DORIS DUKE CHARITABLE FOUNDATION

The mission of the Doris Duke CharitableFoundation is to improve the quality ofpeople’s lives through grants supporting

the performing arts, wildlife conservation,medical research, and the prevention of childmaltreatment, and through preservation of thecultural and environmental legacy of DorisDuke’s properties. In addition to the MedicalResearch Program, the foundation awards grantsin three other program areas:

The Arts Program supports performing artistsin the creation and public performance of theirwork;

The Environment Program, seeks to conservewildlife in the U.S., both flora and fauna, bysupporting efforts to accelerate the conservationof essential habitats; and

The Child Abuse Prevention Program seeksprotect children from abuse and neglect in orderto promote their healthy development.

The foundation also oversees three properties thatwere owned by Doris Duke and are now open tothe public: Duke Farms in Hillsborough, NewJersey (www.dukefarms.org); Shangri La inHonolulu, Hawaii (www.shangrilahawaii.org);and Rough Point in Newport, Rhode Island(www.newportrestoration.org).

C H A R I T A B L E F O U N D A T I O N

D O R I S D U K E

Medical Research Program

This bulletin summarizes many of the past year’s activities and highlights some of ourgrantees. Our focus remains to help strengthen and support clinical research in order tospeed the translation of basic research findings into new cures, therapies and preventions

for human diseases.We are pleased to have been able to sponsor three new grant competitions,which in 2005 awarded grants ranging in size from $170,000 to $2.25 million.

As part of our commitment to streamline our grant review processes while still being inclusive,we eliminated the requirement for nominations for our Clinical Scientist Development Award(CSDA) program and added a stage 1 selection process in which two-page pre-proposals fromapplicants are used to select individuals to submit full proposals.This process appeared to workwell in 2005 and will be used again to select the next group of CSDA grantees in 2006. See theCSDA competition announcement on page 12.

Our international AIDS portfolio continues to support the clinical research and related capacitybuilding needed to care for and treat AIDS patients in the developing world. In that context,we launched a program called the Operations Research on AIDS Care and Treatment in Africa(ORACTA) program (described on page 8) and renewed several grants targeted at developinglow-cost diagnostics for AIDS care.

And finally, Betsy Myers has joined our staff as a new Program Officer. This staffing increasewill enable us to spend more time reaching out to the community and forging collaborationsthat enrich our programs. One of those collaborations has been the Health Research Alliance(www.hea l th ra .o rg) ,whic hfosters collaboration among non-profit, non-governmental fundersto support the continuum ofhealth research and training frombiomedical science to applicationsthat advance health.

We wish our grantees a produc-tive 2006 and we thank ouradvisors for their help throughoutthe year.

Elaine K. Gallin, Ph.D., Program DirectorJessica Fanzo, Ph.D., Program Officer

Elizabeth Myers, Ph.D., Program OfficerLeslie Engel, B.S., Program Assistant

B U L L E T I NDECEMBER 2005

For more information about the foundation, visit www.ddcf.org

Interview with Davd G. Nathan,Chair of Scientific Advisory

Council (p.2)

From left, DDCF grantee Gerald Friedland, M.D., Elaine Gallin, Ph.D.,Tony Moll, M.D. and Neel Gandhi, M.D. at the 2005 International AIDSSociety Meeting in Rio de Janeiro.

Investigators Tackle HIV atHome and Abroad

(p.6-7)

An Epigenetic Test to Assess theRisk of Colorectal Cancer

(p.5)

New Competitions Announced for 2006

(p.12)

From the Staff

S C I E N T I F I C A D V I S O R Y C O U N C I L

2

Reflecting on a half century in clinical researchDAVID G. NATHAN, M.D.

Jessica Fanzo: What piqued your interestin pursuing hematology?

David Nathan: I wasn’t interested in it at allwhen I was in medical school or as an intern. Iwanted to study liver disease. When I got to theNIH I was assigned to a laboratory. I sat downwith the laboratory chief and said I want tostudy liver disease. He was rocking back andforth in that GI chair, and he said, “Tell me, if wewere both in uniform, how many stripes wouldyou have on your sleeve?” I thought for aminute, and I said, “I know, two.” And he said,“How many stripes would I have on my sleeve?”And I said, “four,” because I did know his rank.And he said, “That’s why you’re going to dohematology, not liver disease.” I never had theproblem of choice. It makes life a lot easier. Iactually didn’t like hematology in medicalschool. It was badly taught, but the person who ran the course was one of the greatest men in the history of Harvard Medicine,William B. Castle. He became a massively important mentor in my life. And so, I reallyloved doing hematology as long as he approvedwhat I was doing.

JF: Was Dr. Castle your first real mentor?

DN: He was the first. He was at Boston CityHospital and I was at the Brigham. But I saw himregularly to talk about my work, and he alwayswas tremendously encouraging. I owe a greatdeal to him. He was my first critically importantmentor. And then I went to work at Children’sHospital because I became interested in inheritedblood diseases. That’s when I ran into Charles A.Janeway, who was the physician-in-chief. He wasanother man just like Castle, terribly supportiveand very wise. Castle and Janeway were the twopeople who really made it for me. But I am alsovery grateful to Nathaniel Berlin at NIH, Louis K.Diamond at Children’s and Frank H. Gardner atthe Brigham who gave me my start in the laband in the clinic.

JF: Do you feel that your mentors helpedchange the course of your life?

DN: Absolutely, they did. After all, I had beentrained as an internist for 12 years, or more. Ibecame a medical intern in 1955. In 1966 when

I decided to go to Children’s Hospital to work onthalassemia and other genetic blood disorders,nobody thought that was a good idea. All myfriends said this is dangerous, you’ll never getanywhere, you don’t know pediatrics. It wasCastle who urged me to do it. The reason Imoved to Children’s was not only because of myinterest in genetic diseases, but because I wantedto work for Janeway. I met him and decided Iwanted to work for that kind of a man.

