels of LDL, but they also lower HDL and may also causedirect damage to the artery. The Food and Drug Administration is currently developing new labeling guidelinesfor products containing trans-fatty acids.

linked together and can be metabolized to yield energy. Cho-lesterol, on the other hand, is not a fat at all. It is a largemolecule consisting of fused rings of carbon atoms, and,although it tends to travel with fat in the diet and in thebloodstream, it cannot be metabolized to release energy.

Apples and Pears

Obese people have ample amounts of adipose tissue (fat stores),consisting of cells jam-packed full of triglycerides. Obese peoplealso tend to have a cluster of symptoms that together increasetheir risk of heart attack, and even less dramatic weight excessis associated with increased risk. These risk factors include highblood pressure, high cholesterol, and insulin resistance, a dis-turbance related to diabetes. This suggests that being obese isbad for one’s health. However, the picture becomes more com-plicated when one considers where in the body fat is stored.Obesity-related symptoms are mostly confined to people whohave primarily abdominal fat, a body type known as “apple.”“Pear” body types, people who carry fat on their buttocks andthighs, rarely display these symptoms. Apple and pear are ofcourse extremes; many overweight people lie somewhere inbetween the two types.

The apple and pear body types are not the end of the story.X-ray imaging reveals that people with apple body types maycarry fat either deep inside their abdominal cavity or just un-derneath their skin. While people in the former category showsymptoms linked to high heart attack risk, apple body typescarrying fat just beneath their skin don’t. Clues about whythis is so have been emerging in recent work by Dr. MarcHellerstein, a professor in the Department of Nutritional Sci-ences and Toxicology at Berkeley and director of the diabetesand HIV- metabolism clinics at San Francisco General Hospi-tal. Hellerstein and colleagues used mice to study how meta-

bolically active fat is in different areas of the body. They foundthat fat around the intestines breaks down and is resynthe-sized four to five times faster than fat in other parts of thebody. That means that when a body stores a lot of fat insidethe abdomen, the stored fat (triglyceride) is rapidly brokendown into its component fats, enters the bloodstream, andaccumulates in various tissues around the body. Why is this aproblem? Hellerstein explains it this way: “The basic prin-ciple seems to be that when fat builds up in certain cells suchas in your muscle, your liver, your pancreas, it is not a goodthing. It interferes with the use of glucose—a basic sugar thatyour body uses as a fuel—and it also interferes with signalingpathways.”(Signaling pathways are the ways the cells in yourbody communicate with one another using various chemi-cals.) While this interference is not fully understood in amechanistic way, it is known that the cells in an apple bodytype eventually become resistant to insulin, a hormone thattells many cells in the body to take up glucose and fat fromthe blood. Furthermore, as the liver itself becomes full offat, it starts to release more triglycerides and cholesterol intothe bloodstream. Combined with the reduced uptake by theinsulin-resistant tissues, this means that there are higher lev-els of fat and cholesterol in the bloodstream. This can wreakhavoc in the arteries. Insight into how this occurs begins withan understanding of how fat and cholesterol are transportedin the body.

Shipping Cargo

Cholesterol has gotten a bad reputation for its role inheart disease, since elevated levels of blood cholesterolcan clog up arteries and lead to heart attacks. However,this maligned molecule actually plays several importantroles in our bodies. It is an essential component of cellmembranes, and it is also the precursor for a number ofhormones including estrogen and testosterone.

Cholesterol is not found in any plant products, so for most ofus the dietary sources are meat and dairy products. However,our bodies typically synthesize three to six times as much cho-lesterol as we absorb from our daily rations. In fact, vegans,who subsist solely on plant products, can live just fine withoutconsuming cholesterol.

Hellerstein’s observations might be taken as an indictment of our bodies’adaptive mechanisms of dealing with fats. However, he is quick to pointout that in contrast to our current lifestyles, in our evolutionary history,periodic starvation and high levels of exercise were presumably the norm.

The terms “obese” and “overweight” are not syn-onymous. Both are defined scientifically in terms ofa measure known as body mass index (BMI). BMI iscalculated by dividing a person’s weight in kilogramsby the square of his or her height in meters. Some-one with a BMI over 30 is considered obese, whilea BMI between 25 and 30 is defined as overweight.Despite the prevalence of emaciated super-models,it is also possible to be too skinny. A BMI of less that18 is considered too low. BMI generally tends to bea good measure of how “fat” a person is, but ifsomeone has a much higher or much lower thanaverage muscle mass, then BMI can be misleading.

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cholesterol not used to make hormones or build cell mem-branes must be returned to the liver to be excreted or re-cycled. This second type of voyage uses HDL ships. Thebuilding, loading up, and unloading of lipoproteins requiresa whole variety of protein “workers.”

Photo courtesy of Diane Huang

Both high-saturated-fat diets and high-carbohydratediets (especially those high in sugar rather than com-plex carbohydrates) seem to lead to increased levelsof triglycerides in the blood. However, whether therisk of heart disease is identical for carbohydrate-related or fat-related increases in blood triglyceridelevels is still uncertain. A recent study from ProfessorMarc Hellerstein of the Department of Nutritional Sci-ences and Toxicology at Berkeley and colleagues sug-gests that these two situations may be very differentin terms of triglyceride dynamics in the body. Thiswork by the Hellerstein group was based on newmethodologies, such as the use of stable (non-radio-active) tracers that allow them to investigate dynamicbiochemistry in living systems. According toHellerstein, studying living systems including humansis essential. “The whole is greater than the parts; thewhole has emergent properties. You have to under-stand both. Although reductionism is necessary tounderstand complex systems, understanding the partsis never by itself sufficient because you have to un-derstand the interactions. And interactions are oftenat several levels.”


Since a sizeable proportion of cholesterol is synthesized bythe liver and is needed by various tissues around the body,it must be transported. Cholesterol is not soluble in water;thus, “naked” cholesterol cannot simply be carried in thebloodstream without thoroughly gumming up the works.Instead, lipoproteins act like little cargo ships to ferry cho-lesterol and fats to and from body tissues and the liver. Mostlipoproteins are spherical particles consisting of one or moreproteins and an outer skin of molecules, which have water-soluble heads that face outward and fat-soluble tails thatpoint inward. Cholesterol and fats can be packed in the coreof the lipoprotein for transport. Because the outer skin ofthe lipoprotein particle is soluble in water, it can travelsmoothly through the bloodstream.

Some of the groundbreaking work to characterize the differenttypes of lipoproteins was carried out at UC Berkeley in the 1940sand 50s by John Gofman, now a Professor Emeritus in the de-partment of Molecular and Cell Biology. As a graduate student,Gofman worked on the Manhattan Project to develop the atomicbomb. Switching fields, he later obtained a medical degree anddecided to apply a newly developed technique known as analyti-cal ultracentrifugation to understand how cholesterol travels inblood. His research led to the characterization of the four majorclasses of lipoproteins: very low-density lipoproteins (VLDL),intermediate-density lipoproteins (IDL), low-density lipoproteins(LDL), and high-density lipoproteins (HDL). (The classificationsrefer to where the particles are suspended in a tube of centri-fuged blood plasma.) These findings completely revolutionizedthe way researchers think about cholesterol in the body.

Cholesterol, within the lipoprotein, can go on two types ofvoyages. On the first type of voyage, it travels from the liverto the tissues, which requires VLDL, IDL, and LDL “ships.”Cholesterol is not alone on the ships; triglycerides are fel-low cargo. VLDLs are first built and loaded up in the liver.VLDL is then secreted and is free to voyage around thebloodstream, unloading triglyceride cargo at various tissuesaround the body. As it does so, the ship actually decreases insize, with VLDL morphing into IDL and finally LDL. LDL,and the cholesterol it contains, binds to specialized proteindocks, called LDL receptors, and is taken up by cells. Sincecholesterol cannot be degraded in the tissues, any excess

’

The War in the Rings

So how does all this relate to the clogging up of arteries? Is theartery plugging up with cholesterol the way a garden hose mightget plugged up with dirt? In fact, in the last two decades scientistshave come to realize that unlike what happens in the garden hose,the artery is not a passive bystander in this clogging process, betterknown as atherosclerosis. Arteries are able to sense a build-up ofcholesterol, and they respond to it by sending out SOS signals.These signals are meant to unleash the immune system againstforeign invaders such as bacteria and viruses. This would be a purelyadaptive response back in the days when these were the artery’smain foe. Unfortunately for us modern humans with our dietshigh in fat, the “help” the artery receives in response to this SOSsignal ultimately results in a vicious cycle of damage.

Arteries consist of concentric rings of cells, with smooth musclecells on the outside and endothelial cells—thin flattened cellsthat line internal body cavities—on the inside. Circulating LDLcan cross the endothelial cell layer—more so as LDL’s concen-tration in the blood increases—and become trapped in the ma-trix between the layer of endothelial cells lining the artery andthe smooth muscle cells. This matrix is chemically different fromthe blood in which the LDL usually finds itself. When LDL istrapped in this environment, it becomes oxidized (reacts withoxygen and is chemically changed), which has profound im-plications. Mildly oxidized LDL can cause changes in geneexpression in the overlying endothelial cells. This results in

If you have had your cholesterol tested, you may have heardyour doctor refer to LDL as the bad cholesterol and HDL asthe good cholesterol. Of course, good and bad might be rea-sonable dichotomies in fairy tales, but alas, in real life nothingis so simple. HDL and LDL are both necessary; LDL’s role is tobring cholesterol and triglycerides from the liver to the muscleand other tissues, and HDL ferries excess cholesterol and tri-glycerides back from the tissues to the liver. However, we knowthat having high levels of LDL and low levels of HDL signifi-cantly increases heart disease risk. For example, it is well knownthat before menopause women generally have significantly higherlevels of HDL than men, and women have correspondingly lowerrates of heart disease. However, after menopause, the ratioof LDL to HDL increases, paralleled by an increase in heart-disease risk. Smokers tend to have lower levels of HDL anda correspondingly higher risk of heart disease (although theyalso often have high blood pressure and other known riskfactors for heart disease.)

