WINTER p.4 The science of large numbers p.16 Eric Lander & the cancer code 07 p.10 Hitting the bull’s-eye p.22 It starts with an embryo

LensA New Way of Looking at Science

Hot on cancer’s trail

A PUBLICATION OF VANDERBILT UNIVERSITY MEDICAL CENTER – Cover: Cancer the crab scuttles across the beach, leaving behind a double-helical trail. Lens Photo illustration by Dominic Doyle. Photo credit: Science Faction/Getty Images. A New Way of Looking at Science

WINTER 2007

VOLUME 5, NUMBER 1

EDITOR Bill Snyder

CONTRIBUTING WRITERS Stephen Doster Leigh MacMillan Melissa Marino Bill Snyder

PHOTOGRAPHY/ILLUSTRATION Dean Dixon Dominic Doyle Allen Garns David Johnson Jared Leeds Anne Rayner It is only the vision that can be new; DESIGN Diana Duren/Corporate Design, Nashville but that is enough.

DIRECTOR OF PUBLICATIONS – EUDORA WELTY Wayne Wood

COPY EDITOR Nancy Humphrey

EDITORIAL OFFICE Office of News and Public Affairs D-3237A MCN Vanderbilt University Medical Center Nashville, Tennessee 37232-2390 615-322-4747 E-mail address: [email protected]

Lens is published three times a year by Vanderbilt University Medical Center in cooperation with the VUMC Office of News and Public Affairs and the Office of Research. Lens® is a registered mark of Vanderbilt University.

Our goal: to explore the frontiers of biomedical research, and the social and ethical dimensions of the revolution that is occurring in our understanding of health and disease. Through our Lens, we hope to provide for our readers – scientists and those who watch science alike – different perspectives on the course of discovery, and a greater appreciation of the technological, eco - nomic, political and social forces that guide it.

© 2007 by Vanderbilt University Lens TABLE OF contents W0IN7TER

2 CLOSING IN ON CANCER

3 HIGH -TECH SURVEILLANCE Proteomics, the science of proteins, has raised hopes that doctors one day will be able to detect early cancer from tell-tale patterns of proteins in a single drop of blood. What will it take to bring these methods into the clinic?

4 THE SCIENCE OF LARGE NUMBERS From Shanghai, China, to the American South, modern-day gumshoes are hot on the trail of some of the worst miscreants afflicting the human race. By surveying thousands of participants enrolled in “cohort studies,” researchers are uncovering important clues to cancer and other diseases.

10 HITTING THE BULL ’S-EYE They’re not “magic bullets,” but targeted therapies have dramatically improved page 10 Explosion of drugs for cancer outcomes for many cancer patients. These drugs are not without side effects, however, and some of them cost $10,000 a month. Vanderbilt researchers give an update on the search for better treatments.

15 TURNING GENES ON TO TURN CANCER OFF Cancer can result not only when certain genes are “turned on,” but when others are “turned off” by the attachment of chemical “tags” to the DNA. This tag-driven con - trol of gene expression – called epigenetics – provides a new avenue for stopping tumor growth.

16 THE GREAT AMPLIFIER A driving force behind the sequencing of the human genome, Eric Lander is now tackling the “cancer genome.” More than that, this mathematical wunderkind wants to empower the next generation of scientists with new tools and information so they page 16 A new taxonomy for tumors can “change the world.”

22 IN THE BEGINNING It could be nature’s cruelest joke – the genes and proteins that help sculpt the fertil - ized egg into a complex multicellular organism are also responsible for the birth of many cancers. Understanding the fundamentals of developmental biology could lead to new treatments for patients.

28 A PROBLEM OF SOCIAL INJUSTICE Harold Freeman, M.D., former president of the American Cancer Society, and Jane Weeks, M.D., chief of Population Sciences at the Dana-Farber Cancer Institute, dis - cuss what needs to be done to reduce the disproportionate impact of cancer on racial and ethnic groups, the poor and the elderly.

32 LWALA DIARIES The previous issue of Lens chronicled the efforts of Vanderbilt medical student Milton Ochieng’ to construct the first health clinic in his village in Kenya. Abbie Foust, who spent her summer vacation surveying his village’s health needs, describes her life-changing experiences. page 22 The power of Wnt and Hedgehog

LENS / WINTER 2007 1 B N A O X R I D C N A E E D H T G N I H C T A C

the role that cigarettes play in the disease. Cohort studies, which track the development of disease in large groups over several decades, also may help solve l i the riddle of cancer disparities – why a

r cancer incidence and death rates are t

s disproportionately high, for example, ’

r among African-Americans. e c “It’s where research always starts,” n

a says Jane Weeks, M.D., chief of c Population Sciences at Boston’s Dana- n

o Farber Cancer Institute. “It generates t

o Symphony of knowledge hypotheses. It generates ideas.”

H Charting cancer in cohorts, uncover - Science closes in on cancer ing proteomic fingerprints, discovering clues to cancer in the development of an embryo – all avenues are important. By Bill Snyder “By pulling all of this information together into a symphony of knowledge, we will be able to exponentially expand the rate of effective cancer treatment over the next 10 or 20 years,” predicts Raymond he crab on the cover of this issue of Lens magazine represents all that is DuBois, M.D., Ph.D., director of the Told and new about cancer, the nation’s second leading cause of death after Vanderbilt-Ingram Cancer Center, who heart disease. later this year will become provost and Old, because cancer goes back to the dinosaurs; evidence of malignancies has been executive vice president of academic affairs found in fossils dating back 80 million years. at the University of Texas M.D. Anderson New, because fields as disparate as genomics and embryology are providing new Cancer Center in Houston. hope that a war declared 36 years ago by President Richard Nixon one day will be won. Continued support of cancer research In this issue, Eric Lander, Ph.D., a driving force behind the Human Genome is crucial, he adds. So is nurturing the Project, predicts that cancer patients soon will be able to have complete genomic next generation of scientists. workups to determine exactly what subtype of the disease they have, and which treat - “What makes me most impatient and ments are most likely to work. most frustrated is when I hear young peo - The sequencing of the 20,000 or so genes that make up the human being already has ple’s proposals being criticized for being improved our understanding of the genetic “switches” that turn on tumors. One benefit: too ambitious,” says Lander, who directs a discovery of new compounds that can switch off malignant growth without harming genomic research powerhouse, the Broad normal cells. Institute of MIT and Harvard. Also on the horizon: screening blood tests that harness the power of proteomic “There’s nothing wrong with young “fingerprints” to detect early cancer, even before symptoms occur. people being too ambitious. They should This issue of Lens focuses on the spectrum of research – from basic laboratory studies be too ambitious … the desire to try to do to clinical trials of new drugs – undertaken by scientists at Vanderbilt University Medical something important is a great fuel; it’s a Center, the Vanderbilt-Ingram Cancer Center and colleagues from Boston to Shanghai. great resource.” The story would not be complete, however, without mentioning epidemiology, This, incidentally, is the raison d’être that non-flashy field of medical research that is crucial to understanding what causes for Lens magazine – to explore, to explain, disease and how to prevent it. to inspire … to follow, if you like, the By recording the incidence of lung cancer among Americans over time and corre - double helical trail left in the sand by an lating the numbers with smoking rates, researchers were able to establish conclusively ancient animal. LENS

2 LENS / WINTER 2007 Liebler is heading up one of five The standardization effort mirrors E C

teams across the country to standardize approaches being developed for early N A

proteomic technologies and move them detection of colorectal cancer in the Jim L L

forward. The project, part of the NCI’s Ayers Institute for Precancer Detection I

Clinical Proteomics Technologies and Diagnosis. Liebler also directs this E V

Initiative, was announced during last institute, part of the Vanderbilt-Ingram R

fall’s news conference. Cancer Center. U S Richard Caprioli, Ph.D., co-director of Other Vanderbilt researchers have H

the Vanderbilt team, directs the Mass found proteomic “signatures” that poten - C

Spectrometry Research Center and has tially may improve the early diagnosis E T helped pioneer the technology used to and treatment of lung cancer, and they - H

identify and analyze protein biomarkers in are scanning protein profiles found in the G tissue samples. blood of African-American and Caucasian I H Gordon B. Mills, M.D., Ph.D., direc - women for clues to why African-American s tor of the Kleberg Center for Molecular die more frequently from breast cancer. Markers at the University of Texas M. D. Proteomics “is an incredibly promis - High-tech Anderson Cancer Center, is collaborating ing field,” said Barker, “but until we get with the Vanderbilt researchers. some standardization here, it’s just not surveillance “A lot of the differences between going to move forward. proteins in disease states and normal “If we can move this field forward, we l The power of proteomics health are not differences in the amount s believe we can actually diagnose cancer i a

of the proteins themselves, but in the very early,” she added. “If we diagnose it r t modified forms of proteins that are pres - very early, we can start to really reduce s

BY BILL SNYDER ’

ent,” explains Liebler. Abnormal genes, the burden of this disease and ultimately , r e

for example, may encode abnormal pro - potentially, make it history.” LENS c n

Will fingerprinting cancer lead to its teins, which in turn, trigger a cascade of a arrest? events leading to cancer. To learn more about Vanderbilt’s proteomics c program, go to: www.mc.vanderbilt.edu/msrc. n That’s the hope of proteomics, the “Proteins are commonly dressed up o science of proteins. in many different kinds of modifications t For more on the federal initiative, visit o

Researchers are trying to identify that control their activity and function,” http://proteomics.cancer.gov. H patterns of proteins in blood and tissue he says. “And so the problem is not so samples that reflect the presence of much in identifying the proteins but it’s diseases like cancer in the body. These frisking them, being able to detect differ - patterns, often called “molecular finger - ences in modified protein forms.” prints,” could serve as biomarkers for Vanderbilt’s approach to frisking is early detection. called “shotgun proteomics,” in which “We believe that the future of medicin e proteins from a biological sample are cut is actually going to depend very heavily into small pieces called peptides, ana - on the ability to discover and validate bio - lyzed using mass spectrometry tech - markers in proteomics,” Anna D. Barker, niques, and then put back together. Ph.D., deputy director of the National “Everybody has their own way of Cancer Institute (NCI), said during a news doing shotgun analysis,” says Liebler, conference last fall. adding that his team’s goal is to stan - By improving early detection, biomark - dardize the technology. er s could increase the chances for suc - cessful treatment and survival, noted Nobel laureate Leland Hartwell, Ph.D., president A montage of molecular and director of the Fred Hutchinson images glows with a spectrum Cancer Research Center in Seattle. of peptides and proteins, their In addition, “they will be useful for colors assigned to different managing the cancer process at all stag es, molecular weights, in sections of a rat brain. Images like from risk assessment to early detection these, which were produced to prognosis to therapeutic response by MALDI imaging mass and disease recurrence,” he said. spectrometry, can reveal the Currently, however, there is a lack of distribution of individual standardization of techniques used to proteins in cells and tissues. analyze proteins. As a result, “the overall Image courtesy of Malin reliability of the approach is not currently Andersson, Ph.D., research sufficient to apply it directly to clinical fellow in the Vanderbilt Mass research,” says Daniel C. Liebler, Ph.D., Spectrometry Research Center director of the Proteomics Laboratory in the Vanderbilt Mass Spectrometry Research Center.

LENS / WINTER 2007 3 E M

I Pictured here: Wei Zheng (left) and Xiao T Ou Shu, a husband-and-wife research

A team at Vanderbilt University Medical

T Center, seem to stroll through a A Shanghai market in this photo illustra -

T tion. Two cohort studies they direct in E China’s largest city are providing clues K

C to cancer and other diseases. U B Photo illustration by Dean Dixon E Shanghai photo by Getty Images N O n i a r B e h t f o s r e d r o s i D

T##H####E###S###C###I#E###N###C##E#################### OF LARGE NUMBERS ############################################ COHORT STUDIES SHED LIGHT ON CANCER By Stephen Doster

4 LENS / WINTER 2007 E M I T A T A T E K C U B E N O h t l a e h l a b o l G

LENS / WINTER 2007 5 S

R An example is the landmark Southern the United States in 1989 and 1990 for E Community Cohort Study, which will Ph.D. training at Johns Hopkins B

M very year, 50 modern-day gumshoes attempt to explain why African-Americans University and Columbia University in

U E fan out across Shanghai, China, are more likely than other groups to New York, respectively. N hot on the trail of some of the worst mis - develop and die from cancer. “I was involved in the Iowa Women’s E

G creants that afflict the human race. The study is a collaboration of the Health Study and wrote a paper focusing R

A Armed with survey forms, they Vanderbilt-Ingram Cancer Center, on tea consumption and cancer risk. Most L question the inhabitants of thousands of Meharry Medical College and the studies look at what is bad about diet. I homes. Their goal: to find out why some International Epidemiology Institute thought, ‘We need to focus on what is good people develop cancer and other diseases, (IEI), a biomedical research firm based in about diets to help protect against cancer.’” and others don’t. Rockville, Md. Zheng presented a paper at an annual Begun a decade ago by researchers Since the study was launched four meeting of cancer research where he now at Vanderbilt University Medical years ago, nearly 63,000 adults ages 40 to noticed tremendous interest in research Center (VUMC), the Shanghai Women’s 79 have been enrolled through community focusing on protective foods – not just tea, Health Study has yielded important clues health centers in 12 Southeastern states, but soy foods, fruits and vegetables. to the mysterious connections between including Tennessee. The goal is to recruit “I thought, ‘We have done all these environment, genetics and disease. 90,000 participants. things to identify risk factors. How about For example: “Historically, the home of the African- identifying protective factors?’ So I came • Women who have never smoked but American population in the United States home and developed the proposal to focus whose husbands are heavy smokers are has been in the South,” explains William on dietary protective factors, and the NIH l i at greatly increased risk of dying from Blot, Ph.D., IEI chief executive officer and funded it right away.” a

r the study’s principal investigator. “There So far the study has recruited approx -

t stroke.

s • High intake of soy foods lowers blood had never been an investigation in the imately 75,000 women between the ages ’

r pressure and decreases the risk of both South on this order of magnitude. of 40 and 70 in seven typical communities e c coronary heart disease and bone fractures. “When you start getting up in num - in Shanghai. n

a “Sometimes the associations between bers of people with a particular type of “With an epidemiological study, we c lifestyle and disease are so striking it sur - cancer that approaches 1,000, that gives want to recruit a large number of partici - n

o prises us,” says Wei Zheng, M.D., Ph.D., you pretty good power to start looking at pants in order to have an adequate power t

o who directs the Shanghai study with his environmental and genetic factors,” says to evaluate study hypotheses,” he says. “In

H wife and colleague, Xiao Ou Shu, M.D., Blot, who also is a professor of Medicine other words, the more participants we Ph.D. “We are conducting additional studies at Vanderbilt. have, the more confidence we have about to get more definitive answers.” our research findings.” The Shanghai investigation is known ################ While working with her husband on as an epidemiological “cohort” study. It is this study, Shu realized that more could be designed to track the development of dis - Focus on the good gained than simply studying women. In ease in a large group of people over an Zheng got the idea for the Shanghai 2001, she launched the Shanghai Men’s extended period of time – usually decades. Women’s Health Study in the early 1990s Health Study. To date, 60,000 men have Cohort studies can help reveal the while working at the University of been enrolled, half of whom are married to impact that diet, exercise and other Minnesota. participants in the women’s cohort. lifestyle factors can have on health and He and his wife met at Shanghai “First, we did a small pilot study and longevity. More recently, they’ve been Medical University, where they both discovered that the husbands’ and wives’ used to explore the disproportional impact earned medical degrees and master’s dietary habits are very different, although of disease on different ethnic groups. degrees in public health before coming to they share the same living environment,”