JF: What do you think distinguishes youngclinical investigators today compared to 20or 30 years ago?

DN: I don’t think their goals have changed.These are people who have a real desire to bringthe fruits of science right to the patient andbring the patient to the borders of science. We[DDCF] support translational investigators. Thatgroup has one foot in the lab and one foot in theclinic. I don’t believe that they have changed, butthey are straddling a wider chasm.They arespread out, because the knowledge base both inscience and in clinical medicine has increased somassively in the last 25 to 40 years.

JF: You are a very distinguished scientistand physician, on many committees andboards. You’ve also published extensively,including the article The Seven C’s ofClinical Research. Do you think it ispossible in today’s landscape for younginvestigators to reach the level of achievement that you have?

DN: I know young people who are starting outin clinical research and who are doing it verywell. And, I do believe that’s still possible. If youlook at my CV, very rarely do you see one nameon a paper, or even two. Most of the time, thereare several people, and there are reasons for that.Multiple skills are required for this work. And so,one of those C’s is collaboration. Collaboration isnow critical. To do novel work that is going to

get published in leading journals, you have to beon the cutting edge. It’s very hard to be both askilled clinician and a scientist, and be on bothedges, so you have to have teammates.

JF: Do you see more investigators collaborating now?

DN:Yes, but I think one important issue is therecognition by journals, grant-makers, andschools that collaboration should be encouraged.Doris Duke has a program [the Clinical InterfacesAward Program] that insists on collaboration.

JF: It is difficult when academic centersemphasize the need for first-author publications.

DN: I think one of the biggest problems is thatwe’re still stuck in the old mode of evaluatingpeople. Modern educators are saying that wehave to look at a student’s portfolio, not justtheir grades. I believe we need to look at ouryoung researchers in the same way. If they didcollaborate, how important was their contribu-tion? We need to evaluate them that way, ratherthan saying they must be first or last authors.

JF: Is this beginning to happen within theHarvard system, where you have spent mostof your career?

DN: I chaired a committee at Harvard MedicalSchool that re-wrote the promotion rules. We

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Jessica Fanzo, Program Officer, interviewed David Nathan, Chair of the Scientific Advisory Council for the MedicalResearch Program. Dr. Nathan is a leading hematologist and President Emeritus of Dana-Farber Cancer Institute,Physician-in-Chief Emeritus of the Children’s Hospital and the Robert A. Stranahan Distinguished Professor ofPediatrics and Professor of Medicine at Harvard Medical School. He is the author of over 300 scientific papers, andhas served on many distinguished editorial boards. Dr. Nathan is the author of the book Genes, Blood and Courage,which chronicles events in molecular medicine as they affected one of his patients with an inherited blood diseasewhom he treated for more than 30 years. He is currently working on a book about the role of targeted therapy incancer. Following is an excerpt of the interview.

“Who you work for is very important. Who inspires you to keep on going when it gets tough? I always urge people to pick theirboss very carefully.”

Story continues on next page...

David G. Nathan, M.D.

3

now have a system for promotion that really is based on collaboration.The departments are independent at Harvard so it takes a long time fora change to permeate each department and for the culture of the placeto change. It’s so much easier just to simply count an investigator’spapers. I think it is critically important to make changes that will allowthe clinical investigator to flourish.

JF: When I was at Columbia, working on my post-doc, Iwanted to be more involved at the patient level, but we hadvery little collaboration with clinical researchers.

DN: Right, and that’s a serious deficit for the clinical investigator andthe young basic scientist. Certainly the only way for clinical investiga-tors to be successful, in my opinion, and I emphasize this in thearticle, is to take frequent sabbaticals in basic laboratories, because onemust constantly re-tool.

JF: Do clinical investigators’ institutions allow them to dothat? Aren’t there time constraints?

DN: I must say that at this moment, I’m not terribly sympathetic withthe academic health centers, because they have been making money. Itseems to me, if the clinical investigator is to be considered a criticalfunction of the academic health centers, which is certainly the case,then the institutions have to invest in them.They can’t just expect theseyoung people to support themselves.They need more than Doris Dukeor other foundations can give them. Research funders like DDCF arebeginning to realize this. It will require more of a commitment fromacademic health centers. They can’t just cut their young clinical investi-gators loose. We were cut loose and maybe in some respects that wasgood at that time. It certainly made us independent. But it was adifferent era. We grew up believing we were totally responsible foreverything.That soon became impossible.The load has to be shared.And that’s what I think is missing in this.You can’t have people thrownto their own devices, without support, if you expect them to succeed,and they must have time for retooling.

JF: In terms of your career, is there anything that you wouldlike to do, or wish you could have done?

DN: Along the way there’s a lot of work that I was a cheerleader forbut didn’t do myself.

JF: One of the goals of our program is to support the translation of basic scientific findings into therapies thatimprove health. What are some of today’s biggest challenges?

DN: If you’re going to talk about public health globally, then you’retalking about diseases like HIV, malaria, tuberculosis and malnutrition.They are enormous killers. But in this country the huge challenge iscancer. Cancer has now replaced heart disease as the leading cause ofdeath in this country.

JF: Do you think you have another 10 years left in you tofigure that out?

DN: Well, I don’t know if I’m going to be the one. People are workingon it, no question about it. Big scientists and little scientists. It’s a bigproblem. It’s got to be done and I want to be around when the bandstarts playing.

Nathan, continued...DISTINGUISHED CLINICAL

SCIENTIST AWARD

Established in 1999, this award program has supported 27

outstanding mid-career physician-scientists. Awardees

receive $1.5 million to be used over five to seven years. At least

$500,000 of the award must be used to train and mentor junior

clinical investigators and to encourage cross-disciplinary work

among clinical investigators and basic researchers.