Since the plaques in the artery contain a great deal of cholesterol, but little fat, scientists were surprised to findthat the level of saturated fat in the diet correlates more strongly with heart disease risk than with dietary intakeof cholesterol. There are two reasons for this. First, our bodies are only so efficient at absorbing cholesterol in thediet and we cannot absorb all the cholesterol we typically eat. Second, saturated fat actually increases theamount of VLDL—the precursor of LDL—secreted by the liver. It may do this by protecting Apo-B, the protein partof VLDL, from being degraded. This protein is continuously over-produced in the liver, but the excess is de-graded. If the Apo-B protein is not degraded then it is available to be assembled into VLDL, loaded up, andreleased into the bloodstream. Saturated fat also seems to reduce the efficiency of LDL uptake by the body’stissues. The net effect is a significant increase in blood levels of LDL. However, in terms of dietary implications,few foods containing cholesterol contain low levels of saturated fat. Shrimp and egg-yolks are two exceptions.

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the cells sending out a help signal that attracts precursors ofmacrophages—immune system cells that circulate aroundyour body devouring nasty intruders.

Pre-macrophages that answer the call for help pass between theendothelial cells, enter the matrix, and become macrophages.As the LDL becomes more oxidized, it becomes toxic and dam-ages the endothelial cells. Macrophages detect this oxidized LDLand consume it. However, the damage from oxidized LDL tothe endothelial cells actually encourages the entry of more LDLinto the matrix, setting up a self-reinforcing cycle. While themacrophages continue to consume LDL, they get bigger andbigger. These enormous lipid-stuffed macrophages, referredto as foam cells, become trapped in the matrix beneath theendothelial cells.

The artery attempts to repair the damage being done by theoxidized LDL and the accumulation of foam cells in a manneranalogous to the way your skin might heal over an embeddedthorn. Smooth-muscle cells of the artery can migrate up andover the foam cells in an attempt to contain the damage. The

smooth muscle cells also secrete collagen—a structural pro-tein—resulting in the area becoming a fibrous plaque, a sort ofscarred-over wound. Inflammation can eventually lead to this“wound” in the artery breaking open. When this happens a bloodclot may form because chemicals produced within the plaquecan cause the blood in the artery to coagulate. If the clot is bigenough it will block the artery, starve the heart of blood, andcause a heart attack. Thus, the heart attack is the end of a longprocess, which began years, if not decades, earlier. The build-up of LDL both initiates and sustains the damage cycle, in acomplex process involving several different cell types and avariety of chemical signals, with the artery’s attempts to pro-tect itself playing a key role.

There is some hope in all of this, because HDL—the so-calledgood cholesterol—can enter into the matrix and remove cho-lesterol from the foam cells. This is one of the reasons HDL isconsidered beneficial. Higher levels of HDL in the blood meansmore cholesterol can be removed. However, higher levels ofLDL can overwhelm HDL’s ability to clear out the cholesteroland protect the artery from further damage.

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According to Krauss, there are many people who are at risk forheart disease but who do not appear to be at risk on tradi-tional cholesterol tests. For example, the small, dense LDL traitwould not show up on a typical cholesterol test, which looksonly at LDL, HDL, and total cholesterol. Krauss and his col-leagues’ new company, Cardio Profiles, will for the first timemake blood tests for this and other emerging heart-disease riskfactors clinically available at reasonable costs. The tests of-fered by Cardio Profiles are based on a new methodology called“aerodynamic electrical mobility analysis” developed by UC Ber-keley engineering professor, Dr. Henry Benner. This method canbe used to determine lipoprotein size distributions in about fiveminutes, as compared to a day or two for traditional gel-separa-tion techniques. The new method is based on measuring howcharged particles drift as they are dragged through air by theforce of an electric field. Not only will these tests lead to better

diagnoses, but by allowing clinicians to follow blood concentrations of various risk factors in patientsover time, they may help them to determine the effectiveness of treatment.


The Plot Thickens

The original centrifuge used by Gofman to discover the li-poproteins still remains in working order at UC Berkeley’sDonner Laboratory, and researchers here at UC Berkeleyare still on the cutting edge of lipoprotein research (withstate-of-the-art equipment, of course!) Professor RonKrauss, of Lawrence Berkeley National Laboratory (LBNL)and Chair of the American Heart Association Council onNutrition, Physical Activity, and Metabolism, and his col-leagues are discovering new lipoprotein risk factors, whichare changing the way we think about heart disease. One ofthe lab’s findings is that not all LDLs are the same. It seemsthat small, dense LDLs are particularly predisposed to pen-etrating the endothelial cell layer, becoming oxidized anddamaging the artery. For reasons still under investigation,many obese, insulin-resistant people tend to have the small,dense LDL trait.

Meanwhile, Dr. Trudy Forte, also at LBNL, and her colleagueshave been showing that the lipoproteins we have known aboutfor half a century still have some tricks up their sleeves. Itturns out that besides its role in transporting cholesterol, HDLalso carries important enzymes, one of which, paraoxonase(PON), is thought to be an antioxidative enzyme. (Recallthat oxidation of LDL makes it damaging to the artery wall.)The Forte group has been successful in developing a strain ofmice to study PON’s effects and are using mutation studiesto better understand how this enzyme works. They have bredmice with higher-than-normal levels of PON, and so far theirtest results suggest that these mice have more protectionagainst oxidation. Forte and colleagues are currently deter-mining if elevated PON protects the mice against damage totheir arteries when they are on a high-fat, high-cholesterol diet.According to Forte, “Right now investigators are really look-ing at increasing the amount of HDL that we have circulatingbecause clearly it’s protecting.” In fact, HDL is beneficial inprotecting us against heart disease in at least two completelydifferent ways. As Forte’s research shows, HDL, with PON,is able to act as an antioxidant, but HDL is also essentialbecause its role in removing cholesterol from the foam cellsin the developing atherosclerotic plaque.

Other new pieces of the heart disease puzzle are continuing toemerge, including the role of inflammation. Inflammation re-sults when LDL assaults the artery wall, but many scientists,including Paul M. Ridker and Peter Libby, cardiologists atBrigham and Women’s Hospital and professors at Harvard’sMedical School, are now finding that they can detect chemicalsinvolved in inflammation even before there is any visible LDLbuild-up in the artery. In other words, inflammation maybe preceding the deposition of cholesterol, at least in somepatients. Furthermore, in some patients, it is possible to detecthigh levels of C-reactive protein, a marker of inflammation,even in the absence of high levels of LDL in the blood. Ridkerhas found that measuring C-reactive protein and cholesterollevels provides a more accurate assessment of heart-disease riskthan cholesterol alone. Because cholesterol is needed for cellmembranes, and fat can be metabolized to yield energy, it wouldbe evolutionarily useful for the body to deliver lipoproteinscontaining these substances to a site of injury. Again, heartdisease may be an adaptive response that gets out of handunder the conditions of our current lifestyles. Scientists arecurrently trying to understand what initiates inflammation,and determining if anti-inflammatory medicines can decreaseheart disease risk.

One example of the complexities of heart diseaseresearch is that cholesterol-lowering drugs calledstatins, the largest selling drugs of all time ($30billion sales annually and rising) work through adifferent mechanism than the one scientists origi-nally targeted. The statin drugs inhibit the enzymethat synthesizes cholesterol in the liver, but in thebody this inhibition is partially overcome by syn-thesis of new enzyme. Because liver cholesterol lev-els are tightly controlled, this inhibition also causesthe liver to increase the number of LDL docks onitself, so the actual mechanism by which statinslower cholesterol is increasing LDL uptake from thebloodstream. Now scientists believe that these drugsmay also reduce inflammation in the artery.


Gene Blues

Our diet affects the levels of lipoproteins in our bodies, whichin turn affect the artery wall in a complex, dynamic set ofevents. One piece is still missing from this story. With thesequencing of the human genome, there has been a great dealof focus on the role of genetics in disease, and findings haveshown that indeed, genetics plays a role in heart disease. Forexample, levels of lipoprotein (a)—a particularly damagingvariant of LDL that has a different protein component thanother LDLs—are largely determined by genetics. Further-more, certain genes can predispose you to obesity. Some genescan be favorable as well; Dr. John Bielicki, also at LBNL, isstudying people who have a variant form of HDL’s majorprotein, apolipoprotein A-I, which seems to be particularlyprotective against heart disease.

Understanding genetics is important, because according toKrauss, “If we understand how those genes operate, not onlycan we help to better identify people who have certain ge-netic predispositions, who might benefit from certain treat-ments, but in fact it will lead to new drug discovery based ontargets that we identify.” However, genetic predispositions arenot destiny. As Hellerstein points out, it is the interactionbetween genes and the environment that is key. For example,the Pima Indians on reservations in Arizona have very highrates of obesity, while their highly genetically similar cousinsin the mountains of Mexico have no obesity problems. Heartdisease has become a problem in the United States and aroundthe world only as societies have moved from rural to urbanenvironments and as calorie-rich, nutrient-poor fast foodshave become prevalent. These changes, and the correspond-ing dramatic increases in heart disease, have happened in lessthan one generation, far too short a time for genetic changesto play a role.