“Junior faculty, post-doctoral we’re looking at virtually every people into the Southern fellows and senior investigator s major condition, including psy - Community Cohort Study at the are using our resources in chological effects, kidney Family Health Centers’ other studies – genetics, nutri - stones – you name it.” Portland Clinic in Louisville, Ky. AN tion,” notes Vanderbilt’s Wei For example, the study has “Most of our patients’ Zheng, M.D., Ph.D., MPH, who found that a diet high in sugar- (annual) household income is ENDURING directs the Shanghai Women’s sweetened and diet soft less than $15,000,” she Health Study. “So the cohort drinks, refined grains and says. Many “have been diag - LEGACY studies create opportunities processed meat can raise the nosed with depression ... for other research.” risk of developing type 2 dia - Education, housing, emotional One of the exciting poten - Harvard’s Walter Willett, betes, and that obesity and health – everything plays into tials of cohort studies is that M.D., MPH, Dr.P.H., who weight gain increase the risk of your well-being.” the collected data can be used launched the second Nurses’ kidney stone formation. – STEPHEN DOSTER by other researchers to Health Study in 1989, echoes Emily Beauregard sees the address questions that are that sentiment. “We started potential for a psychological important to their areas of mostly with a focus on cancer study based on a trend she interest – for years to come. and heart disease, but now noticed last year while enrolling

6 LENS / WINTER 2007 S R E R

“When you start getting up in N E Y A B numbers of people with a particular R M E U N

type of cancer that approaches N N A

1,000, that gives you pretty good E G power to start looking at environ - R A mental and genetic factors.” L

William Blot, Ph.D., Principal investigator, Southern Community Cohort Study l i a r t s ’ r

Shu says. “For instance, men like to eat live in apartment towers, dozens of study what is causing cancer, we will never e c

more meat compared to the women.” participants can be found in one building. know the answers.” n a

Most women in China also work out - The interviews are later transferred from “A lot of folks in our area have been c

side of the home. “So there is an opportunit y paper to an electronic form for data analysis. affected by cancer,” adds Emily Beauregar d, n to look at environmental and occupational “In-person interviews improve the who enrolled about 90 people a month o t factors as well.” quality of the data,” Zheng explains, “par - last year at the Family Health Centers’ o

One goal of the Shanghai cohort ticularly across a large population with Portland Clinic in Louisville, Ky. H studies is to determine whether differences diverse educational and income back - “There’s not a lot one person can do in traditional Asian and Western diets grounds. If you asked someone to fill out a to stop disease or make someone who has account for widely varying incidences of form, you may get different quantities and cancer better,” says Beauregard, who is different cancers among residents of China quality of responses. In-person interviews currently enrolled in a master’s degree and the United States. minimize the differences. program in public health. “But if you can Researchers know that Asia and the “Secondly, the response rate is high participate in something that may in the United States have quite different cancer with in-person interviews. We have a long run halt or decrease the rates of can - spectra. In China and Japan, stomach can cer 93 percent response rate. Mailed surveys cer, people feel that is empowering to be used to be the No. 1 culprit followe d by typically get a 25 percent to 40 percent able to do something about it.” cancer of the esophagus; whereas in the response.” Both studies track participants by United States, lung, colon and breast A higher response rate makes it easier name, address, social security number, and cancers dominate. to generalize findings across a population, in Shanghai, by citizenship IDs. The However, the cancer spectrum in he adds. researchers regularly monitor government some parts of China, such as Shanghai, is registries in China and the United States starting to more closely resemble that of ################ that track disease and deaths reported by the United States. For people who move health officials. Participants are also con - from China to the United States, the risk Empower the people tacted periodically to update their disease of stomach and esophageal cancers decrease s The Southern Community Cohort and exposure information. while the risk of lung, colon, and breast Study takes a different tack. Its researchers Biological samples – urine, blood, cancers dramatically increases. rely on community health centers to enroll cheek cells (for DNA) – are sent to The million-dollar question, of study participants, most of whom are VUMC, where they are stored in freezers course, is “Why?” lower income. for future analysis. One hypothesis is that lifestyle factors – Betty Scott, an interviewer at the West “We get boxes from up to 30 different including diet – account for these differences. End Medical Centers in Atlanta, has enrolled centers every day,” Blot says. “The blood The Shanghai studies were designed over 2,600 people into the study. Her inter - is separated into 14 different tubes and to test the hypothesis that the traditional est in the project is more than academic. stored in a freezer bank.” Asian diet, which includes soy foods, bok “I have a history of cancer in my fam - Once the data and biological specimen s choy (Chinese cabbage), white radish, gin - ily,” she explains, having lost her father, a have been collected, the real detective ger root, tea and ginseng, may reduce the brother and a sister to cancer. Three other work begins. risk of diseases including some cancers. brothers have been diagnosed with cancer. “We will do that through a ‘case-con - To find out, the Shanghai studies “Of course, I want to know what is trol’ study,” he says. “… We will identify rely on trained interviewers who go door- causing so much disease,” Scott says. “We everybody, say 500 people … who (have) to-doo r. Because most Shanghai residents all have theories, but until research proves developed lung cancer, and get their blood

LENS / WINTER 2007 7 S

R specimens. Then we choose a control Typically, during the first five years Simply adopting Asian eating habits E group of 500 or 1,000 people (without of an epidemiological study, most of the may not yield the same benefits in the B

M cancer) who are the same age, sex, race, effort is devoted to recruiting study par - United States, Shu cautions. U etc., and pull their blood specimens. ticipants and collecting survey data and “Even though lots of people in the N “Then we look for differences biological samples. The value of the South eat rice and greens, as do people in E

G between the cases versus the controls. cohort study increases as it is followed Shanghai, the specific type of vegetables R

A Meanwhile, we have all this background over the years and cohort members begin and the way the food is prepared is very L information on everybody, their smoking to develop different diseases. different,” she says. history and other factors. The Shanghai Women’s Study has In addition, “the ways soy foods are “If the cause of a disease in this lower already begun to shed light on a number consumed in the U.S. are quite different income population proves to be genetic, of areas. from how they are consumed in China,” we should be able to apply our findings to Among the findings: “Women who are Shu adds. “For example, many soy produc ts higher income and higher education popu - non-smokers but who are exposed to the in the U.S. contain a large amount of lations. Even environmental associations cigarette smoking of their husbands have sugar, while most soy products are con - seen in the study population may apply an increased risk of dying of stroke,” Zhen g sumed in China without the addition of more broadly, but we will examine these says. “We also learned that soy food intake any sugar.” closely before making any extrapolations reduces the risk of fractures, hypertension, As for the Shanghai Men’s Study, to other segments of society.” coronary heart disease and diabetes.” which recently completed recruitment, Shu notes that the smoking rate in this cohort is high – 67 percent. l i “We found that smokers have a lower a WHAT’S CATERPILLAR r body-mass index than their non-smoking t

s GOT TO DO WITH IT? counterparts,” she says, “but more central - ’

r ized obesity or beer belly, meaning they

e The role of the private sector in cancer research c gain more weight around their torso. This n Cohort studies are important research investments, says Harvard epidemiologist a can more be harmful to health than less c Walter Willett, M.D., MPH, Dr.P.H. centralized obesity and may increase the n “They’re necessarily long-term investments, too, and as such, they are particularly vul - o risk of cardiovascular disease and cancer.”

t nerable to cutbacks in research funding,” he says. o “If you have a project in the lab and it goes a year without funding, you can just start H up again,” Willett says. “But when you have dozens of people employed, and you have to ################ maintain active intervention with your participants, you can’t just start and stop without Conflicting results very serious damage.” That’s a major concern, considering the recent drop in federal funding for medical Cohort studies can yield conflicting research, adds William Blot, Ph.D., principal investigator of the Southern Community results. For example, a 2003 study of Cohort Study. California residents that found no relation - ship between environmental tobacco smo ke “The percentage of grant applications that are funded has been cut in half,” Blot says. and tobacco-related deaths contrasts “It used to be that the top 20 percent of grant applications were funded. Last year it sharply with a more recent finding from was only the top 11 percent, and this year the National Cancer Institute’s budget has the Shanghai Women’s Health Study, already been cut by $40 million.” which linked secondhand smoke to an As a result, the private sector is becoming an increasingly important source of sup - increased incidence of cardiovascular disea se, port. stroke and lung cancer. Three years ago, for example, Caterpillar Inc. pledged $1 million to the Southern While conflicting results can some - Community Cohort Study. The Susan G. Komen Breast Cancer Foundation is another times delay effective prevention and major supporter. treatment strategies, they can also lead to Kent Adams, president of Caterpillar Financial Services Corp., says Caterpillar officials new insights, says Walter Willett, M.D., were impressed with the scope of the project. MPH, Dr.P.H., professor of Epidemiology “As we investigated over time,” he says, “it became clear that the people behind the and Nutrition at the Harvard School of Southern Community Cohort Study really had an extraordinary vision of what this work Public Health who launched the second could do. We feel that the study and our participation are an endeavor to ensure that Nurses’ Health Study in 1989. the burden of cancer is reduced for everybody regardless of race or circumstance.” “Efforts to understand the differences Wendy Mason, director of project management for the Komen Foundation, said the (between studies) can result in new knowl - foundation is supporting the cohort study because of its potential to reduce breast can - edge,” Willett explains. “Sometimes the cer disparities. questions being asked are really different “Ultimately, … projects (like this) will shed light on factors that influence breast cancer questions.” risk, which we hope will lead to a better understanding of the differences in mortality Margaret Hargreaves, Ph.D., co- between Caucasian and African-American women,” Mason says. principal investigator of the Southern In corporate America, Adams says, “there is a trend towards a greater emphasis on Community Cohort Study and professor of philanthropy as a demonstration of overall social responsibility.” Internal Medicine at Meharry, is all too “Non-profits (also) are working really hard to raise dollars that they can contribute to familiar with conflicting study results. medical research,” Mason adds, “because it’s something that affects all of us.” “One reason you may see conflicting – STEPHEN DOSTER findings from studies is that people may not

8 LENS / WINTER 2007 f i o A o Heal A Heal M.D f f tha peo maki gatherin al study hav may ther’s w “Then cl ti go t hav eso nv or i he ver c ndigs m m m so osely asn’ curs ing i estigao exam ple e e e erican erican r be can . r “W P R “What H inv th th 90,” ng to l res resach t, ing arge And o of esarch fo argreav at som ano as it asoci based S S kep ol ea e’r r sure li y ple, E tudy. tudy fro much is,” dif iel y ve say ng l rc ers pidem mo wo coh ther arge enough ou ebody r m h,” d tha en of dif on s ated ernt are y resul doing men she re o es can.” val w ou thei M “ rol n rt the s w s fe numbe The younge it Ca specif he reca iol eli planig t me at the uable ave rent s se study h houg came wi ts ing ays. r than nc ki sample Me sa n ogy thos the dife Mex ans ir ons th l f otes. er nds of as rom s poula fa xic rs findgs Bondy, ht ins r br Cen o t U et st and in la in e mile i re ica infor hat ut s a o of a udies nive rge fro ea “Th obe ges s c ights f of n-Amer nt t white t S o n-Ame ha ter o whe a s e out peo pr hor m for t nd nro bre t s s mat s, c a at t rs in ion t c i incpa ompar Ph.D i t . udi a h anc yo numbe pl . n sa ’s ity a t n y a s l as Now ges M Nat a or Da ion s ying e Ho w u e wa long t gr id t tudie ica ric e er. e he ex o and h s jus s.” c ., oups kot f , s l y 5 us a no e ive an y ica n , a T nce pro nd r we’r t t t ton do e s o hat a. n- o it xa f r - , s e Af Am se ei n hi exp ide pa Am acr fe ki the gr ide ed Pictur technial et gar Mar “ ofesr pr studie, making and peol re ds gh . oups t ri os nti nti nce er er di er ca . ri g Whi “The Bl a s ra ic ic s f ns f f me n-A gr i . y y ,” s ot y te t er an an with gatherin oung ri m ce oups i w asitn .y nti Bl enc le of eavs, gr Har n ho of me s ra wo poul i ay rt k thi g ot t nal Inter te ng ou pes ai di her ir l e he f ri me he s ac as as wi n n poi o abe ca s, ” sure in wit f goal to lp studying sub at ev Mexi a n 11 th n s t nt m Bo t r di just Lawn i ent i e the e s h w o s you et xpl and s Medicn, s oki s ns as et om nd y of ve sm eas out i hni ca Ph.D, ual n s , Mathew s a ng r oci t n “co oki en. e y i 12 of t hi you n ly . c s he and r a l McKisak at am have s a at o pe y de m ng year t more can.” And nd w, s s ed poul he es . tudy pa opl t ong y r Mehar “ Me er to but We Walker cul acr w s s r m t i e se ba t ol i s udi xi her t M diferent o i at w t os i ’ h d nat c re ur w s ns can- e ho c i s to es al and di t o e’ xi e o.” al s o t Comunity n. e r specif Medical r i hes s can- ar e w ei n s e s eas di a as healt of i a e dy kep l f e g l - l Coleg arge dinato r educator/ mo to gens an inc me coul inc a caner ear to Health ca avo s l i re nta re re kinds uces y ncr ncer d doing “If as as w , l id , adv l informat i ed ed t eas kel hen a expos o . Centr you t a cer s For re f is ed r s l y ul i ur eas e s spo the t number t k. kno , ai r vei han t t ur t ev is hos r n in of nd eat yo k, es di l e diferen w ex l E L n Nashvile e ance ot s u m t the t ea pos t hat i at o her ha peol may f Tamr ent N s life you n e hig t ur S for s, put is .” we s / e st ome be bec s mor W L ca e yle e ar ,” E ca a r t rin.Cur SN n’t of able N I isk he r a he ly n and pe us e and om (fr m t R E T a pre ame det s e to ople dvise ays t at of o e ve be ect nviro left) c nable . a the a nt have n “ 0 0 2 tc unde ion t You hem ir h t he it of - r 7

DEAN DIXON

9 Hot on cancer’s trail LARGE NUMBERS E Y E - S ’ L L

U BY LEIGH MACMILLAN B E H T G N I T T I H HITTING l i a r t s ’ r

e THE c n a c n o t o H BULL’S-EYE TARGETED CANCER THERAPIES BEGIN MAKING THEIR MARK

Pictured here: Colorized X-ray of a lung tumor.

10 LENS / WINTER 2007 Zephyr/Photo Researchers, Inc. E L N S / W I N T E R 2 0 0 7 1 Global health MOSQUITO’S NOSE E Y E -

S “THESE ARE REALLY EXCITING

’ lan Sandler, M.D., pulls up a L

L A slide on his computer screen that TIMES IN CANCER THERAPY , U shows – in schematic fashion – the signal - B ing pathways inside a malignant cell. At a ESPECIALLY FOR LUNG CANCER. E

H glance, it looks hopelessly complicated. T White arrows indicate the chain of com - TEN YEARS AGO, WE HAD VERY G

N munication between proteins; the arrows

I LIMITED OPTIONS.”