See page 12 for information about the 2006 Distinguished Clinical Scientist Award Competition.

CONGRATULATIONS TO OUR 2004 DISTINGUISHED CLINICAL SCIENTISTS

David E. Fisher, M.D., Ph.D.Children’s Hospital of Boston / Harvard Medical School

Novel Strategies for Treatment and Prevention of Melanoma

Sanjiv S. Gambhir, M.D., Ph.D.Stanford University School of Medicine

Molecular Imaging of Cancer with a Voltage Sensor

Robert S. Negrin, M.D.Stanford University School of Medicine

Regulatory T Cells in Bone Marrow Transplantation

PPhilip J. Rosenthal, M.D.University of California, San Francisco

Translational Studies of Antimalarial Drug Resistance

PPaauull RRiiddkkeerr,, MM..DD..,, MM..PP..HH.., a Professor ofMedicine at Harvard Medical School and a 2000Distinguished Clinical Scientist Award recipient,

continues to make headlines for his studies on factors thatpredict a person’s risk of developing heart disease. Ridker andhis team reported in the January 2005 issue of the New EnglandJournal of Medicine that patients with low C-reactive protein (CRP)levels after statin therapy have better clinical outcomes thanthose with high CRP levels, regardless of the effect of statins onLDL cholesterol. Thus, the ability of statins to decrease CRPlevels may be more important in protecting against heart diseasethan statin’s effects on LDL cholesterol levels.

The C-Reactive Protein Story

Charles Sawyers, M.D., recipient of aDDCF Distinguished ClinicalScientist Award (DCSA) in 2002, is

at the forefront of discovering the nextgeneration of cancer therapies, which willchange the way cancer patients are beingscreened and treated.

Dr. Sawyers, a native of Nashville,Tennessee, began his career at theUniversity of California San Francisco in1991 as a fellow in the Division ofHematology-Oncology. He is an investi-gator of the Howard Hughes MedicalInstitute, a Professor ofMedicine at the Universityof California Los Angelesand the Director of theProstate Cancer ProgramArea at the UCLA JonssonComprehensive CancerCenter. Dr. Sawyers is wellknown for his landmarkresearch treating chronicmyelogenous leukemia(CML) patients withimatinib (Gleevec,Novartis).

The ImatinibBreakthroughDr. Sawyers along with Dr. Brian Druker,another DCSA recipient, found thatimatinib, a drug that targets a moleculethat is dysregulated, produces dramaticclinical responses in patients with CMLwith no or minimal toxicities.

The seminal imatinib work began withobservations in the early 1960s thatleukemia cells from CML patients had aunique chromosomal defect referred to asthe Philadelphia chromosome (where thechromosomal defect was identified).Thischromosomal defect, which is actually a shortened chromosome, occurs in 90% ofpatients with CML.The defect results incells making a defective enzyme, Bcr-abl,

which is a dysregrulated tyrosine kinasethat causes rampant proliferation of cells.By specifically binding to and inhibitingBcr-abl, imatinib arrests the progression ofdisease in CML patients.

While imatinib is initially extremely effective in treating CML patients, thecancer cells of treated patients oftenbecome resistant to the drug.

Dr. Sawyers and his team are busy developing second-generation therapies to treat patients who have developed

resistance to imatinib. One of thosedrugs—Bristol-Myers Squibb-354825 (ordasatinib)—is currently being tested inPhase I and II multi-site clinical trials.

Because imatinib was the first clearlysuccessful targeted drug therapy forcancer, its discovery has galvanized theresearch community. Prior to imatinib,successful cancer treatments usuallyinvolved chemotherapy and/or radia-tion— treatments that damage both cancerand normal cells and therefore haveconsiderable toxicities.

By focusing on specific defects in cancercells, targeted molecular therapy like imatinib spares normal cells. Dr. Sawyers

and other cancer researchers are nowusing this approach to develop novel treat-ments for other types of cancers.

Investigating Other Drug TargetsMost recently, Dr. Sawyers’ group has beenstudying the phosphate and tensinhomolog (PTEN) tumor suppressor genesignaling pathway and its role in cancerssuch as glioblastoma and prostate.In these cancers PTEN is often defective.The defective cells divide uncontrollably.One potential therapeutic target in thePTEN signaling pathway is mTOR. In cellslacking PTEN, mTOR is increased.

Drs. Paul Mischel andGeorge Thomas, twojunior clinical investi-gators working withDr. Sawyers, have devel-oped molecular toolsto determine if apatient’s cancer cellshave defects in thePTEN pathway.

Drs. Mischel andThomas have used thistechnology to selectpatients who mightbenefit from treatment

with an mTOR inhibitor (rapamycin) thattargets the affected pathway and haveshown preliminary evidence of somesuccess in a small proof-of-concept trial inrecurrent glioblastoma patients.Glioblastoma is a particularly aggressivebrain cancer that has not been veryresponsive to existing therapies.

While it is still too early to say if the workof Dr. Sawyers and his collaborators willlead to an improved therapy for glioblas-toma patients, it is heartening that thesuccess of the initial mTOR inhibitor studyhas led to a multi-center clinical trialsponsored by Novartis.

4

DISTINGUISHED CLINICAL SCIENTIST AWARD , CONT.

Charles Sawyers, M.D.

Molecular Targeting for Cancer Therapy

Charles Sawyers, M.D., Professor of Medicine, center, with his team, from left to right: PaulMischel, M.D., Associate Professor of Pathology; Tim Cloughesy, M.D., Associate Professor ofNeurology; Michael Burgess, M.D., Ph.D., graduate student; Neil Shah, M.D., Ph.D., AssistantProfessor of Medicine and 2005 Clinical Scientist Development Awardee; and Ingo Mellinghoff,M.D., Assistant Professor of Pharmacology.