Lace Up Those Running Shoes

Given this understanding of the role of genetics, what do weknow about lifestyle factors? While scientists do not completelyagree whether a high-carbohydrate, low-fat diet is better than,say, the Mediterranean Diet (which is higher in mono- and poly-

unsaturated fats), there is agreement on several things. Com-plex carbohydrates such as those found in whole grains are abetter choice than foods high in simple sugars, which tend toover-stimulate insulin secretion and worsen blood triglyceridelevels. The generally accepted recipe for a healthier lifestyle is toeat more fruits and vegetables (which are rich in antioxidants),and to exercise more.

The role of exercise is critical, as pointed out in the 2002National Academies’ Institute of Medicine Report, whichdoubled the previous recommendations for moderately in-tense exercise to one hour per day. Activities like walkingand gardening, on a regular basis, can decrease insulin resis-tance and risk of heart disease, even if people are still over-weight. In fact, it is possible to be overweight and healthy.While cardio-respiratory health is usually linked to bodyweight, it is a strong independent predictor of heart diseaserisk. Sumo wrestlers may look fat and unhealthy, but they are

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Dr. Trudy Forte, seniorresearch sc ien t i s t a tLawrence Berkeley Na-tional Laboratories, andher co l leagues havebeen trying to better un-derstand how cigarettesmoke affects HDL. Theyhave found that in vitro,chemicals found in ciga-rette smoke can haveseveral negative effectson HDL. For example, it

can cause the major protein component of HDL,apolipoprotein A-1, to attach to another moleculeof A-1. “Cigarette smoke actually takes the pro-tein on HDL and will cross-link it. So one A1 bindsto the other and you can’t break the bond.” Thisinterferes with HDL’s ability to move cargo. Forteand colleagues have also found that cigarettesmoke inhibits one of the protein workers that playsa role in transferring cholesterol out of cells andinto the HDL particle.


actually in extremely good shape. While they eat hugeamounts, they also train for hours every day. Their body fat ispredominantly stored just below the skin, rather than in theabdominal cavity, putting them at very low risk for heart dis-ease. However, when they retire and stop exercising whilemaintaining their eating levels, fat builds up in their abdominalcavity and their heart disease risk typically increases.

Though it may seem surprising, certain types of body fatare necessary. People with rare disorders who have no sub-cutaneous fat (fat just underneath their skin) actually haveterribly high levels of triglycerides and cholesterol in theirblood and high risk of heart disease. Drugs that help thesepeople develop subcutaneous fat actually help to decreaseheart-disease risk. This paradoxical fact is because fat is be-ing removed from the bloodstream, liver, muscle, and othertissues, when it is stored subcutaneously. In other words,subcutaneous fat safely stored away is not doing any harmto the arteries. However, having too much fat, particularly

fat that is more metabolically active like fat in the abdomi-nal cavity, can lead to heart disease by ultimately leading toincreased LDL in the bloodstream. The evidence from Sumowrestlers and people who have no subcutaneous fat showsthat fitness, not fatness per se, might be a more useful focusin reducing heart disease.

Research into heart disease has all of the dramatic twists andturns of a page-turning mystery novel, but unlike the mys-tery novel where good and bad is clear-cut and the pieces ofthe puzzle tie neatly together in the end, research into heartdisease is still yielding many surprises. Dr. Forte points outthat, “We want to take a pill for everything, a pill to get skinnyand eat whatever we want!” While scientists have gained amuch better understanding of the extraordinarily complexset of events leading to heart disease, including the role ofgenes and lifestyle factors such as diet and exercise, it is un-likely that there will ever be a single villain to target with amagical elixir.

Want to know more?

The process of atherosclerosis and the role of inflammatory factors:Atherosclerosis: the New View. Peter Libby, Scientific American, May 2002.

New Diet and Exercise Guidelines:www4.nationalacademies.org/news.nsf/isbn/0309085373?OpenDocument

Trans-Fatty Acids and the Food and Drug Administration Labeling Proposal:www.cfsan.fda.gov/~dms/labtrans.html


Geoff Marcy demonstrating the wobble of a star due to an orbitingplanet. Marcy uses observations of this wobble to infer the existenceof planets around distant stars, and has found 60% of the 102extrasolar planets discovered so far.(Photo courtesy of Martin Sundberg.)

Planets certainly aren’t the most exoticobjects in the Universe. They don’t shineas brightly as stars do; they don’t warp

the fabric of spacetime quite like black holes;and, unlike supernovae, they never explode.Planets have, however, proved to be some of themost elusive objects in the Universe: whileChinese astronomers noted the first recordedsupernova explosion in the year 185 AD, andmodern astronomers had found more mysteriousobjects like quasars and neutron stars by the mid-20th century, the first known extrasolar planetswere discovered less than 10 years ago. GeoffMarcy, of the UC Berekely depar tment ofAstronomy, has spearheaded the search forextrasolar planets from its early days.

Much of what astronomers have learned fromrecently discovered extrasolar planets haschallenged existing theories of planet formation.Conventional wisdom holds that planets form ina disk of gas surrounding a new star. Centrifugalforces and heat from the star make the disk thinand hot at the center, and thick and cool at theouter edge. Planets condense out of the disk like

STRANGE NEW WORLDS

Julie Walters

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What planet hunterGeoff Marcy seesin the wobble ofdistant stars

by noting the effects of their gravity on the motionsof the known planets. After Newton published his lawof gravitation in 1687, the motions of the six knownplanets were well understood. However, in 1781, theplanet Uranus was discovered, and its orbit was soonfound to deviate slightly from the one Newton’s theory

would predict if only the Sun and the known planets were actingon it. The success of Newton’s theory of gravity in explaining themotions of the other planets led astronomers to think that theirregularity of Uranus’ orbit was due to interaction with another,then unknown, planet. In 1845, astronomers predicted theposition of the unknown planet based on observations of Uranus,and in 1846 the planet Neptune was seen, exactly whereastronomers had concluded it must be. Marcy’s group is nowdetecting planets outside our solar system by finding similarperturbations in the motions of distant stars.

Marcy’s team has discovered about 60% of the 102 extrasolarplanets now known, and his research is changing ourunderstanding of how planets form. It is also beginning to answerone of astronomy’s most intriguing questions: are we alone?

On the Shoulders of Giants

Though the planets in our solar system had been studied by theearliest astronomers, the picture of the solar system as we knowit today did not emerge until the Renaissance. The developmentof the theory that describes the motions of the planets beganwith the work of Copernicus and Galileo, and culminated withthe works of Johannes Kepler. In 1600, Kepler, then a professorof astronomy and mathematics at the university in Graz, Austria,was invited to Prague to assist Tycho Brahe in charting the orbitsof the known planets. In 1609, Kepler published the Astronomia

Nova, in which he calculated the orbit of the planet Mars. Theidea that planets exhibit circular orbits had long been acceptedas dogma; however, in Astronomia Nova Kepler proved that theorbit of Mars is an ellipse. This discovery was the basis ofKepler’s first law: that massive objects revolve around each otherin elliptical orbits.

About 60 years after Kepler published his Astronomia Nova, IsaacNewton proposed a general theory of gravitation. Newtondiscovered that, contrary to what Kepler thought, the Sun does

As far as the astronomy community wasconcerned, Marcy says, “[planet hunting]was about as valid as looking for UFOs.”


hailstones in a cloud. Naturally, this model explains our solarsystem very well: small, rocky planets form close to thestar, where there’s less material; gas giants form further out,where it’s cool enough for gases to condense. The firstextrasolar planet to be discovered—a giant planet, abouthalf the size of Jupiter, in an orbit eight times smaller thanMercury’s orbit around the Sun—was, therefore, a bigsurprise. Marcy’s search for extrasolar planets has continuedto turn up surprises, forcing astronomers to rethink manyaspects of planet formation. It has also brought us to thethreshold of answering the question of how common life isin the Universe. While most of the planetary systems foundso far are very unlike our own Solar System and unlikely tohost habitable planets like Earth, Marcy and his fellowplanet-hunters are now discovering a few systems moresimilar to our own.

Surprisingly, Marcy has never actually seen an extrasolar planet.Since planets don’t emit any light of their own, those orbitingdistant stars are too dim to be imaged by today’s telescopes.What little light these planets reflect is completely drownedout by the glare of the host star; it’s like trying to see a firefly afew inches away from a bonfire. Extrasolar planets may,however, be detected indirectly by observing the effect of theirgravitational pull on the stars they orbit. A planet exerts agravitational tug on its host star, which moves the star in aparticular way, just as the pull of the star causes the planet tomove in an orbit. Astronomers can infer the presence of anunseen planet orbiting a distant star from the motion of thestar by carefully monitoring its position or velocity. All of theextrasolar planets found by Marcy and his collaborators havebeen discovered using a technique called Doppler detection,which relies on precise measurements of the velocities of stars.

The techniques Marcy is using in the search for extrasolar planetsgrew from methods that had already been tested in our ownsolar system. Both Neptune and Pluto were discovered indirectly,

not stay perfectly still as the planets orbit around it. Rather,both planet and star orbit around a common point called thecenter of mass. Imagine placing the Sun and Jupiter at oppositeends of a giant seesaw. The center of mass of the two is thepoint on the seesaw where you’d have to place the fulcrum inorder to balance the two masses perfectly. The larger the planet,the farther the center of mass is from the center of the star. Forthe Jupiter-Sun system, Jupiter’s mass is about 1/1000th thatof the Sun’s, so the center of mass is about 1000 times closer tothe Sun than it is to Jupiter. Thus, the Sun orbits a point justoutside its own surface. It does not sweep out an enormous arcas the planets do, but, instead, wobbles slightly as it orbits thecenter of mass of the Jupiter-Sun system. In his search to findextrasolar planets, Marcy looks for this wobble, also known asa reaction orbit, in the motions of stars.