T point here and there, crisscrossing the cell T

I like strands of spaghetti left on a plate. H “I’ll give you a minute to jot this down,” Nobel laureate Paul Ehrlich, M.D., coined of Cancer Research at Vanderbilt-Ingram. Sandler quips, adding that this line draws the term in reference to compounds that “Even the sponsor was surprised at how chuckles when he uses it during lung can - would seek out and destroy pathogenic effective that drug was in causing complete cer seminars. microbes without harming the patient. hematologic and cytologic remissions, The image is actually an oversimplifi - Targeted cancer therapies are envi - remissions where the Philadelphia chro - cation of the molecules and pathways that sioned as the “magic bullets” of cancer mosome disappeared. “drive” the cancer cell and which are targe ts treatment. Ideally, they affect proteins and “And this was done by a single pill for the newest generation of anti-cancer signaling pathways unique to malignant whose main side effects were skin rash, drugs. Seventeen blue boxes on the slide cells and leave normal cells alone. some weight gain and some edema. This l i list 29 different “targeted therapies” that While that ideal has not yet been was remarkable.” a

r are already approved or still in develop - t achieved, the contrast to traditional In the last five years, investigators

s ment, and where in the cell they act. chemotherapy is obvious. have discovered how some patients develop ’

r “The explosion of new drugs that are “Chemotherapy drugs control the resistance to imatinib, by acquiring addi - e c out there to study in cancer is astonishing, ” growth of cancer cells, but they do so in a tional mutations in the bcr-abl receptor n

a says Sandler, associate professor of way that’s kind of like using a hammer to that hinder Gleevec binding. A newly c Medicine and medical director of the kill a housefly on a table. If you bang the approved drug called dasatinib (Sprycel) n o Thoracic Oncology program at the table hard enough, you destroy the fly and is able to bind to the mutated bcr-abl, t

o Vanderbilt-Ingram Cancer Center. He the table too,” says David Johnson, M.D., overcoming resistance to Gleevec in

H recalls that in 1992, when he finished his deputy director of Vanderbilt-Ingram and patients with such mutations. fellowship, it was common not to even past president of the American Society of “Suddenly we have two highly effec - give chemotherapy to patients with Clinical Oncology. tive therapies for CML,” Rothenberg says. metastatic non-small cell lung cancer Likewise, surgery and radiation therapy “This is like the grand slam home run.” because the benefit was still questionable. can cause “tremendous collateral damage,” But CML appears to be a simple Today, chemotherapy and targeted although recent technological advances cancer, primarily driven by one genetic agents are extending life and offering hope have dramatically improved both of these mutation, he adds. to these very same patients. approaches, he says. “What we’re coming to realize is that “These are really exciting times in Among the first of the new targeted the majority of cancers, especially solid cancer therapy, especially for lung cancer,” therapies was Gleevec, whose behind-the- tumors, tend to be polygenetic in origin,” he says David Carbone, M.D., Ph.D., Harold scenes development was described in the says. “It’s more than just a single dysregu - L. Moses Professor of Cancer Research at book Magic Cancer Bullet by Daniel Vasell a, lated pathway, and so blocking a single Vanderbilt-Ingram. “Ten years ago we had M.D., chairman and chief executive officer pathway isn’t really sufficient in the major - extremely limited options.” Today, some of the pharmaceutical company Novartis. ity of cases to cause true tumor regression.” of the new targeted therapies are “nearly Gleevec bounded onto the world miraculously effective.” stage in 2001, with accelerated approval SIGNATURE RESPONSE Carbone cites the effects of the drug from the Food and Drug Administration The more specific a targeted therapy imatinib (Gleevec) in patients with chronic for the treatment of chronic myelogenous is – in terms of its target – the more myelogenous leukemia and gastrointestinal leukemia (CML). restricted is the patient population that stromal tumors, and the drug erlotinib The abnormality that causes CML – benefits, Carbone says. (Tarceva) in select lung cancer patients. the so-called Philadelphia chromosome “The reality is that lung cancer is “It’s like a Lazarus response,” he says. (named for the city in which it was dis - probably 10, 15, 20 different diseases, But as the number of new drugs covered) – was first described in 1960. It driven by different molecular mechanisms climbs, so do the challenges in designing results from a translocation, a rearrange - and combinations that we’re just beginnin g clinical trials to test the new therapies, ment that fuses two genes from different to understand,” he says. “If we could find selecting the patients who will most bene - chromosomes together. This in turn what subpopulations of tumors are driven fit from them, managing the costs of these produces an abnormal protein, a tyrosine by particular pathways, then we could find drugs – thousands of dollars per month – kinase receptor called bcr-abl, which drugs to target those pathways and they’d and moving forward to d evelop drugs drives cells to become leukemic. Drugs be very effective in that subpopulation.” aimed at different targets in the cancer cell. like Gleevec can inhibit the activity of the Carbone’s laboratory was the first to aberrant receptor, and thus block cancer - identify a mutation in the epidermal A RARE LEUKEMIA’S LESSON ous growth. growth factor receptor (EGFR) that The concept of a “magic bullet” to “Imatinib surprised everyone,” says predicts which lung tumors will respond treat disease dates to the late 19th century. Mace Rothenberg, M.D., Ingram Professor to drugs such as gefitinib (Iressa) and

12 LENS / WINTER 2007 E

erlotinib (Tarceva). In a manner similar to Y

One arrow’s not enough E

Gleevec, these drugs bind to and inhibit the - S receptor’s abnormal tyrosine kinase domain. ’ Think of targeted therapies as poison arrows piercing Achilles’ heel. L

“We noted very early on at Vanderbilt L that some lung cancer patients had a great There’s validity to the idea that the new drugs “take advantage of our improved knowl - U B response, but most patients didn’t,” edge of the biology of cancer to exploit weaknesses in its defenses,” says David E

Carbone says. The EGFR mutation that his Johnson, M.D., a lung cancer specialist at Vanderbilt-Ingram Cancer Center. H group found in a patient’s tumor is found “But it’s incredibly simplistic to assume that every cancer will have only one such vul - T nerability. Most cancers are far, far, far more complex than that and will likely require not G in about 10 percent of the U.S. patient N just one arrow into the heel of Achilles, but multiple arrows.” I population, and is “probably the best pre - T T dictor of clinical response to these drugs.” Alan Sandler, M.D., of Vanderbilt-Ingram, and Roy Herbst M.D., Ph.D., of the University I But the single mutation identifies of Texas M.D. Anderson Cancer Center in Houston, are taking just such an approach. H only the “fantastic responders,” Carbone They are studying the impact of two targeted agents, bevacizumab (Avastin), which says. “Most studies are showing that there’s blocks blood vessel formation, and erlotinib (Tarceva), which inhibits the epidermal a much bigger set of lung cancer patients growth factor receptor, in treating non-small cell lung cancer. who will benefit from these drugs.” The early results, reported last June at the American Society of Clinical Oncology Through the National Cancer meeting, suggest that the combination of the two targeted agents is nearly as effective Institute’s Strategic Partnering to Evaluate in improving progression-free survival as Avastin combined with standard chemotherapy. Cancer Signatures (SPECS) program, The median time to progression, the point at which half of the lung tumors began to Carbone and his colleagues are searching grow again after treatment, was 4.4 months for Avastin plus Tarceva, compared to 4.8 l for the “molecular signatures” that will i

months for Avastin plus chemotherapy, and 3.0 months for patients in the chemotherapy a predict which lung cancer patients will r plus placebo group. t benefit from Tarceva. The study comes on the heels of a multi-center clinical trial led by Sandler that demon - s ’

They have found eight proteins in the r

strated that adding Avastin to the chemotherapy drugs paclitaxel (Taxol) and carboplatin e blood that together “really seem to identify c

in patients with advanced, non-squamous, non-small cell lung cancer improved median n patients who will live longer when they a survival from 10.3 to 12.3 months. Additional data and analysis from that trial have c are treated with erlotinib,” Carbone says. been published in the New England Journal of Medicine . n He presented the findings last June at the “Two months may not sound like a lot,” Sandler says, “but that’s actually the first o t

American Society of Clinical Oncology time in the front-line setting of non-small cell lung cancer that we’ve ever seen a target - o meeting in Atlanta. ed therapy improve survival, and it’s the first time in 10-plus years that we’ve seen any H These kinds of molecular signatures agent show an additional survival advantage in this cancer.” or “profiles” will be key to successfully Based on the work led by Sandler, Avastin was recently approved for use in advanced using targeted therapies and moving them lung cancer. It’s now time to study the drug in earlier stage disease, Sandler says, and to earlier stages of treatment. to continue testing rational combinations of targeted therapies. To do that, “we’re going Clinical trials of new drugs start in to have to do a better job of enrolling patients in clinical trials,” he adds. the sickest patients – those with metastatic “The cure for cancer could be sitting on a shelf somewhere, but if we can’t study it, disease for which there is no known effec - we’re never going to know.” tive therapy. These patients have already endured the standard therapies, and the – LEIGH MACMILLAN probability of anything working at that point is probably remote, Johnson says. R E

Unless the drug is tested first in N Y A

patients in whom it is most likely to work. R

This is what happened with the tar - E N N geted therapy trastuzumab (Herceptin), A which is directed against the HER-2 protein (a receptor similar to the EGFR). Herceptin first proved itself in clinical trials in the sickest patients whose tumors had high expression of HER-2. It is now used as an adjuvant therapy – a treatment given usually after the main treatment, to boost its effectiveness – in breast cancer. Herceptin may never have reached that stage if patients in the early trials had not been “selected” for high expression levels of HER-2 in their tumors. “If those initial trials had not been limited to patients with high HER-2 levels, it would have threatened the development of a drug that we know works as long as it is used against the right cancers,” says Carlos Arteaga, M.D., Vice Chancellor’s Alan Sandler, M.D. Professor of Breast Cancer Research at

LENS / WINTER 2007 13 E

Y Vanderbilt. “Herceptin alters the natural E

- history of women with breast cancer over - S

’ THE expressing the HER-2 protein (by increasing L L NEXT their chances for survival).” U B TARGETED WE ’RE HITTING A PLATEAU and facing a gap of several ARE THEY WORTH IT? E years before the next targeted therapies emerge from H Targeted therapies come at a cost.

T THERAPIES pre-clinical and early stage clinical trials, says Mace “The presumption is that targeted

G Rothenberg, M.D., director of the Phase I Drug

N Development Program at Vanderbilt-Ingram. therapies will only cause good things to I

T “So far we’ve seen agents directed mainly at two molecular happen and not bad things. Sadly, that is T

I targets – the epidermal growth factor receptor and vascular endothelial growth factor,” not the case,” Johnson says. He cites studies H Rothenberg says. “We’re now seeing the benefits of those drugs in many common showing that long-term use of both Gleevec cancers, and we’re beginning to understand how best to utilize them. But we have to and Herceptin can cause heart failure. find new targets in order to make the next leap forward in our treatment.” And then there’s the financial cost – up He describes the new targets being explored in the Phase I program – proteins like to $10,000 per month for the newest drugs. transforming growth factor-beta, insulin-like growth factor receptor 1, src kinase, and “There’s no rhyme or reason for the toll-like receptor 9. cost of cancer drugs in this country,” “From a clinical and translational perspective, these are both the best of times and Johnson says. “And what’s interesting is perhaps the most challenging of times,” Rothenberg says. “It’s great to have these newer agents that are going to be novel and may allow us to make substantial that the drug gets the blame for being ‘ineffective’ because it only offers a two- l progress in cancers where we haven’t made much progress – like pancreatic cancer. i week survival advantage. I’m not praising

a “But at the same time, they’re being developed in a much more crowded field. It r the drug for giving you two weeks of t now becomes a challenge to rationally develop combinations that make both biological

s sense and have the best chances of making an impact on a therapeutic level.” survival, but each of us knows that used ’

r Investigators will need to rely on “more robust animal models of human cancer,” in a more appropriate way, we can get e c Rothenberg says, some of which are being developed at Vanderbilt, and on careful these huge benefits that were seen with n

a testing in patients. Herceptin.” c “It’s exciting to be at a place like Vanderbilt where there’s an open dialogue The trouble, Johnson says, is the hype n

o between the clinicians and the basic scientists who have studied these agents in a about the promise of these new drugs,

t pre-clinical setting,” he says. “They are able to guide our decisions about what to look

o which when apparently not met, creates for in the tumor tissue and how to measure it. H “And ultimately we rely on cancer patients, who have been very willing to play an disappointment and cynicism. active role in our research. They want to help us understand the drugs, the cancer, Carbone takes issue with the idea and the biology better, even when it doesn’t directly benefit them.” perpetuated in the lay press that the effec - – LEIGH MACMILLAN tiveness of targeted drugs can be fully assessed by measures of median survival. A QUIVER OF CANCER FIGHTERS “It’s extremely misleading to say that a drug only gives you a six-week survival DRUG APPROVED IN FOR TREATMENT OF BY TARGETING difference, without any additional expla - nation,” Carbone says. Avastin 2004 colorectal cancer VEGF* Survival curves report a population 2006 lung cancer VEGF average. About half of the patients will get no benefit at all and half will have Erbitux 2004 colorectal cancer EGFR “some benefit that’s very real: the tumor 2006 head and neck cancer EGFR shrinks by a measurable amount, the patients feel better, and they live longer,” Gleevec 2001 CML bcr-abl he says. About a quarter of the patients 2002 GIST* c-kit*, PDGFR* will have major shrinkage of the tumor, and in about 5 percent, the tumor will Herceptin 1998 breast cancer HER-2 virtually disappear. “For that 5 or 25 percent of patients, Iressa 2003 lung cancer EGFR that’s a heck of a lot more benefit than a six-week survival difference tells you Nexavar 2005 kidney cancer Raf kinase* about,” Carbone says. “The future is extraordinarily bright,” Sprycel 2006 CML bcr-abl adds Johnson, “if we can stay focused on the real ultimate object of our research Sutent 2006 kidney cancer, GIST VEGF receptor, PDGFR, c-kit and that’s the human being – your sister, your husband, your mother, your child. Tarceva 2004 lung cancer EGFR That’s the target.” LENS

* VEGF – vascular endothelial growth factor; GIST – gastrointestinal stromal tumor; c-kit, Raf kinase – proteins linked to cancer growth; PDGFR – platelet-derived growth factor receptor.

