THE Einstein EDGE TODAY’S SCIENCE

EINSTEINwinter 2008

THE eINSTEIN EDGE TODAY’S SCIENCE ... TOMORROW’S MEDICINE

winter 2008 I Einstein EINSTEIN CONTENTS Winter 2008

3 A Message from the Dean

4 Nanotechnology: The Next Big Thing in Medical Research 10 10 Proteomics: Power to the Proteins

18 Hearts Without Borders

20 Celebrate! Einstein Welcomes New Board Chair

20 24 The Compleat Physician

28 Special Convocation Honors Faculty and Philanthropy

30 To Life!

34 The Amazing Odyssey of Sylvia Smoller 24 40 News from the Labs

43 Remembering Salome Waelsch, Edmund Sonnenblick, M. Henry Williams

EINSTEIN: A publication for faculty, students, alumni, friends and supporters of the Albert Einstein College of Medicine of Yeshiva University.

Einstein I winter 2008 winter 2008 I Einstein EDGE: Today's Science ... Tomorrow's Medicine A Message from the Dean

instein E he T

anotechnology ism in Einstein medical students, and proteomics; along with the technical skills and Nir Barzilai’s studies critical thinking skills imparted by the of centenarians “regular” curriculum. In truth, Einstein and Sylvia Smoller’s students—not only admitted, but also odyssey from self-selected, for their commitment grade school in Poland to becom- to medicine as a caring profession— ingN one of America’s preeminent enter Einstein with these qualities. The epidemiologists; the new course, PDC course serves in part to prevent “Patients, Doctors and Communities” the erosion of these qualities by what (PDC), and Robert Michler, Chair of has been termed the “hidden cur- Cardiothoracic Surgery, who deliv- riculum,” the all too frequent lack of ers extraordinary care, not only to caring observed by students as they patients from our own Bronx com- encounter medical professionals munity, but through his Heart Care working under the strains of our cur- International to patients in Central rent health care delivery systems. America. These are all described in Outstanding science and compas- articles in this issue of Einstein, articles sionate care are twin themes sure that paint a picture of an Institution to be enunciated at the upcoming that performs outstanding research dedication of the Michael Price across a range of size from the sub- Center for Genetic and Translational cellular, as in the innovative imaging Medicine/Harold and Muriel Block studies of John Condeelis and Robert Research Pavilion (CGTM) later this Singer, to entire communities, as in year. The new building will house Dr. Smoller’s Hispanic Community investigators recently recruited to Health Study. Einstein in diabetes, human genetics, Reading these articles, one can’t chemical biology, infectious disease, help but be struck by the unique and the other areas targeted in qualities they reveal of Einstein as a our Strategic Research Plan. A new biomedical research and education Institute for Stem Cell Research and institution: the truly collaborative Regenerative Medicine as well as a spirit of our investigators, typified by new Department of Computational the highly interdisciplinary Einstein and Systems Biology will also find Proteomics Project; a commitment, homes in the CGTM. The research to not only to the science of medicine, be performed there has enormous but to the compassion and humanism implications for human health and without which medicine becomes will surely be the subject of exciting only a mechanical exercise. At articles in future issues of Einstein. Einstein, it isn’t enough to be a world- class surgeon such as Rob Michler. His technical expertise is matched by his dedication to improving the health of less fortunate people in underdevel- oped parts of the world. The PDC course strives to instill the Allen M. Spiegel, M.D. qualities of compassion and human- The Marilyn and Stanley M. Katz Dean

Einstein I winter 2008 winter 2008 I Einstein EDGE: Today's Science ... Tomorrow's Medicine Let’s instein

E Get he T small Nanotechnology: the next big thing in medical research

omedian Steve Martin once entertained audiences with an absurdist routine about giving up hard Cdrugs in favor of a substance whose only effect was to make users small. It was all fun and games, he joked, until some tall people came over or you were reck- less enough to get small while driving. Three decades later, researchers at Einstein are doing Mr. Martin’s “Let’s Get Small” shtick one better. They’re getting really small. It’s not for kicks, of course, but to observe and manipulate biological processes at the nanometer level — the scale of molecules and structures inside cells.

Thanks to a convergence of tech- organs, or whole bodies with a host of nologies—genetic and biochemical unwanted side effects. engineering, supercomputing, “In the future, you are not going advanced microscopy, and micro- to pump drugs into people’s veins chip manufacturing—researchers from a bottle hanging on an IV rack— are gaining unprecedented access that’s a century-old technology,” says to the cellular universe, with far- one of Einstein’s nanotech pioneers, reaching consequences for bio- John Condeelis, Ph.D., professor and medical science and, ultimately, co-chair of Anatomy & Structural for patient care. Biology and co-director, with Robert It is now possible, for example, to Singer, Ph.D., of the Gruss Lipper build cancer detection devices so Biophotonics Center. “Ultimately, we small that a dozen could fit on the are going to develop some kind of Nanobots—robots built on the nano- head of a pin, or to turn on a single way of handling drugs at the cellular meter scale—may one day be used gene in a single cell and watch that and subcellular level, where they therapeutically. This illustration snippet of DNA do its work. Both of have to do their business.” shows a hypothetical nanobot trav- these nanotechnologies are now eling with red cells in the blood. under development at Einstein. How small is small? Nanotechnology may well be Nanotechnology is usually defined as the platform that launches the the manipulation of matter from 1 to era of molecular therapy, in which 100 nanometers (nm) in size—a scale treatments are based on an under- that is meaningless in everyday life. (A standing of what is happening at the nanometer is one billionth of a meter.) cellular level and applied directly to For perspective, a grain of salt is a individual cells rather than admin- 300,000 nm in length while a human istered in broad strokes to tissues, hair is about 100,000 nm wide. Most

Einstein I winter 2008 winter 2008 I Einstein Diagram of a first-generation How small is small? It's all relative. NANIVID (nano intravital device) 3000µm Cover that Dr. Condeelis and his colleagues are designing for use Scored in human tissue. The NANIVID’s Diaphragm individual components are 100µm nanoscale structures. Electrode Contacts

Inlet 1 cm 10-2 m the National Cancer Institute, the 10 mm Array of Electrodes Sponge two scientists have begun building a microchip version of the artificial blood vessel, called a NANIVID, which is short for nano intravital device. 1,000,000 nanometers= 10-3 m An expert in micro-electro- 1 millimeter (mm) everything less than a hair’s breadth is tissue of mice with genetically engi- mechanical systems—which combine invisible to the naked eye. Below that neered tumors. Some 90 minutes later, mechanical elements, sensors, lies the microscopic world, but even a line of tumor cells could be seen actuators, and electronics on a Leonard P. © Andrew Leonard P. © Andrew the best optical microscopes cannot wending its way toward the catheter. silicon wafer—Dr. Castracane was Deer Tick Human hair discern objects less than 200 nm (a With this rudimentary device, the well versed in cramming a lot of stuff Length = 2mm 10-4 m 0.1 mm Width = 100µm 100 µm limitation tied to the wavelength of team could predict whether breast into tiny packages. But this particular visible light). For Dr. Condeelis, that’s cancer cells had the potential to microchip presented unusual chal- where things start to get interesting. metastasize. lenges. First, the basic materials had A few years ago, Dr. Condeelis and Dr. Condeelis realized that he had to be biocompatible. “You have to

orld his colleagues in Einstein’s Analytical the blueprint for a potentially power- prepare these chips so that the cells -5 0.01 mm 10 m Imaging Facility devised a way to ful research and diagnostic tool. At are happy to be around them,” Dr. 10 µm capture the first high-resolution, three- the very least, such a tool could be Castracane explains. The CNSE team

Microw dimensional images of individual useful for learning more about the also had to create nanosponges that tumor cells inside a living animal micro-environment of tumors. In addi- could control release of the “biomo- (see YU Review, Summer 2003). Their tion, it might also prove valuable for lecular bait” (for attracting tumor cells 10-6 m 1,000 nanometers= novel technique is known as intravital early detection of breast cancer well and their associated helper cells) and 1 micrometer (µm) imaging—an amalgam of genetic before clinical signs such as lumps to design hardware and software for Leonard P. © Andrew Leonard P. © Andrew engineering, advanced microscopy, arise, or for monitoring the progres- tiny sensors that could detect and Grain of pollen Bacteria and computer-controlled image pro- sion of cancer in patients with breast discriminate among different tumor Width = 20µm Width = 1µm cessing. It allowed the team to open tumors, alerting doctors to the need cell types by virtue of their unique 10-7 m 0.1 mm a new window on how breast tumor for more aggressive therapy. electrical signatures. 100 µm cells metastasize. But first, the tool would have to Devising a practical method of “We found that the cells move be miniaturized to the point where it retrieving data from the device posed from the primary tumor mass across could be easily inserted into a mam- yet another challenge. In the first- vast expanses of normal tissue— mary gland. It would also have to be generation NANIVID, tiny wires will be

orld hundreds of cell diameters in length outfitted with reservoirs for holding used to get information from the chip. 10-8 m 0.01 mm 10 µm —traveling along a superhighway the growth factors and releasing “But eventually, we are going to of collagen fibers,” he explains. A them in a controlled fashion, sensors develop a way to access the device