It’s a testament to the technical difficulty of finding extrasolarplanets that, though the theoretical underpinnings of the planetsearch have been around for centuries, the first confirmeddetection came less than ten years ago. The first attempts todetect extrasolar planets relied on precise measurement of starpositions, a technique called astrometry, rather thanmeasurement of star velocities. In the late 1960’s, Peter van deKamp of Swarthmore College announced that he had discoveredtwo roughly Jupiter-sized extrasolar planets via astrometry ofBarnard’s star. Van de Kamp devoted most of his life to analyzingphotographic plates of Barnard’s star he and his students hadtaken, precisely determining the masses and orbital periods ofthe two planets by 1982. Other astronomers of his time werenot able to reproduce his results, however, and subsequentobservations of Barnard’s star with the Hubble Space Telescopehave failed to find any evidence of an orbiting planet.

Be Vewy, Vewy Quiet . . .

By the time Marcy began his search, more than a decade ofcontroversy over the Barnard’s star planets, paired with theobservational challenges, made for a climate in the astronomycommunity that was decidedly unfriendly toward planet-hunting. “People would look down at their shoes when youtalked about extrasolar planets,” Marcy says. As far as theastronomy community was concerned, he says, “it was aboutas valid as looking for UFOs.”

In 1982, Marcy began looking for the telltale motions of starsthat would indicate the presence of an orbiting planet. Marcymeasures the speed of a star in its reaction orbit using a physicalprocess called the Doppler effect. We have all experienced theDoppler effect; we hear it when we listen to the siren of a firetruck speeding toward us, for example. As the fire truckapproaches, the siren sounds relatively high-pitched; once it haspassed, the pitch of the siren seems to get lower. The apparentchange in pitch is due to the fact that the crests of the soundwaves emitted by the siren arrive at your ear closer togetherwhen the truck is moving toward you, and farther apart as itmoves away. The extent to which the pitch of the siren changesdepends on the speed of the truck—the faster the truck movestoward you, the higher the pitch seems to be. By measuring thepitch of the siren, you can tell how fast the truck is moving.

The Keck I telescope atop Mauna Kea in Hawaii. The position of eachof the 36 hexagonal segments of its 10-meter mirror is corrected twiceevery second to precisely maintain the mirror’s shape. (Photo courtesy ofW.M. Keck Observatory.)

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By the same token, astronomers can use the Doppler shift todetermine how fast a star is moving. As with the sound wavesemitted by a speeding fire truck, a star’s motion toward theEarth bunches crests of light waves together, while motion awaydoes the opposite. In this case, the frequency of the wave isperceived as color, rather than as pitch. The changes in colorthat Marcy measures are tiny: with the Keck telescope (seesidebar), he is currently able to detect changes of one part in100 million in the wavelength of visible light emitted by distantstars. “That’s a velocity of three meters per second,” Marcysays, “about human walking speed.”

Marcy’s Stars

Marcy’s group is looking for this characteristic motion in agroup of about 1,000 stars. All the stars being monitored byMarcy’s group are main-sequence stars, normal stars like theSun which aren’t changing much in size and which areundergoing nuclear fusion in their cores. These stars have longlifetimes (our Sun, for instance, has been burning hydrogen forfive billion years, and will keep burning for five billion more),so are the most likely objects to support stable planetarysystems, where life may have sprung up.

Main sequence stars are sorted into ‘spectral classes’ by theirtemperature. Marcy is looking at stars with temperaturesbetween about 60 –125% of the Sun’s. Cooler, less massivestars are too faint to detect with even the Keck telescope, theprimary telescope being used in Marcy’s planet survey. Hotter,

more massive stars have more violently turbulent atmospheres,which can confuse Doppler measurements of the star’s orbitalvelocity. “Convection just beneath the surface of a star gives avelocity that can mimic a Doppler shift,” Marcy says. Hotterstars also have more solar flares, and rotate more quickly thando cooler stars. All of this extra motion in hotter stars can bemistaken for motion due to a reaction orbit, making hot starsunsuitable for the extrasolar planet search.

When Marcy began monitoring these stars, he was a postdocat the Carnegie Institution of Washington in Pasadena,California. He started with the 100-inch Mt. Wilson Telescope,watching absorption lines in the spectra of a small group ofstars. Light created in fusion reactions in the center of a star ispartially absorbed in the star’s atmosphere. The absorptionhappens at particular frequencies, each of which is caused by adifferent electronic transition of an element present in theatmosphere. The absorption lines in the spectrum of a star beingtugged around by an orbiting planet are Doppler-shifted as thestar moves. Each time Marcy observes the star, the amount ofDoppler shift gives a measurement of the star’s velocity. Lookingat the orbital velocity of the star as it revolves about the centerof mass of the star-planet system shows periodic variations inthe velocity.

Marcy’s observations at Mt. Wilson were inconclusive; thetelescope there didn’t have the resolution to detect the smallvelocities associated with reaction orbits. Then, in 1984, Marcytook a faculty position at San Francisco State University. There

THE KECK TELESCOPE

The Keck telescopes reside 13,800 feet above sea level, on the dormant volcano of Mauna Kea, on the big islandof Hawaii. Jointly operated by UC Berkeley, Caltech, and NASA (which joined the partnership in 1996), they arethe largest infrared and optical telescopes in the world. There are two identical telescopes at Keck Observatory,each with a diameter of 10 meters: Keck I began taking data in 1993 and Keck II went online in 1996. The Kecktelescopes have a much larger collecting area than had been previously possible, due to their innovative seg-mented-mirror design. Each of the Keck telescopes has a primary mirror composed of 36 hexagonal segments,rather than the solid optics that had been used since Galileo’s time. Traditional telescopes could only get so big:a solid mirror the size of Keck’s would sag under its own weight, changing its optical properties and makingscience observations impossible. The positions of the 1.8-meter segments inside the Keck telescopes are adjustedindividually, and are constantly corrected to maintain the right shape.


he met Paul Butler, who was an undergraduate looking for aresearch project at the time. In 1987, they began using the three-meter telescope at the UCO/Lick Observatory, a Universityof California facility located near San Jose in the Diablomountain range. Since only UC affiliates are officially allowedto use the Lick Observatory, Marcy says, “we asked for thenights nobody else wanted. We observed during the full moon,whenever we could get the telescope.” From 1987 to 1995,Marcy and Butler monitored a group of 120 stars, observingeach only once or twice per year. At Lick, they found whatthey were looking for, stars whose spectra showed absorptionlines whose frequency changed with time.

Wobble, Wobble, Little Star

The period of the variations in the stars’ absorption lines is theorbital period of the star-planet system. With the Dopplerdetection method, Marcy measures both the star’s orbital periodand its speed relative to Earth. Marcy uses Kepler’s third lawto translate these into more physically interesting properties,like the orbiting planet’s mass and orbital radius.

In addition to his discovery that the planets move in ellipticalorbits, Kepler’s observations also revealed that the planets’orbital periods are related to their distances from the Sun.

This discovery is now known as Kepler’s third law: the largerthe radius of the planet’s orbit around the Sun, the longer itsorbital period. Jupiter’s orbital radius, for instance, is aboutfive times larger than Earth’s, and its orbital period is around12 years. Later, Newton proved that the orbital period-radiusrelationship that Kepler found also depends on the mass ofthe star that the planet orbits. Kepler’s third law is an empiricallaw that applies only to the planets orbiting our own Sun.Newton’s theory extended Kepler’s third law to make itapplicable to all solar systems.

Kepler’s third law, along with the law of momentumconservation, relates a star’s orbital velocity to the mass of anorbiting planet. Due to the effects of orbital inclination, or thetilt of the planet’s orbit with respect to our line of sight, Marcydoesn’t actually measure the star’s true orbital velocity, butonly the component of the velocity directed toward Earth. Astar moving in a reaction orbit may wobble alternately towardand away from the Earth. On the other hand, it may wobblefrom side to side, perpendicular to the line between it and theEarth. In the second case, light waves from the star are notbunched up in our direction as it orbits, and Marcy wouldn’tobserve any Doppler shift of absorption lines in the star’satmosphere. For cases between the two extremes, Marcy willobserve some Doppler shift, but only due to the toward-and-away component of the star’s total motion. In these cases,Doppler measurement underestimates the star’s velocity, soMarcy obtains a lower limit on the planet mass.

The search for extrasolar planets has now uncovered stellarwobbles due to over 100 planets. The shortest orbital periodmeasured so far is just under three days. The extrasolar planetwith the longest orbital period, discovered by Marcy’s team in2002, takes nearly 15 years to orbit its host star. The masses ofthe newfound planets are also strikingly varied. The largest isat least 17.5 times the mass of Jupiter, so large that it is probablya brown dwarf, or failed star, rather than a planet.

Expect the Unexpected

The first extrasolar planets to be discovered were not foundwith the Doppler detection method. Nor were they foundorbiting a main sequence star like the ones that Marcy and

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An exaggerated illustration of the Doppler effect for stellar absorptionlines. The bottom spectrum is shifted from the top by an amountequivalent to a star with a velocity of 36 kilometers per secondaway from the Earth. Marcy’s observations detect velocities 10,000times smaller than this. (Image courtesy of Geoff Marcy.)

Butler were monitoring from Lick Observatory. In 1994,three planets were discovered orbiting a strange object knownas a pulsar (see sidebar). The first detection of an extrasolarplanet orbiting a main sequence star was reported on October5, 1995, by Michel Mayor and Didier Queloz of the GenevaObservatory in Switzerland. Their discovery confoundedtheorists: they had found a planet with a mass of about halfthat of Jupiter’s, in an orbit about eight times smaller thanMercury’s orbit around the Sun. The planet’s orbit, around astar known as 51 Pegasi (Peg), was nothing like whatastronomers expected; no existing theory could explain howa gas giant could form at the scorching temperatures so nearthe star’s surface. Marcy and Butler immediately took a follow-up observation at Lick Observatory, and confirmed theexistence of 51 Peg’s companion planet on October 12.

