A Broken Pipeline?

Flat Funding of the NIH Puts

a Generation of Science at Risk.

A Follow-Up Statement by a Group of ConcernedUniversities and Research Institutions

March 2008

364582BS:364582BS 2/13/08 1:10 AM Page C1

You can lose a generation of

researchers pretty fast—in five

or ten years. You create such a

discouraging atmosphere they just

go somewhere else instead of

academic research. We don’t have to

lose 50,000 researchers, just 50

really good ones. Once it happens,

we won’t get those people back.

Joshua Boger, Ph.D.Founder, Vertex Pharmaceuticals,

and Chair, Biotechnology Industry Organization (BIO)

364582BS:364582BS 2/13/08 1:31 AM Page C2

But, as you’ll read on the following pages, eventhe most promising young investigators atpremier academic research institutions are

struggling under tremendous financial pressures.They are having a hard time getting their researchdone—research that could save lives. As a result, ageneration of scientific discovery is at risk.

It’s a shocking development, given that just five yearsago, American medical science was experiencing arenaissance. Between 1998 and 2003, Congressdoubled the budget of the National Institutes ofHealth (NIH), and that critical infusion of financialsupport helped scientists across the country reachhigher and push harder than ever before. Among theresults were the completion of the human genomeproject; the deployment of powerful new researchtools that have opened up new worlds of scientificpossibility; and a feeling that we are poised totransform medicine and effectively prevent, ratherthan just treat, many illnesses and diseases.

In 2003, however, the budget increases stopped andinflation began to erode the purchasing power of the NIH.In FY 2008, the NIH is experiencing an unprecedentedfifth consecutive flat or below-inflation budget.

In competition for limited resources, scientists atevery point along the academic research pipeline arefeeling the destructive effects. Currently, only one infour original research applications to the NIH arebeing funded, and many of those are funded onlyafter lengthy delays and cumbersome reapplications.The system is backlogged with proposals and too feware being funded—impeding scientific progress. As wereported in 2007*, there is a sense of despair amongleading researchers across the country.

Nowhere is the impact more striking than in theresearch labs of the nation’s newest academicresearchers—those who have recently emerged fromyears of rigorous training at the best institutions andare eager to make their mark. These enthusiasticyoung innovators—the future of American medicalresearch—are trying to remain optimistic about theirown prospects and the future of science as theystruggle to keep promising research projects alive.Their concerns and those of their mentors—concernsnot just for themselves, but for the country—arevoiced in the pages of this publication.

“I don’t think one researcher’s funding plightmeans anything much in the scheme of things,but I think my difficult experience is beingplayed out many times over. I hate to think ofall the lost opportunities for scientific progressthat are going unfunded, and the loss ofeconomic competitiveness that will accrue ifthese funding trends continue.”

Anne Giersch, Ph.D., Assistant ProfessorHarvard University and Brigham and Women’s Hospital

America trains the bestscientists in the world.

* Within Our Grasp—or Slipping Away? Published and presentedat a Congressional hearing on March 19, 2007

Just a Few Technologies MadePossible During NIH Doubling

• Treatments that reduced U.S. mother-to-child HIVtransmission from 25% to 1% .

• New gene-based therapies for untreatable neurologicaldiseases such as Huntington’s disease and Lou Gehrig’sdisease ready for human clinical tests.

• A saliva test that detects four molecules that identifyoral cancer with 90% accuracy.

• The clot-busting drug t-PA became the first and onlyFDA-approved emergency therapy to reduce disabilityfrom stroke.

Source: NIH Factsheet, Doubling Accomplishments, Select Examples

1

364582BS:364582BS 2/13/08 1:12 AM Page 1

I’m concerned that most of the folks

who are getting funded are those

who have already been getting

funded. If young investigators are

lost from the pipeline, soon we won’t

have the scientific brain power that

we need to move forward. When the

current scientific giants retire,

where will we be?

Michael Rodriguez, M.D., M.P.H.Associate Professor, University of California

Los Angeles

2

364582BS:364582BS 2/13/08 1:12 AM Page 2

Right now, scientists at American universities andmedical centers are unlocking the mysteries ofhuman health and disease, learning amazing

things like how to disarm viruses and manipulatebone marrow cells to repair and regenerate tissue.Some of this groundbreaking work has already beentranslated into better medical care and outcomes forall of us: cancer rates are dropping, we have a vaccineagainst cervical cancer, and for the first time in nearly50 years, the average cholesterol level for U.S. adultsis in the ideal range—below 200.

These medical advances come at a crucial time forAmerica. Our population is expanding and aging and,even while treatment outcomes are improving, thesocietal burden of chronic disease grows ever greater.Currently, seven of the most common chronic illnesses(including cancer, diabetes, hypertension, and stroke)combined affect 162 million Americans and cost theU.S. $1.3 trillion per year, according to a recent MilkenInstitute report. By 2023, there will be an estimated230 million cases of these diseases, at a cost of $4.2 trillion. Clearly, advances in preventing and efficiently treating these diseases can have a significant impact on the nation’s economic health.

The scientists at our nation’s leading academicresearch centers who devote their lives to conqueringillness and disease are supported, in very large part,by the National Institutes of Health. The partnershipbetween the NIH and U.S. academic researchuniversities and hospitals has been in place since the 1930s. Universities and hospitals contributesignificantly to the research enterprise, particularly inproviding start-up support for junior investigators, butNIH grants are critical to the long-term research thatresults in medical breakthroughs and improved healthand health care for all Americans. Much of thisrigorously peer-reviewed research also helps lay thegroundwork for subsequent advances by America’sformidable biomedical research industry, which buildsupon the publicly available work funded by the NIH.