Nanow determined bunch, these tumor cells for detecting and identifying cells, a remotely,” perhaps using a tiny radio- make a headlong dash for blood ves- transmitter for reporting results, and a frequency transmitter, like that used in sels, which they locate by sensing a port for retrieving cells for further study an EZ Pass, says Dr. Castracane. -9 10 m 1 nanometer (nm) gradient of growth factors, insidiously —quite a small order, as it were. Einstein’s researchers hope to DNA molecule Nanoprobe exploiting the infrastructure laid for “That’s where nanotechnology begin evaluating the chip in labora- Width = 2nm Width = 50nm the normal development and mainte- comes in,” says Dr. Condeelis. tory animals this year. If all goes well, nance of breast tissue. the NANIVID may help answer a host To test whether they had identified The Albany connection of questions about breast cancer, 10-10 m 0.1 nm the critical ingredients needed for the For help in getting really small, for example: What types of cells tumor cells to spread, the team con- Dr. Condeelis turned to James are involved in each stage of the structed an artificial blood vessel Castracane, Ph.D., professor and disease? Why do certain patients (a small catheter filled with growth head of the Nanobiosciences respond to chemotherapy while factors and other substances), which Constellation at the College of others do not? How do tumor cells was then placed inside the breast Nanoscale Science and Engineering (CNSE), University at Albany-SUNY, the first college of its kind. Funded by a five-year, $2 million grant from

Einstein I winter 2008 winter 2008 I Einstein Observing nanoscale phenomena: By attaching fluorescent tags toR NA It’s not exactly riveting viewing— polymerase II (the enzyme responsible for transcription), Dr. Singer until you realize you’re actually watching observed the stages of transcription in vivo and in real time. At left is a gene, life’s fundamental a fluorescently labeled cell with the locus of transcription in yellow. biological unit, do its magic. Messenger RNA is green and the translated protein product is blue. “

for patient care. The inability to see “Capturing these images Single-cell gene-expression profil- nostic test based on this discovery is beyond averages is perhaps the becomes a bioinformatics problem,” ing may provide some clarity. With now being developed for a clinical greatest barrier to understanding the says Dr. Singer, whose studies are Jeffrey Levsky, an M.D.-Ph.D. student trial at Montefiore Medical Center in inner lives of cells and, by extension, funded, in part, by the National at Einstein, Dr. Singer developed a collaboration with another M.D.-Ph.D. to designing therapies that work at Nanotechnology Initiative, a program way to view the expression of as student, Saumil Ghandi. the molecular and cellular level. of the National Institutes of Health. many as 11 different genes in a cell at ” It appears that this barrier has “Each image is 1,000 by 1,000 pixels once, allowing for an unprecedented Stay tuned been surmounted. Dr. Singer and his — that’s a million points of data for glimpse at a cell’s true nature. It’s all too easy to overstate the colleagues at Einstein, in a remark- every image that you take. You can This process was subsequently promise of new biomedical technolo- able feat of nano-engineering, have take 1,000 images a second, so imag- applied to prostate cancer cells, gies. Gene therapy, which has thus crafted a way to trigger the expres- ine the data buildup that occurs.” focusing on five genes that have far failed to live up to expectations, sion of a single gene and observe its This trove of data must then be run been implicated in the disease. is a case in point. Nonetheless, Dr. function in a living cell, a longtime through special computer algorithms Studies revealed that prostate can- Condeelis is convinced that nano- dream of molecular biologists. in order to sort out the subtle, glacially cers of different aggressiveness have technology will make a huge differ- The technique, known as single-cell slow movements of the tagged mol- distinct gene-expression signatures, ence in biomedical research and gene-expression profiling, begins with ecules from the background noise. forming the basis for a diagnostic health care. “It’s like saying, 150 years the transcription factor for the gene The resultant video, pieced test now under development at ago, that chemistry is going to be become resistant to drug therapy? The inner lives of cells under study. (A transcription factor together from the thousands of still Aureon Laboratories of Yonkers, N.Y., important in drug development,” he The research may also point the way “Every cell is doing something is a protein that attaches to and images, is a murky soup of moving a company Dr. Singer helped found. says. “At the time, everybody knew to new strategies for drug design and unique—expressing a combination activates a gene.) Using a trick of smudges dappled with small dots of In practice, such a test could be used it, though they may not have been help clinicians assess whether a par- of genes that is different from other biochemistry, the transcription factor bright color. It’s not exactly riveting to characterize individual cells in the able to give any examples. That is ticular therapy is working. cells,” says Robert Singer, Ph.D., is put under lock and key by binding viewing—until you realize that you’re prostate and determine whether where nanotechnology is today. We As configured, the NANIVID would professor of Cell Biology and co-chair it to a so-called caging group. The actually watching a gene, life’s enough cells have clicked into a know it’s going to be important, and be applicable only to breast cancer. of Anatomy & Structural Biology. The bond is engineered to be photo- fundamental biological unit, do pattern of expression that is cause for I can already give you a thousand “The basic principle might also work possible number of gene-expression cleavable, so that it can be broken its magic. worry. This level of specificity cannot examples of where it’s heading. So, in other cancers that spread through combinations runs into the millions, by a nano-sized sliver of light. In this be attained with other gene-expres- stay tuned.” the bloodstream,” says Dr. Condeelis. making for a lot of cellular diversity, way, the researcher can activate a Applications to cancer sion technologies, such as DNA micro- Dr. Singer is similarly enthusiastic: “But first, we would have to gain even within a highly specific type single gene in a single cell with the flip Still in its infancy, single-cell gene- arrays, which measure the average “The next generation is going to look more knowledge of the cell types of tissue. of a switch. expression profiling is already affect- expression of genes across a large back at our current treatments, like and growth factors involved in But the subtleties of gene expres- The next step is to make the gene ing biomedical research. Dr. Singer is number of cells. chemotherapy, the way like we look those cancers.” sion—the conversion of DNA code visible, which is accomplished by tag- currently adapting the technique to His lab is also applying the tech- at 19th-century practices like studying The Condeelis-Castracane col- into messenger RNA (mRNA) and then ging it with a fluorescent protein that devise a tool for diagnosing the sever- nique to colon cancer. “There is bumps on the head and bleeding laboration marks the beginning of into a protein—are lost on research- lights up when the gene becomes ity of prostate cancer. only one drug, 5-fluorouracil, that is people. Medicine is going to be a formal alliance between Einstein ers. Because of technological limita- active. The corresponding mRNA Presently, it is hard to tell whether effective against colon cancer,” says completely different when we and CNSE to advance education tions, researchers know only the state and the protein that it produces can prostate cancer that is confined to Dr. Singer. “The problem is that only understand what is going on at the and research in nanobiotechnology of an average cell, gleaned from also be made to glow, in different the gland is relatively harmless (as is 30 percent of patients respond to this molecular level.” and its application to health care analyses of the large masses of cells colors, allowing their movements to usually the case) or highly aggressive. chemotherapy, and we have no idea Evidently, Steve Martin was onto (nanomedicine). The programs that are needed to obtain measur- be followed throughout the cell. As a consequence, physicians and who they will be.” As a result, count- something. But getting small is much will focus on six areas: developing able thresholds of biologic molecules. All of this happens at the nano patients are hard pressed to choose less patients are needlessly subjected more than fun and games—it may the nanoscale knowledge base for “Basically, you grind up millions of level and thus is invisible to the naked between conservative treatment, to chemotherapy, dramatically well be the future of medicine. E disease identification, therapy design cells and get an ensemble measure- eye. To view these colorful molecules, (“watchful waiting” which carries with affecting their quality of life and wast- and evaluation, clinical implementa- ment of a huge series of events all the researchers must employ ultra- it the risk that the cancer will spread) ing valuable time for trying second- tion, drug discovery and delivery, homogenized together—all the things sensitive cameras, high-powered and invasive therapies such as surgery and third-line treatments. toxicology detection and cure, and that are going on in all the cells, seen computers and a special microscope (which can involve side effects such Using single-cell gene-expression medical devices and components as an average. But you don’t know known as the intravital imaging as incontinence and impotence). profiling, Rossanna Pezo, an M.D- demonstration and deployment. what an individual cell is doing,” says microscope—the same one that Dr. Ph.D. student in Dr. Singer’s lab, was Dr. Singer. Condeelis uses in his research. able to identify a gene-expression While this may seem like an eso- pattern unique to colon cancer cells teric point, it has enormous implica- that respond to 5-fluoruracil. A diag- tions for biomedical research and

Einstein I winter 2008 winter 2008 I Einstein EDGE: Today's Science ... Tomorrow's Medicine George Orr Remembered I remember once, while talking about lab problems and how to resolve them,

instein he turned his chair completely around

E to face me and said, ‘All I ever want is for everybody to be happy.’” he Dr. Susan Band Horwitz also has T fond memories of Dr. Orr. “George and PROTEOMICS: I published more than 25 papers and reviews together and wrote numer- Power to the Proteins ous grants with never a harsh word between us,” she recalls. “He was a compassionate and kind human being, everal years ago, three that make life possible: They provide he researchers in the Einstein a fine teacher and a superb scientist— structural and skeletal support for all Einstein researchers Biodefense Proteomics Research creative, thoughtful and hard working. organisms, the enzymes that regulate T Center all agree that the center George found science exciting and envisioned a research cellular processes and the compo- S would not exist without the leader- invigorating, and his enthusiasm was nents of cell-signaling pathways that, project for accomplishing ship of Dr. George Orr, who died in contagious. His willingness to challenge when deranged, can lead to cancer. something novel and poten- 2005 at age 57. his colleagues with tough questions The NIAID expressed interest in “George was really the driving made all of us better scientists.” tially lifesaving: analyze the the Einstein White Paper. Then came force,” says Ruth Hogue Angeletti, The Einstein Biodefense Proteomics 9/11—followed a few months later by proteins of protozoan para- a close collaborator with Dr. Orr in Center “was really the culmination of the anthrax-in-the-mail incidents that protein research and the center’s what George wanted to do and would sites as a way to identify killed five people—and the federal co-principal investigator. “He had have allowed him to accomplish so potential targets for drug or focus on biodefense research intensi- the idea for the project, put together many things scientifically,” says Dr. fied. In 2003, the NIAID announced this multidisciplinary team of Einstein Louis Weiss, the proteomic center’s vaccine therapy. plans to award five to 10 contracts researchers and took the lead in writ- other co-principal investigator. “I have to create Biodefense Proteomics ing up the grant application.” no doubt that George would have The researchers—the late George Orr, Research Centers. The key goals of “Almost every morning, George developed many new and interesting professor of molecular pharmacology; the new research program—“to char- and I would talk about proteins, technologies tailored specifically to this Ruth Hogue Angeletti, professor of acterize proteomes of pathogens either in his office or mine,” Dr. biodefense project—and would have developmental & molecular biology and/or host cells [and] to identify Angeletti recalls. “We’d plan experi- had a lot of fun doing so. We’re doing and of biochemistry; and Louis Weiss, proteins associated with the biology ments, some of which he had thought some of the same sorts of things in his professor of medicine (infectious of the microbes”—closely matched up the previous night while smoking absence. But George—with his great diseases) and pathology—submitted the aims expressed by the Einstein his pipe on his back porch. We would energy, deep thinking, tremendous pro- their idea as a white paper early researchers in their white paper. go over good data from recent days ductivity and careful analysis—is really in 2001 to the National Institute of The NIAID listed some 120 organ- or try to interpret unexpected results. irreplaceable.”