By the time Mayor and Queloz announced their discovery,Marcy and Butler had already collected spectroscopic data

from dozens of other stars at Lick Observatory. They hadn’tfound any planets like the one orbiting 51 Peg in part,Marcy says, because they hadn’t been looking for one—they hadn’t, after all, had any reason to believe such planetsexisted. Following the confirmation of the Geneva group’sdetection, Marcy and Butler continued their observations,and reexamined the data they had already taken. In 1996,Marcy’s group repor ted six more extrasolar planetdetections, one in collaboration with a team fromMcDonald Observatory in western Texas. Marcy’s firstdetections were even more surprising than 51 Peg. Thefirst announcement by Marcy’s team involved an enormousplanet, 7.5 times the mass of Jupiter, in a close and highlyelliptical orbit, more eccentric than that of Pluto. In fact,all of Marcy’s early detections were of giant planets wellwithin the region once thought to be reserved for small,rocky planets like Earth, forcing astronomers to wonder,is it our solar system that’s the real oddball?

PULSAR PLANETS

In 1994, Aleksander Wolszczan of Penn State University announced the discovery of three planets orbiting pulsarPSR B1257 +12', a dense, rapidly rotating husk left over from a star’s death in a supernova explosion. Pulsars arehighly magnetized objects; the magnetic field at the surface of a pulsar is about 100 million times stronger thanEarth’s. There was no doubt in astronomers’ minds about whether or not life might be found on these planets—their surfaces are continually baked by X-rays, rendering them inhospitable. Pulsars also spit out jets of chargedparticles from their magnetic poles at nearly the speed of light. These jets produce incredibly powerful beams oflight, which are directed toward Earth periodically as the pulsar spins, creating a periodic flash like a lighthousebeacon. If this “beacon” is moving in a circle, an observer on Earth will see the beacon moving alternately towardhim and away from him, repeating every orbital period. The flashes will be alternately compressed and ex-panded, just like the crests of the siren’s sound wave; this will result in a periodic shift in the frequency of theflashing of the beacon, as seen by the observer.

Pulsars ordinarily pulse with astonishing regularity; they flash on and off with the precision of a clock that losesone second every million years. Wolszczan found an unexpected variation in the frequency of pulsar PSR B1257+12', which provided the first conclusive evidence of an extrasolar planetary system. This system is particularlycurious in that there are at least three planets in it, all of which must have formed after the supernova explosion(less than about 10 billion years ago), since the explosion would have vaporized any existing planets. Theseplanets provided the first of many surprises for theories of planet formation, having formed in an environment sounlike the archetypal stellar disk, and in such a short time. The pulsar planets bear little resemblance to the planetsin our solar system, but their successful detection renewed interest in the search for planets orbiting normal stars,which had its first success just a year after Wolzsczan publicized his discovery.


The wobble velocity of the Sun-like star Upsilon Andromedae over thepast 10 years. The wobble due to the innermost planet has beensubtracted, leaving the effect of the two remaining planets clearly visible.(Image courtesy of Geoff Marcy.)

The dissimilarity between the first known extrasolar planetsand the planets in our solar system is partially due toobservational bias. Very massive planets in very tight orbits areeasier to detect than smaller, more distant planets. The closerand more massive the planet, the greater the tug on the star,and the bigger the wobble. Indeed, the smallest extrasolar planetfound so far is over one tenth the mass of Jupiter, still nearlyforty times Earth’s mass. Planets in tight orbits are also easierto detect, since the host star must be observed for a full orbitalperiod before the details of the planet’s orbit can be accuratelydetermined. Kepler’s third law states that planets in closer orbitstake less time to complete an orbit. So, while Marcy and Butlerwere able to confirm the detection of the 51 Peg planet afteronly a few days of observations, the planet search has onlyrecently accumulated enough data to find planets like Jupiter,which is in a much wider orbit. Technological improvementsthat allow astronomers to see smaller wobbles, and a few moreyears’ worth of data, are expected to turn up some moreordinary-seeming planets. Still, Marcy’s findings to date havedemonstrated that planets, and planetary systems, are far morevaried than anyone had expected.

There’s No Place Like Home?

One of the more recent developments in the search forextrasolar planets is the discovery of multiple-planet systems,which indicates that our Solar System may not be such anoddity, after all. The first multiple-planet system wasdiscovered by Marcy’s group in collaboration with a team atWhipple Observatory in Arizona. It harbors three planets,orbiting a star called Upsilon Andromedae (Ups And), about44 light years away from Earth. The Ups And system isn’t too

much like ours: the closest planet orbits at a distance of only6% of Earth’s orbital radius, completing a full orbit in just4.6 days. After Marcy’s team reported the discovery of theinner planet in 1996, further observation of UpsilonAndromedae unearthed a complicated Doppler signature,indicating the presence of other planets.

By 1999, Marcy and his collaborators had deciphered theDoppler data, revealing two additional planets. The middleand outermost ones are even more massive (two and fourtimes the mass of Jupiter, respectively), and both travel inhighly elliptical orbits. Ups And isn’t expected to harbor anyhabitable planets like Earth. Theoretical calculations predictthat Ups And can’t support another planet. The enormousgravitational forces due to the three known planets wouldwreak havoc on the orbit of any planet small enough to haveescaped detection, eventually flinging it away from the systementirely. Nor are the known planets likely to support life: theinner planet occupies an impossibly hot, close orbit, and theother two probably suffer dramatic temperature changesthroughout their orbits, due to their high eccentricity.However, though Ups And is not perfectly analogous to ourSolar System, it does prove that other, dynamically stable,multiple-planet systems are out there, and it is possible forastronomers to find them with existing technology.

Now at least 10 multiple-planet systems have been foundorbiting main-sequence stars. In June 2002, Marcy’s teamannounced the discovery of another three-planet system, thisone much more like our system in many respects. The innerplanet of this system, orbiting a star called 55 Cancri, hadbeen discovered by Marcy’s team years before. Identifying the

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“The discovery of life on another planetis potentially one of the most importantscientific advances of this century, letalone this decade, and it would haveenormous philosophical implications.”

will emphasize new methods for planet detection, includingthe transit method, astrometry, and coronagraphy.

Transit

Astronomers can indirectly detect the presence of a planet bywatching as the planet passes between its star and the Earth.This event, called a transit, blocks out a small fraction of thestar’s light, causing a dip in the observed brightness of the star.Transit, or occultation, is another technique that has led toimportant discoveries close to home. In 1977, astronomerswatched as Uranus passed in front of a background star. Agroup that was observing the transit were surprised to seethree successive dips in the star’s brightness, rather than the

other two took longer, largely because the outer planet takesa full 14 years to orbit. This planet, known as 55 Cancri “d”,with a mass about four times that of Jupiter, occupies an orbitvery similar to that of Jupiter’s. Finding planets in orbits similarto Jupiter’s is one of the “holy grails” of planet-hunting, Marcysays: these may indicate systems that formed in the same wayour own did. And, like Jupiter, they may make interior planetsmore habitable. Jupiter keeps the inner planets in our SolarSystem safe—its whopping gravitational field deflects cometsand other debris away from the solar neighborhood.Furthermore, calculations have shown that, unlike Ups And,55 Cancri could support a smaller, Earth-sized planet in a stableorbit between its outer planet and two inner planets.

Fifty Ways to Find a Planet

Marcy’s Doppler survey can’t currently measure the velocityof 55 Cancri precisely enough to detect this hypothetical Earth-like planet. The Doppler detection method is subject to errorsdue to a number of factors, including turbulence in the hoststar’s atmosphere and imperfections in the telescope. Anothercomponent of the systematic error involved with the Dopplertechnique is due to changes in the telescope over time. Thiserror can be decreased by observing the target stars morefrequently. Marcy plans to do just that: his group has recentlyobtained a grant from the US Naval Observatory to build atwo-meter telescope dedicated to planet hunting. With the newtelescope, Marcy’s group will be monitoring 50 stars nightly,rather than a few nights per year. Even so, the Doppler detectiontechnique may not achieve the resolution needed to find Earth-sized planets, in Earth-sized orbits, anytime soon. The Sun’swobble due to the Earth has a maximum velocity of only atenth of a meter per second, 30 times smaller than Marcy canpresently detect.

The planet search, primarily by means of the Doppler method,has turned up an incredible series of discoveries. Astronomershope that our knowledge of extrasolar planets will continue toexpand over the next several decades. NASA has initiated aseries of missions, scheduled to launch in the next 15 years,which will attempt to extend the search for extrasolar planetsto Earth-like planets, and even attempt to detect extrasolarplanets directly. Upcoming missions targeting Earth-like planets

A comparison of our solar system and that of 55 Cancri, one of 10 knownextrasolar multiple-planet systems. (Image courtesy of Geoff Marcy.)


KEPLER’S FIRST LAW

Kepler’s first law states that the orbits of all theplanets in our solar system are ellipses, with thesun at one focus. A circle is an ellipse with bothfoci at the same point: the center of the circle. Asthe foci move farther apart, the ellipse becomesmore and more elongated, or less and less circu-lar. A good measure of an ellipse’s deviation fromcircularity is its eccentricity, the ratio of the dis-tance between the two foci to the length of thelonger axis. Earth’s orbit is nearly circular, with aneccentricity of only 1.7%.

one they had expected. This observation suggested that Uranusis surrounded by rings, just as Saturn is. Uranus’ rings are muchnarrower and darker than Saturn’s, and had never been observedin direct imaging.