But the scientific research pipeline is breaking down.Even as substantial advances appear within our grasp—including breakthroughs in Alzheimer’s disease, lungcancer, and depression— they are at risk of slippingaway because the NIH is experiencing a dangerousslowdown in funding. The year 2008 marks the agency’sfifth consecutive year of no real budgetary growth,representing a 13% drop in purchasing power since2003. According to a commentary in The New EnglandJournal of Medicine, “the nation’s biomedical researchenterprise has never experienced a recession of thismagnitude or duration.” The resulting challenge—adequately maintaining the world’s premier researchenterprise with ever-shrinking resources— is part of asituation that some have called a “perfect storm.”

A Cascading Effect

The effects of the NIH budget constraints arecascading down the academic research pipeline,causing leaks and clogs along the way. The overallsuccess rate for NIH research project grants droppedfrom 32% in 1999 to 24% in 2007. That means morethan three of every four research proposals are notfunded. Scientists are forced to spend less time doingresearch and more time writing and rewriting

A Broken Pipeline?

199520.0%

22.0%

24.0%

28.0%

26.0%

30.0%

32.0%

34.0%

36.0%

38.0%

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Fiscal Year

Percentage of Applications or Individual Applicants FundedFiscal Year 1995-2005

R01 Applications Funded

Percentage of NIH R01* Applications Funded,Fiscal Years 1995-2005

3*RO1 Equivalents: RO1, R29, R37Source: National Institutes of Health

364582BS:364582BS 2/13/08 1:12 AM Page 3

grants because fewer applications are funded on firstsubmission (29% in 1999; 12% in 2007). Most successfulgrants now require two or three submissions to the NIHpeer review process before being funded. This trend rep-resents a clog in the system that is causing researchersto abandon promising work, downsize labs, and spendmore time searching for other financial support.Meanwhile, Americans wait longer for cures.

Further down the pipeline, junior investigators arecompeting for limited resources with their well-established mentors. The result: junior researchers aregetting a smaller piece of the NIH funding pie. In 1990,they received 29% of R01 grants (the premier NIHresearch grant, see sidebar on page 5), but in 2007, theyreceived 25% of R01s. Further, while the success rate hasdropped for all R01 applicants, it is particularly low—only18%—for first-time applicants. Junior investigators—whobring energy, creativity, and enthusiasm to the world ofdiscovery—appear to be having the hardest timesurviving in the current system.

The question becomes: how long can junior researchers wait for real funding before they mustbegin to reconsider their career options? Today’sresearchers are waiting an average of four years longerthan they did in 1990 for their first big grant: 43 is nowthe average age of first-time R01 recipients. Seniorinvestigators report that many of the brightest youngminds are leaking out of the pipeline because they nolonger see the promise of a career in academic science.Many are following opportunities in private industry orin places like China, Singapore, India, and the EuropeanUnion, where public investment in scientific research isa top priority.

Further, junior researchers report that they often feelconflicted when mentoring graduate students andpostdoctoral fellows—the newest entries in the

research pipeline. Junior investigators rely on these young apprentices to help them generate the researchdata they need to get NIH funding, but they areresponsible, in turn, for helping those students makesound career choices. “I tell my graduate studentsand postdocs, ‘if you’re truly passionate aboutscience, then this is the best career,’” says DenisGuttridge, Ph.D., Associate Professor at The OhioState University. “Back when a higher percentage ofgrants were getting funded, hard work and innovationwere rewarded, but today there are feweropportunities.”

4

Age at first R01* grant 39 43

% of R01s* that go tofirst-time investigators

1999 2007

1990 2007Then Now

Challenging Times for All Researchers

Especially for Young Investigators

Overall success rate forNIH RO1* Proposals

Success rateon first submission

29% 12%

29% 25%

32% 24%

*RO1 Equivalents: RO1, R29, R37Source: National Institutes of Health

364582BS:364582BS 2/13/08 1:12 AM Page 4

NIH Funding 101:One Grant Stands Out Above the Others

The National Institutes of Health is the major funder ofbiomedical research in the United States. The majority ofits budget—85%—supports scientists at universities andmedical centers around the country whose research aims to prevent and cure disease. Most of the work is fundedthrough grants. NIH awards many different types of grantsfor research (including several early-career training grants,called K awards), but the most important is the R01.

The Research Project (R01) grant is the gold standard inscience—it launches careers. A scientist is not consideredestablished and independent until he or she is awarded anR01, which provides multi-year funds that enable scientiststo hire staff and buy equipment and materials necessary to conduct experiments.

“Assistant professors cannot get going in their careers untilthey get their first R01,” says Denis Guttridge, Ph.D.,Associate Professor at The Ohio State University. “Surethere’s private money, but this is also hard to obtain andthe funding level typically is not sufficient to sustain long-term research that can make a real difference.”

Through NIH’s peer-review process, scientific expertsevaluate grant applications and help the NIH makeselections for funding. In this difficult fiscal climate,reviewers are becoming more demanding and moreconservative in their evaluations. As a result, first-timeinvestigators are facing greater hurdles to becomingindependent investigators.

According to the NIH website: “Entry of new investigatorsinto the ranks of independent, NIH-funded researchers isessential to the health of this country's biomedical researchenterprise.” To support more early career scientists, the NIHhas launched several new programs, including the Pathwaysto Independence Award and the New Innovators Award. Butthese grants go to just 200 scientists each year—a smallpercentage of the bright investigators eager to enter theresearch pipeline.

5

Science is Taking a Hit

Science itself is taking a hit. As the NIH has less grantmoney to award, the scientists who review grantapplications are predictably becoming more and morerisk averse in their evaluations, preferring to seeincremental steps rather than bold visions. Thisconservatism among reviewers is changing the wayresearchers write grant applications and designexperiments. There has been a fundamentalnarrowing of the scientific vision, with the primary scientific query shifting from “what is possible?” to“what is fundable?”