14 LENS / WINTER 2007 pr suc on o pr pl ge me t ne in so- th mye mo T c Ca th ge ma ca c th ne th b Bu A N D M.D., Ce ge cha si pa nu th t li u dr th on ti le o a e ke y o ag le e g e a e e e e ec u n nc us l n n t t se cl n t n nc D u ls c h c e m t l n ge ic t y ic u t gs n h n om e e ec d a te hyl sa Un “h en ei al a u l e NA hyp l y nc a i V E “ L “Al Ep Th Hy Wh Th In Th “W Jo od e s g e ce i bo if e s s e u of ni n rn ge t ex c ex r a n n t l e i r u Ph ch d me r ype rn fe h ed i V d le vi q e s o a s e i ne e omp sp o e st e e d i p m pe r ysp d ige t i ge ve c le t ce m he era az e n a Ce o c wi o , t hey pr pr s, ne o r o ntr t t y h n d r al had e .D ar io n a he o omp e g me r t’ b go l tu u en r (tu s ora r o cin az rs n tu Madrid m ye r ls, t a a e e n e n g n “tur es to e n s s n and h e las me to st ., pie er d a r er de za o sio s en es gula men s m s i et n od ity c ic mo e c n te nig n r a a ag ing th led b a n et ne i c inh g dic tim “epi es e t- and shown a ca thyla n r r, n al lex cytidne histo ic on al ugh d m a p tic io r thyla an ke y ed ea s.” c ” s c i t n ose l, hy te o e, d o n us r u nt l h in th onst n n. . at c ibto te f e. t f ch “ e in ews, o ting ch . fo e r d sup a la ly Da cel c g linca synd as sile m t ter the f of “ colleagues showed Sou – e e n” er an ra a to eneticall tion heir Los to o r mar ms r a ti sting A Da n i whe ne d emical tion” two eth nc nc hor c sta i d nges on c e f e r rated isea n rs d fir a ). e pr that s ogen nced gen them, ce ll ug r cels te o gr a cogen he s the ers the he t o r p ida (V st ma tuer DNA yl” The epig udy An is i d d ame th t r gens mone and in ap pr rize of p o r te sor mes rited s r w a wth. es o r of er r t m d i a t gels. “ lo teins a d bou hat stin tha n e er hey gr i t can t this se ecitabn a “ ds y du ge e ar ces tha d hat e ” publis e r en ti t oking pr n o za) tags, methylaion gen chr in Ca suce tha o gen o neti i co e tr say ndi ep nes t gen ring at – u om fo lev M t op ri g. e Vidaza in ce did t , br ai a ps lif h mechanism ty n identical me omatin-d t pigen e h th dise as t atb a igen es u ms r cr can ” o is es sting c the ave ow r, C or new r ” have taions es hed es – of at el o easin at b ls, cel tags hr to s ptibly. te n Petr Jon th c a n a un ar we in, ack ( a b o ase joine t n o m o r f n ia/No omatin Spanis de le r ce ll , es ogr pr tha be of y a th (Da the ui e die tic a s by y d in clas egion r t two e r tic ap es divson hype ev r te m nd be e shable” defct.” f div ex si l can l o r gl an on whic t ,” d 20 twins n t, co inhibiting cha oved pr Jo ela r tied d in e ar y fo r nor ta say es pr en ce ersing of h t er l o ger , ris r like . ugs dr stud Jon n d e gen) by nes, b f o 05 ce h ce ll methyla r ifyng in gs the e of ugs r is pigen s eing nge s as at th ab ex am pl e ma tio Nati n r. togeh 1 e n e g a r G es sed . . 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R THE G E H T GREAT AMPLIFIER ERIC LANDER’S AUDACIOUS THINKING MAY HELP CRACK THE CODE OF CANCER l i a r t s ’ r e c n a c ric Lander, Ph.D., strides down a sun- n o

t drenched hallway to yet another research o H meeting in the genome center he directs, his face beaming with purpose and excite - Ement. > His bear-like handshake radiates strength; his patience is easily taxed by the pedestrian and the hesitant. But he is anything but intimidating. On the contrary, his sparkling blue eyes and easy smile convey a warmth and vitality that are often described as infectious. > A driving force behind the sequencing of the human genome, Lander is now tackling the “can - cer genome.” He and his colleagues around the country are out to redefine tumors by the genetic changes that trigger their malignant growth, rather than by where in the body they strike. >

BY BILL SNYDER 16 LENS / WINTER 2007 E L N S / W N I R E T 0 0 2 7 17 Hot on cancer’s trail THE GREAT AMPLIFIER 18 Hot on cancer’s trail THE GREAT AMPLIFIER No Hut pr Phot e ar Deutsch witho goi stil (MIT) Maschuet directo apies,” human team mebrs such like and gentic tors h 1 of com E L Eric “evry W es hundre 5 bel ng SN Francis e ide Lander ch plet therf wi y a I “But “I a in n ut it by ins trem to to la nt and com l pati r / do say 200 5 1974. disea charte and ur yea o James actul W o be be p of m a f n’t genom h n ore I eat e nd Barny, ent d (thir T N I the Harv prehns ake the dol can’ Lander Can cer a suce ndous teachr re a w ble dir ecto in w To Lel and pan el in Insti ant Broad Hamilton autom Stuyvesan thera y E t hic ars om fr i Lander’s to ist i R knowig sf c the m d Kely , rs, to amo ive dict pe wo Res ear tu ic de en Ir ul. agi t Univ r 0 2 pie led t he s left) clin r pr r of Ins Har t te rkup ea de e of ne pa unt Pan s ica e 70 r dyna b t of t t m ti s he fo Finkel; er right y t t me ch pose end c High ho ie heir ly wel l ript ine T wha r sit L ute o and … (wil) Fr nt ec Cen and f nts w t mic hes y. give wor ed t s, e ar .” hnolgy , io the Schol hat ilnes fo t’s we’ of Paul Ph with to er “ ter ar n The e r The foundig k. Jes the hav wr s e his . and re dis a of pre hav D. in us mo Zeitz. c other s ong.” ir re ev ouple es ea e , math left cis ing t ’s doc a st , er he se e s r - - meting Medical INSERM, Ph.D, Lander S p ef h p r i c c r o ca he D ge ( t m t pl ki o T “ Co pe m MacA o f P t “ nit it or e es n his hre ri ance om Bro he om eat ne f ro uma ilo ro fo ntl uche nc ade e, nd,” at ) si net rha but Sc pa ea m ject rt, com je i t do tle, ta ic ce e o pla er de at but is y Whil Thos “ “I Lande The Whil ie rc ge Sa t ct f r n ic ps i P ye nt rthur ed o ke rt es ”) iv (right) und cal a nti ne ’v , th h goi unic p (centr) di ads . eopl i i ca 21 n- pr pl test ch Resar ai to wye ar n s in n’t,’ e ro e t y w f t the e I t led to a he ncer f unds f o nl t e o nst et s a ng ). t gno er w or e e i j co Cold e’ f K ur i r, p s c ec t ha mus iv den a w e dou l ing y Fell thi or f hundr the r o ” me at t and Fin wo ay Nationl r the ntri Th w ed E ne w it e e i ho sed w . t to was s s si o ked a er ducat ay. u A ho t chats ti ays s centers it i fr d- ns Spring c r p bt Da r e o ( s al p l ta t t , r S hapen, ld’ fy ul l but c Mar know l begi w om he e p R a t a r C andm and in w gen ee i ki n . hre oj t s l o at t eds r hi vi a w O 1 a hode th urns s a estab i oa “H ne r he ng “B Paris, nc e doe St H l i y, 0-y i it e m. be xf with l on ct e t ons Instiue e e nig dys s t he qua Felous, h Harbo , al el -y um ch e di t of o , ‘ e’ of primaril or ’ r ma st O Lande abo s r ar i na n ea s ea s D th ci s a ea a 50 ver lished fe t G d e Br h sc k t nd ha t David but r, Schol know a ro a t l s .Phi jor l during , o r he a l e m n t ot ut , of za Uni ie w ac y s P fo $ t oad . pe nome t phy. under $100 of i hi P G e 1. nti f bi h.D e l i m r, l hi rc o ic of N.Y. you a nt or i m l eadr ubl l M.D, s 5 m eno l f a ., li ve y ar an Botsein, u n n.” e ia how e , di s (p por , Health s t year b a vem t new b t “But i ., E resp w y ma of l rs oo m a d ot te i f s and At ro s illio st mi kno m c 1986 fe r t ho is di i n con io i s at d t directed hai her no t evr andi nat Ph.D, c re rt do la , ant e y llio ent o r n i c he er un is s n n e ha s w nce nsib ur gg s t l ay peo - s and c ure hen a , - in … n t ce , t ng - s le ? … or s he ar i d n in l - of .” e e ” sequncig sium, Kay Spring Lander Midle l s U w pr ev gr s That r G A peol a cont m m a ect t l s our D M has an f t m G N can net arge at r t ki es hey’ por hat nd es dozen. ar or r ni r al enom os ay edi obel of oup edi es thur our en l s unsw ry hma ti y, , ked w ver Davies, ge es t t tha r e t “ The Ei “Thi Even Lander i ’ be r and s ci o o ng body i s ci r “ s e sc endur or That whic e Ph.D s but paer ces f ner f Y Harbo pages t and Er c or , ne ght listen l has s ne goi t e al m o nk ked aur w w ont it n ou Lande o w la er to When i Pr e,” a s get f y e hic of hat or at a c,” at i i ughin. do a a vi ng bil t t n nd right i hi t ea i t hundr the know i t inue ., t houg t of D.Phil, i io h oj ’ debat t e s oge r s w o ng o ur G ng in M s h H t s l o m t i enor an y Labort t sa goi l n ect w Lande y he a “bi to intely it e t W the r’ s eno f ike m he n k y t I ar human y har N ys oul the s agr i h belif he t T l Syd d, phots f s t ot n eg , as as m out he or a ng f var t g hey gr a ly t ed utr Philp Tom L o mous me Br Br 20 La r e tur s ivat s lot “t hingt he ake d r ca ac “He sc a during uly cie e ist it ney ins Bo r d the to nder on of es to at en o sc nde oad t be nc ienc y. .” e congr to in yea he Sc wa ant M e.” tha genom. of nce,” s sto es e r ient pir G cr a disc tesy cour ive Sa pa come impor er ea t feasiblty Br c ienc d Oxfor amount the chivesAr on t e t r hat s dife n entics G orga se it rs an Ins he ’s r dic t wyer ly s the int e ta pr ge ” an ince en ics is G r quenc a wor us this ega younger a othe in en, .” lent proa apr ge e t pe ofe t lat nome go. al lob ac it nthus s , niz s 1986 r t the e t e he Se t a ar ople among te ut Universty’ ac a at quire e Sc ge t r, s e nc he nt is ies of , rs . han s groups s at “W ly Ph.D, oach a c 1980s tive e e’s or hol and for D fe Huma t of t t oleagu of e che t ional the he was a work tle on is he es pr t sympo nce ing .Phil in ct in of e ha pr wor br t ly cofe t s,” one , op he ualy M have his he to a work Cold oj the t his who ? who othe a . of a n k - for r - - of m e k ’s , r R

investment in expensive technology is now management firm, Pantheon Capital at the University of California, San E I driving the research agenda, rather than Management, in Manhattan. “He reaches Francisco (UCSF), urged him to switch to F I the other way ‘round. out to people and is always very willing to the life sciences. L During a lecture at Vanderbilt share what he knows.” “Even in high school, he’d had an P M

University last fall, the Oxford-trained In 1974, Lander enrolled at Princeton affinity for genetics,” Arthur Lander recal ls. A geneticist joked that he would like to buy University, where he earned his bachelor’s “Lots of mathematicians like genetics. It T A

Lander’s gene sequencers “and throw them degree in math with highest honors. He really fits with the mathematical view of E R

into the sea. That would be the inverse of also met his future wife, Lori, in a consti - the world.” G

the Boston Tea Party.” tutional law class their sophomore year. Lander took a few courses, and E

Yet for Lander, big science is not Married since 1981, the Landers have learned fruit fly genetics at Harvard. He H T about the machines. three children: Jessica, 19, Daniel, 15, also worked with MIT biologist Robert “It’s about taking on the responsibility and David, 12. Horvitz, Ph.D., who would share the of creating datasets of tools, and then put - Lander describes his life as if he were 2002 Nobel Prize with Brenner and John ting them in the hands of thousands of an atomic particle, bouncing randomly Sulston, Ph.D., for their ground-breaking young scientists who make them 50 times into key people. Not knowing what he studies of organ development and pro - more efficient,” he says. wanted to do after earning his doctorate in grammed cell death in the round worm, “So it’s always ‘big science’ in the service mathematics from Oxford, he went to C. elegans. of the individual investigator. That was Boston, he says, “because the probability Then in 1985, in one of those pro - what the Human Genome Project was of productive collisions was higher.” ductive collisions, Lander bumped into about … And that’s what the projects going He joined the faculty of the Harvard MIT geneticist David Botstein, Ph.D. l on here on inherited genetic variation of Business School, where he taught courses i a disease, on cancer, on evolution, on infec - in business management and negotiation. Up to the task r t

tious disease – all of them share that role. Meanwhile his brother, who at the time Five years earlier, in a pivotal paper, s ’

“We’re playing a great amplifier … was earning his M.D. and Ph.D. degrees Botstein and his colleagues Ronald Davis, r e We’re trying to empower a generation of c n remarkable scientists who really want to a c take on the important problems in disease.” n How to crack the cancer code o Productive collisions t o

Empowering remarkable people has H In 2003, 13 years and biospecimens will be “letters” (adenine, guanine, been a hallmark of Lander’s life, at least as $2.6 billion after it started, processed at a central cytosine and thymine) that far back as high school. the Human Genome facility, and distributed to make up the DNA code, at Lander and his brother – now chair Project completed the cancer genome characteri - a cost of $10 per base. of the Department of Developmental and sequence of nearly all of zation centers, which will The current genera - Cell Biology at the University of the 2.9 billion letters of determine which genes are tion of sequencing California, Irvine – grew up in the genetic code that make up selectively turned on or off machines can sequence 1 Flatlands section of Brooklyn. the human being. in the tumors. million bases a day for Their parents were lawyers, but their Now researchers are Genome sequencing about 50 cents a base. A father, Harold, became disabled from mul - tackling what may be an centers will conduct further new generation tiple sclerosis and died when Eric was 11 even more ambitious chal - investigations, looking of machines – now being and Arthur was 10. Pitching in to help lenge – developing an for changes in the DNA tested – may increase with housework and home repairs, the “atlas” that describes the sequence that may be the output to 500 million boys early on developed a strong sense genetic characteristics of associated with specific bases a day at a cost of initiative. the more than 200 differ - cancer types. This informa - that is 100 times lower. Their mother, Rhoda, who died two ent types of cancer. tion will be entered into The machines are not years ago, told the Boston Globe Magazine Last fall the National public databases so that cheap, however. Both the in 1999 that she was mystified by her Cancer Institute and the researchers ultimately can current and new machines sons’ achievements. “They did their thing, National Human Genome use it to improve cancer cost about $300,000 each. and then I paid the bills,” she said. Research Institute diagnosis, treatment and To succeed, The Pursuing an early interest in mathe - announced that lung, brain prevention. Cancer Genome Atlas matics, Eric enrolled in Stuyvesant, one (glioblastoma) and ovarian The attempt to rede - project must push the of New York’s premier math and science cancers will be studied fine cancer by its genetic technology even further so high schools, and became a leader of during a three-year pilot to code has been made pos - that researchers can deci - Stuyvesant’s celebrated math team. determine the feasibility sible by phenomenal tech - pher the complex genetic At age 17, he won the Westinghouse of a full-scale Cancer nological advances during and molecular interactions Science Talent Search prize for a paper on Genome Atlas project. the past two decades. that underlie malignant “quasi-perfect” numbers, but he was much Patients will be asked In the mid-1980s, a growth, and at a reason - more than a math whiz, recalls former to donate a small portion scientist could spend a able cost. math teammate Kelly Pan. of tumor tissue that has day determining the – BILL SNYDER “Eric has what is probably unusual in been removed as part of sequence of 50 to 100 the field of math, a very outgoing person - their treatment. The nucleotide bases, the four ality,” says Pan, who went on to earn an MBA and who now runs an investment For more information, go to http://cancergenome.nih.gov.

