ResearchProfiles in Innovation Downstate 2010

a Century and a Half of InnovatIon Brooklyn: A Laboratory for Advancing On the Cusp of a Science and Health PAge 5 Breakthrough PAge 10 MeSSaGe FROM THE DEAN

hroughout 2010, sUnY Downstate is marking its sesquicentennial. among the many reasons to celebrate this anniversary, one is particu- larly salient: for 150 years, sUnY Downstate faculty members have engaged in basic, translational, and clinical research with the goal of Talleviating suffering and restoring health. some of these investigations have directly transformed medicine, while others produced insights into human physiology and pathology that opened new avenues of research that years later resulted in new ways of preventing or treating illnesses. this issue of Profi les in Innovation features an article highlighting some of the most important scientifi c and medical advances made by sUnY Downstate faculty over the 150 years. these medical milestones span a range of health problems, from heart disease and kidney failure to Marfan’s syndrome and low self-esteem. not unexpectedly, many of these advances have changed more than one fi eld of medicine. Dr. Robert Furchgott’s nobel Prize-winning discovery of nitric oxide’s role in the body is the basis for fi nding new ways to treat heart disease, dementia, cancer, lung disease, infl ammatory joint disease, and other medical problems that affect, literally, hundreds of millions of people worldwide. today, sUnY Downstate basic scientists, behavioral scientists, clinicians, and public health experts are expanding our knowledge of a broad range of healthcare topics. In this issue, you can read about bench research being conducted to under- stand how brain cells communicate; fi nd ways to boost HDL, or “good,” cholesterol; create a mouse model to study the effects of maternal crack bingeing on babies; and elucidate the genetic mechanism by which sleep disturbances increase the risk of cardiovascular disease. You can also read about research aimed at translating scientifi c discoveries into new medical interventions. Downstate researchers are harnessing the power of com- puting and their knowledge of the brain to create a prosthetic hand that works like the real one and testing the blood of heart surgery patients for an antibody that they suspect causes a damaging infl ammatory response after surgery. working in Brooklyn, members of the Downstate community are keenly aware of the health problems of inner-city residents. two new research projects—one examin- ing the reasons for the overuse of emergency room care, the other exploring the causes of health disparities among residents of the borough—are highlighted in this edition of Profi les in Innovation. By fi nding solutions to these problems, Downstate can contribute to solving important challenges confronting our nation. In another way, Downstate is already taking lessons learned in Brooklyn and using them to help people elsewhere. Brooklyn’s diversity is key to the success of Downstate’s International emergency Medical Program, which trains emergency medicine residents to work in other countries and to provide humanitarian relief. In this issue, you can also learn about the sUnY eye Institute, whose goal is to advance basic, translational, and clinical research in the fi eld by creating a collab- orative research program among three sUnY campuses--Downstate, Upstate, and the state College of optometry. and, fi nally, on its tenth anniversary, you can read about the remarkable success of Downstate’s Biotech Park as a scientifi c enterprise, economic engine, and workforce development initiative.

Ian Taylor, MD, PhD senior Vice President, Biomedical education and Research Dean, College of Medicine ResearchProfiles in Innovation Downstate 2010 Contents

02 A Century and a Half of On the Cusp of a Breakthrough Innovation 10 Diana Dow-Edwards, PhD Teasing Influences Apart: A New Model for In-Utero Brooklyn: A Laboratory for Crack Exposure Advancing Science and Health 11 Joseph T. Francis, PhD 05 Eva Cramer, PhD The Repair Man: Brain-Machine Interfaces and the A Biotech Park Grows in Brooklyn Quest for a New Kind of Prosthesis 05 William Brunken, PhD, Douglas Lazzaro, MD 12 Mahmood Hussain, PhD A New Prescription for Eye Research: Collaboration Midnight Oil: Sleep Disturbances’ Impact on Lipoprotein Production 06 Christina Bloem, MD, MPH Around-the-World Emergency Care 13 Henri Tiedge, PhD Travel to the Junction: RNA’s Journey from Nucleus 07 Clinton Brown, MD, Ruth Browne, ScD, MPH to Synapse Same Borough, but Worlds Apart: Research into Inequities in Brooklyn Healthcare 14 Ming Zhang, MD, PhD Once Around the Block: Decoding the Causes of 08 Grace Wong, MBA, MPH Ischemic Injury Partners in Care: The Problem of Acute Care Overuse Meets Its Match 16 Weijun Jin, MD More for the Good: Exploring the HDL Cholesterol Pathway

President Administration Downstate ReseaRch: PRofiles in innovation John C. LaRosa, MD Ivan Lisnitzer is published by the Office of Executive Vice President and Institutional Advancement Research Chief Operating Officer and Philanthropy. Ian Taylor, MD, PhD Debra D. Carey, MS Scientific Editor Mark Stewart, MD, PhD Senior Vice President, Chief Executive Officer, Managing Editor Ina Lancman, MS Biomedical Education and Research University Hospital of Brooklyn Editor Brian Kell Dean, College of Medicine JoAnn Bradley, EdD Writer Elizabeth Galst Mark Stewart, MD, PhD Senior Vice President, Advisers John M. Allen, Ross Clinchy, PhD Dean, School of Graduate Studies Institutional Advancement and Design Bruce Kuo Photography Ernest Cuni Vice Dean for Research Philanthropy

All rights reserved. Address correspondence to Office of Institutional Advancement and Philanthropy, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 93, Brooklyn, NY 11203. A Century and a Half of Innovation

A Century and a Half of Innovation

he Collegiate Division of the name is forever attached to a heart mur- impact that a bust was erected in his Long Island College Hospital mur,” the so-called Flint murmur, says honor at Brooklyn’s Grand army Plaza. t (LICH), the predecessor to Jason Lazar, MD, director of Downstate’s as the decades progressed, research- today’s sUnY Downstate Medical cardiovascular training program. “But ers at LICH continued to provide lead- Center, was launched on March 29, austin Flint had considerably greater ership in american medicine. Jean 1860, in the City of Brooklyn at a time achievements.” Redman oliver, MD, a kidney spe- when formal medical education was still at a time when infectious diseases cialist who chaired the Department of largely theoretical and lecture-based. claimed thousands of lives and epidemics Pathology from 1929 until 1954, revo- LICH’s founding proved to be a semi- were common, the widely published and lutionized the understanding of human nal event in U.s. medical history. the respected Dr. Flint was an early advocate kidney function using a technique college, one of 47 medical schools in of germ theory, the idea that microorgan- known as microdissection. “Before the country at the time (there are now isms spread many forms of infectious oliver, no one had been able to explain 132), was the first in the country to inte- disease. “In an era when surgeons were how kidney nephrons” — kidneys’ func- grate direct patient care with lectures still performing operations bare-handed, tional units — “relate to kidney func- and classroom study. “the Long Island he was a tireless proponent of hand wash- tions and disease,” says nephrologist College Hospital,” wrote the Brooklyn ing,” Dr. Lazar notes. still, Dr. Flint’s big- Garabed eknoyan, MD, co-founder of eagle newspaper the day after LICH’s gest innovation was his popularization of the International association for the opening, “starts with means which will the stethoscope and the listening to heart History of nephrology and a professor of enable them not only to succor the and lung sounds for diagnostic purposes. medicine at Baylor College of Medicine. afflicted, but to establish a College for “Because of Flint’s influence,” Dr. Lazar “Dr. oliver’s research underpins much instruction, the benefits of which will be says, “the stethoscope became an impor- of what we know about kidney function experienced over the whole country, and tant tool in medical practice and remains today.” reflect distinction on the city in which it one to this day.” Dr. oliver’s contemporary at LICH, is located.” among the next generation of inno- Alfred Adler, MD, had a similar impact that article was prescient. since the vators at the medical college was its own on the field of psychology. an austrian- medical school’s beginnings in Brooklyn 1863 alumnus Alexander skene, MD, born contemporary of Freud, Dr. adler Heights in the spring of 1860, its faculty LLD. a leader in american gynecology, served at LICH from 1932 until his has contributed to the transformation he wrote a textbook, Treatise on the death in 1937. Dr. adler, who coined of medical practice around the world. Diseases of Women, that was described the term “inferiority complex,” believed among its researchers and clinicians in 1894 as the “best work ever written” mental health professionals could effect positive changes by focusing on patients’ Among Downstate’s researchers and clinicians are a strengths, says Richard watts, PhD, an Nobel Prize winner, the developer of a revolutionary adler scholar at sam Houston state imaging technology, a pioneer in the use of the heart-lung University. “at a time when psychol- machine, and the inventor of a kind of microsurgery that ogy focused on what was wrong with people,” says Dr. watts, “he was a pro- has allowed for corneal transplants, to name just a few. ponent of an optimistic and positive psy- chology that has had a profound impact are a nobel Prize winner, the developer in the field. Dr. skene was the first to on current clinical practice.” of a revolutionary imaging technology, identify the para-urethral glands, later the post-world war II era brought a pioneer in the use of the heart-lung renamed the skene glands. He also with it a period of tremendous growth machine, and the inventor of a kind of developed a number of innovative surgi- in the medical school and in its research microsurgery that has allowed for cor- cal techniques. “He was able to provide capacity. In 1950, the College, which neal transplants, to name just a few. women with great relief,” notes Kathleen had, by then, separated from LICH, Downstate’s tradition of medical e. Powderly, CnM, PhD, an expert on merged with the newly established innovation goes back to its very begin- Dr. skene’s career and the acting director state University of new York to form nings, with LICH faculty member of Downstate’s Division of Humanities the sUnY Downstate Medical Center. Austin Flint, sr., MD. “austin Flint’s in Medicine. so great was Dr. skene’s such was the importance of expanding