In 1999 and 2000, a transit of an extrasolar planet that hadalready been discovered by the Doppler survey was observedindependently by both Dave Charbonneau at Caltech and GregHenry at Tennessee State University. This was an excitingdiscovery for the planet-hunting crowd. It provided the firstindependent confirmation that the newly found planets—previously detected only indirectly—really existed.

The Kepler mission, scheduled for launch in 2007, will be aspaceborne telescope that will search the stars for the smallchanges in brightness that signify a transiting planet. Lookingfor transits is a lot different than looking for wobbles: eachtransit only lasts a fraction of a day, and they only occur once inthe planet’s year. A star’s wobble, on the other hand, iscontinuously detectable—the Doppler velocity search hasoperated by observing the target stars only a few nights a year.The transit search must be carried out differently: Kepler willkeep its one-meter telescope fixed on a roughly 25-square-degree patch of sky, constantly monitoring about 100,000 starsin its field of view. Kepler is designed to operate for four years,so that it will observe at least three transits for an Earth-analogocculting system.

Astrometry

It is possible to detect the reaction orbit of a star via astrometry,as van de Kamp attempted to do with Barnard’s star. Thistechnique has already been successfully used to detect “dark”stars, a class of objects that includes white dwarfs and blackholes, orbiting normal stars. It has been difficult to apply thistechnique to the detection of Earth-like planets, however, sincethe reaction orbits induced by Earth-like planets are so muchsmaller than those induced by stellar-mass objects.

The Space Interferometry Mission (SIM), scheduled for launchin 2009, will search for planets via astrometry, by takingextremely precise measurements of stars’ positions. SIM willmeasure the positions of stars to an accuracy of a few millionths

of an arcsecond; in terms of distance, thatmeans that SIM will tell astronomers theposition of a star within 10% out to a distanceof nearly 100,000 light years. In other words,SIM could easily read this article fromgeosynchronous orbit. SIM’s unprecedentedprecision will allow astronomers toastrometrically detect Earth-like planetsorbiting nearby stars, and Jupiter-like planetsout to about 3,000 light years.

Coronagraphy

If the star about which an extrasolar planetorbits suddenly stopped emitting light, theplanet would not be lost in the star’s glare,and astronomers would be able to observe itdirectly. That’s the idea behind thecoronagraph, an instrument that artificiallyeclipses a bright object to reveal fainter, nearbyobjects. The coronagraph is so named becausethe first instrument of this kind was designedto study the corona, the Sun’s diffuse outeratmosphere.

The main instrument aboard the TerrestrialPlanet Finder (TPF), a spacecraft still in theplanning stage, will be either a coronagraph,or an interferometer operating in the infrared.A design will be selected in 2006, based on available technology.Whatever the design, TPF’s main goal will be to directly detectsmall, Earth-like planets. TPF will also analyze the emissionfrom these planets’ atmospheres, in order to determine theconcentrations of gases like ozone, carbon dioxide, and methaneat the planets’ surfaces. Atmospheric chemists may use thisinformation to deduce whether or not the planet could supportlife, or even whether or not life already exists on the planet.

To Boldly Go?

Just ten years ago, there were no known planets outside ourSolar System. Geoff Marcy and his fellow planet hunters havenow found over 100 extrasolar planets and 10 extrasolar

Feature



planetary systems. The 2001 decadal review of astronomy andastrophysics, prepared by the National Research Council, hasidentified the planet search as one of the astronomycommunity’s top priorities for the coming decade, stating that,“The discovery of life on another planet is potentially one ofthe most important scientific advances of this century, letalone this decade, and it would have enormous philosophicalimplications.” Upcoming missions like Kepler and SIMpromise to make the next 10 years even more interesting forplanet enthusiasts, extending the search to planets much likeour own. In the next 20 years, missions like the Terrestrial

An artist’s conception of the planetary system orbiting 55 Cancri. In the foreground is the outermost, Jupiter-like planet with a hypothetical icy moon.(Image courtesy of Geoff Marcy/Lynette Cook.)

Want to know more?

exoplanets.org

Planet Finder may give astronomers the means to answer thequestion: how common is life in the Universe? So it looks asif planets are turning out to be just as exciting as all thoseother, more exotic objects. But then, Geoff Marcy could havetold us that 20 years ago.

BSR: What first got you interested in look-ing at the possibility that aneuploidy mightcause cancer?

PD: The study of animal viruses thought tocause cancer under the auspices of the NCI'sVirus-Cancer Program. There are a few ani-mal viruses that cause tumors as fast as theyreplicate. These viruses contain so-calledoncogenes, which my colleagues and I discov-ered here in Berkeley 30 years ago. But themajority of the animal tumor viruses—the so-called leukemia viruses and the DNA tumorviruses like SV40—seem to cause the diseasesthey are named for only after long latent peri-ods, if at all. In other words, only months toyears after infection.

This paradox struck me first when I was writ-ing a Perspectives article on tumor virusesfor Cancer Research in 1987. What could theseviruses do long after infection, or what elsehappens in virus-infected animals that wouldcause cancer?

The answer was ANEUPLOIDY (an abnormalbalance of chromosomes)! Indeed, the answerwas already in the literature, although totallyneglected. Nobody talked about aneuploidy atthat time. Instead, oncogenes were thought tobe the cause of cancer. The presence of aneup-loidy in those slow-forming viral cancersbegged the question of where the aneuploidyof viral tumors came from. Again, the litera-ture helped to find the answer. Over 40 years

THE MAVERICK SCIENTISTA conversation with Peter Duesberg

Peter Duesberg is inthe news again. In re-cent years, Dr.Duesberg drew agood deal of wrathwith his assertion thatHIV does not causeAIDS. But today he istaking on a new field(and controversy): can-cer and what causes it.

The prevailing opinionin the cancer researchcommunity is that can-cer is the result of anaccumulation of muta-tions in tumor suppres-sor genes and

oncogenes (cancer-causing genes). Though Dr. Duesbergidentified and mapped the first oncogene in 1970, henow contends that aneuploidy—an abnormal number ofchromosomes—is the cause of cancer.

“[Aneuploidy] is by far the most massive geneticabnormality of cancer—thousands of extra genes ormissing genes,” he says. “And yet it was, and still is,the most neglected candidate for the cause—a fasci-nating combination.”

The Berkeley Science Review recently interviewed Dr.Duesberg, a professor in UC Berkeley’s department ofMolecular and Cell Biology, to ask him about his mostrecent work with aneuploidy.

Peter Duesberg of the MCB Department arguesthat cancer’s cause is aneuploidy, an abnormalbalance of chromosomes. (Photo courtesy ofMartin Sundberg.)


Counterpoint

five wheels, no brakes, red headlights,etc). The analogy also explains why an“activating” gene mutation, or an acti-vated assembly-line worker in our anal-ogy, is unlikely to generate cells with newproperties like those of cancer, becausethe rest of the assembly line would con-tinue at its old rate—no matter howmuch faster the mutant assembly-lineworker could work.

BSR: You liken the process by which acarcinogenic aneuploidy emerges fromrandom aneuploidy to the evolution ofa new species. Can you elaborate uponthis analogy? How valid is it?

PD: A species is defined, in part, by aspecific number of chromosomes. Forexample, humans have 46 and micehave 40. Indeed, the number of chro-mosomes defines the species barriers,because successful sexual reproductiondepends on matching compatible chromo-somes. It is for this reason that aneuploidcancers can be defined as species of theirown. The numerous cancer-specific phe-notypes, par ticularly autonomousgrowth, that are generated by aneup-loidy distinguish the cancer species fromthat of its host or hostess.

BSR: If you could live your careeragain, would you change anything?

PD: About as much as you can change,given the same 46 chromosomes andabout 60,000 genes I have in these chro-mosomes! I would possibly be morediplomatic than I was, when I firstdiscovered the many paradoxes of thevirus-AIDS hypothesis and of the now-prevailing gene-mutation hypothesis ofcancer. But I would not be a scientist who

ago, the DNA tumor viruses were foundto be very potent aneuploidogens, induc-ing random aneuploidy right after infection.We have recently found that eventually acarcinogenic aneuploidy emerges fromrandom aneuploidy, since aneuploidy isinherently unstable, i.e., chromosomesare reassorted autocatalytically. Thisprocess is slow—just like the evolutionof a new species via a new chromosomeassortment.

However, the slow leukemia viruses donot cause aneuploidy on their own; theyjust benefit from spontaneous aneup-loidy. When a spontaneous, aneuploidleukemia destroys the immune system,the “leukemia viruses” are active, and thusdetectable, because leukemia destroys theimmune system. Since these and otherpassenger viruses become active afteraneuploidy caused the leukemia, theywere thought to be the causes of the leu-kemia—post hoc, ergo propter hoc.

So the DNA tumor viruses and leukemiaviruses are slow carcinogens, even thoughthey are fast viruses, because they dependon induced or coincidental aneuploidy tocause cancer. In view of that I took up thequestion of whether aneuploidy could bethe cause of all cancers.

BSR: How does aneuploidy causecancer?

PD: The power of aneuploidy to generatecancer or other abnormalities becomesimmediately obvious if one compares thecell to a car factory and chromosomes toassembly lines. Unbalance these assemblylines and you get highly abnormal carsfrom entirely normal parts (e.g., cars with

ranks acceptance by the mainstreamhigher than scientific discovery. Sincewe all live only once I would rather berespected by the next generation for alasting scientific contribution, than by thecurrent one for work that is popular nowbut scientifically flawed.

So working outside the think collective isnot all bad, once you have tenure like Ido. But it would be lethal for a youngAmerican professor without tenure,trying to make a career in the currentfunding system in the United States.


Want to know more?

Retroviruses as carcinogens andpathogens: expectations and reality.Peter Duesberg, Cancer Research Vol.47, pages 1199–1220.