5

In his role as the Director of the JohnsHopkins University School of MedicineGenome Center in Epigenetics, Andrew

Feinberg’s work is persuading even theskeptics that epigenetic changes canmodify cancer risk.

Epigenetics is the study of heritablechanges in gene function that occurwithout changes in DNA sequences(genetic mutations). Everyone inherits twocopies of each gene—one maternal andone paternal. Conventional geneticsteaches us that the gene copies inheritedfrom each parent are equally expressed.But we now know that this is not alwaysthe case.

EpigeneticsSometimes a copy of a gene inheritedfrom one parent is modified so that it isless active or silenced compared with thecopy from the other parent.This is calledgenomic imprinting, and it is offering anew twist in the genetic basis of cancer.

Dr. Feinberg’s interest in epigenetics wassparked by a patient with Beckwith-Weidemann Syndrome (BWS), whichpredisposes patients to cancer includingWilms’Tumor, a rare childhood kidneycancer. BWS patients display abnormal

activation or imprinting of several genesof chromosome 11, including the genethat controls the synthesis of insulin-likegrowth factor II gene (IGF2).

In 90-95% of the population the IGF2gene inherited from the mother issilenced (inactive). However, theremaining 5-10% of people exhibit a lossof imprinting, making both of their IGF2gene copies active.This phenomenonresults in increased production of growthfactor and is common in BWS patientswith Wilms’Tumor.

Colorectal CancerExpanding his studies beyond tumors inBWS patients, Dr. Feinberg and hiscolleagues examined the possibility thatsimilar loss of imprinting for IGF2 mightbe associated with more common cancers.In 1998, they found that tumor cells from30% of colon cancer patients expressedtwo active copies of the IGF2 gene.Importantly, enhanced IGF2 levels werealso present in normal colon segments ofthose cancer patients, suggesting that theloss of imprinting for the IGF2 geneincreased these patients’ risk of developingcolon cancer.

The group has also studied this phenom-enon in mice.This past year theypublished a seminal paper in Sciencesupporting the link between loss ofimprinting of the IGF2 gene and intestinaltumors in mice.They showed that micegenetically engineered to express twoactive copies of IGF2 along with a geneticmutation predisposing them to intestinaltumors were twice as likely to develop

intestinal tumors as control mice thatexpressed the predisposed intestinal tumor mutation but only one active copy of IGF2.

With a new five-year $2.25 million CIAPgrant, Dr. Feinberg’s team is developing aquick test that assesses the number ofactive copies of the IGF2 gene in order toidentify individuals at a higher risk ofdeveloping colorectal cancer. A 2003 CIAPplanning grant, already enables them toshow that a person’s IGF2 status can bemonitored in a small blood sample. If theyare successful in using this simple test to identify people at higher risk of developing colon cancer, early intervention may help lower their risk.

“We hope to develop a practical test in thepopulation to intervene before the canceroccurs.This is a radical departure fromhow we currently look at cancer mortalityreduction,” Dr. Feinberg said, adding thattoday physicians can only look for signs ofearly-stage tumors. “I think it could be atleast as effective to identify people at riskand then intervene to reduce the chancesof developing a tumor. As odd as thatsounds for cancer, that is what we havebeen doing in cardiology for a long time.”

Pioneering a New Approach to Detect Cancer Risk

C L I N I C A L I N T E R F A C E S A W A R D P R O G R A M

Andrew P. Feinberg, M.D., M.P.H.Marcia Cruz-Correa, M.D., Ph.D.Francis M. Giardiello, M.D.Elizabeth A. Platz, Sc.D., M.P.H.Christi Iacobuzio-Donahue, M.D., Ph.D.Holly Taylor, Ph.D., M.P.H.Benjamin Wilfond, M.D.Hengmi Cui, Ph.D. Andrew Feinberg, M.D., M.P.H.

CLINICAL INTERFACES AWARD PROGRAMEstablished in 2003, the Clinical Interfaces Award Program (CIAP) seeks to catalyze activity at the interface of clinicaland other research areas by supporting the formation of new collaborations and strengthening existing collaborationsof outstanding scientists across disciplines. Five-year grants of up to $2.25 million (as well as small 18-month planninggrants) have been awarded to teams of investigators addressing important clinical questions that require multidiscipli-nary approaches. See page 12 for a list of 2005 CIAP grantees. We thank the members of our outstanding review panel,chaired by Ken Chien, M.D., Ph.D., for their efforts in helping us select the awardees.

6

CSDA GRAN T E E S TA C K L E H I V / A I D S

Dr. Shaffiq Essajee’s career has led

him from his home country of

Kenya to the United States and

back again. Dr. Essajee, a 2001 Clinical

Scientist Development Award (CSDA)

recipient, is an Assistant Professor in the

Department of Pediatrics at the NYU

School of Medicine and the Associate

Director of NYU’s International HIV

Program.

Shortly after receiving his CSDA grant, Dr.

Essajee returned to Kenya to

recruit the pediatric HIV patients

needed to conduct his Doris Duke-

funded project entitled, “The

Mechanisms and Clinical

Importance of the Viral Disconnect

Phenomenon in HIV-Infected

Children Treated with HAART.”

Lacking enough patients in the

U.S. for his project, Dr. Essajee

moved his study overseas. “The

need to establish a research

program outside of the U.S. in

a resource-poor setting is a

reflection of our national success

in eliminating vertical transmission of

HIV from mother to child,” he said.

Returning to Kenya and BeyondIn 2001, Dr. Essajee established the AIDS

Research and Family Care Clinic (ARFCC)

in Mombasa, Kenya, which is the first

pediatric HIV research care clinic in the

country. The ARFCC is a collaborative

partnership between the NYU School of

Medicine and the Kenyan Ministry of

Health. In addition to honing his skills as

a clinical investigator, Dr. Essajee became

an effective fundraiser for the ARFCC

which has been supported by a number

of funders, including King Cole Inc., a

non-profit that supports innovative HIV

programs in the developing world.There

are currently 100 children enrolled in the

clinic.