The writer is indebted to Kathleen Powderly, CNM, PhD, acting director of Downstate’s Division of Humanities in Medicine, for her original research on Downstate’s history and for her as- sistance with this article. Dr. Powderly and Jack Termine, former DMC archivist, John Zubrovich and Aaron Cormier of Biomedical Communications have compiled a lively online timeline of Downstate’s 150-year history. It can be viewed at www.downstate.edu/sesquicentennial/index.html

02 DOWNSTATE RESEARCH 2010 the capacity of Brooklyn’s only academic medical center that in october 1954 President Dwight David eisenhower laid the cornerstone for the Basic sciences Building on Clarkson avenue. Chandler McCuskey Brooks, PhD, chaired the Department of Physiology then. a renaissance man with interests in theology and philosophy, he made significant contributions to the study of cardiac and neuronal electrophysiol- ogy, neuroendocrinology, and the auto- nomic nervous system. Dr. Brooks was also the first dean of Downstate’s school Austin Flint, Sr., MD Alexander Skene, MD, LLD Jean Redman Oliver, MD of Graduate studies, which opened in 1966. His experiments uncovered how changes in the heart’s electrical activ- ity can lead to fatal arrhythmias. and his research laid the groundwork for the development of the cardiac pacemaker. “He was a physiologist of the body, not of a cell, an enzyme, or a molecule,” write his collaborators Kiyomi Koizumi, MD, PhD, and Mario Vassalle, MD, in a memorial essay. “He was a true physi- ologist who wanted to understand the secret mechanisms of the extraordinary human machine.” Dr. Brooks’s contemporary evelyn Witkin, PhD, who worked at Downstate Alfred Adler, MD Chandler McCuskey Brooks, PhD Evelyn Witkin, PhD from 1955 until 1971, “was a transfor- mative figure in science,” says Graham walker, PhD, the american Cancer Beginning in the late 1930s, while at the of cardiac repair that was previously society Research Professor at MIt. she University of Minnesota, Dr. Dennis unimaginable.” studied the cellular responses to Dna and his colleagues had begun design- the 1950s, ‘60s, and ‘70s were damage. the human body undergoes ing a machine that could perform the the period in which ophthalmologist tens of thousands of genetic insults daily, functions of the heart and the lungs, Richard C. troutman, MD, spearhead- and such injury can result in health thereby making open-heart surgery pos- ed the development of sophisticated problems that include cancer, neurologi- sible. In 1951, Dr. Dennis performed ophthalmic instruments and complex cal disorders, immunological illnesses, the world’s first open-heart operation. surgical techniques that are still in use and accelerated aging. though the machine worked perfectly, today. among them: corneal transplants, Dr. witkin was one of the first the patient did not survive, due to the intraocular lens implantation, in which women elected to the national academy complexity of his condition. In 1955, an eye’s clouded lens is replaced by a of sciences. Dr. witkin established that after moving to Downstate, Dr. Dennis clear plastic one, and refractive surgery cells can become resistant to radiation, again performed open-heart surgery for improved eyesight. these accom- and, working alone in her lab, later went using a heart-lung machine, and this plishments are all the more remarkable on to identify proteins that can repair time the patient survived. It was the given that Dr. troutman began his work Dna damage. says Dr. walker, “evelyn world’s second successful operation during an era when eye surgery was witkin played a key, early role in helping using a heart-lung machine. “Creating still performed without magnification. us understand that cellular responses to a machine that could substitute for the Collaborating with microscope manufac- Dna damage have enormous implica- heart and the lungs was a technical tour turers, he developed the first high-preci- tions for human health.” de force,” says Jeffrey Borer, MD, chair of sion microscopes for surgical use, thereby the record of innovation at sUnY the Department of Medicine and chief of founding the field of ophthalmic micro- Downstate during this period attracted cardiovascular medicine at Downstate. surgery. “He gave ophthalmology the Clarence Dennis, MD, a pioneer in the Dr. Dennis’s contributions to the field, push it needed to enter the modern era,” development of the heart-lung machine. Dr. Borer says, “made possible a type says Douglas Lazzaro, MD, professor

03 2010 DOWNSTATE RESEARCH A Century and a Half of Innovation

and chair of Downstate’s Department would be impossible. says Dr. Friedman, no effective diagnostic methods before of ophthalmology. “Conditions that pre- “our machine validated the idea that kid- MRI was developed.” viously led to blindness for millions of ney failure doesn’t equal death.” the 1998 nobel Prize winner people are now treatable, thanks to Dr. In the 1970s, Raymond Damadian, Robert Furchgott, PhD, chair of the troutman’s ingenuity and perseverance.” MD, performed his early work on mag- Department of Pharmacology from In the 1970s, eli Friedman, MD, who netic resonance imaging (MRI) and 1956 to 1988, had a similarly profound in 1964 founded the first federally funded developed at Downstate the world’s first impact on the world of cardiology. In dialysis clinic, went on to invent the por- whole-body MRI scanner. the technolo- 1980, Dr. Furchgott discovered that a table hemodialysis machine. He accom- gy uses magnetic fields and radio frequen- then-unidentified “endothelium-derived plished this only 14 years after the first cies to visualize body tissue. It is hard relaxing factor” allows for the relax- patient with chronic kidney failure began to overstate how profoundly MRI tech- ation of the muscle cells in blood ves- ongoing dialysis treatment. Inspired nology has “revolutionized diagnostic sels’ walls, and plays a crucial role in the by the fact that short-term dialysis had imaging,” says MRI expert Bill Bradley, regulation of blood pressure. In 1986, been performed on wounded soldiers MD, PhD, chair of the Department of Dr. Furchgott established that eDRF with acute kidney failure on the Korean Radiology at the University of California, was the gas nitric oxide. the nitric oxide war battlefield, Dr. Friedman designed san Diego. In fact, a 2001 survey of top pathway is now being explored as a treat- the attaché case-sized machine to make internists ranked MRI as one of the two ment for a host of illnesses, including the treatment available to patients who most important medical innovations of heart disease and pulmonary hyperten- needed to travel far from the country’s the previous 25 years. “Dr. Damadian sion. “the discovery of nitric oxide and few dialysis centers. the device also thought MRI technology would be useful its function,” said Dr. Valentin Fuster, spawned home dialysis, which remains in tumor detection,” says Dr. Bradley. “It then president of the american Heart popular among rural patients for whom turns out, it’s useful for detecting a wide association, in a 1998 interview, “is one commuting to far-off treatment centers range of diseases and conditions that had of the most important in the history of cardiovascular medicine.” In the late 1980s, a post-doctoral stu- dent at Downstate, Brendan Lee, MD, PhD, was part of a team of researchers who discovered the genetic mutation that causes Marfan syndrome, a some- times fatal disease of the body’s connec- tive tissue. Dr. Lee was also the first to clone the gene — an incredible technical achievement at that time. that cloning confirmed the link between the genetic mutation and Marfan syndrome. “these discoveries were major breakthroughs for the entire field of connective tissue dis- ease,” says Josephine Grima, PhD, the national Marfan Foundation’s vice presi- Clarence Dennis, MD Richard C. Troutman, MD Eli Friedman, MD dent of research and legislative affairs. a century and a half after its begin- nings at LICH, sUnY Downstate con- tinues this tradition of innovation. In fields as diverse as HIV and diabetic reti- nopathy, the brain’s extracellular matrix and angiogenesis, among many others, its faculty makes discoveries and invents devices that change the way medicine is practiced. since 2006, many of these world-changing researchers have been featured in this annual publication. Like their predecessors, Downstate’s current faculty offer “succor to the afflicted,” and their research generates benefits that will be experienced, in years to come, across Raymond Damadian, MD Robert Furchgott, PhD Brendan Lee, MD, PhD the country and around the world.