Debate surges over the origins ofgenomic defects in cancer. Jean Marx,Science Vol. 297, pages 544–546.

A normal human cell has 46 chromosomes(top); an aneuploid cell has extra, missing andabnormal chromosomes (bottom).(Image courtesy of Rhong Li.)

If you have spent a cumulative total of three months ormore in England, or six months or more elsewhere inEurope, you can no longer donate blood in America. The

reason? You may have eaten mad cows. Mad cow, more sci-entifically known as bovine spongiform encephalopathy(BSE), is a disease that causes severe degeneration of nervecells. The brains of infected cows end up full of holes(spongy-looking, hence the name spongiform) and the ani-mals become uncoordinated and eventually unable to standup. The initial outbreak of BSE in Britain, and subsequentoutbreaks in France, Germany, many other European coun-tries, and most recently Japan, have led to mass slaughtersand incineration of hundreds of thousands of cattle (BSE-afflicted cows often along with their healthy herd-mates).

Here in the US, the blood donation ban is based on two assump-tions. First, cows in this country do not have BSE. Second, ifyou have eaten beef from mad cows in Europe, you may beharboring an infectious agent in your blood. Both of theseassumptions represent scientists’ best guesses based on in-complete information, and like all guesses they may turnout to be wrong. However, some suspect an even darkermotivation for the blood policy. Professor Kate O’Neill ofthe department of Environmental Science, Policy and Man-

agement (ESPM) at UC Berkeley, has been studying policydecisions related to the BSE epidemic. She had this com-ment on the assumptions behind the new blood-donationpolicy: “I think it’s a way of deflecting people’s attentionfrom what the risks are here of getting BSE. There’s some-thing interesting to me about the way that what is a foodcrisis in Europe is a blood crisis here. If BSE were to cropup here and get into the food system then this would be auseless measure. The supreme confidence that BSE is notgoing to emerge in any epidemic way in the US, that’s whatthis blood ban tells me.”

So could you really get BSE from eating beef? Does the bloodpolicy make sense? Will there be enough blood donors?Could there be mad American cows? And what should webe doing to keep BSE out of this country? Clearly there is alot of uncertainty, both official and popular, about BSE andwhat it means for our blood, our food, and our health. Howworried should we be?

Weird Science, Cannibals, and Jumping the Species Barrier

The reason scientists are so uncertain about the dangers of BSEis that the infectious agent that causes the disease is unlike any

IN THE FACE OF UNCERTAINTY

Batty bovines andempty blood banks

Sherry SeethalerSherry Seethaler


Perspective

pathogen they have ever discovered. Mad cow disease iscaused by prions. Prions are not bacteria, nor are they vi-ruses. Prions are proteins.For scientists, the idea thata protein alone could causea disease was absolutelystunning. Professor StanleyPrusiner of the department of Neurology at UC San Fran-cisco, won the Nobel Prize in medicine in 1997 for discov-ering prions. Since Prusiner first isolated prions in 1982,they have been implicated in an increasing number of hu-man and animal diseases.

The BSE-related blood donation bans are new; in August of1999, the Food and Drug Administration (FDA) bannedblood donations from people who had spent six months ormore in Britain, and in October 2001, the American RedCross (ARC) imposed the current, even more restrictiverules. However, prion diseases are not new. Scrapie, a dis-ease that infects sheep and goats and is now known to becaused by prions, has been around since the 1700s. Alsocaused by prions are several rare diseases in humans, someof which are genetic and some of which seem to arise spon-taneously. In the 1950s, there was an epidemic of aneurodegenerative disease called Kuru among the Forepeople of Papua New Guinea. The disease probably arosespontaneously in one member of the tribe, but was spreadduring cannibalistic feasts, where tribal members ate thebodies of their deceased relatives.

While scientists recognized that cannibalism could spreadprion diseases, they did not think these diseases couldcross the species barrier. This is based on the fact thatscrapie has been around for hundreds of years and hasnever infected humans eating sheep and goats. When madcow disease appeared in Britain in 1986, scientists soonrealized that it was spread when cows were fed processedmeat and bonemeal from other cows, a then-common practicein many countries, including the US. Few worried the diseasecould infect humans. Tragically, this meant that the Britishgovernment failed to take immediate action to protectits citizens. By 1996, the connection was made between

BSE in cows and a new prion disease in humans, the symp-toms of which were similar to those of Creutzfeldt-Jakob

Disease (CJD), arare spontaneousprion disease longrecognized in hu-mans. However, this

new disease, dubbed variant CJD, or vCJD, differed in itsonset (vCJD often claimed much younger victims thanCJD) and in the pattern of deterioration of the brain.The link connecting vCJD and BSE has become morecertain based on molecular comparisons of the strainsof prion involved in these and other diseases.

A Dearth of Donors

The decision to ban blood donations from people who havelived in Europe is based on very limited information. Thereis no known case of any prion disease in humans, includingvCJD, being transmitted via a blood transfusion. However,one experiment showed that blood transfusions could trans-mit BSE from one animal to another. Since there is currentlyno way to test for prions in the blood, the blood ban is aprecautionary measure based on very little science, but withsignificant implications.

According to Becky O’Connor, spokesperson for the Ameri-can Red Cross at Blood Services, Northern California Re-gion, nationwide only 5% of those eligible donate blood.Only 2–3% of eligible Northern Californians donate bloodand 30% of the blood needed in Northern California comesfrom other states to make up for the shortfall. We only havea one- to two-day supply of blood in the US. If the supplydrops to one day or less, some states enact a specific physi-cian approval process for non-emergency transfusions, inorder to conserve blood for disasters. Like many people,you may think blood availability will not really affect you,but blood transfusions are not rare. In fact, the ARC esti-mates that 50% of us will need blood transfusions in ourlifetimes. This is because blood and blood products are nownot solely used in the case of trauma and surgeries, but alsoas a treatment for many diseases. For example, platelets—


“The supreme confidence that BSE is notgoing to emerge in any epidemic way in the

US, that’s what this blood ban tells me.”

cell fragments in the blood that help to prevent bleeding—are used to treat cancer patients undergoing chemotherapy.

The ARC is quite dependent on blood drives at colleges anduniversities. However, many college students spend timeabroad. Because of privacy rules, the specifics of what po-tential donors are turned away and any percentage relativeto the vCJD restrictions are con-fidential. According toO’Connor, since October of2001 there have been 42 blooddrives affiliated with UC Berke-ley; 2,738 donors presented and530 of those were deferred. O’Connor estimates that 10–15% of all deferrals are related to vCJD guidelines. Thesepercentages are not insignificant when one considers howtight our supplies really are.

A Numbers Game

The current blood donation rules are based on a sort of num-bers game. No one really knows, but it is possible that aslittle as 10 grams—a marble-sized amount of beef—couldcontain enough infectious prions to cause vCJD. This is be-cause, even though they don’t have any RNA or DNA to helpthem, prions can replicate inside the body. This was a big sur-prise until scientists found that most, if not all, vertebrates,including humans, have prion proteins in their bodies, forexample, in brain cell membranes and in some cells of theimmune system. These normal prions may play a role in com-munication between cells, in cell adhesion, or in protectingcells against environmental stress. The difference betweenthese normal prions and the infectious prions lies in the waythe prion proteins are folded. The way a protein folds—itsthree-dimensional structure—is absolutely key to its function.Unlike normal prions, infectious prions have a three-dimen-sional structure that causes them to clump together in insolubleaggregates, which either directly or indirectly damage braincells. If infectious prions could not replicate in the body, itwould take a very large dose of them to cause the extensivedamage characteristic of BSE. However, infectious prions canrecruit normal prions to their ranks. When normal prionscome into contact with the infectious prions, the infectious

prions act as a sort of template that causes normal prions tomisfold. This sets up a chain reaction, with the newlymisfolded prions now serving as templates.

In theory, then, one could develop vCJD from eating a singlehamburger. Since prions are concentrated in the nervous sys-tem, hamburger, which might contain bits of brain and spinal

cord, is more risky than steak. Fur-thermore, while cooking the pinkout of your hamburger is enoughto kill dangerous bacteria and evenviruses, prions remain unscathed.Even the usual sterilization proce-

dures used for surgical instruments are not enough to destroyprions; this requires incineration. Of course, it is not realisticto ban blood donations from anyone who has traveled to Eu-rope within the last 20 years. So the FDA and the ARC haveenacted a policy that will reduce risk by 85%, according toARC estimates, without decimating the eligible donor pool.

The truth is that we really have no idea who will succumb tovCJD and who, if anyone, could transmit the infection throughtheir blood. So far, less than 150 people (mostly in Britain)have died of the disease, despite the vast numbers of peoplewho were likely exposed to tainted beef. Estimating futureoutbreaks of vCJD requires knowing the incubation periodof the disease—the time between being exposed to infectiousprions and showing symptoms of vCJD—and the factors thatmake a person susceptible to it. However, neither of thesedisease characteristics is known. The incubation period maybe anywhere from 10 to 60 years. Furthermore, people whohave a certain genetic variant of normal prions may be lesssusceptible than others, but it is not clear if they are truly lesssusceptible or just take longer to develop symptoms.

A simple test to detect prions in the blood would make itunnecessary to ban blood from people who have lived inEurope, and make sure that people who have spent shortperiods in Europe are not harboring infectious prions in theirblood. However, this would not be a panacea either. Cur-rent FDA and Center for Disease Control regulations statethat donors must be informed if their blood tests positivefor HIV or other diseases. It is ethically necessary to inform


Only 2–3% of eligible Northern Californiansdonate blood, and 30% of the blood

needed in Northern California comes fromother states to make up for the shortfall.