Because of his expertise and experience

in Kenya, Dr. Essajee was recruited to

become the Senior Advisor in Pediatrics

for The Clinton Foundation HIV/AIDS

Initiative (CHAI). A project of the

William J. Clinton Foundation, CHAI

launched a pediatric program with the

goal of providing antiretroviral treatment

(ART) to 10,000 children in developing

nations around the world by the end of

2005. Dr. Essajee spent most of the

year traveling for CHAI to Lesotho,

Cambodia, Uganda and other countries

in Africa and Asia to help establish HIV

treatment programs for children and to

troubleshoot problems.

“It’s amazing to take one’s experience

from the realm of the individual patient

and move it into the realm of public

health,” he said.

“Pediatric training,” said Dr. Essajee, “has

been a footnote on the bottom of most

national training programs.” He hopes to

change this by working with existing

pediatric training programs to review

their curricula and give them construc-

tive feedback, as well as link them to

other training programs.

Facing Unique Challenges In his travels, Dr. Essajee has also

encountered a phenomenon that he refers

to as the “X Factor.”

“There are often people who have been

trained in pediatric care, have the

drugs available, have access to

children, but they just can’t pull

all those pieces together and get

kids enrolled into treatment

programs,” said Dr. Essajee, who

looked at various models to alleviate

this problem.

He believes that the best solution to

the “X Factor” is to place preceptors

into struggling clinics to facilitate

the implementation of pediatric

treatment programs. Uganda has

had considerable success, with 400

children on ART, and he is hoping

to place doctors from that country in

neighboring African countries to act

as preceptors.

“The experiences this year will greatly

facilitate the research I’ll do next year in

Kenya with my ongoing DDCF funding,”

said Dr. Essajee.

“It’s a tremendous gift to be able to do something that serves an important need that not nearlyenough people are doing. It’s veryhard work, but a great privilege.”

Shaffiq Essajee, M.A., B.M.B.Ch., center, at an orphange in Cambodia.

Shaffiq Essajee, M.A., B.M.B.Ch.

Establishing Clinics for HIV-Infected Children

7

Dan Barouch, a 2002 Doris DukeClinical Scientist DevelopmentAwardee, is tackling today’s

greatest medical challenge—developing avaccine for HIV. An Assistant Professor inMedicine at Harvard Medical School, hestudies DNA and adenovirus vector-basedvaccines for HIV.

Adenoviruses are a frequent cause of acuteupper respiratory tract infections, i.e.“colds.”They are easily recognized by theimmune system and can be engineeredinto recombinant adenoviruses expressingforeign molecules such as parts of the HIVvirus. Newly engineered adenovirusescontaining pieces of the HIV virus havebeen shown to elicit potent antigen-specific cellular and humoral immuneresponses making them good vaccinecandidates.

Dr. Barouch’s vaccine work is scaling upconsiderably because of the U19 AIDSVaccine Development grant he recentlyreceived from the National Institutes ofHealth.This five-year $19.2 million grantentitled “Novel Adenovirus Vector-basedVaccines for HIV-1” aims to advance HIV-1 vaccine candidates that utilize novel

adenovirus vectors into clinical trials inthe United States and sub-Saharan Africa.His collaborators in this project includeCrucell Holland BV, a Dutch biotech-nology company.

“This new award was based in part onthe clinical trials and the adenovirusseroprevalence studies that were donethrough my Doris Duke grant,” Dr.Barouch said.

Vaccine Development RequiresCollaboration and Patience Much of Dr. Barouch’s research requiresworking in large collaborative teams. Herecently collaborated with Dr. BruceWalker, a 1999 recipient of theDistinguished Clinical Scientist Award. Dr.Walker also received DDCF support toestablish the HIV Pathogenesis Program atthe Doris Duke Medical Research Institutein Durban, South Africa.

Using serum samples from HIV patientsthat Dr. Walker’s group collected, Dr.Barouch found that pre-existing neutral-izing antibody titers for the type ofadenovirus (serotype 5) used in currentvaccine trials were 10-fold higher in sub-

Saharan African samples compared withserum samples from residents of theUnited States. This observation willcomplicate testing of current adenovirus-based HIV vaccines that use the serotype 5adenovirus in South Africa.To circumventthis problem, Dr. Barouch and hiscolleagues are now working on adenovirusvectors developed using differentadenovirus strains.

Despite the complexities and specialchallenges of this kind of research, Dr.Barouch remarked, “With vaccine researchin particular, and even more so with HIVvaccine research, one needs a lot ofpatience, but hopefully there will be long-term gratification. I cannot imagine amore important biomedical problem fromthe standpoint of human life cost than theHIV epidemic.”

Daniel Barouch, M.D., Ph.D.

Developing a Vaccine for HIV

From left to right: Daniel Barouch, M.D.,Ph.D.,Photini Kiepiela, Ph.D. and Hoosen Coovadia,M.B.B.S., M.D. from the Doris Duke Clinical ResearchInstitute at the University of KwaZulu-Natal, South Africa.

CLINICAL SCIENTIST DEVELOPMENT AWARDEstablished in 1998, the Clinical Scientist Development Award (CSDA) supports junior physician-scientists as

they begin their clinical research careers. See page 12 for information about the 2006 competition.