04 DOWNSTATE RESEARCH 2010 Brooklyn: A Laboratory for Advancing Science and Health

A Biotech Park Grows in Brooklyn

espite its wealth of scientific and vaccines; BioCangen, which designs biomedical talent, new York assays for cancer detection; and Bio- DCity has long lagged behind signal Group, a producer of devices that areas like Boston and san Francisco in record brainwaves. “Having these differ- attracting and retaining small and mid- ent kinds of spaces means we can provide sized biotechnology companies. smaller companies with larger facilities the reason is simple, says eva as they grow,” Dr.Cramer says. Cramer, PhD, Downstate’s vice presi- Because “science courses do not ade- dent of biotechnology and scientific quately equip science majors for employ- affairs and a distinguished service pro- ment in biotech labs,” Dr. Cramer says, fessor of cell biology. “there’s a lack of the incubator’s one-month workforce affordable lab space.” development component teaches under- envisioning a solution that could graduate students biotech job skills. benefit emerging biotech firms, and to date, the program has helped more Downstate and new York City scien- than 90 students find work in the field. tists as well, Dr. Cramer and colleagues Eva Cramer, PhD “these students are well received by a devised in 2000 a plan for a biotechnol- wide range of employers, from the City’s ogy incubator, a lab facility that provides in a March 2010 article in Crain’s new Medical examiner’s office and the new already-built bench and office space York Business, is one of only two biotech York Blood Center, to the american at reasonable prices. “we started with incubators in the whole of new York Museum of natural History,” Dr. no real estate, no money, just the idea City. It includes the 24,000-square-foot Cramer says. a number of graduates are that we could capitalize on the synergy advanced Biotechnology Incubator and a employed at the incubator itself. between companies and our faculty and state-of-the-art synthetic chemistry facil- “Faculty members now have a place students,” Dr. Cramer recalls. ity. the proximity of both helps facili- to pursue their entrepreneurial projects that idea has grown into a tate interactions between the companies right next to the school,” Dr. Cramer Biotechnology Park adjacent to the cam- and Downstate’s faculty and students. says. “our medical and graduate stu- pus, a larger facility on the Brooklyn BioBat, a 486,000 square-foot facility for dents can experience the excitement of waterfront called BioBat, plus an edu- more mature biotech companies, is based working at biotech start-ups. and the cational program that prepares college at the former Brooklyn army terminal. dream we had ten years ago has been science majors for jobs in biotechnology. tenants include the International aIDs built, and continues to grow, right here the Biotechnology Park, featured Vaccine Initiative, a developer of HIV in Brooklyn.” A New Prescription for Eye Research: Collaboration

ith more faculty, there’s the faculty of these schools more collaboration, and as well as faculty from stony “W more possibilities.” so Brook University’s school of says william Brunken, PhD, profes- Medicine and the University at sor of cell biology and ophthalmology Buffalo school of Medicine & about the recently launched sUnY eye Biomedical sciences. through Institute. Dr. Brunken co-directs the the sharing of resources and eye Institute with John Hoepner, MD, intellectual capital, the eye chair of ophthalmology at the Upstate Institute is poised to turn new Medical University in syracuse, and York’s state University system David troilo, PhD, vice-president of into one of the nation’s power- sUnY state College of optometry. houses in basic, translational, the program is a collaboration among and clinical vision research. William Brunken, PhD Douglas Lazzaro, MD

05 2010 DOWNSTATE RESEARCH Brooklyn: A Laboratory for Advancing Science and Health

the eye Institute’s most important between 250,000 and 300,000 patients,” already, the establishment of the achievement to date is the creation Dr. Brunken explains. “with the appro- eye Institute helped attract nationally of a mechanism for collaboration and priate ethical guidelines in place, this renowned glaucoma researcher John communication where none existed offers a powerful tool for research Danias, MD, PhD, to Downstate. “I was before. “In the past, a lot of our vision that cuts across a wide demographic excited with the prospect of working with researchers worked in their own silos,” spectrum.” a number of diverse investigators and explains Douglas Lazzaro, MD, chair- the eye Institute’s investigators expanding my clinical and translational man of Downstate’s Department of also hope that their new collaboration research,” Dr. Danias says. “Downstate ophthalmology. “now, using our listserv will attract to the field of vision research provided those opportunities and the and our web site”— sunyeye.org — “we’ll investigators in related disciplines such eye Institute expanded them further.” be able to communicate much more effi- as biochemistry, material science, and the eye Institute also represents a ciently with our colleagues about the sci- epidemiology. “the problems we’re model for similar research programs in entific questions we’re pursuing and the looking at — diseases of the retina and the large sUnY system. Plans for collab- resources we have to offer each other.” neurodegeneration — are big problems,” oration and cooperation, such as those one of these resources is the patient Dr. Brunken says. “they’ll benefit from at the foundation of the eye Institute, population that receives care at sUnY- the involvement of researchers with are at the heart of Chancellor nancy affiliated hospitals. “Collectively, that’s other areas of expertise.” Zimpher’s new vision for sUnY. Around-the-World Emergency Care

ot long after Haiti’s dev- astating earthquake this n winter, ten Downstate medi- cal faculty, residents, and nurses were on the ground at the University Hospital in Port-au-Prince, provid- ing around-the-clock emergency room care. “the hospital was having trouble getting 24-hour staffing in the eR, and we were willing and available to do that,” explains Christina Bloem, MD, MPH, clinical assistant professor of emergency medicine. the group’s effort was an example of the medical school’s International IEM members (from left): Ernest Garnier, MD, clinical assistant professor; Debra Barrow, RN; Robert emergency Medical Program in action. Gore, MD, clinical assistant professor; Dr. Christina Bloem; Marie France Senat-Zephir, RN. “shortly before the earthquake, we had begun collaborating with a clinic in the emergency medicine as a specialty in to date, the emergency Medicine town of terrier Rouge, in northern Haiti, other countries.” Department’s faculty and residents helping them build capacity,” says Dr. In fact, emergency care like that pro- have established collaborations with Bloem, the program’s director. “and this vided in the United states is scarce in medical facilities in Jamaica, turkey, work became part of what I hope will most parts of the world. “a lot of places south africa, Romania, Lesotho, India, be multi-year project now.” In fact, the don’t have pre-hospital systems. they and Brazil, as well as in Haiti. “when group returned to Haiti in april. don’t have ambulances,” Dr. Bloem we were there,” says Dr. Bloem of the International emergency medicine is notes. In many countries, physicians department’s relief work this winter, “we the newest subspecialty in Downstate’s who staff eRs have none of the spe- were able to utilize the many skills we nationally renowned emergency Medicine cialized training in trauma and other have learned in central Brooklyn: han- Department established in 2006, emergent conditions that emergency dling large volumes of patients, working the International emergency Medicine medicine doctors in developed nations with diverse populations.” Program trains residents in what Dr. have. “one of the things we teach our “at Downstate,” she adds, “you learn Bloem identifies as the two branches of residents is how to share their medi- to be open to other cultures and other international emergency medicine: “one cal expertise and their knowledge about methods of healthcare delivery. that is humanitarian relief, disaster relief. structuring emergency medical sys- serves us well, in Brooklyn and in our the other is more academic, developing tems,” Dr. Bloem says. international endeavors.”