Allergy and Infectious Diseases. isms as candidates and grouped Paul Leonard © Andrew Their proposal would involve pro- them into three categories— Photomicroscopist Andrew P. Leonard teomics—the study of the proteins A, B and C (see page 17 for list of took these pictures of the two expressed in a given cell, tissue or selected organisms). Coincidentally, parasites under study at the Einstein “Instead, all the laboratories involved The two parasites under study at a three-dimensional network of organism so as to identify them the Category B organisms included proteomics center. At left are two in our contract are located right here Einstein—Cryptosporidium parvum microtubules and filaments known and determine their structure and Cryptosporidium parvum and C. parvum cysts. At right, invading at Einstein. This reflects the fact that and Toxoplasma gondii—belong to as the cytoskeletal scaffold. Located how they interact with each other. Toxoplasma gondii—the two water- a human fibroblast, is aT. gondii we had all the necessary expertise— the ancient phylum Apicomplexa. beneath the cell’s outer membrane, The entire complement of proteins borne intracellular parasites that the tachyzoite (in purple), the life stage in terms of biology, proteomics and This phylum contains numerous pro- this dynamic internal membrane expressed in a given cell, tissue or Einstein researchers had proposed that causes disease in humans. Both bioinformatics—within our own walls.” tozoan pathogens, the most famous structure contains proteins that organism is known as its proteome. for study in their White Paper. And images were taken using a field The Einstein Proteomics Center of which is Plasmodium, the parasite maintain cell shape, anchor internal For the last decade, the spotlight furthermore, Einstein was ideally posi- scanning electron microscope. exemplifies a rapidly growing trend that causes malaria. structures and—thanks to actin and has shone on genomics—the study tioned for the collaborative effort that in biomedical research in the United C. parvum and T. gondii have both myosin fibers—gives Apicomplexan of the structure and function of a proteomics center would require. States: interdisciplinary programs that been implicated in waterborne dis- organisms their ability to glide. Both all the genes in an organism. Its “In preparing our proposal for the In 2004, the NIAID announced that marry biology with hard sciences such ease outbreaks caused when people waterborne parasites are discussed in centerpiece has been the Human NIAID, it was very easy to put our contracts were being awarded to as physics, engineering, mathemat- swallow their oocysts—the resting, more detail in the sidebars on pages Genome Project, the effort to map research team together,” recalls Dr. Einstein and six other biodefense pro- ics and computer technology. Such egg-like stage that is highly resistant 13 and 14. the sequence of nucleotides in every Angeletti, the center’s co-principal teomics research centers. Einstein’s programs mark a shift in focus from to chlorination and other water disin- The Einstein researchers won’t single human gene. But this emphasis investigator. “We were in the same contract: an impressive $10.9 million individual genes and molecules to a fection techniques. The two parasites attempt to identify the entire on genes tends to obscure the real building complex—all within a couple for five years. Among all the chosen “systems biology” that encompasses can contaminate water supplies with proteomes of the two parasites, esti- payoff from studying them. of hundred yards of each other—we proteomics centers, Einstein enjoyed entire organisms and their interacting relative ease, and better treatments mated to number 4,000 proteins in C. Deciphering genomes—of knew one another and we’d all col- a unique, and noteworthy, distinction. networks of genes, proteins, cells and are needed for the infections they parvum and 6,000 in T. gondii. Instead humans and other organisms—is laborated in the past. Plus, Einstein “We are the only proteomics cen- tissues. A key goal of the Einstein pro- cause—the major reasons that both they’re focusing on three “subpro- useful mainly for helping scientists has a special strength in infectious ter that does not involve a consortium teomics center, for example, is iden- are considered potential biological teomes” that are thought to contain understand the proteins that genes diseases. So these were our major of several different institutions,” Dr. tifying important protein interactions weapons. proteins crucial to parasite survival encode. While genes make proteins strengths in competing for one of Orr noted in the summer of 2004, that could be interrupted by drugs C. parvum and T. gondii share the and might therefore offer good tar- possible, proteins do all the things those NIAID contracts.” shortly after the contract took effect. or vaccines. defining feature of all Apicomplexa: gets for drugs or vaccines:

10 Einstein I winter 2008 winter 2008 I Einstein 11 Asexual Replication

Contamination of food and water

Sexual Oocyst Reproduction Meiosis Discovering Protein Interactions Life Cycle

arasite proteins that interact that existed among proteins in vivo. combinations for that parasite. Once Harris Illustration: Tatyana Pwith other proteins may be good The protein mixture is chopped into the interacting proteins are identified, candidates for targeted therapies. thousands of peptides, some of which a three-dimensional model of the pro- The Analytical Core Cryptosporidium Parvum To learn which of the dozens or are cross-linked. Analyzing a cross- tein complex can be created (right). Identifying the proteins of these two hundreds of proteins in parasite linked peptide with mass spectrometry This model shows two homodimeric parasite species begins with the work C. parvum was identified a century ago, but not until 1976 was human cells interact to form complexes, yields a spectrum that identifies the (identical) proteins crosslinked at a of the analytical core, headed by cryptosporidiosis first reported. The parasite lives and replicates in the researchers prepare a mixture of linked peptides (left). To find which pro- contact point (red circle). Proteins that Dr. Angeletti. An enzyme such as intestines of warm-blood animals, which excrete the parasite’s infec- proteins derived from T. gondii or C. teins these linked peptides belong to, turn up in many different protein-pro- trypsin is added to the preps to break tious oocysts in their feces. parvum cells and add cross-linking researchers map the peptides against a tein interactions are probably critical the proteins into peptides—short When oocysts are swallowed—either from contaminated drinking chemicals to restore connections library consisting of all possible protein to a parasite’s viability. protein fragments 10 to 20 amino water or food—they rupture, releasing sporozoites that invade intesti- acids long. Then, Dr. Angeletti’s group nal cells. The sporozoites go on to replicate, eventually resulting in the uses mass spectrometry to measure formation of new oocysts. Animals and people infected by swallowing • The oocyst wall proteins. The Einstein are harvested from the calves’ feces media and broken apart under high the mass—specifically the mass-to- C. parvum oocysts can experience acute intestinal distress. proteomics center recently identified and shipped to Einstein. pressure (1,000 pounds per square charge ratio—of the peptides as they Since C. parvum’s tough oocysts are relatively resistant to chlorination, water and characterized all the proteins By contrast, T. gondii is grown in inch). The soluble proteins are then come off a liquid chromatography treatment that includes proper filtration is crucial for keeping oocysts out of drinking comprising C. parvum’s oocyst wall. tissue culture (human fibroblasts) “fractionated”—separated and column. (Whole protein molecules water. Waterborne outbreaks attributable to C. parvum are notable for affecting in Einstein’s proteomics laboratory. grouped by molecular weight. are extremely difficult to analyze in a many thousands of people. Several such outbreaks have been traced to drinking- • Proteins bound to the inner mem- Researchers harvest the tachyzoite Using electron microscopy, mass spectrometer, and measuring water sources contaminated by runoff from feedlots containing infected cattle. brane complex. Lying just beneath stage of the life cycle, which causes researchers examine these fractions, a whole protein’s mass provides only Acute symptoms of cryptosporidiosis include severe diarrhea, nausea and the plasma membrane, this special- disease in humans. or “preps,” to find those containing limited help in identifying it.) abdominal cramps. For most people, these symptoms subside after two or three ized structure contains transport The aims of the Einstein proteomics the three proteomes of interest— By revealing the mass of a peptide, weeks. But in people with weakened immune systems such as the elderly or AIDS proteins, proteins that are crucial for project are to identify parasite pro- oocyst wall, cytoskeleton and internal mass spectrometry helps researchers patients, infection with C. parvum can cause prolonged diarrhea and dehydration motility and proteins crucial to the teins (i.e., to correlate experimental membrane. (Below is an electron determine how many amino acids that can be fatal. parasites’ ability to invade host cells. data with the protein predictions micrograph showing a T. gondii prep; comprise that peptide and which The largest known C. parvum outbreak occurred in 1993, when a breakdown in derived from the parasites’ genomes) the arrows point to microtubules in particular amino acids are present. In a Milwaukee water filtration plant resulted in 400,000 cryptosporidiosis cases and • Proteins of the cytoskeletal scaffold. and to characterize them—determine the cytoskeleton.) The proteins are addition, mass spectrometry can be contributed to the deaths of more than 50 AIDS and chemotherapy patients. Largely In addition to actin and myosin, the their amino-acid sequences, their further processed in different ways, used to reveal the sequence of the to prevent similar C. parvum outbreaks in New York, the city is building a $2.1 bil- cytoskeletal scaffold contains tubulin functions, whether they are modified depending on whether they’re amino acids in the peptide. lion filtration plant in Van Cortlandt Park in the Bronx to filter water from the Croton proteins and signaling/regulatory after their initial formation (so-called intended for the project’s target watershed system, which provides New York with 10 percent of its drinking water. complexes including kinases and posttranslational modifications), how validation core or its analytical core. The Bioinformatics Core When its genome was sequenced in 2004, C. parvum was described as “a rela- phosphatases. crucial they are to parasite viability, Following mass spectrometry, parasite tively pared-down organism” with only nine million DNA base pairs and eight chro- how they compare with proteins in proteins reduced to tens of thousands mosomes. (By contrast, humans have 3.2 billion base pairs on 23 pairs of chromo- Harvesting and other parasites and humans, and how of peptides of known size or mass somes.) Given this paucity of base pairs, it’s not surprising that noncoding, or “junk,” Fracturing Parasites they interact with each other. (See must now be reconstructed with the DNA is virtually absent in C. parvum—less than one percent of the total—making C. parvum can’t be cultured in vitro, “Protein Interactions” sidebar above.) aid of computers—which is where Dr. genomic and proteomic analysis relatively straightforward. However, researchers but its oocysts can be obtained in Before proteins can be identified Andras Fiser comes in. An associate are unable to continuously culture C. parvum in the laboratory, so it’s not susceptible large amounts from infected ani- and characterized, the parasites must professor in the department of bio- to gene knockouts and other types of genetic manipulation. mals. At the Tufts University School be pulverized so their proteins can be chemistry at Einstein, Dr. Fiser directs C. parvum’s no-frills genome makes it heavily dependent on its host for nutrition of Veterinary Medicine, laboratory- separated. This work is done by the the proteomic center’s bioinformatics and energy—reliance unusual even for a parasite. In contrast to bacteria and most reared, pathogen-free calves are project’s protein separation/develop- core. Bioinformatics (also called com- other protozoan parasites, for example, C. parvum lacks functioning mitochondria, infected by a standard strain of C. ment core, headed by Dr. Weiss. putational biology) uses computer the energy-producing organelles typically found in cells.