Congratulations to the 2005 CSDA Recipients

I N T H E U . S . A N D A B R O A D

Michelle Asha Albert, M.D., M.P.H.,Brigham and Women’s Hospital/Harvard Medical School“Black Women’s Health Study and Cardiovascular Risk”

Corey Casper, M.D., M.P.H., University of Washington School of Medicine“HHV-8 Replication and Progression to Malignancy in Africa”

Sekar Kathiresan, M.D., Broad Institute of MIT and Harvard“Osteoprotegerin Pathway Biomarkers, Genes, and CVD”

Jeffrey R. Keefer, M.D., Ph.D.,Johns Hopkins University School of Medicine“Pharmacological Modulation of Fetal Hemoglobin”

Allison A. King, M.D., M.P.H., Washington University School of Medicine“Cognition in Children with Sickle Cell Anemia”

Matthew E. Mealiffe, M.D., University of Washington School of Medicine“K7: A Gene for Hodgkin’s Lymphoma Predisposition”

William Pao, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center“Acquired Resistance to Targeted Therapy in Lung Cancer”

Pavan R. Reddy, M.D., University of Michigan“Immuno-modulation by Histone Deacetylase Inhibitors”

Neil Shah, M.D., Ph.D., UCSF School of Medicine“Perfecting Targeted Therapy for Human Malignancies”

John J. Strouse, M.D., Johns Hopkins University School of Medicine“Cerebral Blood Flow in Sickle Cell Disease”

Rochelle P. Walensky, M.D., M.P.H., Massachusetts General Hospital/Harvard Medical School“The Impact and Value of Routine HIV Testing in South Africa”

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Tugela Ferry, KwaZulu-Natal, South Africa

Sub-Saharan Africa is home to 60%of all people living with HIV. InSouth Africa alone, over 5.4 million

people, or one in four adults, are livingwith HIV/AIDS. Furthermore, the HIVepidemic is entangled with the rapidlyexpanding tuberculosis (TB) epidemic:2/3 of TB new cases also have HIV, andTB is the leading cause of death amongpeople living with HIV worldwide.

Supported by the Doris Duke CharitableFoundation along with the IreneDiamond Fund and the President’s Fundof Yale University, a team led by GeraldFriedland, M.D., of Yale School ofMedicine, with investigators and clini-cians from the Nelson R. MandelaSchool of Medicine, Doris Duke MedicalResearch Institute and Philanjalo, a localcommunity-based organization in SouthAfrica, are determining how to bestintegrate HIV treatment with the treat-ment of TB in both the large city ofDurban and in rural Tugela Ferry in theKwaZulu-Natal province of South Africa.

Their initial work at the Prince CyrilZulu Communicable Diseases Clinic(Durban Municipal TB clinic) demon-strated that a once-a-day HIV treatmentregimen combined with a standardrifampin-based TB treatment regimenduring TB/DOT (directly observedtherapy) is effective and well tolerated.

Most importantly, their showed acontinued adherence with self-medication of HIV medications aftercompletion of TB therapy.

A similar treatment strategy is nowbeing tested in a rural Zulu commu-nity where most families livewithout electricity and piped water.The Sizon’qoba project is based atthe Church of Scotland Hospital, aprovincial government hospital inTugela Ferry that was one of the firstsites to issue antiretroviral therapy inKwaZulu-Natal. With committedSouth African clinicians and scientists ledby Dr.Tony Moll, the Director of theChurch of Scotland Hospital, this projectis designed to determine the relativerisks, benefits and cost effectiveness ofintroducing antiretroviral therapy intoexisting TB treatment programs in arural setting.

Patients with active and newly diagnosedTB are tested for HIV, and if the test ispositive, they have the opportunity toreceive treatment for both diseases.Under supervision, patients constructand package a month’s supply of theirown regimens in individual dailypackets. To ensure adherence, commu-nity-based treatment supporters fromthe Zulu community visit the homes ofpatients daily, compounded with

monthly visits to the hospital to monitorefficacy and side effects.

The early results of this project havebeen heartening, with excellent adher-ence and clinical response and minimaltoxicity. Patients who otherwise wouldhave died are taking their medicationsuccessfully for both diseases and aresurviving.This success shows thatHIV/TB treatment is possible in some ofthe most resource-poor settings.

If shown to be effective, these U.S. andSouth African investigators hope theirintegrated HIV/TB strategy can beapplied to other sites in resource-poorsettings to improve the outcomesof both diseases.

OPERATIONS RESEARCH ON AIDS CARE AND TREATMENT IN AFRICA

This past year, the Doris Duke Charitable Foundation launched a new grant competitiondesigned to support operations research related to AIDS care and treatment in Africa (ORACTA).The goal of the program is to increase knowledge about how best to deliver antiretroviral treat-ment (ART) in Africa to improve the outcomes of the roll-out and scale-up of ART. Sixteen teamsof investigators working in 6 African countries were chosen from 77 applications using a peer-review selection process. Grantees will receive two-year grants of up to $200,000 each.

A complete list of the 2005 ORACTA grantees can be found at www.ddcf.org/mrp-oracta.

We wish to thank the committed investigators who helped us review these projects.

Patients demonstrating self-constructed monthly medicationcalendars in KwaZulu-Natal, South Africa.

I n t e r n a t i o n a l

9

A I D S P r o j e c t sFor over 15 years, the Rakai Health Sciences Program hasconducted epidemiologic, clinical health service and basic scienceresearch and provided medical services to a rural population inthe Rakai District of southwestern Uganda. This program is acollaboration between the Uganda Virus Research Institute of theMinistry of Health and researchers at Makerere University,Columbia University, and Johns Hopkins University. With assis-

tance from DDCF, the National Institutes of Health, and the GatesFoundation (plus loans from Johns Hopkins and ColumbiaUniversities) the Rakai Program opened a new clinical and labora-tory facility in the rural Rakai district in spring 2005. This newfacility will allow for expanded research and training programs.DDCF also supported training stipends for African researchersworking on Rakai Program projects.

Rakai Health Sciences Laboratory Opens in Rural Uganda

The Rakai Health Sciences Lab in Uganda. Dancers celebrate outside the lab at its opening.