06 DOWNSTATE RESEARCH 2010 Same Borough, but Worlds Apart Research into Inequities in Brooklyn Healthcare

here’s a joke among peo- ple whose primary lan- “t guage isn’t english,” says Humberto Brown, Ma, director of health disparities/new constituency develop- ment for the arthur ashe Institute for Urban Health (aaIUH). “If you tell a medical provider you’re not good at english,” Mr. Brown quips, “he or she will speak very loudly, as if the volume will solve the communica- tion problem.” the ashe Institute, which has an office on the Downstate campus, works closely with faculty and staff on pro- grams dedicated to improving the well- Members of the Brooklyn Health Disparities Center (from left): Humberto Brown; Dr. Clinton Brown; being of vulnerable urban populations. Dr. Tracey Wilson; Kweli Henry; Dr. Marilyn Fraser White; Girardin Jean-Louis, PhD, co-director, a study the Institute conducted found Research Core, associate professor of medicine; Dr. Ruth Browne; and Ferdinand Zizi, MBA, clinical instructor of health sciences. many older Latinos didn’t access health- care that was available to them because Brooklyn, we see severe disparities in the common goals,” says Center Director “their issues were talked about at a vol- areas of cardiovascular disease, infant Clinton Brown, MD, an associate profes- ume that allowed everybody to hear.” mortality, HIV and aIDs, asthma, and sor of clinical medicine at Downstate. this finding and Mr. Brown’s anec- other chronic health conditions,” notes since the Center’s founding, its dote illustrate one reason why health Brooklyn’s Deputy Borough President faculty has trained Downstate cardio- disparities exist in the United states Yvonne J. Graham. vascular fellows in health disparities and in Brooklyn in particular. a recent to help understand the causes of research. It established the summer survey by the Robert wood Johnson these disparities and to provide solutions, Institute Program to Increase Diversity Foundation found that Brooklyn ranked Downstate, the arthur ashe Institute, in Cardiovascular Health Disparities 58th out of 62 new York state counties in and the Borough President’s office lev- Research, which instructs junior scien- terms of health outcomes. Residents of eraged their long-term relationships to tists from around the country in those new York City’s poorest neighborhoods, establish, in 2004, the Brooklyn Health same research issues. It developed inno- including many who live in the areas Disparities Center (BHDC). “the BHDC vative curricula to train hair stylists to surrounding Downstate, have life expec- is the place that brings together research- become lay health advocates who can tancies four years shorter than those in ers and advocates who work both within teach their customers about cardiovas- the city’s most affluent districts. “In the University and outside of it to pursue cular health and disease, and it has built

Hispanics Who Speak Spanish as Primary Language Have More Deaths Due to Diabetes: Racial/Ethnic Disparities Problems Communicating with Their Physicians are Widening

50% Deaths per 100,000 adults 43% 60 Race/ethnicity White 50 Black 26% 23% 25% 24% Hispanic 25% 40 17% 12% 11% 30

20 0% Doctor listened to Patient Had question, One or more 10 some or only a understood some didn’t ask problems with little or only a little communication 0 1990–1992 1993–1995 1996–1998 1999–2001 Rates are age-adjusted. Hispanic–English at home ■ Hispanic–Spanish at home Sources: Bureau of Vital Statistics, NYC DOHMH; U.S. Census 1990 and 2000/NYC Department of City Planning

07 2010 DOWNSTATE RESEARCH Brooklyn: A Laboratory for Advancing Science and Health

a strong network of community-based organizations that advises the Center on A Tale of Two Neighborhoods: Access to Healthcare in Brooklyn community health issues. Percent of adults not receiving needed medical care in the past year: now, with funding from the nIH’s Central Brooklyn (Bedford-Stuyvesant, Crown Heights) 14% national Center on Minority Health Northwest Brooklyn (Brooklyn Heights, Park Slope) 5% and Health Disparities (nCMHHD), “the BHDC is laying the groundwork for Percents are age-adjusted. future research and policy recommen- Source: NYC Community Health Survey, 2002 dations to combat health disparities,” says tracey wilson, PhD, the Center’s with an urban public health program.” the Center staff has begun training research core co-director and associate the nCMHHD funding will also enable 40 such organizations in community- professor of community health sciences. the Center to place these students in based participatory research, in which to achieve these ends, the Health paid summer internships at local com- members of the communities affected Disparities Center is enhancing its munity-based organizations “to conduct by conditions or issues under study act already existing relationships. “this is surveys and needs assessments and to as full participants in the research pro- really a capacity-building grant,” explains disseminate information,” she adds. also cess. “we believe that this community ashe Institute Ceo Ruth Browne, scD, strengthened by this grant is the BHDC’s involvement is key to identifying reasons MPH, who is also co-director of the involvement with community-based for health disparities,” Dr. white says. Center. the Center is now designing a organizations, such as the Caribbean to further its policy-change goals, curriculum on health disparities research women’s Health association, the arab- the Center is “teaching community- for high school students who partici- american Family support Center, and based organizations how to make rec- pate in the Institute’s Health sciences the Haitian Centers Council. “these ommendations to legislators and other academy. “the academy is a program groups really have their fingers on the policy makers,” says BHDC policy ana- we run here on the Downstate campus,” pulse of their communities,” explains lyst Kweli Henry, MPH. Dr. Browne explains, “where faculty and Marilyn Fraser white, MD, the BHDC’s all of these efforts can lead to the graduate students teach talented minor- co-director of community engagement elimination of the health disparities that ity students in a three-year, after-school and the aaIUH’s associate director of prevent many in Brooklyn from living science enrichment program, coupled research and training. long and healthy lives. Partners in Care: Acute Care Overuse Meets Its Match

esidents of northern and central residents’ health while keeping medical of environmental and occupational Brooklyn suffer from startlingly costs down. and her ambitious Brooklyn health sciences in the Department R high rates of infant mortal- Healthcare Improvement Project (BHIP), of Preventive Medicine; Michael ity, HIV/aIDs, cardiovascular disease, supported by a new York Healthcare Lucchesi, MD, chair of the Department and other illnesses. they also overuti- efficiency and affordability Law grant, is of emergency Medicine and medical lize high-cost emergency room (eR) and designed to make that happen. the proj- director at University Hospital of inpatient care. one measure of this over- ect will, first, investigate the factors that Brooklyn; Howard s. Berliner, scD, pro- utilization is highlighted by this fact: the impact health and healthcare provision fessor and chair of the Department of eR at University Hospital of Brooklyn in its 15 zip-code, mid-Brooklyn study Health Policy and Management at the (UHB), Downstate’s teaching hospital, area. then, employing a unique public/ school of Public Health; Dorothy Fyfe, was designed, in 2001, to treat as many private/community partnership, it will MPa, assistant vice-president for plan- as 25,000 patients annually but in 2009 develop recommendations and solutions ning; and Michael Gusmano, PhD, of saw 73,000. that can benefit residents, healthcare the Hastings Institute. what is the connection between providers, and insurers alike. “we hope,” says Dr. stellman, “that these two phenomena? In this endeavor, Ms. wong is joined our unique stakeholder collaboration Grace wong, MBa, MPH, Downstate’s by two groups: an advisory panel made can continue, in order to address the vice-president for managed care and clini- up of community leaders, government many pressing healthcare needs in our cal business, has decided to find out. representatives, health insurers, and community.” she is motivated by a belief that business owners; and a team of one of the project’s most power- Brooklyn’s healthcare resources can academics. Her colleagues include ful tools is GIs technology. Geographic be employed in ways that can improve Jeanne stellman, PhD, a professor information systems technology