parvum, and the resulting oocysts The parasites are placed in liquid L.M. Weiss Photo courtesy of Dr. technology to analyze the kinds of

12 Einstein I winter 2008 winter 2008 I Einstein 13 The challenge for the gene prediction

Contamination of food and water programs is identifying the 10 percent of the full genome that codes for Acute infection actual proteins... Oocyst “ Tacyzoites tides—which, in turn, are used to vali- of previous gene predictions, most the amino acid methionine in all life date the peptides predicted by the involving human and other mam- forms, for example. When scanning L.M. Weiss Photo courtesy of Dr. databases. It’s an effort that requires malian genomes such as the mouse a DNA sequence that may be thou- Above: A host cell nucleus’ repeated cycles—what researchers or monkey. So it’s not surprising that sands of bases long, a gene-predic- view of the invading T. gondii Bradyzoites call “an iterative process.” The task software “trained” to predict human tion algorithm will ideally select the tachyzoite cytoskeleton. (tissue cyst) here is similar to assembling a 10,000- genes and proteins might not do well open reading frame that correctly” piece jigsaw puzzle by constantly on ancient parasites—particularly one determines the amino acid sequence Congenital infection switching your attention between the like T. gondii. encoded by the gene—which is not evolving puzzle and the picture on “This parasite’s 14 chromosomes always easy. As shown in the illustra- Harris Illustration: Tatyana the box, but with the added compli- offer a complex genome that we tion below, starting the reading frame cations of initially having many more believe contains about 6,000 genes, at one base instead of another can Toxoplasma gondii large data sets generated by genom- pieces than are needed to recon- with approximately 88 to 90 percent yield different codons and therefore ics and proteomics research. struct the picture and without seeing of its DNA consisting of non-protein- different amino-acid sequences. T. gondii is one of parasitism‘s great success stories: It can infect Fortunately, the genomes of both T. all the details of the picture. coding regions,” says Dr. Fiser. “The All these difficulties meant that Dr. any warmblooded animal, and it has infected more than half the gondii and C. parvum have recently Predicting proteins from nucleotide challenge for the gene prediction Fiser and his colleagues would first world’s people, including 50 million Americans. Infected people been sequenced and translated sequences is not always straight- programs is identifying the 10 per- have to verify the T. gondii gene pre- carry thousands of the organisms, many of which reside in the into “gene prediction databases,” forward: Many genes can code cent of the full genome that codes dictions before they could validate brain: In contrast to C. parvum, which is content to infect intes- meaning that software programs for more than one protein, and a for actual proteins and to properly T. gondii’s proteins. Their first step tinal cells, T. gondii is skilled at penetrating cells throughout the have transformed the long strings of gene’s protein product can be modi- reconstruct the splicing of all these was to pool the four gene prediction body and crossing the blood-brain barrier. adenines, thymines, guanines and fied before being translated into a coding pieces, and that’s where they databases for T. gondii to obtain all An infection with T. gondii usually feels no worse than a mild cytosines in the parasites’ genomes protein. Fortunately, the effort went make mistakes.” possible genes—a total of 30,000 case of the flu, and the vast majority of infected people experience no serious into genes—and, by extension, into smoothly with C. parvum and its Failing to recognize T. gondii pro- non-redundant predictions. “Since we effects. But T. gondii can cause serious brain damage when a healthy immune the amino acid sequences of the uncomplicated genome (see sidebar teins known to be real was just one of expect to find about 6,000 genes in T. system is lacking—in AIDS patients, the elderly, and fetuses, for example. Also, parasites’ proteins. on page 13). In fact, the proteomics the problems that Dr. Fiser observed. gondii, this meant that some 24,000 of pregnant women who become infected for the first time by T. gondii may pass Dr. Fiser provides the gene predic- center recently completed charac- The more common failure of the these gene predictions would turn out it on to their fetuses, who may experience significant brain damage, particu- tion databases to Dr. Angeletti’s terizing the C. parvum oocyst wall gene-prediction software was in pre- to be incorrect,” says Dr. Fiser. larly if infection occurs early in pregnancy. Each year up to 4,000 children in analytical core, which carries out proteome. But T. gondii proved a dicting the starting and ending posi- The next step was to take advan- the U.S. are diagnosed with congenital toxoplasmosis. computer-generated (“in silico”) pep- more difficult challenge. tions of proteins—a problem inherent tage of the peptides experimentally Members of the cat family are largely responsible for T. gondii’s success. All tide predictions on the databases. For “We used four different gene pre- in the nature of the DNA code itself. derived through mass spectrom- cat species can carry T. gondii in their intestines, where the parasite matures example, the enzyme trypsin—often diction databases for T. gondii, and a The triplet genetic code is etry and use them to differentiate and sexually reproduces to form oocysts. A cat can shed 100 million oocysts in used to break down proteins for mass big surprise for us was the low accu- universal—the DNA nucleotides between real and bogus gene its droppings after a single infection. spectrometry—always forms peptides racy of each in predicting proteins adenine-thymidine-guanine code for predictions. This involved mapping Oocyts can survive in the soil for more than a year. They are responsible by cleaving proteins after lysine or —on the order of 30 percent,” says Dr. for environmentally transmitted T. gondii infections, including: cases in arginine residues. So the analytical Fiser. “About 375 clusters of T. gondii which people are exposed to oocysts by handling infected kitty litter; certain core carries out an in silico trypsin proteins had been experimentally foodborne cases of toxoplasmosis (e.g., when people eat salads or other foods digest on the gene prediction data- derived, and our preliminary results rinsed in contaminated water); and—perhaps most important—waterborne base to obtain predicted peptides had indicated that these clusters outbreaks caused by T. gondii. Swallowed oocysts release sporozoites, which likely to match the ones obtained by could be used to validate about then replicate and ultimately transform into tachyzoites—the life stage that mass spectrometry. 1,500 proteins. But our databases rec- rapidly infects organs throughout the body and causes disease in humans. The two groups of data—the ognized only a small fraction of these The most famous waterborne T. gondii outbreak occurred in Victoria, B.C., experimentally derived peptides and proteins that we knew were real. This in 1995, when heavy rains overwhelmed a municipal water treatment facility’s the peptides predicted by in silico was a sobering experience for all of capacity to filter out oocysts. Some 100 people developed toxoplasmosis, which calculations—are then turned over us—to realize just how far we were was traced to contamination from cougar feces. to Dr. Fiser. His task: to “map” the from understanding the proteome of The second route of human infection is through eating undercooked pork or peptides obtained by mass spec- this organism even though we had a The sequence of DNA bases above can be read in six possible reading other infected meat. T. gondii forms protective cysts in the muscles and other trometry against the gene prediction full genomic sequence in hand.” frames—three in the forward (5' to 3') and three in the reverse (3' to 5') direc- tissues of animals (including humans) that it infects. These cysts contain T. databases so parasite proteins can One reason for the difficulty stems tion. This illustration of the three forward-direction reading frames shows gondii’s bradyozite life stage; when raw or undercooked contaminated meat is be identified and characterized. from the very nature of gene predic- that the same sequence of bases can be interpreted as three entirely different eaten, bradyozites released in the intestine transform into tachyzoites, which Essentially, Dr. Fiser uses the gene tion databases: They are theoretical, amino-acid sequences depending on whether the gene-prediction algorithm spread and replicate in the body. Toxoplasmosis cases in the U.S. are divided prediction databases to validate the result of software calculations starts translating at a, t or g (stop codons=*). equally between those caused by environmental exposure and those from eat- the mass-spectrometry-derived pep- using algorithms refined by thousands (Diagram courtesy of University of Wisconsin–La Crosse.) ing infected meat.