In 2003, in response to the lack of affordable, simple diagnos-tics needed to monitor HIV/AIDS patients receiving antiretro-viral therapy in low-resource areas, the Doris Duke Charitable

Foundation awarded nine two-year grants of $200,000 each tosupport the development of low-cost point-of-care CD4 cell andHIV viral load assays appropriate for use in sub-Saharan Africaand other low-resource settings.These assays are important toolsfor healthcare workers managing AIDS patients in the field.

The recipients of the 2003 diagnostics grants gathered inFebruary 2005 to attend a DDCF-sponsored workshop held inconjunction with the 12th Conference on Retroviruses andOpportunistic Infections.The Forum for Collaborative HIVResearch convened the Doris Duke grantees and other stake-holders to review the technological approaches being used todevelop point-of-care diagnostics for HIV/AIDS treatment and todiscuss ways to develop and commercialize new assays.

Three of the nine diagnostic projects funded by DDCF in 2003received renewal grants in 2005.They are listed at right. Two ofthese projects are developing tests to monitor CD4 cell levelswhich may be ready for field testing within a year.The thirdproject is using cutting-edge technologies to assess HIV viral loadand is at an earlier stage of development.

Alan Landay, M.D. from Rush University Medical Center(Chicago, Illinois) working with Suzanne Crowe, M.D. andDavid Anderson, Ph.D. from the Macfarlane Burnet Institutefor Medical Research & Public Health (Melbourne, Australia) andTom Denny, M.Sc. from New Jersey Medical School (Newark,New Jersey) are using reverse flow and dipstick platformtechnologies along with antibodies targeted against cytoplasmicand extracellular CD4 domains to design a simple device toquantify CD4 T-cells.

Matthew Steele, Ph.D., M.P.H. from the Program forAppropriate Technology in Health (PATH: Seattle, Washington) incollaboration with scientists at PortaScience (Mount Laurel,NewJersey) is developing a semi-quantitative test for determiningCD4 T-cell counts that employs two steps: a manual CD4+ purifi-cation step followed by a colorimetric assay using a PortaScience-manufactured PortaWBC™ device.

Steven Wolinsky, M.D. and Chad Mirkin, Ph.D. fromNorthwestern University (Chicago, Illinois) are developing a testto detect HIV nucleic acids utilizing gold nanoparticle probes anda bio-bar code amplification system that will be capable ofmonitoring HIV viral loads.

Catalyzing the Development of Low-Cost Diagnostics for AIDS Care

These grants were awarded as part of the 2003 Innovation in Clinical Research Award (ICRA). For more information about the grants discussed here, visit: www.ddcf.org/mrp-icra.

10

Matthew Albert, M.D., Ph.D. 2002 Clinical Scientist Development Awardee and head of the Laboratory ofDendritic Cell Immunobiology at the Institut Pasteur in Paris, France, is one of 25 investigators to receive a prestigious2005 European Young Investigator (EURYI) Award. Established in 2003, EURYI awards of up to 1.25 million Euros aregiven to outstanding young scientists working in any area of scientific research to help build the next generation ofEuropean scientists. Dr. Albert moved from Rockefeller University to Institut Pasteur in 2004.

Nina Bhardwaj, M.D., Ph.D., 2001 Distinguished Clinical Scientist Awarded was selected as the top ResearchLeader in Medical Treatment in Scientific American’s “Annual salute to the top fifty scientists in the world leading the wayin the realms of research, business and policymaking” for her pioneering work on the role of dendrites in HIV andcancer therapy.

Joseph DeRisi, Ph.D. 2003 Clinical Interfaces Awarded received the 2004 MacArthur Fellowship from theJohn D. and Catherine T. MacArthur Foundation for his exceptional merit and promise of continued creative scientificwork. He also was awarded as a Howard Hughes Medical Investigator for the class of 2005.

Andrew Marks, M.D. 2000 Distinguished Clinical Scientist Awarded has been elected to the NationalAcademy of Sciences and received the prestigious 2005 American Heart Association Basic Research Prize.

Olufunmilayo Olopade, M.D. 2000 Distinguished Clinical Scientist Awarded received a 2005 MacArthurFellowship from the John D. and Catherine T. MacArthur Foundation for helping to improve the outcomes of womenof African heritage with breast cancer.

Deborah Persaud, M.D., 1999 Clinical Scientist Development Awarded and Associate Professor at the JohnsHopkins University School of Medicine, received the prestigious 2005 Elizabeth Glaser Scientist Award, a five-yeargrant that will support her pediatric HIV/AIDS research.

Kevin Volpp, M.D., Ph.D. 2002 Clinical Scientist Development Awarded received a Presidential Early CareerAward for Scientists and Engineers in June 2005 for his work using health economics to analyze and improve thequality of health care and preventative practices.This award is the highest honor bestowed by the U.S. government onoutstanding scientists and engineers beginning their independent careers.

Highlights of Recent Grantee Accomplishments

The Consortium to Examine Clinical Research Ethics(CECRE), funded by the Doris Duke CharitableFoundation and the Burroughs Wellcome Fund, is the first

major non-government financed effort to collect primary dataand critically examine human subject protection. Consortiummembers include: Angela J. Bowen, M.D., Western InstitutionalReview Board; David M. Cocchetto, Ph.D., GlaxoSmithKline;Ezekiel J. Emanuel, M.D., Ph.D., National Institutes of Health;Ruth R. Faden, Ph.D., M.P.H., Johns Hopkins University; Alan R.Fleischman, M.D., New York Academy of Medicine; Kenneth A.Getz, M.B.A., CenterWatch; Dale Hammerschmidt, M.D.,University of Minnesota; Carol Levine, M.A., United HospitalFund; Jeremy Sugarman, M.D., M.P.H., M.A., Johns HopkinsUniversity.