The harmful effects of these breaks in the scientificpipeline are felt, ultimately, in America’s health andeconomy. Conservatism and delays at the researchbench reduce the scope and pace of scientificdiscovery and, eventually, the rate at which medicaladvances improve health outcomes for all of us.

And while NIH’s total budget of $29 billion appearssubstantial, it represents only 5.5% of the $2.1 trilliontotal U.S. health care spending every year, according toResearch!America. A strong investment in high-qualityresearch is the key to prevention and treatmentadvances—and reduced health care spending.

The early-career researchers profiled on the followingpages are the answer to improving the health of allAmericans, reducing the burden of disease on theeconomy, and retaining our position as a global leaderin medical research. But, as you’ll read, America’sbrightest young academic scientists are in aprecarious position.

364582BS:364582BS 2/13/08 1:12 AM Page 5

The Long Road to a Career inAcademic Science The road to becoming an independent biomedicalresearcher is long, and not for the fainthearted. Manyyears of schooling and specialized training standbetween a student committed to solving the world’smedical ills and the research pipeline.

Obtaining a Ph.D. is the most common route to a careerin academic science. After four years of undergraduateeducation, students go on to earn an advanced Ph.D.degree, which takes an average of six years. Next comesthe specialized training of a postdoctoral fellowship—sometimes three years, but often five, six, or more—where the fellow masters the techniques andapproaches of laboratory research. Then comes a juniorfaculty appointment—assistant professor—at aresearch university. Only then does academic tenurebecome a possibility, and it is entirely dependent onreceiving that first R01 grant.

Some researchers pursue the dual M.D./Ph.D. degree tobecome a physician-scientist and do translationalresearch that bridges the laboratory bench to thepatient’s bedside. Researchers who follow this routetake on medical school as well as a Ph.D. education,followed by a medical residency to learn how to care forpatients and a postdoctoral fellowship to learn theropes of a lab. For both types of researchers, manyinstitutions provide support to help them get started,but after those first few years, they must obtain theirown funding, the majority of which comes from NIH R01grants. The average age for receiving the first R01 grantis 43 for Ph.D.s — even later for M.D./Ph.D.s.

“What a strange business this is: We stay inschool forever. We have to battle the systemwith only a one in eight or one in ten chanceof getting funded. We give up making a livinguntil our forties. And we do it because wewant to help the world. What kind of crazyperson would go for that?”

Nancy Andrews, M.D., Ph.D.Dean, Duke University Medical School

“In tight funding times, there’s a tendency tofund the well-established investigators, butthe incubator areas, where junior investigatorstend to thrive, must be kept fertile as wellbecause that’s where the future lies.”

Larry Schlesinger, M.D.Professor, The Ohio State University

“With this tight funding situation, I’vestepped away from riskier stuff. My salaryand that of everyone in the lab is dependenton my getting grants. You become very savvyto what is fundable.”

Pampee Young, M.D., Ph.D.Assistant Professor, Vanderbilt University

“We all got federal funding to support ourgraduate studies. After investing in eightyears of training followed by many moreyears of residency, now there’s no parachute.Are they going to let us freefall? It doesn’tmake any sense. Why not support us to thepoint of independence when we can makepotentially huge impacts?”

Isla Garraway, M.D., Ph.D.Assistant Professor, University of California Los Angeles

6

364582BS:364582BS 2/13/08 1:12 AM Page 6

“In my lab, we’re changing the way people with lung cancer get treated. If I had had more

resources, what we’re doing today could’ve been done months ago, a year ago. We could be

saving lives every day.”

Anil Potti, M.D.Assistant Professor, Duke University

7

364582BS:364582BS 2/13/08 1:12 AM Page 7

“I was shocked that Rachelle Gaudet

was having so much trouble getting

grants. She’s an outstanding scientist

with a great track record as a trainee.

Her grants were beautifully written,

with very clear, very mature thinking.

It looks to me like she has it all. The

others featured in this publication,

and the institutions they represent,

suggest that they are as talented and

well-trained researchers as you will

find anywhere.”

Nancy Andrews, M.D., Ph.D.Dean, Duke University Medical School and former Dean, Basic Sciences and Graduate

Studies, Harvard Medical School

8

364582BS:364582BS 2/13/08 1:12 AM Page 8

The 12 exceptional early career researchers onthese pages were selected by senior scientists anduniversity leadership for their potential to make

important contributions to science. They are devisingnew ways to manipulate adult stem cells to repair theheart, revealing the critical pathways involved in cancerand progressive brain diseases, and using new tech-nologies to detect the earliest stages of kidney disease.Their mentors are excited about their work, and NIHreviewers express enthusiasm—even as they send theyoung researchers back to the drawing board wheregrant proposals often are made more conservative in aneffort to get funded. The funding doesn’t come easy—ifat all. At a time when their innovative thinking shouldbe nurtured, these researchers are jumping throughmultiple hoops, facing successive rejections andreduced funding levels. Their stories are symptomaticof what is happening in academic research labs acrossthe country.

Misfolded Proteins and DegenerativeBrain DiseasesMisfolded proteins wreak havoc in the brain in severaldevastating diseases, including mad cow disease,Alzheimer’s, Huntington’s, and Parkinson’s diseases.Brown University’s Tricia Serio, Ph.D., has determinedhow prions, strange proteins that act like infectiousagents, multiply and spread so quickly to convertother proteins in the cell into a misfolded mess that issometimes toxic. With this knowledge, Serio’s group ispoised to explore some “intriguing possibilities forreversing” the spread of these damaged proteins.Although reviewers said her ideas were very innova-tive, they also called them too risky—and turneddown her funding request twice. She joined thefaculty at Brown as an assistant professor in theDepartment of Molecular, Cellular Biology, andBiochemistry in 2002, but her first R01 didn’t comethrough until 2006. She was only able to push herresearch forward because she had money from othersources, including a 2003 Pew Charitable Trust grantrecognizing her as one of America’s most promisingbiomedical researchers.