08 DOWNSTATE RESEARCH 2010 captures, analyzes, and presents loca- tion-related data. BHIP will use it to create a sophisticated, block-by-block map that “will help us identify the fac- tors that impact health among the study area’s one million residents,” Ms. wong says. the map will also help assess the state of healthcare provision in the study area. Included will be healthcare providers’ hours of operation, languages spoken, and types of medical care offered. that information will be integrated with data on “health status, health service utilization, socio-economic, and housing indicators, as well as a variety of other variables affecting the community’s well-being,” Ms. wong says. though the project is in its initial stages, its researchers have already iden- From left: Dorothy Fyfe; Dr. Jeanne Stellman; Priya Pasram, MPH, project coordinator; and Grace tified many of the causes of acute care Wong with the map of Brooklyn ER visits. overutilization: Patients frequently come to the eR for non-emergencies because after the BHIP has collected and complex medical problems addressed at “there is a shortage of primary care in analyzed all of its data, the project one facility, rather than having to shuttle the area,” Ms. wong says. In fact, 14 of leaders will meet with organizations, among medical offices. Insurers might the 15 zip codes under study have been including the Brooklyn Chamber of well realize a financial benefit from pay- deemed medically underserved areas by Commerce, the healthcare workers’ ing doctors extra to see patients on week- the federal government. Patients who do union 1199seIU, eight health insurers, ends or evenings, so that they don’t incur have primary care providers often don’t six hospitals, community groups, senior the cost of expensive eR visits. the prop- have access to them during evenings centers, and the Brooklyn Borough er use of resources would improve the or on weekends. other neighborhood- President’s office, to formulate solutions healthcare that area residents receive, specific issues include substance abuse, to the area’s healthcare problems. and by extension, their health. mental illness, and patients’ inability “we envision new incentives for BHIP’s findings and recommenda- to afford medication. Difficulty in navi- healthcare providers to make primary tions may have much wider applica- gating the fractured healthcare system and specialty care more available in the tions as well. one private insurer told plays a role as well: “often, patients feel neighborhoods under study,” Ms. wong Ms. wong, “Your borough’s the toughest their medical issues can be dealt with notes. Unnecessary use of acute care can healthcare area in the country. If you can more quickly by going to the eR than by also be reduced, she believes, by the cre- fix Brooklyn, you can fix the nation.” being ping-ponged among specialists,” ation of multispecialty ambulatory care Grace wong, for her part, sees that Ms. wong explains. centers that allow patients to have their the possibilities abound.

Rate of Ambulatory Care Sensitive Admissions per 100,000 Emergency Department Visits Without Admission, 2006-2008 Hospital Admissions, 2002 United Hospital Fund Neighborhood Rate of ED visits without Median household United Hospital Fund Neighborhood Rate ofa dEmD ivsissiiotsn wpietrh o1u0t0 Median houisnechoomlde admissiorne spiedre 1n0ts0 income2 000 re2si0d0e6n t-s 2008 2000 2006 - 2008 Greenpoint 33 $ 27,205 Greenpoint 33 $ 27,205 Williamsburg-Bushwick 43 $ 21,160 Williamsburg-Bushwick 43 $ 21,160

$ 48,476 BrooklynBrooklyn Heights-Park Slope Slope 26 26 $ 48,476

BedfordBedford Stuyvesant-Crown Heights Heights 43 43 $ 26,514$ 26,514

EastEast New YorkYork 48 48 $ 25,574$ 25,574

SunsetSunset Park 37 37 $ 29,754$ 29,754 BoroughBorough Park 17 17 $ 31,781$ 31,781

$ 34,194 EastEast Flatbush-Flatbush 33 33 $ 34,194

Canarsie-Flatlands 30 $ 44,113 Canarsie-Flatlands 30 $ 44,113 Bensonhurst-Bay Ridge 22 $ 40,307 Bensonhurst-Bay Ridge 22 $ 40,307 Coney Island-Sheepshead Bay 27 $ 31,375 Coney Island-Sheepshead Bay 27 $ 31,375

Blacks are two to four times more likely than whites and Hispanics to be Source: Michael K. Gusmano and Daniel Weisz. 2010. “Assessing Access to Primary Care in Brooklyn,” April 22, 2010. hospitalized for potentially preventable conditions Source:Original Michael analysis K.of StatewideGusmano Planning and Daniel and Weisz. Research 2010. Cooperati “Assessingve System Access (SPARCS) to Primary data Care by authors. in Brooklyn,” April 22, 2010. Original analysis of Statewide Planning and Research Cooperative System (SPARCS) data by authors.

09 2010 DOWNSTATE RESEARCH On the Cusp of a Breakthrough

Teasing Influences Apart: A New Model for In-Utero Crack Exposure

ne doesn’t hear much about the crack-cocaine epidemic o these days. the news articles about crack-exposed newborns, so com- mon at the epidemic’s outset in the mid- 1980s, have disappeared from the front pages of the nation’s newspapers. and the epidemic itself peaked in 1990. nevertheless, every year in the United states, an estimated 165,000 women smoke crack while pregnant, accord- ing to the federal substance abuse and Mental Health services administration. In the last decade, more than a million crack-exposed babies have been born. Clinicians have studied the devel- From left: Susanna Popp, PhD, research associate; Ning Zhao, MD, senior research associate, with Dr. Dow-Edwards. opment of children exposed in utero to this purified, smoke-able form of Dow-edwards, “we can set in motion a development of those same brain areas cocaine since the epidemic began. they series of experiments that will inform our that cause cravings in adults,” Dr. Dow- have documented problems with behav- scientific understanding of the effects of edwards observes. ior and attention, deficits in language in utero crack exposure on offspring.” to better explore these effects, Dr. and cognition, lower academic achieve- Dr. Dow-edwards has been using rat Dow-edwards and her lab have devised ment, and lower IQs. neuroimaging has models, albeit imperfect ones, to study a model that employs a difficult-to- revealed anatomical differences in brain crack’s impacts since the epidemic start- implant jugular cannula in combina- development between crack-exposed and ed more than 25 years ago. “Crack was tion with frequent intravenous dosing. otherwise healthy children. But, because a huge public problem then. as someone the cannula allows Dr. Dow-edwards many children exposed to crack in utero who had been researching the effects of and her research group to inject cocaine are raised in homes with drug-using and/ in utero alcohol exposure, I had the tools directly into the rats’ bloodstream. or mentally unstable parents, separating to join other researchers in investigating now, they are working to achieve the the impacts of prenatal crack cocaine this new problem,” she says about her kinds of crack-use sequelae that human exposure from other influences on brain early involvement in the field. mothers develop: severe weight loss, development, behavior, and cognitive Crack bingeing is the most common miscarriage, and premature birth. “If we function is difficult. form of cocaine use among pregnant can identify a sub-toxic but very robust studies with animal models can help women. Yet, to date, the evolution of a dosing pattern, then we will be sure answer questions about crack’s impact rat model of bingeing behavior has been we have an accurate model of human on exposed offspring. But to date, the slowed by difficulties in determining in utero exposure,” Dr. Dow-edwards only models available to researchers appropriate dosing levels and the com- says. offspring from such a model could conducting studies in pregnant rats and plexity of certain surgical techniques. enable her lab to more accurately explore their progeny have been ones that mimic “a more accurate model can move the crack’s impacts. “we also want to exam- maternal nasal cocaine use rather than research in this field forward,” Dr. Dow- ine whether enriched environments crack bingeing, which gives users a faster edwards says. improve outcomes for offspring,” she and more intense “high.” nasal cocaine use differs from crack says, “and to look at reward circuits and Diana Dow-edwards, PhD, is attempt- use in that nasal cocaine is metabolized cognitive function.” ing to rectify that problem. a professor of more slowly and is less likely to lead to all this research is aimed at help- physiology and pharmacology and of cell drug cravings. By contrast, “crack leads ing doctors and social service providers biology, Dr. Dow-edwards is using fund- to very rapid increases and decreases understand crack-exposed children’s spe- ing from the national Institute of Drug in drug levels in the brain,” Dr. Dow- cific needs and challenges. “Ultimately, abuse to develop a first-of-its-kind model edwards explains. Crack users frequently the information we uncover,” Dr. Dow- of crack bingeing in pregnant rats. “If binge for 12 hours or more. “In the fetus, edwards says, “will end up helping we can establish this model,” says Dr. these two phenomena may influence the kids.”