14 Einstein I winter 2008 winter 2008 I Einstein 15 the peptides (which were known to Targeting Proteins looking at full genome microarray that comprise T. gondii’s cytoskeletal NIAID Category A, B & C be “real”) against the gene predic- Then comes the task of winnowing expression patterns,” says Dr. Fiser. scaffolding. Tubulin, of course, is also Priority Pathogens tions and looking for “hits”—instances down all those proteins (2,600 have “By combining our protein interaction found in human cells, where it forms where experimentally derived pep- now been identified in T. gondii) to and gene expression data, we can the spindle fibers that direct the Category A: High priority agents; tides matched up with sections of the achieve the ultimate goal of the pinpoint proteins that are membrane- movement of chromosomes during include organisms that pose a risk to gene prediction database. Einstein biodefense proteomics bound, experimentally validated by cell division. Pioneering research in national security because they The more extensively a predicted project: find those proteins that mass spectrometry, highly interacting the laboratory of Einstein’s Susan Band • can easily be disseminated or gene was covered by hits, the higher might make good drug targets. For and strongly expressed. Targeting Horwitz has shown that the drug Taxol transmitted person-to-person the likelihood that the gene predic- both parasites, that task begins with these proteins may allow us to disrupt inhibits cancer-cell division by target- • cause high mortality, with potential tion was valid. “We need to see comparative genomics: matching all essential protein complexes and ing these tubulin proteins. But T. gondii for major public health impact decent coverage—perhaps 10 or newly identified proteins against the selectively kill the parasite.” tubulin appears to be special. 15 percent of the proteins covered human genome—and eliminating “We have found several different • might cause public panic and by peptide hits that are not overlap- any that resemble human proteins. The Target Validation Core tubulin proteins that are highly modi- social disruption ping—to conclude that a particular “To qualify as a potential drug Once proteins of interest have been fied and seem to localize to specific • require special action for public predicted gene is valid,” says Dr. Fiser. target, a protein will ideally be unique identified through the proteomics areas of the T. gondii cytoskeleton,” health preparedness “We never expected that we’d to that parasite and should certainly collaboration of Drs. Angeletti and Immunofluorescence microscopy of says Dr. Weiss. “They’re very interest- need to validate T. gondii’s gene be very different from any human Fiser, those proteins are further inves- T. gondii tachyzoites performed in ing and probably relate biologically Examples prediction database, and the process proteins,” says Dr. Fiser. That way, if tigated to establish whether they are Dr. Weiss’ laboratory. The tachyzo- to the cytoskeleton’s dynamics and Bacillus anthracis (Anthrax) has been extremely time-consuming,” a drug is developed that targets the indeed good therapeutic targets. ites were labeled with an antiserum specialization as an organelle. These Clostridium botulinum (Botulism) Dr. Fiser notes. “But it represents one protein, it will affect only the parasite These studies are carried out by Dr. made against peptides specific to modified tubulins are possibly unique Yersinia pestis (Plague) of the major achievements of this and not its human host. An extra Weiss, the co-principal investigator of SAG1, a tachyzoite surface antigen to the Apicomplexa—I’m pretty sure Variola major (Smallpox) and project. This is by far the largest-scale benefit would be if the target shows the Einstein biodefense proteomics that localizes to the parasite’s outer we’ll also find them when we look at other pox viruses empirical validation of the predicted a strong similarity to proteins in other project and co-director of its target membrane. C. parvum’s cytoskeleton—and that Ebola virus genome for any organism.” organisms against which a drug has validation core. The core’s other uniqueness would make them poten- (Ebola hemorrhagic fever) Once a predicted gene has been already been developed.” co-director is Dr. Kami Kim, professor tially good therapeutic targets.” validated, it can in turn be used as a Potential key proteins are then in the departments of medicine and in on the cell membrane of T. gondii. Dr. Weiss notes that attacking tubu- Category B: second-highest priority template for the main task at hand: examined to see if they (or the genes microbiology & immunology. Such experiments help to confirm the lins is a tried-and-true strategy. “There agents include those that annotating, or conclusively validat- encoding them) interact with other “Part of our task is to establish that cellular location of specific peptides are lots of successful antiparasitic ing, the T. gondii proteins them- proteins or genes in the parasite. these proteins are located where and proteins. drugs that target tubulins, such as • are moderately easy to disseminate selves. As the hits on the database “We know, for example that these they’re predicted to be in the para- For any protein of interest, the albenazole for treating both Giardia • cause moderate morbidity and accumulate, increasing numbers of parasites have an important inner site,” says Dr. Weiss. He does this by ultimate target-validation strategy is and helminths and mebendazole for low mortality T. gondii proteins are validated and membrane structure that they use to injecting a mixture of its peptide com- to knock out the gene that codes for treating helminths such as pinworm,” • require enhanced disease surveillance identified (matched against the gene invade host cells,” says Dr. Fiser. The ponents into rabbits and obtaining it and observe the effect on the para- he says. “So there’s clearly precedent prediction database). The illustra- goal here is to identify proteins critical antibodies that are then tagged and site. “Ideally, we’ll find that knocking for zeroing in on the cytoskeleton in examples tion below shows a protein that has to this membrane’s structure. added to the parasite to see where out that gene will prove lethal to the general and tubulins in particular as Coxiella burnetii (Q fever) we develop our list of candidates that been partially identified by mapping ”We are analyzing data for more they localize. parasite, and then we know we’ve Rickettsia prowazekii peptides against the gene prediction than one million known protein inter- “These antibody studies show us got an excellent therapeutic target,” may be good protein targets.” (Epidemic typhus) database. actions and, to help narrow our focus, what proteins belong to specific says Dr. Weiss. The responsibility of the Einstein Escherichia coli 0157:H7 structures within the parasites,” says One problem: no technology exists biodefense proteomics center ends (Diarrheagenic E. coli) MYVHLVQQGEALAATPLLATEAERTETQKRAERSQCRNVQEGAGGESRRTLPFSGRAAGRVGFFAGGNASPASRR Dr. Weiss. “Over time we build up for knocking out genes in C. parvum, with identifying targets. “After that, KRQRPGDRGHCRRSREEARHETDKRTAPGFALCGQASSQSHLFSPQLADEATPNEVARRHFKPVLPPVFSSPTGV inventories of proteins belonging to mainly because this parasite can’t it’s up to other researchers to take Vibrio cholerae (Cholera) VTVPCNDTDLVNKQDEVNNAPHVLSAQDQDILASLFPNTINTNFCLLAPASGDRQASSEPLRVGVVLSGGQAAGG critical parasite structures such as the be cultured throughout its entire life our results and design the drugs or West Nile virus HNVICGIFDYVKRVNPASTVFGFLGGPHGVFSHEYVELTEAIIDKYRNMGGFDMIRSGRHKIETDEQKQKSLEIC cytoskeleton or the internal mem- cycle. “What we do here is to heter- vaccines that can eliminate these (West Nile virus encephalitis) EKLQLNGLVVIGGDDSNTNAAILAEYFKSKGSSTSVCGCPKTIDGDLKNRFVEISFGFDTACKTYCQQIGNLMRN AMTGGNTYHFVRLMGRSASLITLECALQTHPNYTFIGEEVMAKKQSLRQLVEALVDLVEARYAKGKQYGVVLLPE brane complex.” ologously express C. parvum genes in parasites as threats to human health,” GLIEFIPEVGVLINEINHIVAAGDFEVSKLTPESRSVFEELPESTRRQLLLDRDPHGNVQVAMIHTEKLLMQMTE To more accurately pinpoint a T. gondii and observe the effect,” says says Dr. Weiss. Category C: Third-highest priority SELQKRGFQGTFLAQSHYLGYEGRSGYPSDFDATYCYGLGNVAGALIQNKVTACMAVLKDMSSSSNPLDWKAAGI protein’s location, an antiserum can Dr. Weiss. Discoveries made by the Einstein agents include emerging pathogens PLTKMMNLETRKGKANVPVIKKFLVDIERPLFQAFAQVRDAMRLEDVYQIPGPMQLNTPTPVLPYTLVGAPSTAS be “affinity purified” so that it contains Alternatively, Dr. Weiss can look proteomics center may also prove that could be engineered for mass LLSSSSPQSLGHSRLEFEPLLNPLLLQKETAVVAGAAAHPGAEACNAHIQALFPALGAEAKDFFGGACKLQKAQK antibodies specific to a single pep- for homologs. “In other words,” says useful against one of the world’s dissemination in the future because of IKEKCAVGVVLVGPERPGYANVLCGLVQRVALLGGTVKGFKGARGLLTNDCVVIGEKEAAAQRNQPGFVLLGRTE REEAELFTKEGMKQAAATLQAAGVAALVMIGGTTLHAAVLSELLASQRQPIRVVCVEPSGDLGRFPAHGALQLLK tide. “The crude rabbit antiserum with Dr. Weiss, “if C. parvum has a gene biggest killers. “We’re badly in need • availability ELTGKDIVVGSPDAKAMCPGISSTFQQLAGCRGLGFDTETKVASEMIANLLTDSNSAAKYFYFCQVSGGLEAECE its mixture of antibodies is poured onto we’re interesting in targeting, is there of more effective drugs against • ease of production and dissemination VGLQTHPNVVLSSQQFKTKTLGEIVTFVADAVKARAALKKNFGVAVINENLFALNKELRDLAVEIHLHFLTHPPQ a column containing the peptide of a closely related version of that gene Plasmodium, which is responsible for PASGVCLALTADEEAALMAALSPASRELFTSLPVTFQHKLIRDIEVHQFPKAILRFPAHELIAAMVAAVLKKEKD interest,” Dr. Weiss explains. “We then in T. gondii? If so, we can study the the more than one million malaria • potential for high morbidity and AGTFSGSFSPLCFEFSDSTERAFQKQDGVSSLGRLHLTGQKKRTQRYWKDVGLGFQTPRLAKESKYVDKKCPFTG wash away everything else and elute effect of knocking out that gene in T. deaths that occur each year,” notes mortality and major health impact NVSIRGRVIKGMVISTKMKRAVVIRRNYLHFVPKYSRFEKRHKNVTCHLSPCFEQVKEGDIVTAGQCRPLSKTIR FNVLKVEKNQVFGNSPQLPESA off only those antibodies that have gondii and extrapolate the findings Dr. Angeletti. “Plasmodium belongs bound to the peptide of interest, to C. parvum.” to the same Apicomplexa family as Examples The identity and sequence of this T gondii protein’s 1,297 amino acids were leaving us with a peptide-specific our two parasites and resembles them Mycobacterium tuberculosis obtained from a gene prediction database. The Einstein researchers com- antiserum. We’ve done that for many Tallying the Targets very closely both genomically and (Multidrug-resistant tuberculosis) pared this prediction with experimental results from mass spectrometry. The of the proteins of interest to us.” After vetting hundreds of proteins this proteomically. So we’re hopeful that Other Rickettsia (Rickettsial diseases) colors signify the different levels of confidence in the validity of these peptide The photomicrograph on page way, the researchers are particularly therapeutic targets we identify in Nipah virus (Nipah virus encephalitis) matches, or “hits.” Red: more than 60% confident; blue: 30% to 60% confident; 17 shows that the antibody made excited about tubulin proteins—the T. gondii and C. parvum may help in Yellow fever virus (Yellow fever) green: less than 30% confident. against the peptide SAG1 has zeroed building blocks of the microtubules defeating malaria as well.” E Influenza viruses (Flu) Rabies virus (Rabies)