Unlocking the Mechanics of Painand Heat SensationOur bodies sense pain and temperature through pro-teins on the surface of our cells. Associate ProfessorRachelle Gaudet, Ph.D., of Harvard University, isattempting to discover how these proteins work.Gaudet calls the proteins she studies the “windowsand doors” of cells because they let chemicals moveinto and out of cells and also help cells perceive theirsurroundings. One of the proteins, called TRPV1,enhances the pain signals caused by inflammation,which plays a key role in arthritis, heart disease, andin autoimmune diseases like type 1 diabetes.Unlocking the secrets of TRPV1 may lead to earlierdiagnoses and better treatments for these conditions.Gaudet was recently awarded her first R01 grant afterfive years of submissions and resubmissions. “My firstand second applications were scored low and weren’tfunded,” she says. “I submitted a similar proposal tothe National Science Foundation, which scored theproposal very high but declined to fund it becausethey were certain it would win NIH funding.”

An Inspired Generation“I’m excited about the work we’re doing andI want to keep it going.We have lots ofpotential to have a positive impact on somereally devastating diseases that humankindis facing.”

Tricia Serio, Ph.D.Brown University

“My first NIH grant proposal was veryambitious – it was riskier, but had amuchhigher payoff. I was proposing to go all theway to solving the structure of the wholeTRPV1 protein, which is a challengingproblem. People call it one of the lastfrontiers in structural biology to be able tocrystallize membrane proteins.”

Rachelle Gaudet, Ph.D.Harvard University

9

364582BS:364582BS 2/21/08 6:24 AM Page 9

Revolutionizing Lung Cancer

Diagnosis and Treatment

Patients with the smallest lung tumors are usuallyoffered surgery but not chemotherapy, even though30% of these early stage tumors recur after surgery.Doctors have not had a way to know whose cancerwould recur and whose wouldn’t. But AssistantProfessor of Medicine Anil Potti, M.D., and hiscolleagues at Duke University have identified uniquegenetic patterns in tumors that make it possible topredict which early-stage tumors are more likely torecur and should be treated more aggressively. Potti’swork also dramatically improves the odds of choosingwhich chemotherapy drug from among the four or fivechoices is likely to work best for individual patients.The genetic test has been approved for clinical trials in50 medical centers and will involve approximately 1,200cancer patients. But even though Potti’s discovery wasnamed one of the top science stories in 2006 byDiscover magazine, he has not yet been able to obtainR01 funding.

Targeting Prostate Cancer Stem Cells

Prostate cancer, once it spreads, is notoriously resistantto treatment. Stem cells within the prostate stimulateuncontrolled cancer growth, but are very rare and difficult to grow. Isla Garraway, M.D., Ph.D., AssistantProfessor in the Department of Urology at the DavidGeffen School of Medicine at UCLA, is developing aunique approach to find, grow, and mark these stemcells. She can induce the cells to aggregate intospheres, which stimulates their growth. She is working

to identify markers on the stem cells so they can be targeted with treatments. Garraway’s work is inspiredby her father, who died from prostate cancer. She hasreceived grants from the Department of Defense, whichhas special programs for research into ovarian, breast,and prostate cancers; the Prostate Cancer Foundation;and a private donor. A National Cancer Institute grantfor minority scientists was helpful, though it only provided 25% of what she requested. She had to askher institution to step in and help cover her costs. She’snow trying to build a portfolio of research findings tohave a shot at an R01. She expects the process to taketwo or three years with multiple submissions.

Age-Related Hearing Loss: Most Common,

Least Studied Sensory Disorder

Half of us will experience significant hearing loss by age65, yet very little is known about this age-relateddisorder. While great progress has been made inidentifying the genes involved in inherited forms ofhearing loss, not a single gene has been found for theage-related version. Assistant Professor Anne Giersch,Ph.D., of Harvard University and Brigham & Women’sHospital, aims to change that. By searching for geneticdifferences between mice that lose their hearing asthey age and those that don’t, she hopes to translateher findings to identify people likely to experience age-related hearing loss and intervene before their world isshrouded in silence. But NIH funding eludes her.Giersch had been working under a mentor’s R01 togather the preliminary data needed to seek her ownfunding, but the mentor’s grant was not renewed.

10

Photos (left to right): Tricia Serio, Rachelle Gaudet, Anil Potti, Isla Garraway

“Identifying high-risk patients is one thing, butwe’re going into a patient’s room and sayingnot only do we know that you are at high riskfor your cancer coming back, but now we cantailor therapies to your particular tumor.”

Anil Potti, M.D.Duke University

“Prostate cancer is a very painful and hard wayto end life. It is critical to find better therapies.Targeting the stem cells in prostate cancercould be a big breakthrough.”