LENS / WINTER 2007 19 R

E “He certainly is competitive,” Green I

F “And he’s here (in the lab) with all of says his former collaborator. “That can creat e I

L a tension because you’re both collaboratin g P these young, very bright people … and competing in a sense at the same time , M

A trying to come up with ideas first. But

T who don’t want to go home they’re overall, you get past that, and I actually A

E think competition really drives science.” R so excited … We’re blown away. ”

G In 1990, the National Institutes of

E Health (NIH) and Department of Energy

H (DOE) officially launched an ambitious T international effort – dubbed the Human Genome Project – to determine the Ph.D., of Stanford and Mark Skolnick, Meanwhile, he and Botstein churned sequence of every human gene. Ph.D., and Ray White, Ph.D., of the out half a dozen papers detailing their That year Lander, a recipient of one of University of Utah had proposed a method methods for mapping complex genetic the project’s first grants, founded the to map the entire human genome using traits. With the help of Philip Green, Whitehead Institute/MIT Center for restriction fragment length polymor - who, like Lander, was a mathematician- Genome Research to exploit recent advances. phisms or RFLPs. turned-molecular biologist, they put those Among them: automated DNA RFLPs are pieces of DNA that have methods to work at a Massachusetts sequencing machines, and “shotgun” been sliced apart by restriction enzymes. biotechnology company called sequencing, in which randomly sliced up l i In 1978, researchers at UCSF discovered Collaborative Research Inc. fragments of DNA are cloned and a

r that one of the restriction fragments from “What the company was trying to sequenced, and – with the help of power - t

s patients with sickle-cell anemia differed in do was to identify lots of these RFLP ful computer programs – pieced back ’

r length from normal fragments from peo - markers and then determine where they together in proper order. e c ple without the disease. were on the chromosomes by finding their Others were racing to embrace the n

a Botstein and his colleagues reasoned locations relative to each other,” Green new technology. In 1998, former NIH c there were many such genetic differences recalls. This approach was called genetic scientist Craig Venter, Ph.D., shocked the n

o between individuals. Most were probably linkage mapping. scientific world when he announced that t

o innocuous, but theoretically they could be At the time, researchers could map his new company, Celera, would sequence

H used as markers to create a map of the only three or four markers at a time. the human genome by 2001 – several entire human genome. Green and Lander met frequently to dis - years earlier than the target date set by Mathematical methods available at cuss ways to construct maps with many the Human Genome Project. the time, however, were not up to the task more markers, and independently devel - Urged by Lander, among others, the of unraveling the intricate web of genetic oped software programs to implement public effort reorganized its priorities to interactions that contribute to complex their ideas. produce a rough draft sequence first and a disorders like cancer or diabetes. In 1987, the team, led by Collaborative final finished product later. “It became clear that what was needed Research senior researcher Helen Donis- Lander’s center became the largest of was somebody to think about this problem Keller, Ph.D., published the first genetic the project’s top five gene-sequencing who had mathematical tools beyond what linkage map of the human genome. operations. The others were Washington I knew,” says Botstein, now director of Princeton’s Lewis-Sigler Institute for Integrative Genomics. Eric Lander shows photos he’s taken of Masai So he asked around and eventually children during a trip to Kenya (at left); he and was directed to Lander. Within a week of Daniel prepare to feast on chili crabs in their meeting, “we had a lot of stuff Singapore (below left); and he shares a quiet worked out,” Botstein recalls. moment with Jessica, now 19 (below). Thus began what Lander happily Photos courtesy of the Lander family describes as his “chaotic career path.” In 1986, on Botstein’s recommenda - tion, Nobel Prize-winning virologist David Baltimore, Ph.D., invited Lander to become a fellow of the Whitehead Institute for Biomedical Research in Cambridge. “When I met Eric, I knew immediatel y that he had enormous potential,” says Baltimore, the institute’s founding directo r, who went on to become president of the California Institute of Technology (Caltech). The next year, Lander received a five- year MacArthur Foundation “genius grant” to support his innovative applicatio n of statistics to the study of genetics.

20 LENS / WINTER 2007 R

University in St. Louis, Baylor College of “And (Lander’s) here with all these cancers?’ And in each case you are compar - E I

Medicine in Houston, the DOE Joint young very bright people from Harvard ing it to the normal genome that the F I

Genome Institute and the Wellcome Medical School and MIT who don’t want person started with. L Trust Sanger Institute near Cambridge, to go home they’re so excited.” “There’s background noise; there are P M

England. Asked what he wanted to do once the (random) changes that occur. But … if A

In June 2000, the race ended in a sequence was completed, Lander said he’d you see a gene mutated 10 percent of the T A

“tie:” Celera and the Human Genome like to apply the new knowledge to help time, that’s no accident,” Lander says. “It E R

Project jointly announced working drafts patients. “That whole notion appealed to must be playing an important, causal role. G

of the human genome sequence. The pub - me,” says Broad, who began talking to So by simply collecting enough data, the E lic genome project went on to complete a officials at Harvard and MIT. genome should be willing to tell us which H T final sequence three years later. In June 2003, Broad and his wife genes matter.” announced a $100 million gift to establish Lander shrugs off criticism that The Blown away the institute that bears their name. Cancer Genome Atlas project is too expen - In October 2001, Lander and his col - Eighteen months later, they doubled their sive or simply can’t be done. The proposed leagues were filling in the gaps in the philanthropy to $200 million. cost would be less than 3 percent of the sequence when Eli Broad called him up, Within their sparkling labs near the National Cancer Institute’s budget, he and asked if he and his wife Edythe could MIT campus, institute researchers are notes. And, the technological hurdles will visit his lab during a visit to Cambridge. applying genomic tools to better under - be overcome. The important thing is to Broad, founder of two Fortune 500 stand a wide range of ailments, from nurture visions of what might be. companies and a Caltech trustee, previousl y malaria and tuberculosis to psychiatric “What’s the biggest product of this l had been introduced to Lander by disorders, diabetes – and cancer. place? It’s scores of people who have come i a

Baltimore. Through their foundations, Cancer lends itself to genomic inves - out of the genome center and the Broad r t

Broad and his wife had made major tigations because it’s a genomic disease, Institute who … (are) willing to work s ’ contributions to the arts and education, Lander explains. together, to do the heavy lifting necessary r e and recently had begun to support med - “We’re not talking about common, to change the world,” Lander says. c n ical research. pre-existing genetic variations,” he said. “It’s faith, a confidence that the way a c “This was Saturday,” Broad recalls. “We’re talking about new mutations that to change the world is to get information n

“So my wife and I go to see his lab and arise in each tumor. and tools into the hands of as many people o LENS t we’re blown away by 140,000 square feet “So once you have a sequence of the as rapidly as possible.” o of robotics and computers working 24 human genome, you can then ask, ‘How H hours a day decoding the human genome. does (this tumor) differ amongst 400 lung

Bonanza or boondoggle?

Can the sequence of the ing project is misdirected, pre - funded, and has almost disap - That’s worth emphasizing, human genome be used to mature and too expensive. peared.” particularly since the technolo - find genes that cause cancer? Jonathan King, Ph.D., pro - Margaret Spitz, M.D., profes - gy required by The Cancer A study published last fall in fessor of Molecular Biology at sor and chair of Epidemiology Genome Atlas project hasn’t the journal Science suggests MIT and a founder of the at the University of Texas M.D. been developed yet. that it can. Council of Responsible Anderson Cancer Center in “There’s no way they can Researchers at Johns Genetics, worries that the Houston, disagrees. afford even for over a billion Hopkins University in emphasis on genetics has “Most of the really impor - dollars to screen all the genes Baltimore, compared the overshadowed prevention. tant environmental causes of in all the tumors they want,” protein-coding regions of “I’m not arguing against get - cancer have been identified,” says Mark Skolnick, Ph.D., genes in 22 samples of breast ting all of the information we says Spitz, who serves on the whose team at the University and colorectal cancer to the can about the nature of National Cancer Institute’s of Utah and Myriad Genetics corresponding “normal” tumors,” King says. “But the Board of Scientific Advisors cloned and developed diagnos - sequences. After eliminating information collection should and who was a member of the tic tests for the breast and errors and normal variations, not take the form that working group that recom - ovarian cancer genes BRCA1 the study yielded 189 candi - obscures the basic fact: most mended The Cancer Genome and BRCA2. date cancer genes, most of human cancers are caused by Atlas project. “But they know the cost of which had never been seen in carcinogens that act on you in “But the epidemiologic focus sequencing went down a thou - tumors before. your lifetime. should now be on studying sandfold during the time of the Francis Collins, M.D., Ph.D., “Recognition that carcino - these exposures in the context Human Genome Project, and director of the National Human gens damage the genes in of the genetic background of they expect it to go down a Genome Research Institute, tumor cells opens the avenue the subjects,” she says. thousandfold again,” Skolnick called the study “a big shot in to prevention as a major anti- “There are good epidemiologic says. “… So they’re going to the arm” for The Cancer cancer strategy,” he says. “At studies ongoing. Of course, we push the frontier.” Genome Atlas project. the present time, however, should fund more, but we – BILL SNYDER Not so fast, say other scien - research in this area is totally don’t have unlimited tists who believe the sequenc - inadequate and woefully under- resources.”

LENS / WINTER 2007 21 G N I N N I G E B E H T N I in the l i a r t

s What developmental biology ’ r e c can teach about cancer n a c BY MELISSA MARINO n o t o H IT COULD BE NATURE’S CRUELEST JOKE – “These developmental molecules that cell biologists know and love – our the molecules that give us shape at the begin - favorite proteins that operate in the early ning of our life also can lead to the end of it. ¶ embryo – are the same molecules that seem to go haywire in cancer,” says Jason The genes and proteins that help sculpt a single Jessen, Ph.D., assistant professor of cell, the fertilized egg, into a complex multicel - Medicine and Cancer Biology at lular organism are also responsible for the birth Vanderbilt University Medical Center. The rapid and exponential cell divi - of many cancers. ¶ This link between embryo - sion, differentiation and cell movements genesis and tumorigenesis has been suspected that characterize embryonic development bear a close resemblance to those involved for more than a century, but only within the last in tumor initiation and metastasis. 20 years have the striking molecular similarities “It does make sense because in the between these two monumental events come developing embryo, so many things are happening: cell migration, cell specifica - into focus. tion, cells interacting with each other,” Jessen says. “So, if those proteins get activated in an adult cell, it’s no wonder it can have dire consequences.” Definitive links between the two processes have been a long time coming, mostly because of the academic divide between the separate cultures of develop - mental biology and cancer research. Now Illustration by Allen Garns that divide is beginning to close.

22 LENS / WINTER 2007 Y R U T N E C H T 0 2 E H T G N I P P I K S h t l a e h l a b o l G

Painting of a mouse embryo, from a light micro - scopic image provided by Richard Behringer, Ph.D., UniveLrsEitNy oS f /TeWxaIsNMT.EDR. An2d0er0so7 n Cancer Cent2e3 r. G

N One of the first links between cancer doing in a Drosophila embryo?’” says (adenomatous polyposis coli) gene – a I

N and embryogenesis was made in the Jessen. “It’s a classic example of the two component of the Wnt pathway – were

N early 1980s. worlds coming together.” required for the initiation of colon tumors. I

G Roel Nusse, Ph.D., and Harold Wnt is probably best known for its Researchers have already identified E

B Varmus, M.D., identified a cancer-causing involvement in one of the earliest aspects more than a dozen Wnt ligands (proteins

E “oncogene,” which they called int-1, in a of development, the formation of the pri - that bind Wnt receptors and initiate signal - H

T mouse model of breast cancer. When int-1 mary body axis. ing), and new components of the pathway is activated or turned on by the “integra - “You have a ball of cells, and somehow are being cloned and added to the already N I tion” (thus its name) of a mouse mammary this signal tells the ball of cells which complicated system at a rapid pace. tumor virus into its DNA, a tumor forms. parts form the head and which form the “It really looks like a mess,” Lee says. Around the same time, Christiane tail,” says Ethan Lee, M.D., Ph.D., assis - “I would say we are basically ‘stamp col - Nusslein-Volhard, Ph.D., and Eric tant professor of Cell and Developmental lecting’ right now, putting together a Weischaus, Ph.D., who were studying Biology at Vanderbilt who studies the picture that is very complex.” development of the fruit fly, Drosophila , Wnt pathway in frog ( Xenopus ) embryos. found that a gene they called wingless In 1989, Andrew McMahon, Ph.D., Finding the switch was involved in setting up the polarity of and Randall Moon, Ph.D., demonstrated To make sense of the overwhelming the embryo. When the protein encoded that injection of the int-1 (Wnt-1) gene data on this pathway, Lee and colleagues by the gene is defective, the fly fails to into Xenopus embryos induced the forma - developed a mathematical model to exam - develop proper body segment boundaries – tion of a secondary axis, resulting in a ine how the pathway is regulated. They and wings. two-headed tadpole. found that a protein called axin may be l i Nusse and colleagues soon deter - “This was critical because it was the the limiting factor. a

r mined that the two seemingly unrelated first biological assay for int/Wnt-1, and it “Based on the model, we can propose t

s genes were homologs – genes similar in linked a proto-oncogene to a developmenta l that controlling axin levels and its ’

r structure, function and evolutionary origin , process,” Lee says. turnover is the major way by which the e c and found throughout the animal kingdom . This multipart pathway has a number pathway can be regulated,” Lee says. n

a So the names (int-1 and wingless) were of other developmental roles in patterning “Perhaps that is the way the pathway can c combined, and Wnt was born. the brain, heart and limbs and possibly in be turned on or off. n

o “I can imagine that they were thinking: stem cell differentiation. Additionally, “Interestingly, the genes that this t

o ‘What in the world is this cancer protein mutations that activate the Wnt pathway pathway turns on are classic examples of

H have been linked to cancers of the colon, proto-oncogenes,” he says. Researchers skin, blood, liver and several other tissues. believe that if they could find a way to One of the strongest links between selectively switch the pathway “off,” they Wnt and cancer was revealed with the could halt tumorigenesis. discovery that mutations in the APC Toward that goal, Lee and colleagues are taking advantage of high-throughput screening methods and an in vitro model based on extracts of Xenopus embryos that Lee developed as a postdoctoral fellow. “We were able to recapitulate the pathway in a test tube,” says Lee. This method provides an efficient tool to screen for molecules that either inhibit or acti - vate the pathway. “We’re now using this assay to do drug screens,” Lee says. “The idea is that if any of these molecules work out, they could be

At Vanderbilt University Medical Center, Ethan Lee, M.D., Ph.D., (top) Jason Jessen, Ph.D., (far left) and Michael Cooper, M.D., (left) are study - ing the striking similarities between the development of an embryo and the growth of a tumor. The two fields “have intersected in a wonderful way,” says Cooper.