Perspective

people if they have HIV because it can be spread via sexualcontact. Since vCJD currently has no cure, people mightnot want to donate blood for fear of being told that theyhave a fatal, incurable disease. Unlike HIV, there is no rea-son to think that vCJD can be spread via sexual contact, soif a blood test does become available, donors should be giventhe option to not be informed of their prion status.

Clearly, the blood ban is imper-fect. We need all the donors wecan get, and while the ARC esti-mates there should be plenty ofeligible donors even taking intoconsideration the BSE-related ban, there aren’t enough will-ing to donate. The ARC has embarked on a multi-million-dollar campaign to educate the public about the need, butwe are still faced with blood shortages. A major disastercould wipe out the on-hand supply very rapidly. However,the ARC is backed into a corner. They have to convince thepublic that the blood supply is safe. This is especially true inthe wake of the HIV/AIDS fiasco, where in the 1980s peoplewere infected with HIV via blood transfusions. (Blood isnow routinely tested for HIV.) Kate O’Neill agrees that theblood ban is probably necessary to maintain trust. On theother hand, she points out that restrictions on blood dona-tions may deter potential eligible donors. “Blood donationis altruistic and important to people as an act of communitybecause there aren’t so many acts of community left in so-ciety. People are disillusioned with voting and so on. Peoplelike to feel that they’re going to be welcomed and not hitup with these lengthy questionnaires.” Furthermore, evenmore eligible donors may become discouraged if the ARCdecides to extend the blood donation ban to travelers to yetmore countries (Japan, for example).

Upping the Ante, Loopholes, and Tradeoffs

There isn’t a simple solution to the blood crisis. We needmore science. We need to know if vCJD can be transmittedby blood. We need to know if procedures l ikeleukodepletion—removing white blood cells, which tendto be the reservoir of infectious agents in the blood for mostdiseases—could prevent transmission. In the meantime, for

all the care to keep our blood supply free of prions, do theUS authorities know for certain that our cattle herds areBSE-free? Could a food crisis be brewing here?

The US Department of Agriculture (USDA) and the FDA havetaken a number of steps to keep BSE out of the country. Theybanned the importation of cows, sheep, and meat productsfrom BSE-affected countries, and slaughtered and tested ani-

mals imported before the newrules were enacted. The practiceof feeding rendered meat andbonemeal to cattle was banned.The USDA did this faster than the

Japanese authorities, which may explain why BSE has shownup in Japan but not here. Also, unlike in many other coun-tries, in the US meat and bonemeal were not usually fed tovery young cattle, since grain here tends to be relatively cheapand plentiful and is considered a better source of nutrients.In general, older cattle, which were given rendered meat andbonemeal, are less susceptible to BSE. In 1990, the US alsobegan to test cattle for BSE. This year, 12,500 cow brains willbe tested. This has raised some concern because it is still onlya tiny percentage of the more than 100 million cattle in theUS. However, Dr. Donald Klingborg, Associate Dean for Ex-tension and Public Programs, School of Veterinary Medicineat UC Davis points out that the USDA concentrates on test-ing cows most at risk for BSE, for example, cattle that arehaving trouble standing, a symptom of BSE. BSE has neverbeen found in any cattle in the US. Klingborg believes thatthere are “lots of ways to argue that we don’t have sufficientsurveillance, but in reality the way they’ve [the USDA] strati-fied the surveillance I’d be surprised if we didn’t find it shouldit be here.” According to a study by Harvard University’s Schoolof Public Health, the US is “highly resistant” to the introduc-tion of BSE, and BSE is unlikely to become established in theUS. This study is currently undergoing peer review.

Even if we don’t have BSE in our cattle herds at present, itcould still arise. One concern is that a prion disease calledchronic wasting disease (CWD), which infects elk and deer,could find its way into cattle in the US. CWD was initiallyidentified 35 years ago in Colorado, and is now found in 10states and two Canadian provinces. It is not certain how CWD


“In reality the way they’ve [the USDA]stratified the surveillance I’d be surprised

if we didn’t find it should it be here.”

is transmitted in elk and deer. Since elk and deer don’t eateach other, it must be spread via another means, possiblythrough contact with bodily secretions or via insect bites. Itis not known if this disease can infect cattle. There is alsoconcern that hunters who eat elk and deer may become in-fected. So far there is no evidence that this has happened orcan happen, but these risks cannot be ruled out and it is wiseto continue to follow the CWD epidemic very closely.

Another area of concern is that despite the bans to preventthe feeding of rendered meat and bonemeal to ruminants likecows and sheep, it can be fed to non-ruminant animals likepigs and chickens. Unfortunately, there is often no system inplace to prevent commingling of feed while it is being manu-factured or packaged. Cross-contamination has been foundto occur, and there simply aren’t enough USDA inspectors toenforce the regulations. Furthermore, since we don’t reallyknow how BSE arose to begin with, it would seem wise tostop feeding meat and bonemeal to any animals intended forhuman consumption. After all, who’s to say we won’t get madpigs or mad chickens? Transmissible spongiform encephalo-pathies, like BSE, are believed to arise spontaneously at a rateof one in one million. While this is rare, as we have seen withBSE and Kuru, cannibalism can permit the dramatic spreadof these diseases.

However, as Klingborg points out, we fed rendered meatand bonemeal to cattle as a protein supplement for half acentury without problems. Also, some scientists think thatchanges in the rendering process made in Britain in the early1980s may have been what led to the BSE epidemic. Thosechanges included the reduction of temperatures at whichthe carcasses were processed, which could have permittedinfectious prions to survive the rendering process and bespread to cows in countries using British meat and bone-meal. Why this temperature change could have had an impactwhen infectious prions can only be destroyed by incineration isnot entirely clear.

Despite these reassurances, why not err on the side of cau-tion and ban the feeding of meat and bonemeal entirely? It’sa matter of resources. According to Klingborg, “To replace

the ruminant-origin meat and bonemeal will take an addi-tional three million-plus acres of soybeans and create hugeissues relating to disposal, as this material can no longer be‘recycled.’ It is a difficult challenge!”

There are no simple solutions to the BSE issue. Clearly ev-ery decision—be it blood bans, feed bans, or the decisionto wait and see—has tradeoffs. Although BSE has not beenfound in American cattle, the issue does provide consider-able food for thought. In reality, BSE is just one issue in thegreater context of our unending drive to increase agricul-tural product yields while decreasing production costs.While we have stopped feeding cheap recycled body partsto cattle, other controversial practices continue. Most ofour crops are grown with a heavy input of pesticides andchemical fertilizers; livestock are raised in tight quarters,and are given hormones and antibiotics not just to cure dis-eases, but to make them grow faster. The result is that herein the US food is plentiful and cheap. Most of us take thisfor granted, think little about how food appears on storeshelves, and sometimes react with short-lived outrage whenwe hear that we are eating products of new biotechnologies,or learn of the way livestock are treated. In the meantime,our regulatory agencies do the best they can to balance theneeds of consumers, farmers, and industry.

Choices made by the food industry, like feeding animal-derived products to herbivores, may leave consumers feel-ing disenfranchised. In reality, consumers are the ones withthe power. Eating less, wasting less, buying food at localfarmers’ markets (because shipping products long distanceshas environmental costs), rejecting food raised in certainways, and realizing that a diet high in animal protein isunsustainable on a small planet are options we have. Ofcourse, we shouldn’t reject new practices out of fear ormisinformation. Pasteurization was once controversial, butfew people today would choose to drink unpasteurizedmilk. On the other hand, we should ask questions, demandanswers, and recognize that our choices have far-reachingconsequences. After all, who would have thought that feed-ing cows to cows would impact our blood supply?


Perspective

Photo courtesy of Roy Caldwell

Want to know more?

Sex identification and mating in the blue-ringed octopus,Hapalochlaena lunulata. Mary W. Cheng and Roy L.Caldwell, Animal Behaviour Vol. 60, pages 27–33.

ib.berkeley.edu/labs/caldwelll

The Back Page

A native of Indonesia and thePhilippines, the 2-cm-long maleblue-ringed octopus (H. lunulata)is unable to determine the sex ofpotential mates

Eight Legs O’ Love:Sex habits of the pygmy blue-ringed octopus

Colin McCormick

When it comes to sex, we humans are lucky. With a few notable exceptions, you and I can tell at a glance the gender of anyonewe meet. That means we don’t have to waste time, energy, and expensive candlelit dinners on someone who might turn out to have

the wrong plumbing. But life’s not so easy for the blue-ringed octopus (Hapalochlaena lunulata), as Mary Cheng and Professor RoyCaldwell of the Integrative Biology department have discovered. The males of these pygmy cephalopods (which, by the way, pack a deadly

poisonous bite) are totally unable to determine the sex of another H. lunulata nearby. In fact, they’ll jump any other H. lunulata that wandersby, male or female, and have even been observed attempting interspecies mating (in that respect, they’re not so different from certainhumans, who will remain nameless).

All this is not to say that H. lunulata males don’t wise up pretty quick if they’ve put the moves on another hombre. Male-male couplings,observed Cheng and Caldwell, typically last only 30 seconds, and the initiating octopus removes his hectocotylus (a modified third arm

that delivers the spermatophore goods when the mood is right) amicably. But when luck is with him and he’s found a lady, he staysplugged in for an average of almost 3 hours, letting go only after the female fights him off.

This sexual blindness may have to do with the blue-ringed’s normally reclusive nature. They are “mostly asocialanimals,” says Caldwell. “They do not encounter other individuals that often and it probably pays to check out

potential mating partners whenever they are encountered.” Female H. lunulata can store sperm,but they use it only once, since as with most octopus species they lay a single clutch of

eggs and then die. That’s one more respect in which we humans shouldconsider ourselves lucky.

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Berkeley Science Review - Spring 2003

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