16 Einstein I winter 2008 winter 2008 I Einstein 17 Hearts without Borders These children and countless others have all had successful recoveries. The OR is in a state of constant activity, perhaps the busiest pediatric heart surgery program in the world at a given time.

hen infants are diag- allowing the team to move on to the nosed with a serious Dominican Republic. Last year, the heart defect, they are team began shifting its focus to routinely ushered into El Salvador. theW O.R. for surgery. Afterwards, these “As you can imagine with this sort tiny patients can look forward to of work, you never quite leave your long, healthy lives. At least, that’s the prior site. Every year, we still send small scenario in the developed world. In teams to Guatemala City and Santo many countries, however, pediatric Domingo, maybe a dozen people to heart surgery isn’t an option. Children focus on specific operations or other with defective hearts are simply sent needs that the country might have,” home, with little hope for the future. says Dr. Michler, who in 2003 was This dismal picture is beginning awarded the Official Order Heráldica to brighten in a few places, thanks de Cristóbal Colón for his humanitar- to the efforts of Robert E. Michler, ian work in the Dominican Republic M.D., and his generous colleagues by then-President Hipólito Mejía. and benefactors. Dr. Michler holds Heart Care International has had the Samuel I. Belkin Chair at Einstein requests for help from countries in and is professor and chairman of nurses, and hospital administrators Then, we stay for about two to three Asia and Africa but has no immediate cardiothoracic surgery at Einstein and who are willing to engage in this weeks of recovery, in which we transi- plans for long distance expansion. Montefiore Medical Center. sort of intensive onsite training tion the care of these children over to “Perhaps we will expand in time,” In 1994, Dr. Michler and his wife, experience.” the local physicians and nurses.” says its founder. “It’s more logical Sally, founded Heart Care Inter- Since its inception, Heart Care All told, a typical mission trip may for us to concentrate on Central national, a not-for-profit organization International has operated on involve the participation of more than and Latin America, simply because whose two-fold mission is to bring more than 600 children and treated one hundred Heart Care International of its proximity and the fact that pediatric heart surgery to developing hundreds more in Guatemala, the volunteers and the transportation of many members of our team speak countries and to train local health- Dominican Republic, and El Salvador. some 15,000 pounds of supplies and Spanish.” E care professionals to do the work After conducting about 20 four- equipment, including medicines, themselves. to-five-week-long “mission trips,” the echocardiography units, and heart- “We are not a group that will go organization functions with the effi- lung bypass machines. to a country and focus entirely on ciency of an Indy 500 pit crew. Each “It costs about $2,500 per patient, performing procedures and then trip begins with the arrival of a screen- which is extraordinarily low, com- leave,” says Dr. Michler. “We make ing team, which works alongside pared to U.S. standards,” says Dr. a minimum five-year commitment local doctors to select candidates for Michler. Heart Care International to a country. We look for situations surgery. A week later, a second team underwrites all expenses, including in which we know there are doctors, —enough surgeons, anesthesiologists, airfare and lodging for the volunteers, perfusionists, operating room nurses, through donations from individuals critical care nurses, intensive care and corporations. specialists, and respiratory therapists For local clinicians, “the learn- to staff the host hospital 24 hours a ing experience is immeasurable,” day—follows for an intensive round of Dr. Michler says. In Guatemala, the surgery, usually lasting a week. team helped establish a regional We are not a group that “We’ve done as many as 50 to 60 cardiac center in the capitol. After operations in a single visit,” says Dr. five years, it was largely self-sufficient, will go to a country and Michler. “In effect, it becomes the busiest pediatric heart surgery pro- focus entirely on performing gram in the world at that given time. “procedures and then leave... Robert E. Michler, M.D. 18 Einstein I winter 2008 ” winter 2008 I Einstein 19 CELEBRATE!

he American Museum of Natural History’s Hall of Ocean Life was the spec- tacular setting in which TDr. Ruth Gottesman was warmly welcomed as the new Chair of Einstein’s Board of Overseers. The gala celebration was held on October 16th, and more than 500 guests gathered to mark the historic occasion. Dr. Gottesman is the first faculty member to lead Einstein’s Board as well as the first woman to hold the office.

(continued on next page)

20 Einstein I winter 2008 winter 2008 I Einstein 21 Dr. Ruth Gottesman prompting the audience to proclaim, “Hats off to Einstein!”

Since 2003, Dr. Gottesman has served as Vice-Chair of the Board (l to r) YU President Richard Joel, YU Board Chair Morry Weiss, Einstein Chair Emeritus Ira Millstein, of Overseers, where she has had a Board Chair and honoree Ruth Gottesman, Board Vice-Chair Elliot Wolk, and Dean Allen M. Spiegel. particular interest in educational programs and has been a determined advocate for the interests of Einstein In her new role, Dr. Gottesman students. Her advocacy led to the succeeds Ira M. Millstein, who was creation of a Board Student and named Chairman Emeritus. Mr. Educational Affairs Committee, Millstein and Elliot K. Wolk, a Vice- which she chaired. Chair of the Board, co-chaired the Dr. Gottesman received her glittering evening. undergraduate degree from Barnard Dr. Gottesman, Professor Emerita of College and her Ed.D. degree Pediatrics at Einstein, joined the Board from Teachers College, Columbia of Overseers in 2002, after a distin- University. Both institutions have guished 33-year academic career at honored her with the designation the medical school. It began in 1968 of “Distinguished Alumna.” She is a when she joined Einstein’s Children’s member of the Board of Trustees of Evaluation and Rehabilitation Center Teachers College. E (CERC) to develop a program for children with dyslexia and other learning disabilities. She went on to serve as CERC’s Director of Psychoeducational Services and later as Director of the Adult Literacy Program. In 1999, she became Founding Director of The Gala video featured a special guest appearance by investor Warren Buffet. the Fisher Landau Center for the Treatment of Learning Disabilities, Dr. Ruth Gottesman surrounded by her family. a new division of CERC that was established to provide interdisciplinary services to individuals of all ages with learning disabilities.

22 Einstein I winter 2008 winter 2008 I Einstein 23 EDGE: Today's Science ... Tomorrow's Medicine

instein

E p The Compleat Physician

he o

m this. They just take the history, usually a ith an innovative new course, “Patients,

Doctors, and Communities,” the Albert Einstein too fast, and then give their recom- t

m P mendations, usually too fast.”

r College of Medicine has combined a wealth Physicians tend to pay even less

P o i

u attention to health promotion and

r fe o of material about communication, ethics, T H disease prevention, or to population

n s Whumanism, professionalism, population health, and preven-

e n health, Dr. Kuperman adds. “It’s a

u s

v h tion into the third-year clerkships — rounding out the skills disgrace. You never even think about i i m o going to your physician for advice c st

e h needed for effective clinical practice in the 21 century. n i about health maintenance or nutri-

a a tion, for example. These are important

n e a c t n issues that need to be addressed in

l a More than a few patients have a Today, humanism and professional- medical education.”