Photos by Anne Rayner

24 LENS / WINTER 2007 G

used as tools to study the pathway – and N I

further down the line, as potential drugs Embryo’s cellular ‘dance’ may N to inhibit the pathway.” N I

Lee is screening the large catalog of choreograph cancer, too G E

small molecules available through the B

Vanderbilt Institute of Chemical Biology, E

One of the classic examples of aberrant activation of a develop - H

as well as extracts from medicinal plants T and herbs through Harvard University’s mental pathway in cancer is the APC gene, a component of the N high-throughput screening facility. Wnt signaling pathway. I Although currently there are no People with mutations in this gene, named for adenomatous chemotherapeutic drugs that specifically polyposis coli, a pre-cancerous polyp found in the colon, have a inhibit the Wnt pathway, pharmaceutical high risk of developing colorectal cancer at a young age. and biotech companies have taken an Prostaglandins appear to be involved. Researchers at interest. Vanderbilt University Medical Center and elsewhere have found “In the future, I think you’ll see more that drugs like aspirin, which interfere with prostaglandin signaling, companies targeting developmental path - can reduce colorectal cancer risk by up to 50 percent. ways with the realization that they play a “We’ve been on a quest for the last 10 years to understand role in cancer,” Lee predicts. why such a simple drug leads to such a significant reduction in Jessen is also attempting to unite the cancer risk,” says Raymond DuBois, M.D., Ph.D., director of the worlds of developmental and cancer biology Vanderbilt-Ingram Cancer Center. l with the help of a tiny tropical fish. Developmental biology may help solve the mystery. i a

Zebrafish have a long history in Prostaglandins are hormone-like substances involved in a wide r range of physiological functions, including pain, inflammation and, t developmental biology research. Their s in the case of a particular prostaglandin, PG E , colorectal cancer. ’ embryos are transparent and develop out - 2 r e side the mother. They also develop rapidly Last year, Vanderbilt researchers led by DuBois and Lilianna c Solnica-Krezel, Ph.D., professor of Biological Sciences, identified a n and are inexpensive to maintain, making a c zebrafish embryos an efficient model for new role for prostaglandins in early embryogenesis. n studying genetic and environmental factors They found that prostaglandins help choreograph the intricate o

cell movements during the gastrulation phase of early embryonic t

that influence early development. o development in zebrafish. While indispensable for development H Treating zebrafish embryos with an inhibitor of PG E synthesis research, they haven’t been widely used in 2 cancer research – yet. slowed down the cell movements of gastrulation. As a postdoctoral fellow in the lab of Blocking one of the prostaglandin receptors, EP4, caused Vanderbilt developmental biologist Lila similar abnormalities. The shapes and trajectories of embryonic Solnica-Krezel, Ph.D., Jessen realized that cells were normal; they simply moved much more slowly. one of the key developmental events he was This suggested that prostaglandin signaling through the EP4 studying in zebrafish – gastrulation – might receptor regulates the speed of cell movements during gastrulation. offer some insights into the aspect of cancer The results highlight how perturbations in this pathway might that is the most deadly – metastasis. influence the spread of cancer as well as development. “The movements that happen in cancer might be, to some Cell migration extent, recapitulation or modification of the normal migratory Gastrulation is a time in early devel - program that happens during normal development,” Solnica- opment when an initially amorphous ball Krezel says. of cells begins taking on its adult shape In 2005, researchers at the National Institutes of Health due to rapid and extensive cell movement s. reported a direct link between the Wnt pathway and prostaglandin signaling. PG E increased the transport of Wnt- Metastasis also is characterized by cell 2 movements – cancer cells break off the associated transcription factors into the nucleus of cultured col - primary tumor and spread throughout orectal tumor cells and enhanced proliferation. “Understanding the role of the newly defined PG E - regulated the body. 2 “My main interest is trying to under - transcription factors and gene products may reveal additional ther - stand the fundamental migratory difference s apeutic targets,” DuBois wrote in a commentary on the NIH study. between metastatic (invasive) tumor cells Together, these two studies show that prostaglandins could and primary (non-invasive) tumors,” regulate two cell activities, cell proliferation and movement, Jessen says. He is currently searching for involved in tumor formation and metastasis, respectively. molecular signals in the Wnt pathway Their results could help explain how prostaglandins influence that might underlie cell motility during the development of colorectal cancer, and provide clues about both metastasis and zebrafish gastrulation. the chemopreventive effects of non-steroidal anti-inflammatory A major goal of the Jessen lab is to drugs like aspirin. develop a model of melanoma, a deadly – MELISSA MARINO form of skin cancer, by transplanting human melanoma cells into zebrafish embryos. The idea of using the zebrafish

LENS / WINTER 2007 25 G POINTING THE WAY TO CANCER N

I Researchers at Vanderbilt University Medical Center have found that attachment of N cholesterol to Sonic hedgehog, a mammalian version of the Hedgehog protein, controls N I finger and toe development in mice. The paws of a normal mouse embryo are shown in G

E panels A and D. Mice lacking cholesterol-modified Sonic hedgehog (panels B and E) B have malformed digits, while those expressing half the amount of Sonic hedgehog E without cholesterol (panels C and F) develop extra, ectopic digits. In addition to directing H

T development, the Sonic hedgehog pathway – named for the video game character – is

N also involved in a number of human conditions, including cancer. I

Image courtesy of Chin Chiang, Ph.D., associate professor of Cell and Developmental Biology at Vanderbilt. From Yina Li, et. al., PNAS USA , April 25, 2006; 103(17):6548-53. © 2006 National Academy of Sciences, U.S.A.

embryo to model a disease that afflicts more traditional approach, using the myself as trying to fill in some of the key humans is very exciting, Jessen explains. zebrafish embryo to determine how pro - gaps in our knowledge.” “We can manipulate the embryonic teins associated with cancer and metastasis Another pathway involved in both environment to determine what kind of regulate cell migration normally, such as embryonic development and cancer is the environmental cues (such as the Wnt during gastrulation. “Hedgehog” (Hh) pathway. First identi - fied in fruit flies, it is named for the short l pathway) might influence tumor cell “It is important to remember that for i

a migration.” the majority of cancer proteins, we know and prickly appearance of fly embryos that r

t An added benefit of zebrafish cancer very little about how these proteins func - have an abnormal Hh protein due to a

s models is the ease and cost-effectiveness of tion to control basic cellular activities genetic mutation. ’

r Like Wnt, Hh is a secreted signaling

e doing in vivo drug screens. such as motility,” Jessen says. c molecule involved in the patterning of the

n “What’s interesting is that fish While both cancer and development

a embryo. Also like Wnt, Hh appears c tumors look very similar to human are exceedingly complex processes, insights

n tumors,” Jessen says. “And you can bathe about developmental pathways like Wnt linked to the formation of tumors in those o (zebrafish embryos) in chemicals and look are slowly beginning to reveal the genetic tissues where it is required for develop - t

o for molecules that inhibit or promote underpinnings of tumorigenesis. ment – the cerebellum, foregut, prostate,

H growth of the tumor.” “It’s so complex that no one lab or skin and lung, for example. Jessen is also combining developmen - company is going to come up with the In some cases, the Hh protein “may tal biology and cancer research through a answer to cancer,” says Jessen. “I see tell some cells to proliferate,” says Michael

that an abnormality in the Hh IV gliomas may be different determine that, we need a pathway might be involved in (than the others),” Cooper good animal model.” their development. says. “This may suggest that While Cooper plans to devel - Michael Cooper, M.D., assis - not all stem cells – and not all op an animal model, a Clinical Pathway to tant professor of Neurology, cancer stem cells – would be Scientist Development Award has teamed up with Reid the same. he recently received from the glioma? Thompson, M.D., director of “It’s a controversial idea,” Doris Duke Charitable The Hedgehog (Hh) signaling Neurosurgical Oncology, to he adds, “but our data sug - Foundation will support a pathway plays a critical role in examine Hh pathway activity in gest that grade IV gliomas prospective clinical study to embryonic development and brain tumor samples stored in may arise from a cell type assess Hh pathway activity in has been linked to a number of a tissue bank that Thompson that’s not Hh responsive, gliomas that have been surgi - different types of cancer. established. where grades II and III gliomas cally removed from patients. Researchers at Vanderbilt To date, they have found that may arise from an Hh-respon - Those patients will then be University Medical Center are the Hh pathway is activated in sive cell type.” followed long-term. now examining its role in one certain types of gliomas – While the results suggest “I’m a clinician, but my of the most fatal types of brain those of intermediate grades II that Hh activity might someday research has been at the basic tumors – gliomas. and III, but not in the most be useful in predicting tumor science level,” he says. “So Gliomas are the most com - advanced grade IV tumors behavior, the role of pathway this award is taking (the mon type of primary brain (known as GBMs, or glioblas - activation in the tumor is not research) to the next level, and tumors (meaning they arise in toma multiforme). Importantly, yet clear. it gives me a chance to learn a the brain and not from else - they have found that the Hh “It is guilt by association at whole new set of skills.” where in the body). These pathway is activated in what this point,” Cooper says. “We – MELISSA MARINO tumor cells resemble glia – appear to be progenitor or still need to know what the cells in the brain that support stem cell-like cells. pathway is doing. We think that and nourish the neurons, and “Investigators have specu - it may have a role in tumor some studies have suggested lated for some time that grade growth and invasion, but to

26 LENS / WINTER 2007 straed si prosenchal mi birth to Gentics nali defcts j prof chemo tow how Ho l wi t acti Inde, “stem to of on l self proces d mutai pathwy cel cal div the i b respond tha pathwy reciv ti Hh devl ron,” respond certain cel “i renwal Neuro sue cel St C erv ik oki tor ut evl ngl sue’ o t f, the tumo ld e e pki in id h may -renwal s,” ed ular s va ine ard ng. ro per, the mos signal esor m cel in apernc. Beachy W Whil When “Hh “S T Mo cel l co e, w ng opm opm ike hol ted fo defcts ing a le ng s he lo ns cel gl therapui mo Co el ons tem ls,” mpo ce orki central earl and (terao l. li r way f the The beco ano t st cel r turnove the tel gy M.D, o orm at becaus s s to by io opr neag l exam Uni the to exact at i oper i f o fo ent, ental ls regul st the into regul l ” e n mpo rtant ly, mas. ti f depns ike l can Hh ho say ier ng H ma at cel rmati Hh unds the acti theory a cy th at l Jo f sue Hh m Mol sevr tha cel mes resa ation and proces or y, vers ep sencphaly , h of w res si theo Va cl gens) an ly-positned hns but ple. lous tha H w say. adult m ocur s ates i an ins cyl ate by vati gnal … pathwys ithe pa pathwy Coper, “We n s opa the the pathwy ecul it earch y h , ha ve or nderbilt of c it col dysreg i on. know to more have prima t h thway t truc ch a ca i Hopkins y, al s and target. to hes of not and n opia sita ng cel choles an mine proge c elf-r li a on lea fac tera “In P hod. i ry dife ’ve ncer so ar an’t a may Coo nte um Th the an un number hil tumor be nd a ste fe injur or gue e wha Biolgy Wnt only st io in st fa s d div ula en to le ce ex r a co is r l (de who i te and nt p y re to e lo c a t fe m . be p n em firs r nit typ ta s c r a a te bec t ar se genic he m a tumo ls er s e pec uch me e m aus is s I ha When pe c bra ntia t r w i n’t qui t Be i l wi n ve a , pr r y ne s t a ca cumlat ed, e ce mpa i . ha - t o s e t ct ol ions ting es, was fo ge t or kno Cope t br loc ome ur mos o te is r a ot ye pos o with te lopment ype e or ofe ll ng, use a d in pla a o a r iva t d be r led rm a r te chy, c pla m ne s ain, ne f r e a her rige a dly pro ). st s p mo a pr a t els J c s nor rt pr demon nd wn or s ce t sible nd ha ex t ohns ar ce omp r ra t c ting ca udy alo si tur wher d a umor birt t t ce o ion e t e oge ye of le t or og en i hat o dult l likey Hh ur ticu genit ami f to pair nge d r o t pro ge ca n nes point Ph.D, mal o fro t – ls . ft e c ng d a c be ned wa he f.” t hol t r tha ned , a by ing of s le s e h nito hes of ype n the es lip, a m t e l is is.” ne ni larly of unds in sig t s a - he o s t a o to he or d , t the i f is ng ed n- r e by u s - s, a r r- - - - whos c o requi int was ni the opme be p si mod i w interf com ul rec the be act di whi de in leagu of in requi cy shr chem inv com pha spec val a no say may re v de v fu n ne w ca nc e ta l” ye a rat ha bi ri f r ngle bio er s ar at ol os ca fe ve t H c t t a e el at er m ei iv ue rs cl ink s da m lo es el o ic r ycl e rm nim ch s H el ogy o ct bo enc pounds pounds ta inh use e f th e Co h, mi vi “W Coo They Si “S Cyc “Thi Wh “Ca tr eav f at lo have f pam t e r, nly ie i al r r es p ering w ot at er nt; al y ie h-ge i nt i s, p ed e cul io rd e uct opa ng ac nce as t e n ed gat gic c ca o lds th e i ro thus me n en ta oper ing l s ing her d be epha ra pe r xpe hav Hh n hem al ed n er e m have ta t nce bi lo per et h ol eut t f f n t i fo ng. he ar s by ine rs ar r i ur i s a h ,” cel cam al ed tho o mi se t the ke ight gure mo pam eat e n ner te ev ape thi tr ad ha t nim pr ha and r av wi ri e , l i c w t er . ut i r mo ic th be s e ct t i H inh ar ic ly s sus t d, inh cho l a ance ,” t de l p igna me ne dem n a an oduc ay And e ev o it ught s bi i ra s hos tr del a s th of at ntua i ed at s e a uti at hw a o ng e numbe h c nt l em br it i ine d r h b be a Coper Hh velo f al le l bi r di have pec t adi peut d ol s o er po l, in rom c esul now a nt cti co tr ee cho pat bi d ch s bi est ne s. n er lear s c o e o i cho r g c Co rt l o c s co ogy !” tr tum n . g ef but ea ul i e ot na ut s ,” n cover an c a mpa l i nstrated tr t te ve, ti and t es ng a o t h s ly t s pme uct er io i in e ed me um hw yo tm end a s cel t gent hat oper ys le i i e l i ns br ea ng l d le s Co t t r bl uch c ed. estero w gnal bei de bef ol nal tha r om h e i w e “ st – det and or ni c i f ok ng t te st t d tha ur H as re r s l e de e ay nie e t or sa . or o r he o , a f er pondi y, n nt. Hh w s s el s ng er , e o f o d r If su ly s nder t h pe en e e but ,” ev h t ys pa r er s hor e the ct i f ol r “but t e as cane t w s s at s. Beachy ng ol by se t ar devl H e w lt s l r t hei s t t m . r hes ben t s fo th , ar had ed hi as i d ypes ed he s m ar he e t w i r gnal h r s mo we igna s t me o a i by r f m e dur e ibl ng. s ays in uch h r c ned e ul od l w know s e pr h pr now ’ m s e ef rs os gr d t re opm n t mi n i dif che e i umo i t . ot wa m hi i i t t fectiv , i odi . nhi ot ficatio - l t n w ng A done ow er hat ng and i “ bi a s t it ng ng ei i i s s But om hat s ei o nd mi y.” at l c n pect t r f ent ar m bi n t a im hol hey no i n t r dev s oge n h cat t t h epa val ca enes c ehow echa i t must t o L t t a o n t o al i ypes m w EN o he o ac n l n i l be el by ue on s - - in S e - g e , s - - s - - , Ilustraion ne a p ugs. dr t Esent S sim caner i bi br c t ac di g t ca ex na ac ge t ca an in t e r e he a e e r a s ol nd sc g a i i p sc t n t l ne ne nt ot t nt n, n le s iv n e hways, r plif b W wi pot o es i e ignal e h f s c a a d ng s od wi in gl fe ve Th Hh nt al ex er t d n n r inc e “ si ied a i ial t e This t e ct ent g l y om e e r P tu e h pr e tr e r in on c G and r a a s by t s d ha lude i e d n r W t h es gg l ct t t t f eg ra ial es epr r a. i p na . ra wit c or h t at “S , i nt i , Dominc h s t h n ilu e e r si T ns a me o ce o r e Hh Li m ed he r mo t d a h em ac t rs on t s nu n p ar ge h he c ke nd . ug st e l te r l only ” nt o r ri t a u ot d E L gets . c c P signa ot iv br r ne entaio pt h n l rs ( ation a s le ug F at fr ß- ar br P e f at h l r yo o i a i l ui t u in Doyle d iz N o c nt c en e i fi th h c r e a st si s u a n h zl d t fa ) nic r s f S t ing r , i s lin ri e t a e or ed h g f ac l s t ed f e f e m ew “ t n ly o a d / sh ß n a e ni nu s F g t g , i -c ” a c e i new W il p de h d ep ri r c a r n, o ge t of l l y e wh at p a ou el d e cl i (S zz l n or ke o r N I n ws u g t a velo ev n ar o d e t l ne e g l ul t l s mo the thwa l er gh ar e t f ed y he es u su ni if a a S el R E T n r c a tr to a s s comp e i te nti- m t n as e t .” si pment, o ) a r s. e Gl , . i an y ver wer d two t t f pm n o n r g o a h ys e r c a T W e caner ge ot s na i i c ey ad d p hi nd n gu e me ce pr n e en e 0 0 2 he o a a ne xe s lin g in t ma e tt e - la co lso o p p f t. m n irs te p r te r t to te t o o e r n r li g - r o in n - r d t - 7 - - - - 27 Hot on cancer’s trail IN THE BEGINNING 28 Hot on cancer’s trail PROBLEM OF SOCIAL INJUSTICE