Isla Garraway, M.D., Ph.D.UCLA

364582BS:364582BS 2/13/08 1:12 AM Page 10

11

Tissue Scarring Responsible

for Lung Disease—and More

No one knows what causes a lung disease calledidiopathic pulmonary fibrosis (IPF), but half of patientsdiagnosed with this lung-scarring ailment die withinthree to five years. After seeing countless patients in theVeterans Affairs and Vanderbilt University hospitals andknowing that treatments are ineffective, William Lawson,M.D., Assistant Professor, Division of Allergy, Pulmonary,and Critical Care Medicine at Vanderbilt University, tookaction. His studies—using mouse models, geneticstudies, and samples of human tissues—have shownthat the alveolar epithelial cells, which are responsiblefor exchanging oxygen and carbon dioxide in the lungs,are key to this disease. He’s made the progress he hasbecause of institutional support and foundation grants.He applied for his first NIH grant, known as a “K08award”, in 2004, without luck. “That was my first realslap in the face,” he recalls. But he regrouped, andresubmitted what he calls a “less ambitious” researchplan, and finally, in 2006, was awarded a K grant. “Rightnow, new investigators are heavily subsidized by theirinstitutions,” Lawson says. “If we didn’t have that inplace, we couldn’t get our research done.”

When the Body Attacks Itself:

Lupus and Kidney Disease

When she learned that a disease called lupus hadkilled her high school classmate, Carthene Bazemore-Walker, Ph.D., knew what her research could do. ThisAssistant Professor in the Department of Chemistry atBrown University is using ultra-sensitive technologiesfrom the emerging field of proteomics to identifychanges in the urine that reveal the early stages ofkidney damage due to lupus. Two million Americans,mostly women, have lupus, a disease in which thebody attacks itself. Diagnosis can be difficult becausethe body can decide to attack any organ. Kidneydisease is one of the worst consequences. Bazemore-Walker’s work has potential for developing newtherapies and for helping with other kidney-relateddiseases, such as diabetes. Yet, she has not been ableto obtain a grant from the NIH. “I’m not quite newfaculty in the eyes of the reviewers because I’ve hadmy Ph.D. more than 10 years. However, I’m juststarting a lab due in part to the time I spent in ateaching position,” she explains. “This puts me in avery uncomfortable situation.”

Photos (left to right): Anne Giersch, William Lawson, Carthene Bazemore-Walker, Jill Rafael-Fortney

“At the bench, I want to try to answer some ofthe questions that frustrate me in the clinic.I want to figure out the pathways that mightyield new therapies for the patients I see withlung disease.”

William Lawson, M.D.Vanderbilt University

“I’ve dissected the inner ears of all thesedifferent mice—those that lose their hearingearly and those that don’t—and those tissuesare just sitting in the freezer, waiting. I haven’thad the money or the help to go any furtherwith the experiments.”

Anne Giersch, Ph.D.Harvard Medical School and Brigham & Women’s Hospital

“I wanted to understand what took myfriend’s life.”

Carthene Bazemore-Walker, Ph.D.Brown University

364582BS:364582BS 2/13/08 1:12 AM Page 11

Photos (left to right): L. Kristin Newby, Denis Guttridge, Pampee Young, Michael Rodriguez

New Target for Heart

Disease and Muscular Dystrophy

By studying heart failure in mice with musculardystrophy, Jill Rafael-Fortney, Ph.D., has revealed aprotein change that may help people with this muscle-weakening disease—as well as the larger population offive million Americans living with heart disease. ThisAssociate Professor in the Department of Molecular andCellular Biochemistry at The Ohio State University andher cardiologist partners at OSU discovered that theproduct of this gene, a protein called claudin 5, is atexceptionally low levels in 60% of people with heartfailure. This is a completely novel target that couldpotentially stop heart failure before damage is done.“This could really wind up as a new treatment for heartfailure in a few years,” says Rafael-Fortney, who iswaiting to hear if her NIH grant application to test theprotein in animal models will be funded. “This proteinfills the gaps of all we didn’t understand. Thecardiologists are jumping up and down.”

Predicting Patients’ Risk for Heart Attacks

When heart muscle is dying, a protein called troponinbreaks apart and leaks into the bloodstream. KristinNewby, M.D., Associate Professor of Medicine at DukeMedical Center, is studying how troponin and othermarkers in the blood can help physicians determine apatient’s risk for heart attacks and stroke before amedical crisis occurs. With a particular interest inwomen’s cardiovascular health, Newby also hopes touse these markers to tailor therapies to individual heartpatients. An NIH “K grant” supported her researchthrough 2003, and she is currently revising her secondR01 grant submission based on reviewers’ feedback.She remains optimistic about receiving funding. In themeantime, she is supporting her research throughgrants from the pharmaceutical industry.

The Pathway to Muscle Wasting

in Cancer and Muscular Dystrophy

People with cancer often waste away, losingtremendous amounts of muscle mass; it’s what killsnearly one third of cancer patients. Denis Guttridge,Ph.D., Associate Professor in the Department ofMolecular Virology, Immunology, and Medical Geneticsat The Ohio State University, was the first scientist toshow that a pathway relevant to some inflammatorydiseases, such as rheumatoid arthritis, is alsoimportant to muscle wasting in cancer, and musculardystrophy. In 2002, when the NIH budget was stillexpanding, Guttridge received his first R01 to studythis signaling pathway (called NF-KappaB). He got it

12

“For our current R01 application theapproach is completely novel. Reviewerstold us we have good data, a strong team, andwell-thought-out experiments. We didn’t getfunded just because there were others goingfor their second and third round who werewaiting in line.”

Jill Rafael-Fortney, Ph.D.The Ohio State University

“The process of getting NIH funding can be acareer in and of itself. It takes time, and youhave to be persistent.”

Kristen Newby, M.D.Duke University

364582BS:364582BS 2/13/08 1:12 AM Page 12

13

on his first try. He applied for his second R01 after theNIH budget flattened—applying before his first R01ran out because he knew it could take a year or two toget it. He was right. It took three attempts, finallycoming through in late 2007.