CECRE recently published results of a survey of 63 U.S. medical schools on the costs of their institutional review boards (IRBs).IRBs are responsible for ensuring that clinical research is beingconducted ethically and the rights of study participants areprotected. Data on the salaries of IRB members, time spent onIRB work, cost of space, equipment, supplies, and travel, and theuse of outside sources indicated that IRB operating costs at the63 surveyed schools range from $170,000 to $4,705,000(median of $750,000) with low-, medium-, and high-volumeinstitutions having a mean cost of $402,369, $805,620 and$1,150,417 respectively. This study is likely to serve as a refer-ence for policy makers as well as research institutions allocatingresources to clinical research.

New England Journal of Medicine 352;17 April 28, 2005.pg 1825-1827.

CONSORTIUM TO EXAMINE CLINICAL RESEARCH ETHICS

11

Clockwise from top: Fellows and program leaders line up to take abow following the talent show; Elaine Gallin, Ph.D. and Karen Zier,Ph.D., Mount Sinai School of Medicine program leader; fellowsRoopali Bansal (L) and Karina Arbatova (R); fellows PuneetMasson (R) and Brian Bateman (L).

2006 CLINICAL SCIENTIST MEETING

CLINICAL RESEARCH FELLOWSHIP PROGRAM

The Clinical Research Fellowship (CRF) program encouragesmedical students to pursue careers in clinical research byproviding them with an opportunity to participate in a

research project of their choice for one year under the mentor-ship of an established clinical researcher at one of 10 outstandingmedical schools (listed on the right). In addition to a $25,000stipend, benefits include health insurance, supplementaryresearch and training funds and financial support to attend theannual CRF and other research meetings.

The 2006 CRF annual meeting will be held May 22-24 at DukeFarms and the Bridgewater Marriott in Hillsborough, New Jersey.This meeting will overlap with the Doris Duke Clinical Scientistmeeting, giving young investigators a chance to interact withother Medical Research Program grantees.

• Columbia University College of Physicians and Surgeons• Harvard Medical School • Mount Sinai School of Medicine• University of California, San Francisco School of Medicine• University of Iowa Roy J. and Lucille A. Carver

College of Medicine • University of North Carolina at Chapel Hill

School of Medicine• University of Pennsylvania School of Medicine • University of Texas Southwestern Medical

Center at Dallas • Washington University School of Medicine in St. Louis • Yale University School of Medicine

Please visit www.ddcf.org/mrp-crf for more information about the CRF program.

PARTICIPATING MEDICAL SCHOOLS

Photo highlights of the 2005 CRF Meeting in Tarrytown, New York

The 2006 Clinical Scientist Meeting will be held May

21-23, 2006 at Duke Farms and the Bridgewater

Marriott in Hillsborough, NJ. Clinical Scientist

Meetings are held every other year and provide

grantees with the opportunity to present their

research and meet one another.Named for the mermaid fountains that once completely surrounded it, theMermaid Pool at Duke Farms became Doris Duke's outdoor swimming pool aftershe remodeled it in the 1930s for her personal use.

medical research program bulletinDecember 2005 • Leslie Engel, Designer

Jessica Fanzo, Photo Editor

2005 CLINICAL INTERFACES AWARD PROGRAMIn 2005, three teams working at the interface of clinical and basic sciences received five-yeargrants of $2.25 million each:

“Clinical Application of Molecular Imaging to Oncology” Massachusetts General HospitalMichael V. Seiden, M.D., Ph.D.,, Arlan Fuller, M.D., Jeffrey Supko, Ph.D., Debra Bell, M.D., Mukesh Harisinghani, M.D.

“A Mitochondrial Basis for Metabolic Syndrome” University of Califoria, IrvineDouglas C. Wallace, Ph.D., J. Jay Gargus, M.D., Ph.D., F. Sherwood Rowland, Ph.D., Donald R. Blake, Ph.D.,Bruce J.Tromberg, Ph.D.

“Development of the First Test for Common Cancer Risk in the General Population” Johns Hopkins University School of MedicineAndrew P. Feinberg, M.D., M.P.H., Marcia Cruz-Correa, M.D., Ph.D., Francis M. Giardiello, M.D., Elizabeth A. Platz, Sc.D., M.P.H.,Christi Iacobuzio-Donahue, M.D., Ph.D., Holly Taylor, Ph.D., M.P.H., Benjamin Wilfond, M.D., Hengmi Cui, Ph.D.

See page 5 for a description of the program, or visit www.ddcf.org/mrp-ciap for more details.

Clinical Scientist Development Awards Fostering Careers in Clinical Research

CALL FOR PRE-PROPOSALS

This program supports junior-level physician-scien-tists conducting clinical research in cardiovasculardiseases, cancer, AIDS and other infectious diseases,and sickle cell anemia and other blood disorders.

Up to 12 awards of $135,000/year for three years willbe made to investigators at the instructor or assistantprofessor level.

Formal institutional nominations are not required.Interested physician-scientists meeting the eligibilityrequirements should submit a brief pre-proposal.

Full details and instructions are available at:www.ddcf.org/mrp-csda.

Application DeadlinesPre-Proposals Due: January 31, 2006Invited Proposals Due: April 18, 2006

Distinguished Clinical Scientist AwardsRecognizing Excellence in “Bench to Bedside” Research

CALL FOR NOMINATIONS

This program supports mid-career physician-scientistsconducting “bench-to-bedside” (translational) researchin any area of clinical investigation.

Up to five awards of $1.5 million over five years will bemade to investigators at the associate professor levelor higher who have an established translational clinicalresearch program and an outstanding mentoringrecord.

Academic medical centers and other non-profitresearch institutions in the U.S. can nominate up to twocandidates.

Full details and instructions are available at:www.ddcf.org/mrp-dcsa.

Application DeadlinesNomination Packages Due: February 14, 2006Invited Proposals Due: June 6, 2006

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