ILLUSTRATIONS BY DAVID JOHNSON O R A H D L E L , N A M E E R F Q SN / .D . M W T N I & E R SO 0 2 A 70 CIA A PROBL L R c Haor needs cancer Fer eman Cancer Fer eman gyer Soci di Cancer authori We por School She Popul and Rese cancer They er I lo eks fessor es ctor ety, d i l acr h, s at d s i ati JU N er p to a ty F of i o c se oke Ca He Co s cts o er eman, o c n aer . me is has n b e o f hai p o Pu er al l ra e whi n or th u f Sc medi mber the wi th mbia He d ci bl ar th r fessor e a man se one i c th a nd i e e c Di Nati al th h l nces v r Da c li and He th sp L M.D., s Per o al Uni e n c to ens tudie o na-F f d k o ari al f Pol o th di nal h e r ve a f b vers at th e th e ties er s e etwe thni Medi edi arber duce i nti e and , s cy th EM pr Cancer ctor NCI’s a Pr ity wa c to al . o e nd esi c and n, en e c r SI T Ja Da an gr ys i th si i Ce o dent Bi n c n a ne f dent’s oups Bo race, on hi e e na-F nd Ma Ne l to nter th l Ins e a d Sn W adr f e t w i i p nagement o s mpor ve cer arber o ti eeks, , Hvaar r or fes ptor ipoonr ate f Ralph yder f Y ptoyver for tute’s the the of e ork Cancer the Outcomes Scientific sor poor via Cancer American City. M.D., Divis d wi Lauer n the Center Medical of confer gap and at Panel, and OF ion A CE quality clinical dis the l Ins leading cancer, Center Advisors, impact the of cuss and to ence Cancer titute. Har and School, not Reduce elderly of sur Policy vadr w call. for hat of - . reso are, i to reaso detrmi straegi del may treamn care may acesing i i usefl go i f F tha do a a i w i d tho ti may unawre patiens ated prefncs get healt and/o po We Wh b caner measurd w o F d H n nsurace acto tsel n n s n e ut u isp re re vely ow d her el d nc particul ry n’t orl understa play the treamn ek tc isea ema i ema se l y ver efcti urces, t I f. first e tha s: That’ Fi S They P are rs a have have have with … ns he of y om r mi know econd a wel seti t hysi rites So giv n: n: struce i ther naly It’s care in o inf are tha e r n hig if cul f nat ga E g usef or and g e o o I We’r of patiens cause o e n’t ht genral very we’r orm the s l ve ui de inadequ dif biase fo arly … by f p s? f cians po ngs. w m posi lder to ar uneqi ture, thes l e ar a syt the al, fo the cause es r w hetr be ul … ther po have gue ay ore trea qual fic i eldr o ve be o di coping r we n heal he one ed f twe f whi a in t th e in pat trea em mi ulti ry al bl w e c l not is el goi r cari el caner we ther key m l of problem if f urent tha tme tha a di eft so het i outc e derly derly be and ped youn estyl, th closing en di ectiv bout ly ty w m has nis l are o eanig ient ch ca re ong the ng es sparite to te it t ut ng adr hat me have spar en ay hat doi out compne patie nts. car car ’s the gr hing wit caus it wit the om reimbu po ma ma (in) th a t s. ger r po f he nts fac so ems ou th a o – e t l c e or e. e I . ng pa it i o e te or fe t a vide h i r sa st a ke e h The hav de i And alt t s put ve tha re s nc p nc with nts e ies e e t fe na t s de sing nt t spe ys mi tie mor the s he pat t me s ca . c c not t a of t a difcult rt w ha i itude o th e h e t s o he a pr de n hem tme t . h i i al re t e nce ive nc e ure n r y de nts a no nd em. y may nt c in as c And ca ient t se pot c l we pr e ogr rdina pro pa ifc ta t r quat ultr y may tha t wi linc thr it o peo fe re ed a pro rit s he ment gap nc re r , n nts the r tr lit ov we re gi v may tha tie of ent a t t ve ot or is They and re es c blem. s lac y t ea e o be h uci tme c sy e ple y ider t tive e ble e as a nts anc aly a s tio r he y la e. list hav e the lde ne t in clo ? se t ca the the re y ial st l fr k e major a s me a rg e a t be to vi ng oc ms y Th i lec t s om te nts e n nd have hey s of s e ria r sed. als ir – e m d y ar - ly rs i nt - a o ly - - s e l f , o s s be inc cat them ove soc ha Y y tr wi with tha fr to We thi be and adre o om hav ve l u ‘ e io s a ia ludi Why rl ks ’ e ar I poi s T We fl n l t aps an be s : t s l io his ex r el ur i hen ung he The sy eal njus ng en nt r, d ves so pec ’r ry fol st bot ar ‘ e l va Yes me co help y the . em t t e o t nea a go re t her lowi … lue ic h f the t nd le ov at , hey s publ of e al o cul ri e’ dispa s, … ed er f … ag ed r s pol ng ng col of t t he bel tur hos a hapeni t f i ue ho he w the a c i thi se t uc o ri h i a cy i e he het r e w ef r t s u t l next i ectal ques o y r e i c o nd s r es d f peol s end a t ir her el ns i ys udy di t o cr n e cl e r evant he ex ng?’ l t t sp t ye t e es em i hat o he of is ds m ons cancer s ca r e i ar a t whi s e s ’ not t behav bec re s r nt , he t p begi . obs t ys que it t o co her gi a he ies? ch t t aus m s t peo em v m hat er t s i e er n en udy . o t I m c va i e ve w . s Ho on t pl cal ou uni o t ti i s l e us on l w l at n - - Wh ha Ha Fr s Ha tha nat i and we who to bar sy who ge t com na vi ng t a s e a r re t d rl rl t io r t bou t em a a man i i ga t m le t i em em ( n e We Thi So w n ng r on al t o t r e uni t e f s at er 198 6 r at i im i s w ve w el : br on t t Ho Ho i s e ed o had 70 c n t a Thi s a e … i hat pa eas po s i a at t s get es 199 0 … se ed s s a to n a per pi pi … or t ct t t t pub l c f s ti o pr he t he y und am t t i t (t uch ca up e ing s a a o and m cen t l onl o obl r l l h at nce r a e at peo pl e a o a i as nd a d wi e co s s ver as t y … em s hed ispa t uni n pr hro s … d i he nce p l ur ) 3 n en of l H pa i og p r 9 a e g e u t t ec I at a t t a f h h et 2 p s al i ra w g ti r r t i con m t u t r e ve i l ha it p 2 er h o e e ou h e m r r i t ap - c n m e r ed o s cen ap ha nt t t) yea r e o y s t cl h gh of I ca l . u er u s a s? e , i e t w u re a w nt e dl w t n an ou s r d I h l s h as ur f s of ed a p h y ho r ed d eal or en in , A J d y t er o vig ia g com tr at t wi N ve t a l p er t p i ca t h gn h i p ea E s od h ha at vi eop em n e eo p a y n me W a te car os t ie n p g ti t E . ed en g ar . d. E nt l ed . on l e K e t e ed d i S o n - , M . D .

Hot on cancer’s trail PROBLEM OF SOCIAL INJUSTICE E

C We began to see real dramatic results… In budget shrinks, as it is right now, that’s the Weeks: Obviously it is a critically important I

T the six-year period ending in 2000, the five- first thing to go. challenge in oncology now to move from a S year survival of breast cancer patients at one-size fits-all to a more tailored approach U J Harlem Hospital was 70 percent, compared Are we not investing enough in to treatmen t. But my guess is that this N I to the previous 39 percent. these kinds of studies? movement is going to make care in special - L ized centers even more important. It’s going A I How important are cohort studies Weeks: I would say we are absolutely not to make cancer care even more expensive, C

O and epidemiological research? investing enough. and, if anything, it’s going to widen rather S than narrow the pre-existing gaps. F

O Weeks: I think Dr. Freeman’s story about Freeman: I fully agree with the need to So I think there is a moral imperative to the navigator program, it’s a little like invest more money in these areas … but address inequities at the same time that we M

E penicillin. You know, it’s so obviously maybe even an overriding issue is that the are pushing forward the science, otherwise L

B worked that it’s definitely worth pursuing. problem of disparities finally comes down the situation will get worse, not better ... O

R But what other things would work? to delivering what we already know … Careful studies have shown that when

P Are there lower cost alternatives that There is this huge disconnect African-American patients, for example, are would also work? Do we best put our between our discovery system and our treated in the same way as their white coun - resources into re-engineering the health delivery system … To the extent that we terparts, their outcomes are very similar. care system or providing one-on-one sup - don’t connect what we find to helping The gaps that we are seeing are not port for individual patients? I think those everyday people, I think it’s a moral and about biology. They’re about failure to are the open questions, and the best way ethical dilemma … get what we know works to the patients l i to begin to answer those questions is with The biggest thing we could do to who need it. And as what we know works a

r cohort studies and epidemiology. reduce disparities this day and this year changes over time, those disparities are t

s It’s where research always starts. It would be to apply everything we know, that not going to go away. This is not a prob - ’

r generates hypotheses. It generates ideas. we believe should be done for people, to all lem of genetic differences. This is a social e c Then you can narrow down with a ran - people, irrespective of their race, their eth - problem. n

a domized trial of a specific intervention nicity, their age, their sex or their ability to c and test to see whether it works. It’s very pay. That I think is the great challenge ... Freeman: The peculiar thing about progress n

o inefficient to do that without first under - You cannot solve the disparities prob - without equity is that the cutting-edge t

o standing the lay of the land, and that’s lem solely within biomedicine. Something progress tends to widen disparities as

H what the cohort studies and epidemiology else has to occur … If the problems are opposed to narrowing them. The things do for you. occurring in communities, which they are, that you discover are going to be very costly then we need to bring in the social scien - for an individual patient – to have a genetic Isn’t it difficult to ensure continued tists like sociologists, anthropologists, even profile, for example. funding for studies that last a long the historians to help us to understand I think we should push forward with time? what’s going on in our communities. this work, and I’m certainly in favor of And if the problem is inequity, and spending what is necessary to move our Weeks: I think it is true and there are several at its core I believe it fundamentally is a understanding of carcinogenesis at the reasons for that. One of them is the equity problem of inequity that drives disparities , molecular level ahead … But the moral issue. we need to consider even the extraordinary problem is that as we do that we don’t If you are a congressman and you have possibility that, at its heart, maybe dispar - seem to be paying attention to applying great health insurance and disparities are ities are related to human rights and the technology to all people. not a part of your life and you’re looking at civil rights. the way the NCI spends research money, Weeks: I think the message that we need to you want them to spend every single dime Won’t deciphering the genetics of communicate to our leadership is that, as in on finding the cure for the cancer that you abnormal growth through The all other investment strategies, it’s crucial might get. It’s human nature. Cancer Genome Atlas project, for to have a balanced portfolio. And when research funding is ample example, help reduce disparities by I’ve found that to be a useful and there’s plenty to go around, it’s also leading to more rational and suc - metaphor, actually. It goes back to some - great to spend some money on understand - cessful treatments? thing that we all understand in our daily ing the causes of disparities. But when the lives, which is the importance of pursuing multiple options at the same time. Even though the science couldn’t be more exciting and absolutely should be CENTER FOR OUTCOMES AND POLICY RESEARCH pursued, it needs to be combined with The Center for Outcomes and Policy Research was established in 1995 by its current research that will allow us to … get effec - director, Jane Weeks, M.D., at the Dana-Farber Cancer Institute in Boston. tive treatment to the patients who are not Among other projects, the center oversees the Cancer Care Outcomes Research and getting it today. Surveillance Consortium (CanCORS), a five-year study of 10,000 patients with newly diag - nosed lung or colorectal cancer. And one of the appealing things about The study is examining patterns of care, symptom control, health outcomes, costs that is that it has the potential to yield and other factors with the goal of improving quality of care. health benefits immediately, as opposed to a long-term benefit which is where the For more information, visit www.dfhcc.harvard.edu and search for “outcomes.” exciting basic science is taking us.