To Repair a Damaged Heart—

and Maybe Block Tumor Growth

Pampee Young’s research straddles two exciting,seemingly contradictory, areas of research—bothinvolving adult stem cells from bone marrow. As anAssistant Professor in the Department of Pathology atVanderbilt University, Young and her colleagues haveidentified a type of stem cell that promotes tumorgrowth and progression. They have identified a keyplayer that instructs these cells, which are a form ofwhite blood cell, to help the tumor. The scientistshope to learn how to re-educate the white blood cellsto attack the tumor. They are also using similar stemcells to promote repair and regeneration in hearttissue damaged by a heart attack. The heart wasthought to be irreparable, but these and other earlystudies suggest repair is possible. Since arriving atVanderbilt in 2003, Young has done clinical work—running the blood bank—to cover 25% of her salaryand reduce the stress of finding grants. She haspulled together several institutional and foundationgrants to fund her research. In the fall of 2007, shefinally received her first R01 on her second revision.

Improving Diagnosis and

Treatment of Depression

Depression is under-diagnosed and under-treated inAmerica, particularly among low-income and minoritypopulations. When Michael Rodriguez, M.D., M.P.H.,Associate Professor of Family Medicine at UCLA,assessed Los Angeles’ public health clinics, he foundthat physicians were only identifying 25% of peoplewith depression, and most of those were not receivingstandard treatments. Today, following interventionsdesigned by Rodriguez and his colleagues,approximately 70% of patients are receiving thecorrect diagnosis and treatment. Rodriguez is a healthservices researcher who has received funding for hisresearch on violence prevention and the healthcareneeds of vulnerable populations from a variety ofsources. His work on depression is funded by a grantfrom the National Institute of Mental Health, but thegrant has been cut repeatedly.

“Twenty-four hours a day, seven days a week,you’re thinking about your grant proposals andwondering how to survive in this world wherefewer people are getting funded, and proposalsthat are funded aren’t being fully funded or arebeing cut.”

Michael Rodriguez, M.D., M.P.H.UCLA

“My goal is to take these bone marrow-derivedadult stem cells, which are easily obtained,and see how far we can take them to developnew therapies.”

Pampee Young, M.D., Ph.D. Vanderbilt University

“I’m hoping for what every basic scientisthopes for: that the science I do will lead tounderstanding, in my case, of how we canmodulate this signaling pathway to benefitcancer patients with muscle wasting andpeople with muscular dystrophy.”

Denis Guttridge, Ph.D.The Ohio State University

364582BS:364582BS 2/13/08 1:12 AM Page 13

“Without effective national policiesto recruit young scientists to the

field, and support their research overthe long term, in 10 to 15 years, we'll

have more scientists older than 65than those younger than 35. This is

not a sustainable trend inbiomedical research and must be

addressed aggressively.”

Elias A. Zerhouni, M.D.Director, National Institutes of Health

14

364582BS:364582BS 2/13/08 1:12 AM Page 14

The early career scientists profiled on pages 9-13—and many like them across the country—have the training, drive, and intellectual

firepower to improve America’s health through theirinnovative research. They are products of a systemthat has led the world in scientific discovery andinnovation. They have attended the best schools andbeen mentored and trained by world-renownedscientists, but the discouragement they feel becauseof these five years of inadequate support for the NIHbudget is having widespread repercussions.

“Five years ago, there was a sense of optimism aboutgoing into science,” says Susan Lindquist, adistinguished investigator at MIT and former head ofthe Whitehead Institute. “The difference today is realand noticeable. And it’s tragic because we’re just nowgetting to the point where our understanding ofbiological science is going to lead to trueimprovements in life and health.”

Senior scientists, many of whom fill a crucial role asmentors and trainers of young investigators, also feelthe pressure to keep their own research going as thevise tightens around the NIH budget. They too mustapply multiple times to get NIH funding and findoutside sources to fill the gaps left by trimmed-backgrants and escalating research costs.

The effect of these financial pressures cascades downto junior investigators, postdoctoral fellows, andgraduate students. “For us junior investigators,watching experts in the field having trouble gettingfunded is devastating,” says Vanderbilt’s WilliamLawson. “We ask ourselves: How am I, as anunknown, going to be successful? That feeling—questioning your ability to be successful—isconcerning and real.”

As the senior scientists work overtime to stay afloat,mentoring takes a back seat. “It’s very hard to get asenior faculty, who was just rejected on his secondsubmission for R01 funding, to take the time to reviewyour work,” says Vanderbilt’s Pampee Young. “Yetwithout mentoring, a young scientist just can’t make it.”

The Hardest Hit

Many early career scientists are trapped in a research“Catch 22”. They can’t get the NIH R01 funding theyneed to establish a lab and launch an independentcareer because NIH reviewers say they don’t have thedata to support their grant applications. Yet thepreliminary data and proof that experiments willsucceed is hard to come by without that very funding.Many of these young scientists are pursuing radicallynew approaches to medical challenges. Some ofthem, like Harvard University’s Rachelle Gaudet, arecreating whole new fields of science. The data theyneed cannot be taken off the shelf.

Really exciting science is harder, takes more effort,and comes with more risk. Yet, limited resources areforcing NIH review committees to be moreconservative in their funding decisions. “Thereviewers want to see proposals that are highly likelyto succeed. They don’t want you to chase outlyingideas,” Lawson explains.

“The current flat funding of NIH is causing even juniorpeople to be very conservative, and it’s just not theright time to be conservative,” says Gaudet. “If youstart out conservative, you might never go on to askor answer the really big questions.”

Roadblocks to Innovation and Ingenuity

15

364582BS:364582BS 2/13/08 1:12 AM Page 15

16

Exiting the Pipeline

Every scientist interviewed for this publication knewtalented people who had left the pipeline becausethere were better opportunities elsewhere. Some stayin science, but go to industry or laboratories abroad.Others leave science altogether. When good scientistsleave academic science, the investment that wasmade in their training is lost.