10 DOWNSTATE RESEARCH 2010 The Repair Man: Brain-Machine Interfaces and the Quest for a New Kind of Prosthesis

t’s not often one hears scientists talk about their contracts with I funders. But ask assistant profes- sor of physiology and pharmacology and of biomedical engineering Joe Francis, PhD, if he has an idea about when the fully functioning, robotic prosthetic hand he’s been working on for the last several years might become an operat- ing reality, and he says, with an impish smile, “it has to be done in four years, by definition of our contract.” the contract with the U.s. military’s Members of Dr. Francis’s lab (from left): Marcello DiStasio, candidate for MD, PhD; Shaohua Xu, MD, PhD, postdoctoral fellow; Brandi Marsh, candidate for MD, PhD; Dr. Joseph T. Francis; Pratik Chhatbar, Defense advanced Research Projects MD, candidate for PhD; John Choi, candidate for PhD; Mulugeta Semework, candidate for PhD. agency (DaRPa) calls for him to deliver a prosthetic hand that works like a real or missing part with an artificial compo- Randall Barbour, PhD, a professor of one — moving when its user thinks nent,” he explains, matter-of-factly. pathology and biomedical engineering, about moving it and feeling things the scientific questions involved in Dr. Francis is investigating whether almost the way a real hand does. But the developing these prostheses are, obviously, the electrodes can be eliminated hand is not all Dr. Francis is developing incredibly complex. In the case of the pros- altogether. near-infrared spectroscopy for DaRPa. Dr. Francis is also at work thetic hand, there is the issue of commu- — Dr. Barbour’s specialty — may enable on a computer-based, prosthetic brain. nication between the user and the hand the brain and the prosthesis to commu- that’s right. a computer-based, pros- itself. at present, that communication is nicate wirelessly. thetic brain. accomplished through electrodes implant- Dr. Francis is also studying force con- “Basically, we’re trying to take what ed in the user’s brain that connect to the trol, the ability to gauge and regulate the we’ve learned about the brain from ani- computerized prosthesis. But, to date, the intensity of hand movements. For the last mal experiments and reproduce in a electrodes scientists have implanted in several years, Dr. Francis has been working computer model all the different parts animal and human brains have remained with laboratory animals to better under- of the brain that we’ve looked at. then, viable for a few years at most. after that, stand the many steps involved in this pro- we’ll put them together in a simulation, scars form around the electrodes, or, the cess. “we would like the person to be able and, after that, have that computer- electrodes shift their position, causing to control how hard they’re squeezing ized brain interact with a person’s real their malfunction. another person’s hand, how softly they’re brain. If there’s anything missing — if to help solve this problem, one of Dr. holding a pen,” Dr. Francis explains. part of the brain has been debilitated by Francis’s graduate students is designing Moreover, a successful robotic hand, a stroke, if there’s literally a part missing nanotube-enhanced electrodes so thin he says, will be able to “feel” things — — we’ll be able to replace that damaged they can’t trigger scarring. and, with the texture of a baby’s skin, for instance

Generation of a somatosensory neuroprosthesis: Dr. Francis uses these images to compare neural responses in the somatosensory cortex to natural touch (A) and microstimulation (MiSt) with small electrical impulses delivered to the somatosensory thalamus (B). Shown also are the peri stimulus time histograms for these two types of input utilizing a 3D and 2D representation of this information for comparison. A very similar activity is achieved under VPL MiSt (ventral posterior lateral thalamus microstimulation) as under natural touch.

11 2010 DOWNSTATE RESEARCH On the Cusp of a Breakthrough

— not just hold them. “we’re working there’s a steep transition of new learning group will try to apply these computer- with developers of prosthetic skin and required,” Dr. Francis explains. ized models in the aid of animals with prosthetic bones to make it happen.” In collaboration with william Lytton, central nervous system injuries. the proposed brain prosthesis is, in MD, a professor of physiology and phar- all of this work, of course, sounds some ways, an extension of Dr. Francis’s macology, neurology, and biomedical like something out of an arthur C. earlier research. Because both the hand engineering and an expert in the com- Clarke novel. But to Dr. Francis, this and the brain must respond to novel puter modeling of brain-cell activity, Dr. research is simply part of a lifetime’s environments and situations, computer Francis’s group will “conduct some very interest in brain-machine interfaces, and models of the brain’s learning ability are detailed modeling of individual brain a demonstration of compassion as well. central to both projects. “Really, this is cell activity. we will also do some less “with these prostheses, we want to see if about modeling learning, so that com- detailed modeling of larger brain cell net- we can help people do 95 percent of what puter agents” — computer programs works and see which ones are most effec- they were doing before,” Dr. Francis says. that perform tasks — “can help when tive,” he explains. then, Dr. Francis’s “More than that would be even better.” Midnight Oil: Sleep Disturbances’ Impact on Lipoprotein Production

ight-shift workers — everyone from nurses to police officers n to researchers at the British antarctic survey station — suffer from cardiovascular disease and metabolic syndrome at rates that are sometimes five times greater than their peers work- ing the day shift. Metabolic syndrome is a cluster of medical conditions which includes high cholesterol and is linked to heart disease and stroke. though researchers have document- Dr. Mahmood Hussain’s lab (from left): Xiaoyue Pan, PhD, research assistant professor; Irani Khatun, ed this phenomenon, to date, they have candidate for PhD; Dr. Hussain; David Bowman, BS, research support specialist; Joby Josekutty, had trouble understanding its causes. candidate for MD, PhD; Joyce Queiroz , MS, research support specialist; James Soh, candidate for MD, PhD; Jahangir Iqbal, PhD, research assistant professor. But now, with funding from the national Institute of Diabetes and Digestive and of his career researching lipid formation, lost this diurnal regulation of lipoprotein Kidney Diseases, Mahmood Hussain, came to the question of how disruptions production,” and continued to produce PhD, a professor of cell biology and in circadian rhythms influence lipid pro- lipoproteins around the clock. pediatrics, appears to have brought its duction when Xiaoyue Pan, PhD, one of to further explore the day/night etiology to light. Using laboratory mice, his post-doctoral fellows, approached him cycles’ impact on lipid production, Dr. Dr. Hussain has recently discovered with the previously unexplored idea. she Hussain turned to mice that had muta- that circadian rhythms — our 24-hour had studied circadian rhythms as part of tions in the Clock gene. Clock is a mem- activity/sleep cycles — and the geneti- her PhD thesis. “I said, ‘that’s fantastic! ber of a group of “genes found in every cell cally controlled mechanisms that regu- Let’s get started’,” Dr. Hussain recalls. that regulate the body’s 24-hour cycle,” late them play a significant role in the Drs. Hussain and Pan with members Dr. Hussain explains. Clock genes are production of lipoproteins. Lipoproteins of their lab first experimented in nor- themselves switched on and off within a are a group of soluble proteins that com- mal mice, disturbing their natural sleep/ part of the brain called the suprachias- bine with and transport fats (lipids) in wake cycles and measuring the resulting matic nucleus, which is sensitive to light. the bloodstream. excess accumulation changes in lipid levels. Mice are natu- “Clock mutant mice cannot sense prop- of these low-density lipoproteins in the rally nocturnal. and “when we fed them erly when daytime is and when night- plasma is a major contributor to heart during the day instead of during the time is,” Dr. Hussain explains. Rather disease. “when our circadian rhythms night, they switched the timing of their than having to keep his mice awake 24 are disrupted,” Dr. Hussain explains, activity and their lipid production from hours a day, the Clock genetic mutation “we absorb more lipids and have more nighttime to daytime,” Dr. Hussain did the work for him. as a result, like lipoproteins in the blood.” explains. “But when we kept them in many night-shift workers, the mutant Dr. Hussain, who has spent much constant light for five whole days, they mice were active and eating for many