30 LENS / WINTER 2007 E war the the outc thi a ex ni put thou d is like ove S L Ric Fre c t er ens i ho I m f w ha v pl F M a c b ha c G P AK h s t i s t e pe p h t w a ten ty, sea am t n an t he ha o D s a a u om oci em t nd v hat sy e e a h r e har e an … un ak e g ne ac e hi nk 1 sam wa n’ r en m n Y C W T i om n ve ad o sa ul ys be Y ne gh I A W ef ul in se tot dic n tio t wh pl cl as ch o an: o in g he r ct up lo dic pl big ge s as m et ’s t G t e d e e’ ore if hon me thi DA lso d y d u . iolgy, ; , ( i the t the el e. al s s iona in n es ie e. a the He t’ al n e s y ics You ag ve it im t al it it D ic it have ap ppr Ni e th e we in ic in lo tor yo u l w If s t ways E si fy VI nk t , te d t s l N e ’s to hi s h mon W hat per w ora y w to im t is Res per fe c mu … t azi e g ) gi ca als w t par n p re, genius t a he SE yo rest gen t ar xon is o m l i avoide d s wa he e e oxi ge t be er ei of t t s fu i a th d th a G e re p le s s e a iod ri y r OF at s houl u o ore dan d Oxf we s ne , ch t A ghbor the irec earc al so n s pr utting s ge n lieve ent ey nding gh t s o at p ll y t one im we ome th population m on dec ma D. in na te re got o urn go de to mu di s eo p wa ‘ gr oble rembr norma t nly pol en mor g in ord ntion. pe rf Phi wa spe d int ask tha ge r ’t of s al i to wa re es s cla d e te t n h ea lar rej or on’t li ba ys personal ic ed d tatio lig h of ra to n’t t w eed our le many my hoo ctor gh tl ly r a ti o Counci b t, ct l., a s r m n red of THE i e ed; that ect ck t . access U ec ti l a ed is . ing n a es ne ecause those ha t pe rs on be the out a … Uni res s nt We go eig 10 bu ni com tl a th to man l’ t re o en s a ds th to n y That e he to o soci y a of f v an a i nd four on … s ds earch ve that to in . 0 t t u s w wn ht ri at ersi t: research. th j . can research … to w do fi of war u co n … 1 pl h k e the gh t, I l’s y t pa di as , yr t t st it ha gh to ay ho se e us 97 o o ad thin ha no t o y be that t m A ex. ies cer seas it … n at ty, go e ha n w ears can st f lea s as ( ve ua care, t b ou merica again 1 e - t vol p W w so e the ar … e t t a , , ai k It a l e g m di fir Presi wo f g r d) w s … uti ’s o h com u B ORLD mo … e ug ng f … st t ou st no erri o rse n u Sci adj so pr c th pe Se U so so bet PH it tr th in in que re ot a wo rk e th cal it’s g on? a r He o han t h o w s ld den o n o ca y (We) t r v te mu 2 t l he at e e o scie f r me me I It’s It t e o at o at at n o iv lla o L I here ol e u re te o to ba is no n thi as all, d of pl s l an . b ver o n do n ne e tle r in wh P I gi vin - ti Are t ige su - r k e ce rsi ct e bly w on ce peol a d po pe t on n Ge sw g nt ge n e so : t G fa w i e k e g t temp g profes l ty n s r to a opl in hr s E E R n ist n n t er n i th ir i comes ce are n gen l o a r t’s be lon ot ome eti tha t ou a of we d i p do prob ap ti req its how ical o th where s bio th tak ri i ur . n e s be nly e ha e ci i is . f eop … n ve gh . E N to teli i re c d ey at gh Wa g goi pl es do? n a sta that, e ence t o n part, get thin ui med e s , the is sor tha a complent w evi bout w to ha p ts. gi Sc pr y m al of P lem hav le T We n place it got di , hav c res … r shingto, on erspecti n t r n genc h. d elatd ne overis is w l ove em h v th ta ien get An g t spari to thei into l fut of gs sor bu t ical DN so e e D., out iv hat because then dering L now e s it e ( to the ble E ey t h to d app to ature NS o lu tha the e ring, ces C to … ure f di ave f fair there A, ts s r or or omputer profes ) w I th be and tio behav ties sci w w th be fferen t t abi b think d teach we ind … w roach to ve. han the of hat and A a it e real and i we o made ethics e to ence poin ns tha o t’ no, ar h t w But kn to lity medical s ethi lev w to are p . d Bu shou an up hy a shif at a n e eo i - o t . o peo s th us ot el t y w to in so d l t pl to - of wel evel t ri giv it of so luti ple ho to of ten e di dif th ldn’t v p cial l qu li en civ ay. sparities w to E f sor of di Ha be beca c o sytem I lon the peol i u tha y ti w the r n r the betr’? en s e co al geno s ferent es as ea esa ve o on ea who w ha o IC R se on 3 d o e r w i l n i We It The to mmu fro w the il do ect ckl v r f ie n n sor time u g d t equi j s peo don’t rs, tr ar in v of pu la hu s g . usti access. the terly i a ha and the u god e bu s a un the ol … m N A L Ho o? rch) … st y germli rd m se, hav shou s into ou Bi co Br bri bli gr a ma a of ple way s w t g ty of d nity ce, i n C n w a w i i fi we … n olgy M We mmun ha eat oa n certai ev cs ets r gen erstand c h also d s i an vi S D v e e for v bio j i l . forma a gen ca o u i so or n edi e irrespec poli yst olvi to E n ola no s we’ ldn’t olv an n d r real ma w man w cr must re s e R competn n w o y lutio ds con to n and hav eti m sta In ri n ork t d utsid ea e edi sa so , ca ems pri e eti ed te nl n w v ke cy sk a P ed o sti ev do i gen c e of ev e cial g ma t y, l ti rs ties fi r e h.D, nly e y be va c bly privacy? a ters, i S n ITM - over out on ri come olutin, denc 20, sure tue, n en to posibly ‘I the rc - i and s chol: ( Biolgy e ght cy nage nformati strucion e to ying tr could h. c for therapy how omplex director and ques patien cur ent we 3 tha so we profes along at their bilon tha h For of o pa l C the i La Hos P a on The E H T to s ea gens n u As a en tp:/ w tha or to pro to do it. can focu - u d rk ti at tr i have get the ould dershi 1 ts r mor ter M pi en 24th ea ytr Ra Pr en - it - Av in … com ta emori / A R t ev ch sed lph a ra Corp en e ca l. n en lph S p i to d mu u r H P L n La La tr R A M Gen Chi Thi Uta toda wa 20th ma evol speci Inf prof even c of ben dr ti heal Mi abor peol be in an sta e, on ti gr es. form Ha a a on . a et u on la a l 4 n’t u n Hum Thi I on d h r st a dr t orma s n na s the r ef dev m esa S o h, r rlem’s i persona u n ur en et esor It ut ty. t d en w a of a y ti loa K n e open ma t hi at cen es open a betwen i y tr n ged m kes A L S lmost E L ma en i es S on hen ex i ho i a fr ti cs, KS IC OLN s k w elopi on pledg i er an ci eve ic al C ade s to sue n-K ti on, om rch, n tha s t a c a of ent en ytur , w to al gi U i th cs, t ’s N , entr.or g s ba y are c s t In the ed of li par N we’ yt r La a ly o ent n the t etri t E R t w a S e v or t regula a vi the or i l he s n c. he er i no bi e. educa n l t e x come U fi n Medi di when ke i dif y g i / hin sit ma wel l , tn i re n w wa un th c y ur es ni an st ev l i Ma f rects N thi a cen W on gen n begi sue, elct or be hen Pol Of K feren ershi 20 a C v e n ew ma i n g y er Gen other de. s. t , ersi N I que n i d ger, nk $ di C o g cal ty: te w Ca Ph. a ter, el ce t the t i ome we 5 We a cer, i his n n s E 3 i be Ca son model on … ric R E T l se it They’ gen djunct a n tha eral Ra , p n i ty mi t w the N pula i D. n dva s t cer a i n be n there from w fi un ng t betwen o ca born ha eds f a n … ty T lph of l o o Myr cer , w ar rst t a Ha hi erat n d ca i w R E n’t der evolu nd a on n you ca t orks, If C d … of ve ti ch s w n … s ce 0 0 2 rlem, w u a n ia ? use of e re se ion the i - g ’ l d … … v i e - t 7 31 Hot on cancer’s trail PROBLEM OF SOCIAL INJUSTICE S Pictured here: Abbie Foust embraces chil - E

I dren from Lwala, a village in Kenya where

R she conducted a health survey. A I D A L A W L

She struggled every day to feed her children because she was too weak to work in the farm (just like the rest of the community, she lives on subsistence farming). Often, she relies on neighbors to give her family food … I went over to the 2-year-old boy of the family, who had a clubbed foot and

l couldn’t walk very well, and scooped him i

a up in my arms … He hugged my neck r

t and held onto my hair and nuzzled his

s face into mine. I tried to set the little boy ’

r down … but he wouldn’t let go. He e c wrapped his legs tightly around my waist n a

c Lwala diaries and hugged harder – and that’s when the

n tears came for both of us … o t

o (a postscript) August 1 About a week ago I visited an

H orphanage called Sally Orphanage, where Editor’s note: The previous issue of Lens chronicled the efforts of Milton Ochieng’ – now a third- 120 AIDS orphans live ... Sally Orphanage year medical student at Vanderbilt – to construct the first health clinic in Lwala, his village in is located near the Tanzania border … where Kenya. Last summer, after earning her undergraduate degree from Vanderbilt, Abbie Foust spent HIV rates are as high as 40 percent … 10 weeks in Lwala helping Ochieng’ conduct a health survey. Here are excerpts from her e-mail The death rate is so high … the govern - journal, which can be found at www.lwaladiaries.blogspot.com. ment is running out of land in which to bury people … Parts of the village were May 27 Oyare (good morning)! almost ghost towns. Hut after hut after I can’t believe I’ve only been here three days. This place is amazingly inspiring, hut was empty because all their occupants beautiful and heartbreaking at the same time … There is no electricity … and no run - were dead from AIDS … ning water … I met a 17 year old, Emily, who was I am staying in the home of the Ochieng’s … The first day they took me to a very the eldest of 40 – yes, 40 – AIDS orphans sick woman in the village who was vomiting and weak … The clinic isn’t running yet, so in a single homestead (it’s what happens there was nothing we could do except massage her back and feet and keep her company ... when women are in remote villages, have no access to birth control, and don’t have June 3 Lwala is quickly becoming my second home … I am now used to showering any say in using condoms). Emily was a with one bucket of water and a cup. I am used to having beans at every meal … mother who got pregnant after sleeping I am even becoming accustomed to the extreme poverty that is prevalent in this with a sugar cane worker in a field who community – poverty that can be seen in the distended bellies of children (and in) the offered her 100 shillings (the equivalent of lack of books and chairs in the local primary school … It doesn’t make me any less sad $1.50). She accepted the offer because she and angry every time I see it, though … hadn’t eaten in three days … We started the health surveys on Wednesday … Some days we walk over two I’ve experienced some of the hardest hours to get to a certain village and go from hut to hut … We interview the mothers; moments of my life here. I’ve seen some of some … as young as 14 ... the most devastating sights … followed You’d be surprised how many mothers say their kids have had convulsions and by some of the most beautiful and inspira - blood in their stool – both of which are NOT good. I am also learning how many of tional … I have seen incredibly capable, the children are not vaccinated in this area … intelligent people in Lwala leading the effort to build the clinic … June 19 We had the privilege of speaking to a woman who is openly HIV positive – I leave Kenya … with the hope that I something that is very rare in Lwala. Even though 30 to 50 percent of the population can encourage others to become equally is infected with HIV, people are incredibly secretive about it ... touched by what’s happening in Lwala and This woman, an AIDS widow, had seven children, five of her own and two that around Africa. There’s so much good that she took in from her sister and brother-in-law who both died with AIDS a year ago. we … can collectively accomplish … LENS

32 LENS / WINTER 2007 NEWS ABOUT LENS

FEATURED SCIENTISTS NAMED “AMBASSADORS” FOR RESEARCH

Three scientists featured in the summer 2006 issue of Lens magazine have been named to a new national group that aims to increase awareness of – and make the case for greater U.S. investment in – global health research. James Hildreth, M.D., Ph.D., Sten Vermund, M.D., Ph.D., and Peter Wright, M.D., are among the first 27 “ambassadors” named to the Paul G. Rogers Society for Global Health Research. Global health issue wins international The society was launched last summer by Research!America, a non-profit award for best periodical alliance that advocates to make health research a higher national priority. Named for the former Florida congressman and Research!America chair emeritus, the socie - Lens magazine has won a 2006 ty was established with a $1.2 million grant from the Bill & Melinda Gates Global Media Award for Excellence from Foundation. the Population Institute for its summer As ambassadors, Hildreth, Vermund and Wright will meet with opinion leaders issue on global health. Editor Bill Snyder accepted the and decision makers, make presentations to non-scientific groups and write newspa - award for Best Periodical during a cere - per columns about the need for global health research. mony Dec. 6 in Washington, D.C. Hildreth directs Meharry Medical College’s Comprehensive Center for Health The Population Institute is an interna - Disparities Research in HIV; Vermund directs the Vanderbilt Institute for Global tional, non-profit organization that works Health; and Wright is chief of the Division of Pediatric Infectious Diseases at to achieve “a world population in balance Vanderbilt. LENS with a healthy global environment.” The annual Global Media Awards are given to recognize “outstanding contribu - tions to greater awareness of population, environment and resource issues.” Other awardees included USA Today , Best Major Daily; NOVA’s “Rx for Survival,” Best TV Documentary; and Al Gore’s “An Inconvenient Truth,” Best Film Documentary. Previous winners in the Best Periodical Category have included Scientific American and TIME Magazine . WRIGHT VERMUND HILDRETH LENS

Lens Editorial Board

Jeffrey R. Balser, M.D., Ph.D. Ellen Wright Clayton, M.D., J.D. Michael C. Kessen, B.A. Anesthesiology, Pharmacology Genetics & Health Policy, Pediatrics, Law Director, Corporate & Foundation Relations Associate Vice Chancellor for Research Co-Director Medical Center Development Center for Biomedical Ethics and Society Andrea Baruchin, Ph.D. Joel G. Lee, B.A. Medical & Educational Administration Raymond N. DuBois, M.D., Ph.D. Associate Vice Chancellor Director of Strategic Planning Medicine, Cancer Biology, Medical Center Communications Office of Research Cell & Developmental Biology Director, Vanderbilt-Ingram Cancer Center Lee E. Limbird, Ph.D. Gordon R. Bernard, M.D. Pharmacology Medicine John H. Exton, M.D., Ph.D. Chair, Biomedical Sciences Assistant Vice Chancellor for Research Molecular Physiology and Biophysics, Vice President for Research Pharmacology Meharry Medical College Randy D. Blakely, Ph.D. Pharmacology, Psychiatry Steven G. Gabbe, M.D. Mark A. Magnuson, M.D. Director, Center for Molecular Neuroscience Obstetrics and Gynecology, Molecular Physiology & Biophysics, Medical & Educational Administration Medicine Peter Buerhaus, Ph.D., R.N. Dean, School of Medicine Director, Center for Stem Cell Biology Nursing Director, Center for Interdisciplinary William N. Hance, B.A., J.D. Lawrence J. Marnett, Ph.D. Health Workforce Studies in the Director, Office of News and Public Affairs Biochemistry, Cancer Research, Chemistry Institute for Medicine and Public Health Director, Vanderbilt Institute of Chemical Biology George C. Hill, Ph.D. Richard Caprioli, Ph.D. Microbiology & Immunology John A. Oates, M.D. Biochemistry, Chemistry, Pharmacology Medical & Educational Administration Medicine, Pharmacology Director, Mass Spectrometry Research Center Associate Dean for Diversity in Medical Education

LENS / WINTER 2007 33 Confocal microscope image shows muscle cells developing within a cardiac infarct, heart tissue that has died due to lack of oxygen. The image, created by researchers at New York Medical College’s Cardiovascular Research Institute in Valhalla, pro - vides visual evidence that ischemic injury can trigger activation of cardiac stem cells, some of which can regenerate damaged heart muscle.

Image courtesy of Jan Kajstura, Ph.D., and Piero Anversa, M.D., Cardiovascular Research Institute, New York Medical College. From Konrad Urbanek, et. al., PNAS USA , June 14, 2005; 102(24):8692-7. © 2005 National Academy of Sciences, U.S.A.

IN THE NEXT ISSUE :

Crush of clots Diabetes increases the risk of heart disease. Vanderbilt researchers are trying to find out why.

Sudden death Genetic factors contribute to abnormal heart rhythms, a leading killer in the United States.

At the cutting edge Stem cells and other advances could lead to new ways to heal an injured heart.

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