“I have a colleague here, a junior faculty who doesgreat science, yet his grants go unfunded. I wouldnever consider him the kind you’d want to weed out,”says Vanderbilt’s Pampee Young. Adds BrownUniversity’s Tricia Serio: “When I started at Yale, therewere 30 Ph.D.s in my program. As far as I know, I’mthe only one who stayed in academic science.”

Compromise, Improvise

Researchers consistently work long hours, putting inthe time to get the results. They know that scientificadvances come slowly. But they are spreadingthemselves too thin.

Scientists are writing more grant applications, castingwider nets for funding, and receiving more rejectionsfrom NIH. “Even for the lucky few who get funding, it is common for a grant to get a cut right off the bat,”explains UCLA’s Michael Rodriguez. “Once you’re downto the bone, how can you shave off more bone withoutthe research suffering?”

With their NIH grants, investigators must cover salaries,as well as equipment, chemicals, and any animal costs.The technology and equipment that today’s sciencerequires is costly. Carthene Bazemore-Walker, of BrownUniversity, uses mass spectrometry technology todetect minute levels of proteins in the urine and blood.This one piece of ultra-sensitive machinery costs$450,000 to $750,000.

Academic research institutions are increasing theirsupport to give young scientists some extra time tobuild their research portfolios, so they can generate thepreliminary data that NIH requires for most of itsgrants. But researchers eventually must findindependent funding. Private foundation and industryfunding are becoming more important—and morecompetitive. “The private foundation money is whathelps young researchers like me. But I can see thateven those grant awards are becoming smaller eachyear,” says Duke’s Anil Potti. With the limits on NIHfunding, foundations are being overwhelmed by grantrequests. For example, the Prostate Cancer Foundation,which has supported Isla Garraway’s studies at UCLA,was able to fund only 63 of the 420 competitiveresearch proposals it received last year.

To stay afloat, researchers are juggling multiple roles(scientist, clinician, teacher, mentor) while they awaitNIH grants. Harvard’s Anne Giersch and others arguethat research is suffering: “No one is concentrating juston research anymore—we all have half a dozen jobsnow.” Garraway, a physician-scientist, agrees: “A lot ofmy colleagues are taking on more clinical work, sincethey don’t have the funds to support their research.”Yet they fear letting their research languish.

Maintaining our Competitive Lead

The U.S. has a long history as the world leader inmedical research. Yet academic and industry expertsare deeply worried that our position is in jeopardy.Joshua Boger, president of the biotechnology industrygroup BIO, and head of Vertex Pharmaceuticals,expressed his concern: “We could wake up one day andfind out that U.S. science is not in the lead anymore. Toregain the lead at that point would be very, verydifficult. Other countries see the connection betweenbasic science and societal benefit with more vigor andconviction than exists in the U.S.”

364582BS:364582BS 2/13/08 1:12 AM Page 16

Foreign-born scientists, for example, who receive theirtraining in America’s best labs are increasinglyattracted to opportunities overseas. “The scientistswho have cultural ties elsewhere have other optionsin their sights. I know some people who are nowhappily back in India or China,” adds Boger. “They’veopted out of the U.S. problems and have seized anopportunity to build overseas.”

NIH Director Elias Zerhouni says it himself: Americanmedicine is on the cusp of a transformation: from anincreasingly costly reactive mode, in which people seek a doctor’s help when sick, to predictive, preemptive, personalized medicine. The first signs of thistransformation are occurring today. Breast cancertreatments, for example, have become morepersonalized. A test exists that identifies 16 genes thatpredict how aggressive the cancer is. That means 70,000breast cancer patients every year may not have toundergo chemotherapy! The opportunity to realizesimilar advances many times over exists, but long-termbudget shortfalls mean opportunities lost.

The Class of 1998

For the up-and-coming researchers who emergedfrom graduate school around 1998—just asCongress committed to doubling the NIH budget—the world of biomedical research was brimmingwith opportunities and promise. The youngresearchers profiled in this report experienced thisexhilarating time firsthand. Their focus was onmaking new discoveries and their potential toprevent and cure diseases. But the outlook fortoday’s students is starkly different. They areworried about the research money. Can they get it?Should they try?

Vanderbilt University’s Pampee Young, aphysician-scientist who started her postdoctoraltraining in 1998 at Washington University in St.Louis, recalls: “I was a postdoc during thedoubling. I saw everyone happily getting lots ofgrants. Now there’s a great deal of fear.”

Today’s research climate has completely shiftedthe way incoming scientists see their prospects.“My students in introductory graduate levelcourses have a much clearer view of thedifficulties of being a biomedical scientist than Ihad at their age,” says Tricia Serio of BrownUniversity, who did her postdoc training in SusanLindquist’s lab at the University of Chicago from1997 to 2002. “I was trained when the NIH potwas full, and one in three proposals were beingfunded. People never talked about difficulties infunding. We talked about science.”

17

“Funding the sure things instead of the big,risky ideas is like slowly walking up the stairsinstead of taking the elevator.”

Susan Lindquist, Ph.D.Member and Former Director of the Whitehead Institute,and Professor of Biology, Massachusetts Institute ofTechnology

364582BS:364582BS 2/13/08 1:12 AM Page 17

“The risks [of continued flat funding of NIH] are that people who have diseases that five or tenyears from now should be curable are going to have to wait a lot longer. The knowledge isthere, and we have the people who know exactly what to do to study the things that turn intocures. But they don’t have the funding to do it.”