t i i i

o s story about a physician who is tact- ism is taught in medical schools all

s l

i s less, brusque, insensitive, uncommu- over the country. Yet, many would The Einstein solution

o n m t m nicative, or just plain unprofessional. argue that educators are still doing Einstein was among the first medical h My own tale involves a prominent too little to make practitioners more schools to weave clinical content, n orthopedic surgeon in Manhattan caring and communicative. They’re including the skills of doctoring, whose office wouldn’t or couldn’t certainly not doing enough to coun- into the pre-clinical half of the cur- tell me when he might get around terbalance the pressures that chip riculum, beginning in the early 1970s. to reading my X-rays and MRIs. After away at these desirable traits, such These innovations set the stage for two weeks and several fruitless phone as the bottom-line business mental- Introduction to Clinical Medicine calls, I followed up with a fax. No ity that permeates the health-care (ICM), a two-year-long program that response. Then, in an end-run around system and the prevailing house features intensive training in commu- his staff, I sent the surgeon an email. staff culture that effectively teaches nication skills, plus workshops on eth- Finally, he called back, mainly to fledgling physicians to reduce their ics, culture and spirituality, comple- scold me for my impertinence and workload and discharge patients as mentary and alternative medicine, impatience, letting me know, rather soon as possible, above all else. violence, public health, and other bluntly, that he had sicker and more “Professional behavior has dimin- topics. A mainstay of the preclinical important patients to tend to. When ished,” says Albert S. Kuperman, years since 1988, ICM is taught in par- we finally got around to discussing my Ph.D., associate dean for educational allel with courses in the biomedical case, it was clear that he had listened affairs and witness to five decades sciences, achieving a rough balance to little of what I had said during my of medical practice. “A lot of it has between the arts and the sciences exam. In effect, he had reduced me to do with communication skills. of medicine. to a “shoulder injury” that possibly Communication encompasses and Whether any of these early lessons needed surgery and that would be embraces many aspects of medical in the healing arts are reinforced in squeezed into his busy O.R. schedule education—it is not just history taking, the clinical years is left to chance, at his convenience. or finding out what is wrong and then however. “It’s random,” admits Dr. Apparently, he skipped class the expressing what needs to be done Kuperman. “It depends on the clini- day they taught communication skills to fix it. It is dealing with the patient’s cal sites, the patients, the physicians, in medical school. More likely, his cultural, spiritual and religious beliefs, which differ from student to student. alma mater didn’t teach any formal with the patient’s lifestyle and socio- We hope that at the end of full clerk- classes related to humanism or profes- economic status, with quality of life ship year, they get it all. But they don’t sionalism in medicine back in the day. issues, with the fact that the patient get it all.” For generations, medical educators may already be practicing some As often as not, students leave assumed that the skills of doctoring form of alternative or complementary these lessons in the classroom. were simply too amorphous to be medicine. Many physicians ignore all “The clerkships are viewed as a teachable, or that students would different world,” says Dr. Kuperman, absorb these abilities through osmosis. “In the third year, students are seeing Well, some did and some didn’t.

24 Einstein I winter 2008 winter 2008 I Einstein 25 Einstein was among the first medical schools to weave clinical content, including the skills of doctoring, into the pre-clinical half of “the curriculum...

patients, thinking, ‘Now, I’m doing interpreters, end of life issues, medical making students better people and real doctoring.’ If anything, they errors, and promoting behavioral more about not making them worse. should be enlarging and enriching change in patients. Before class, stu- A driving force behind all this is the the foundations of the doctor-patient dents are asked to prepare by iden- recognition of the toxic effects of the relationship, not forgetting about tifying a patient or clinical situation clinical teaching environment. We all them.” ” from their own clerkship experience know the ways in which our profes- In 2004, at Dr. Kuperman’s behest, that relates to the topic at hand. The sional ideals were chipped away the Division of Education established sessions include a mix of personal and during our third year. We’ve all lived three new committees that were group reflection, didactic instruction, through the adversarial relationship asked to enhance the teaching of and skill practice, often ending with a between the doctor and patient that communication, ethics, humanism, reflective writing exercise. is a part of the house staff culture. ‘I know how to take care of patients. professionalism, population health, To make the most of these sessions, The goal of a busy house officer is to I don’t need somebody to teach and prevention throughout the the PDC team recruited 20 senior fac- get patients out as quickly as possible, me how to be a warm and caring curriculum. ulty from across the clinical spectrum, reduce his or her workload as much doctor.’ She’s learned a lot being a The committees concluded that including generalists as well as subspe- as possible, and buff up the chart— practitioner. You do grow in that role.” “the material has to be taught in clini- cialists—a veritable who’s who of the which is resident-speak for ‘cover Finally, what will happen when cal context, that is, in the third and Einstein faculty. your behind.’” these medical mensches hit the real fourth years,” says Paul Marantz, M.D., PDC was launched in June of last Regulators have cut down on mar- world of clinical practice, which M.P.H., associate dean for clinical year, starting with the Class of 2008. athon shifts for interns and residents provides little time (or reimbursement) research education. In addition, com- in recent years, easing these pres- for this ideal kind of doctoring? “They mittee members felt these teachings For and against sures somewhat. “But you still have are still going out into a dysfunctional should be integrated across courses “There are reasonable arguments the same basic set of motivations,” system,” Dr. Marantz acknowledges. and disciplines, rather than bundled pen, certainly not at the level we had against this change,” admits Dr. contends Dr. Marantz. “And you’ve “That is part of our agenda, to teach into one or two stand-alone courses. envisioned. It could have created Marantz, who was PDC course direc- added to the mix this rather unprofes- about health-care systems and health “We then began to clamor for a major political battle. Much to my tor for its first year. “First of all, we are sional concept of the doctor watch- policy, and to see if we can begin to some time in the curriculum that we relief, it really didn’t. The clerkship an evidence-based culture, and we ing the clock. In my day, if the patient train the doctors who are going to could ‘own,’” says Dr. Marantz. “The directors had to give up about every lack the evidence that the doctors was sick, you stayed until the patient change the system for the better.” reality is, if responsibility for teaching third Friday afternoon over the course we are turning out really are that bad. wasn’t sick. There is a very different the material were left to the various of the year, a good chunk of time. For all the complaining of patients professional inculcation going on if Complaints and plaudits would be more desirous than ever of clerkships, it was not going to hap- I think people realized this was the that doctors don’t listen, the literature you say to that intern or resident that As for students, the reaction to PDC is enhancing and enriching their skills.” right thing to do. Reform of this sort suggests that patients malign doctors among your top priorities is leaving mixed. The last thing the Class of 2008 “There is nothing like a require- was talked about ten years ago but in general but like their own doctor. A on time. And then they go out into wanted to hear was that a whole ment to kill a good idea,” he adds ran into a brick wall. So, times have lot of what is causing dissatisfaction practice, where making money is a new course was being added to the with a hearty laugh. “Seriously, the changed.” among patients, one could argue, is major motivation. All these incentives clerkship year, which, after internship, turnout for extracurricular enrichment After two years of deliberation, the more systemic than it is personal.” are opposed to the basic concept of is probably the hardest 12 months in a activities, such as the student-run curriculum reform team, guided by A stronger argument, in his view, medical professionalism, which is that physician’s career. course on social medicine, is amaz- Drs. Marantz and Steven C. Martin, is that the skills and attitudes that you have to put the patient first.” Not surprisingly, the most coming. Unfortunately, you have to have associate professor of medicine and constitute the compleat doctor Still, there are skeptics who doubt mon complaint is that PDC is too some requirements. I think our stu- of epidemiology and population aren’t teachable. “Can you create a the value of PDC and like-minded demanding. “We worked them too dents do understand that the entire health, unveiled “Patients, Doctors, mensch”—a good, caring, sensitive curriculum reforms. Dr. Marantz hard in the beginning,” Dr. Marantz curriculum cannot be elective, that and Communities,” or PDC, a series of human being—“if the person isn’t comes home to one every night. “I’m admits. “It was a mistake, and we’ve you can’t say, ‘I’m interested in the 20 Friday afternoon sessions stretching already one when they get to medi- married to a doctor who thinks that changed the assignments.” kidney, but the hell with the heart.’ I from the closing months of year two cal school?” Dr. Marantz asks. “This is trying to teach this stuff is ridiculous,” More than a few students have don’t think you would want a doctor to the end of year three. During each what you learn from your mother. We he says. “She’s a doctor in practice, complained that the lessons have like that.” session, students meet in small groups can’t fix this at the stage of medical I’m not. So, she doesn’t want an egg- little value and occasionally cover Mimi McEvoy, MA, CPNP, co-direc- with a single faculty preceptor to dis- school. It’s a reasonable argument, head like me to tell her, ‘You weren’t old ground. “I’m puzzled that they tor of ICM and assistant professor of cuss such topics as the use of medical but it is not a good enough argument trained properly in terms of doctoring are not as accepting,” says Dr. pediatrics, is not that surprised by the for us not to try.” skills.’ She says, and she is quite right, Kuperman. “As students becomes student feedback. “We are attempt- Turning this argument on its head, more experienced, and see patients ing to change the culture of medical Dr. Marantz continues, “It has been in the real world of the clinical education. As educators, we believe humbling to realize that it is less about environment, you would think they (Continued on page 42)

26 Einstein I winter 2008 winter 2008 I Einstein 27 Einstein Academic Convocation Honoring Faculty & Philanthropy

Nir Barzilai, M.D. (l) with Irwin R. Merkatz, M.D. (l) with Ingeborg and Ira Leon Rennert Moise Safra