12 DOWNSTATE RESEARCH 2010 more hours than their normal counter- Diurnal Variations in Plasma Lipids and MTP parts. the animals’ plasma lipid lev- els — especially their levels of so-called triglyceride-rich aPoB-containing lipo- proteins — increased “to very high levels and remained high throughout the day” when compared to their normal siblings. Dr. Hussain’s research also led to the A schematic diagram explaining molecular mechanisms contributing to daily observation that “Clock mutant mice are changes in plasma triglyceride using another transcription factor known as SHP to MTP. Changes in MTP contribute to diurnal variations in plasma triglyceride. prone to atherosclerosis” — hardening of the arteries — indicating that “disrup- tions in circadian rhythms may predis- regulation of plasma triglyceride. “sleep disruption is a hallmark of pose individuals to this disease,” he says. Having teased apart the mechanism our age,” Dr. Hussain notes. social Dr. Hussain’s experiments have illu- by which sleep disruptions increase cir- changes brought about by the television, minated the pathways by which these culating lipid levels in laboratory mice, the Internet, and frequent air travel, aPoB-containing lipoproteins are formed. Dr. Hussain hopes to explore further as well as the global marketplace, have “we found that the Clock gene actually the implications of those findings. How increased the numbers of people with regulates another transcription factor might sleep disruptions affect heart and interrupted and insufficient sleep. For called sHP (small heterodimeric part- kidney function? and, are there processes example, some traders wake up at 3 a.m. ner), and sHP regulates MtP (micro- that can reduce lipid accumulation and to watch the european markets, and somal triglyceride transfer protein),” lipoprotein formation in mice that are there is a steadily increasing number of a transfer protein that plays a pivotal active almost 24 hours a day? He has transcontinental business travelers, who part in the formation of aPoB-containing another ongoing research project support- frequently cross time zones. “It’s impor- lipoproteins. In earlier research, Dr. ed by the national Heart, Lung, and Blood tant to understand,” Dr. Hussain says, Hussain was the first to identifytP M Institute to look into ways to inhibit MtP “how this lack of sleep is affecting our as a key protein involved in the diurnal as means to lower plasma lipids. cardiovascular health.” Travel to the Junction: RNA’s Journey from Nucleus to Synapse

ow does the brain interact with its environment? what is the H process through which inter- nal and external stimuli influence brain cell activity, and with that activity, brain function? For years, these questions have fas- cinated Henri tiedge, PhD, a professor of physiology and pharmacology, who explores them at their most basic sci- entific level. In particular, Dr. tiedge is enthralled by the subject of neuronal Rna translation. that’s the complex and largely mysterious process by which Dr. Tiedge, standing in the center, and members of his laboratory (from left): Jun Zhong, PhD, research the genetic information stored in brain assistant professor; Taesun Eom, PhD, research scientist; Ilham A. Muslimov, MD, PhD, research cells’ Dna is used to create ribonucle- scientist; and Anna Iacoangeli, PhD, research assistant professor. ic acid (Rna) molecules that are the — are involved in synapse structure and to the synapse. and, given that large instructions for creating proteins. In function,” Dr. tiedge explains. “they amounts of this genetic information neurons, the Rna itself can travel to underlie the whole panoply of higher travel to synapses and are stored there remote parts of the cell where synapses brain function.” until, often much later, the need arises are located, and build proteins on site. Dr. tiedge wants to understand what for the information to be synthesized “these proteins — neurotransmitter enables the genetic information that is into protein: what controls how this receptors, ion channels, protein kinases stored in a neuron’s Dna to find its way genetic information gets to remote sites,

13 2010 DOWNSTATE RESEARCH On the Cusp of a Breakthrough

and what controls the use of this infor- right stop, and arrive at their desks at the function,” Dr. tiedge says. mation to build proteins on site? beginning of the workday? Is there some- His new research in this area, funded these are essential questions. “the thing that prevents the commuters from by the national Institute on Drug abuse, process of reacting to stimuli by trans- disembarking too soon and wandering explores how drugs of abuse, such as opi- lating Rna into proteins is basically aimlessly around downtown Brooklyn? ates, impact neuronal Rna translation. what allows the brain to interact with to learn the answers to these ques- “once we understand all of the com- the outside world,” explains Dr. tiedge. tions, Dr. tiedge and his team perform ponents in this process of neuronal the localization of proteins at synapses experiments in cultures of rat brain Rna translation, we can think about enables communication among brain cells, small pieces of brain tissue (“brain how to address diseases such as autism cells. this communication, in turn, is slices”), and postmortem human brain and alzheimer’s,” Dr. tiedge says. His responsible for many of the basic pro- tissue. they have also developed mouse research on how drugs of abuse impact cesses in which the brain is involved models. “we have found,” Dr. tiedge neuronal Rna translation may help — learning, memory, language, emo- explains, “that gene expression at the explain mechanisms of action of these tions, to name just a few. Deciphering synapse is governed by a type of Rna drugs and aid researchers in develop- the neuronal Rna translation process called” — not surprisingly — “regula- ing more effective treatments to reverse may explain much, not only about tory Rna.” Using knock-out mice that addiction. But his research has broad normal brain function, but also about are missing certain of these regulatory implications for all of neuroscience. abnormal brain function. Malfunctions Rnas, Dr. tiedge has demonstrated “Basically,” Dr. tiedge says, “this type of in neuronal Rna translation appear that synaptic Rna translation into research has the ability to explain how to underlie autism, alzheimer’s dis- local proteins is instrumental in normal brain cells function as a person interacts ease, and a form of mental retardation brain function; his knock-out mice have with his or her environment. this work known as Fragile X syndrome, research- hyperexcitable brain cells, and the ani- may one day help explain a fundamental ers say. Certain drugs of abuse may have mals themselves are prone to seizures. part of who we are.” long-term effects on consciousness and Much more research behavior by altering the ways brain cells in this area remains to make critical proteins. “Brain function,” be done. the traveling Dr. tiedge says, “depends on how these instructions that Rnas Rnas are localized and translated at receive come in the form of synapses over time.” ensembles of nucleotides Knowing that lay audiences may have — molecules made up of trouble understanding molecular brain nitrogenous bases, sugars research, Dr. tiedge is fond of analogiz- and phosphates — called ing the process of neuronal Rna trans- “codes.” “at the moment, port to a new York City commute. How we only understand some do straphangers know which subway to of the codes that get board in Manhattan in order to arrive certain classes of Rna RNA transport along dendritic microtubules. Trans-acting factors at sUnY Downstate in Brooklyn? what out of the cell’s nucleus (TAFs) interact with dendritic targeting elements (DTEs) that are information, in what form, allows them where they’re made, to contained within transported RNAs. RNA-containing particles are to catch the right train, get off at the the synapses, where they thought to be transported by molecular motors such as kinesins. Once Around the Block: Decoding the Causes of Ischemic Injury

ore than 1.25 million or disrupted blood supply — followed by as well: inflammation that results from americans suffer from heart reperfusion injury. a post-ischemic autoimmune response M attacks each year. another Until recently, scientists believed that follows reperfusion. “when I came 800,000 are affected by stroke. a rare that the tissue damage these ischemic to Downstate in 2005, I began discuss- form of blood-flow blockage in the intes- events precipitate is mostly the result of ing this new concept with cardiologists tines that affects about 35,000 people blood-flow blockage. But, Ming Zhang, and other clinicians,” Dr. Zhang recalls. annually has a fatality rate of more than 70 MD, PhD, a research assistant profes- “It was quite a novel idea for them. But percent. all these conditions have one sor of anesthesiology and cell biology, now that we have more research to back thing in common: ischemia — inadequate has discovered there is another cause up this concept, clinicians are becoming