Nancy Andrews, M.D., Ph.D.Dean, Duke University Medical School

18

364582BS:364582BS 2/13/08 1:12 AM Page 18

Biomedical research must remain a viable,exciting career option for bright young minds, ifwe intend to maintain U.S. leadership in

science and apply all the discoveries of the pastdecade to fight diseases. However, due to a stagnantNIH budget, young people are questioning theviability of a career in academic research. They seethe difficulties faced by scientists all along theresearch pipeline, and some are looking elsewhere.Those who stay in research are facing great hurdles,and it’s slowing down progress. Five to 10 years is allit takes to lose a generation of promising minds whohave the drive and energy to solve the mysteries ofdisease, devise ways to make Americans healthier,and reduce escalating health care costs.

Congress renewed its commitment to U.S. biomedicalresearch just a decade ago. The countless basicresearch discoveries from that period of healthybudget increases are finding their way to the clinic.Now is certainly not the time to pull up stakes.

America’s early career scientists need to hear that theU.S. intends to maintain its vibrant researchenterprise, and in turn, its leadership in science. Theyneed to be given the support to do the researchthey’ve been trained to do. A return to consistent androbust funding—that substantially overcomesinflation—is critical to fix the broken pipeline and setthe U.S. back on course to fulfilling the promise ofbasic research and improve the health of all people.

We Can’t Afford to Lose a Generation of Committed Scientists.

“The lack of funding for young, deserving,talented scientists is devastating for theircareers. The period of time that youngscientists spend aggressively attempting toacquire their first extramural grant is becomingunacceptably prolonged. This is having manynegative consequences of great impact.”

Larry Schlesinger, M.D.Professor, The Ohio State University

19

“We’re choking the engine of innovation andingenuity in science in this country. If wedon’t fund the research, it’s going to gosomewhere else, to other countries or toprivate entities that may not be as open ordedicated to sharing results because theyhave commercial interests. ”

L. Kristin Newby, M.D.Duke University

“I expected to get NIH funding within the firsttwo or three years of becoming a juniorfaculty member, but it took five years. Mymentors told me that my experiences withNIH aren’t surprising these days. They don’tthink I’m in trouble or that my research is introuble; they think NIH is in trouble.”

Rachelle Gaudet, Ph.D.Harvard University

364582BS:364582BS 2/13/08 1:12 AM Page 19

Nancy Andrews, M.D., Ph.D., Dean, Duke UniversityMedical School

Carthene Bazemore-Walker, Ph.D., AssistantProfessor, Department of Chemistry,Brown University

Joshua Boger, Ph.D., Founder and CEO, VertexPharmaceuticals, and Chair, Biotechnology Industry Organization

Isla Garraway, M.D., Ph.D., Assistant Professor,Department of Urology, University of California Los Angeles

Rachelle Gaudet, Ph.D., Associate Professor ofMolecular and Cellular Biology, Harvard University

Anne Giersch, Ph.D., Assistant Professor, HarvardMedical School and Brigham & Women’s Hospital

Denis Guttridge, Ph.D., Associate Professor,Department of Molecular Virology, Immunology, andMedical Genetics, The Ohio State University

William Lawson, M.D., Assistant Professor, Division ofAllergy, Pulmonary, and Critical Care Medicine,Vanderbilt University

Susan Lindquist, Ph.D., Member and Former Director of the Whitehead Institute, and HHMIInvestigator and Professor of Biology, Massachusetts Institute of Technology

L. Kristin Newby, M.D, M.H.S., Associate Professor ofMedicine, Duke University

Anil Potti, M.D., Assistant Professor of Medicine,Duke University

Jill Rafael-Fortney, Ph.D., Associate Professor,Department of Molecular and Cellular Biochemistry,The Ohio State University

Michael Rodriguez, M.D., M.P.H., Associate Professor,Department of Family Medicine, University ofCalifornia Los Angeles

Larry Schlesinger, M.D., Professor of Medicine,Molecular Virology, Immunology, Medical Genetics,and Microbiology, The Ohio State University

Tricia Serio, Ph.D., Assistant Professor, Department of Molecular, Cellular Biology, and Biochemistry,Brown University

Pampee Young, M.D., Ph.D., Assistant Professor,Department of Pathology, Vanderbilt University

Featured Scientists

20

364582BS:364582BS 2/13/08 1:12 AM Page 20

CreditsPublication Steering Committee

Kevin Casey, Harvard University

Kristen Elwell, Harvard University, Project Manager

Jerry Friedman, The Ohio State University Medical Center

Don Gibbons, Harvard Medical School

Maureen Goggin, Partners HealthCare, Inc.

Tim Leshan, Brown University

Richard Stoddard, The Ohio State University

Dale Tate, University of California Los Angeles

Paul Vick, Duke University

Jeff Vincent, Vanderbilt University

Photo Credits

Cover: Big Stock PhotoInside cover: Big Stock PhotoPage 2: Big Stock PhotoPage 4 (left to right): Veer, Big Stock PhotoPage 5: Big Stock PhotoPage 6 (l to r): Big Stock Photo, Duke UniversityPage 7: Duke UniversityPage 8: Big Stock PhotoPage 10 (l to r): John Abromowski; Justin Ide/Harvard NewsOffice; Duke University; UCLAPage 11 (l to r): Graham Ramsay; Anne Rayner; JohnAbromowski; The Ohio State University Medical CenterPage 12 (l to r): Duke University; The Ohio State UniversityMedical Center; Anne Rayner; UCLAPage 14: The Ohio State University Medical CenterPage 16 (l to r): Duke University, Big Stock PhotoPage 17 (l to r): Duke University, Big Stock PhotoPage 18: PhotoDisc

Other Credits

Writers/Editors/Production Management:Teri Larson, Burness CommunicationsCori Vanchieri, consultant

Design: Salas Design Company

364582BS:364582BS 2/13/08 1:12 AM Page C3

Harvard University

www.BrokenPipeline.org

364582BS:364582BS 2/20/08 9:37 AM Page C4