14 DOWNSTATE RESEARCH 2010 interested in how the process works.” Indeed, Dr. Zhang’s research in humans and in laboratory animals may soon lead to the development of an agent that can help minimize the damage this autoim- mune response generates. Dr. Zhang’s interest in the causes of ischemic injury stems from research he conducted as a post-doctoral student at Harvard. “My mentor had a project on autoimmunity and inflammation,” he recalls. “as I became involved, I saw the many potential applications of this research.” In 2004, Dr. Zhang and col- leagues were the first to publish on the subject, using laboratory animals to document the phenomenon in cases of intestinal ischemia. “we discovered that with ischemia, Dr. Ming Zhang and members of his laboratory (from left): Chihyuan Mark Lai, PhD student; cell membranes get damaged and intra- Haekyung Lee, PhD student; Amie Kim, MD student; Dr. Zhang; Georges Labaze, MD, clinical cellular components” — cell contents, in research coordinator; Yunfang Joan Hou, MD, instructor, ECRIP fellow; Julie Rushbrook, PhD, professor (Dr. Zhang’s collaborator); and Karan Gulaya, BS, research assistant. other words — “are suddenly exposed to the immune system,” Dr. Zhang explains. ischemia, too,” he explains. “the blood event, paramedics or emergency room “when blood vessels are reperfused, the vessels are clamped off to allow the sur- personnel could inject this agent to block body’s innate immune system, which geon to operate on the heart.” when the the autoimmune response.” Likewise, has never before encountered these ‘self’ clamps are removed, blood flow to the surgeons and anesthesiologists could components, goes on the attack. Certain area is reestablished. “to help us ascer- administer such an agent during surgery, antibodies dock onto the injured cells tain whether IgM plays a role in post- prior to reperfusion. and destroy them.” these antibodies are ischemic injury, these surgeons are col- Dr. Zhang has already been working a variant of the immunoglobulin, IgM. lecting samples of blood from patients’ to make that possibility a reality. “while since Dr. Zhang first discovered this pro- hearts before surgery and after,” Dr. I was at Harvard, I developed a short cess in intestinal ischemia, he and other Zhang says. His lab then tests the IgM peptide that can target the early reac- researchers have documented it in ani- levels in those samples in an effort to tion between the autoimmune antibody mal models that include other types of ascertain whether this phenomenon is and the self antigen,” Dr. Zhang says. ischemic injuries, such as heart attack, also a significant problem in humans. (His mentor has started a biotech con- trauma, burns, and surgery. Dr. Zhang believes his research has cern to further develop and market this with funding from the national tremendous translational potential. treatment.) now, Dr. Zhang is designing Heart, Lung, and Blood Institute, Dr. “Imagine that a high-risk person — and testing potential chemical reagents Zhang is currently testing whether someone who had already had a heart to block this autoimmune response as humans have similar responses. to con- attack or a stroke — could carry an injec- well. “we have great hope,” he says, duct this research, he has enlisted sev- tion ‘pen,’ like the epiPens that people “that targeting this pathogenic IgM will eral of Downstate’s cardiac surgeons. who have severe allergies carry,” he says. help minimize injury in a whole host of “In cardiac surgery, you have a kind of “If the person had another ischemic ischemic events.”

Myocardial infarction is tracked by red fluorescent dye and non-ischemic tissue is traced by blue fluorescent dye. Inflammation in the myocardial tissue is Autoimmune natural IgM (red fluorescence) and complement C3 (green fluorescence) tracked with green fluorescent staining are present within the intestinal tissue following ischemia. of complement C3.

15 2010 DOWNSTATE RESEARCH On the Cusp of a Breakthrough

More for the Good: Exploring the HDL Cholesterol Pathway

igh-density lipoprotein (HDL) HDL, you have to inhib- cholesterol is known as the it lipase.” soon, he dis- H “good” cholesterol. though its covered that endothelial function in the human body isn’t entire- lipase production and its ly understood, HDL cholesterol likely persistence were con- removes from plaques on blood-vessel trolled by enzymes called walls the excess low-density lipoprotein proprotein convertases (LDL) cholesterol that is detrimental to (PC), which can reduce heart health. In fact, the higher an indi- lipase levels. “this came vidual’s HDL cholesterol level, the lower as a surprise to us,” he the risk of cardiovascular disease and of notes. earlier scientifi c dying from coronary heart disease. research had shown that But much of what scientists know PCs play several roles in about HDL cholesterol is speculative, the human body. they based on epidemiological data, rather Weijun Jin, MD activate viruses such as than on hard science. In particular, human papillomavirus the pathway that regulates the produc- clinical neurologist in China. “a lot of and saRs and facilitate “cancer metasta- tion and longevity of HDL in the blood my patients suffered from strokes and sis by activating proteins that allow cancer stream — “perhaps 70 percent of it” — heart disease,” he explains. cells to spread,” Dr. Jin explains. But prior remains largely unknown, says weijun Currently, there are no effective to Dr. Jin’s investigations, “PCs had not Jin, MD, an assistant professor of cell methods of boosting HDL cholesterol been associated with lipids at all.” these biology. thus, explorations into ways levels that do not pose signifi cant side enzymes seem to play a pernicious role in to increase HDL cholesterol levels and effect risks. “In the clinical setting,” the human body, but Dr. Jin believes their realize the accompanying benefi ts, are, Dr. Jin says, “you can use niacin [a B infl uence “may be dependent on the site for the most part, in their infancy. vitamin] to increase HDL levels by 15 of action. If we are right, targeting these But, with funding from the national to 30 percent. But the side effects are particular PCs should effectively regu- Heart, Lung, and Blood Institute, Dr. Jin very uncomfortable.” these include late HDL cholesterol in the bloodstream is working to fi ll that information gap. hot fl ashes, itching, and gastrointesti- without impacting other systems.” His interest in HDL cholester- nal problems. exercise can raise “good” Building on this knowledge, Dr. Jin ol stems from his early work as a cholesterol levels “maybe by 7 percent,” and his team experimented with boost- says Dr. Jin. and a daily alcoholic drink ing and blocking PC levels in mice. the Inhibition of hepatic proprotein “maybe gives you another few percent. results? In one experiment, using a gene convertases using a specific inhibitor, But, at best, these are all marginal.” transfer that increased PC levels, Dr. profurin, reduced plasma HDL-c levels Impressed that statin drugs such as Jin’s team raised HDL levels by 50 per- in vivo. atorvastatin (Lipitor) have made great cent. with another type of gene transfer, Plasma HDL-c strides in lowering LDL cholesterol lev- they lowered HDL cholesterol levels to els, reducing heart disease incidence, zero. along the way, Dr. Jin has also and decreasing cardiac deaths, Dr. Jin developed an assay that can test PC lev- wondered whether it might be possible els in the human blood stream. to untangle the HDL production path- now, Dr. Jin plans to investigate way and thereby facilitate the develop- whether his PC-boosting method is ment of an HDL-boosting drug that effective in inhibiting as well as treating could offer similar cardiac benefi ts. atherosclerosis in mice. “we’re hoping working with human cell cultures that we can get rid of the plaques, or, bet- Plasma HDL-c was monitored over a two-week and animal models, he and his labora- ter yet, prevent their formation entirely,” period after vector administration. Student t tests, tory colleagues began by studying an he explains. were used to compare profurin with the control enzyme called endothelial lipase “that Dr. Jin’s research “is basic science,” vector, AdNull. Both groups had four mice. The error bar represents a standard deviation and * hydrolyzes” — breaks down — “the he says. “But if our project is a success, p<0.05 and ** p<0.001 are confi dence intervals. HDL cholesterol in your blood stream,” it will likely point the way to additional Cell Metabolism 2007 explains Dr. Jin. “If you want to increase therapies for heart disease.”

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