ast fall, Einstein held a his special interest in the role of the health, and director of the division of potentially lead to new treatments for special academic convo- fungus, Cryptococcus neoformans, in translational genetics, was invested a wide variety of diseases including cation to honor 10 faculty causing disease. as the Sidney L. and Miriam K. Olson cancer and heart disease. Dr. Stanley members who were invested Robert W. Marion, M.D., profes- Chair in Cardiology. Dr. Morrow’s also serves as Associate Director for Lin endowed named professorships sor of pediatrics and of obstetrics & research focuses on genetic defects, Laboratory Research of the Albert made possible by major philanthropic gynecology and women’s health, including one that leads to malforma- Einstein Cancer Center. contributions to the College of and director of Einstein’s Children’s tions of the heart, pharyngeal appa- In addition, eight faculty mem- Medicine. Evaluation and Rehabilitation ratus, palate, and thymus gland. bers who recently were awarded Dean Spiegel and Richard M. Center, was invested as the Ruth L. Jeffrey E. Pessin, Ph.D., professor tenure at the medical school were Joel, President of Yeshiva University, Gottesman Chair in Developmental of medicine and director of the recognized at the convocation. They presided over the convocation cer- Pediatrics. An Einstein graduate, class Diabetes Research Center at Einstein, are: Laurie J. Bauman, Ph.D., professor Eric E. Bouhassira, Ph.D. with Jeffrey E. Pessin, Ph.D. (l) with Ingeborg and Ira Leon Rennert emony. The faculty who were invested of 1979, Dr. Marion is widely renowned was invested as the Judy R. and of pediatrics; Joan W. Berman, Ph.D., President Richard Joel at the event were: as pediatrician to the Aguirre twins, Alfred A. Rosenberg Professorial Chair professor of pathology; Mark E. Girvin, Nir Barzilai, M.D., professor of Clarence and Carl, who were co- in Diabetes Research. medicine and of molecular genet- joined at birth and separated in a Dr. Pessin recently ics, and director of Einstein’s Institute series of landmark operations at joined the Einstein for Aging Research, was invested as Montefiore Medical Center. faculty as Director of the Ingeborg and Ira Leon Rennert Irwin R. Merkatz, M.D., professor the Diabetes Research Chair in Aging Research. Dr. Barzilai and chair of obstetrics & gynecology Center. He is widely has been instrumental in establishing and women’s health, was invested renowned for his the role of genetics in longevity and as the Chella and Moise Safra Chair investigations of insulin discovered the first longevity gene in Obstetrics & Gynecology and regulation of the glu- in humans. The National Institutes of Women’s Health. Since his appoint- cose transport system Health recently awarded him a grant ment as chair of obstetrics and and mechanisms con- Arturo Casadevall, M.D., Ph.D. (l) Bernice E. Morrow, Ph.D. with YU President Richard Joel of $9.25 million to further his study of gynecology in 1981, Dr. Merkatz has tributing to the onset with Dean Allen Spiegel the genetics of aging. been the architect of a marked of diabetes. Eric E. Bouhassira, Ph.D., profes- expansion of the Department’s mis- Liise-Anne Pirofski, sor of medicine and of cell biology, sion, which now more fully addresses M.D., professor of was invested as the Ingeborg and the healthcare needs and issues of medicine and of Ira Leon Rennert Chair in Stem Cell women throughout their lifespan. He microbiology & immu- Biology and Regenerative Medicine. is renowned for his pioneering work in nology, and chief of the division of Ph.D., professor of biochemistry; Dr. Bouhassira began studying human treating preterm labor and has cham- infectious diseases, was invested as Richard B. Lipton, M.D., professor and embryonic stem cells in 2001 and pioned efforts to eliminate disparities the Selma & Dr. Jacque Mitrani Chair vice-chair of neurology and Benson was the organizing force behind the in health outcomes, many of which in Biomedical Research. Dr. Pirofski’s Faculty Scholar in Alzheimer’s disease; three-year, $3-million center grant for continue to exist among women and research has led to new insights into Bernice E. Morrow, Ph.D., professor of human embryonic stem cell research newborn infants in the Bronx. the immune response to microbes molecular genetics and of obstetrics Robert W. Marion, M.D. with that Einstein received from the Federal Robert E. Michler M.D., professor that cause meningitis and pneumo- & gynecology and women’s health, Pamela Stanley, Ph.D. with Ruth L. Gottesman and government in 2005. and chair of cardiothoracic surgery, nia. Dr. Pirofski is an Einstein graduate, as well as Olson Chair in Cardiology; President Richard Joel President Richard Joel Arturo Casadevall, M.D., Ph.D., was invested as the Samuel Belkin class of 1982, and has been a mem- Jeffrey Pessin, Ph.D., professor of professor and chair of microbiol- Professorial Chair. Dr. Michler is co- ber of the medical school’s faculty medicine, director of the Diabetes ogy & immunology, and professor director of the Montefiore-Einstein since 1988. Research Center and Rosenberg of medicine, was invested as the Heart Center. The Center was Pamela Stanley, Ph.D., profes- Professorial Chair in Diabetes Leo and Julia Forchheimer Chair recently named one of just seven sor of cell biology, was invested Research; Gary J. Schwartz, Ph.D., in Microbiology & Immunology. Dr. cardiothoracic research facilities in as the Horace W. Goldsmith Chair. professor of medicine and of neu- Casadevall has developed an innova- the U.S. and Canada to take part in Renowned for her pioneering roscience; and Elizabeth A. Walker, tive approach to treating melanoma a collaborative network conducting research in the glycosciences. Dr. Ph.D., professor of medicine and of that is currently in clinical trials. His studies to improve technologies used Stanley’s studies have played an epidemiology and population health, research may also reshape scientific in treating cardiovascular disease. important role in advancing this as well as director of the Prevention thinking about energy sources in Bernice E. Morrow, Ph.D., professor promising new scientific discipline, and Control Division of the Diabetes Robert E. Michler, M.D. (r) our universe. At the core of these of molecular genetics and of obstet- which involves the study of biological Research and Training Center. E Lisse-Anne Pirofsky, M.D. with Dean Allen Spiegel seemingly varied areas of study is rics & gynecology and women’s sugar polymers. This research could with Dean Allen Spiegel

28 Einstein I winter 2008 winter 2008 I Einstein 29 EDGE: Today's Science ... Tomorrow's Medicine If we cured cancer, on average we would add just one

instein year to the life span ... But if we found pathways E that protect people from all age-related diseases, he T “ we could add decades to our lives ... hat is the secret to Despite these tantalizing findings, a long, healthy life? Dr. Barzilai notes that “the connection An answer of sorts between lipoprotein size and disease can be found in two is still murky.” Evidence suggests that Wphotographs published in the April larger LDLs are less able to cling to To Life! 2006 issue of PLoS Biology, a research blood vessel walls, which translates A tiny fraction of people live—and live well—to journal. The black and white photo on into less buildup of arterial plaque, the the next page, circa 1910, shows four precursor of heart disease” and stroke. the age of 100. A multidisciplinary team of researchers siblings, ranging in age from about As for bigger HDLs, they may carry at Einstein is delving into the genetic and physiological six months to nine years, charmingly more cholesterol out of the blood components of extreme longevity, with the goal of devising posed around a now-antique baby vessels and into the liver for excretion carriage. Ninety-five years later, all from the body. new therapies to evade or delay life-threatening diseases. If four siblings—each looking remark- Next, Dr. Barzilai and his colleagues they are successful, the rest of us might one day approach ably chipper—gathered to recreate traced the genesis of the oversized that rare triple-digit milestone and enjoy the long journey. this family portrait. Revealingly, none particles to a variant form of the gene of the siblings has led a particularly that makes cholesterol ester transfer- healthy lifestyle. In fact, the sister (left) Siblings, circa 1910, and (right), 95 years later, participants in Einstein’s ase protein, CETP, which is involved in (color photo, far left), pictured here Longevity Genes Project. the regulation of lipoproteins. He has at age 104, had been a smoker most since discovered two more potential of her life, reluctantly giving up the Molecular Genetics. Dr. Barzilai did quality of those years. The impact on “longevity” genes: a variant of the habit after she turned 100. (She not set out to be a latter-day Ponce society in terms of decreased health gene coding for apoliprotein C-3 still keeps a pack in her desk, just de Leon, the Spanish explorer who care costs, personal well-being and (which is thought to slow the break- in case). wandered the Caribbean 500 years many other positive benefits would down of trigylcerides) and a variant If ever there were evidence that ago in search of a rejuvenating be incalculable.” of the gene for adiponectin (which exceptional longevity resides in the spring. An endocrinologist by training, seems to play a role in improving genes, this is it. Dr. Barzilai began his research career Longevity genes insulin action and decreasing blood Of course, two photos do not a studying the metabolic pathways that To learn more about longevity, Dr. vessel inflammation). scientific proof make. But a growing lead to diabetes, a leading cause Barzilai turned to the most logical number of studies do suggest that of disability and premature death. resource: centenarians. He began Whither Social Security? centenarians—roughly one out of Over time, he realized he could have by searching their blood for unusual Dr. Barzilai’s studies raised the excit- every 10,000 individuals—owe their a greater impact on overall human characteristics. Almost immediately, ing possibility that human life could long lives primarily to quirks in their health by studying the fundamental he discovered that super-seniors be extended with drugs that mimic DNA and not to being vegetarians, processes of aging rather than a spe- did not necessarily have favorable the action of these anti-aging genes yogurt eaters, teetotalers, marathon- cific disease like diabetes. levels of high-density and low-density and metabolic pathways. A wave ers, or eternal optimists. Indeed, some “If we cured cancer, on average lipoprotein particles (HDLs and LDLs), of press coverage followed, with centenarians are downright gluttons we would add just one year to the the body’s “good” and “bad” choles- stories in The New York Times and on or sloths and yet are “immune” to the life span,” says Dr. Barzilai, explaining terol. What they did have was abnor- CNN, NOVA, and the BBC. (Today, a myriad diseases that send others to his evolution as a researcher. “If we mally large lipoproteins—comparable Google search for “longevity genes” an early grave. cured heart disease, it would add to those of young, healthy, and vigor- brings up more than 1.7 million hits.) The first of these DNA quirks was another two years, and so on. But if ously athletic men and women, as he The media attention was under- discovered in 2003 by Nir Barzilai, we found pathways that could pro- reported in 2003 the Journal of the standable if perhaps premature. M.D., who is the director of Einstein’s tect people from all age-related dis- American Medical Association. As Dr. Barzilai points out, his studies Institute for Aging Research, the eases, then we could add decades Further analysis revealed that have demonstrated only an associa- Ingeborg and Ira Leon Rennert pro- to our lives and also increase the individuals with outsized lipoprotein tion between longevity genes and fessor of Aging Research at Einstein, molecules tend to have a lower inci- and professor of Medicine and of dence of heart disease, hypertension, and diabetes. And centenarians with good cognitive function were nearly three-fold more likely to have outsized lipoprotein molecules compared with centenarians with poor cognition.

30 Einstein I winter 2008 winter 2008 I Einstein 31 ...the length of our days will be enhanced by good physical and mental functioning. This is the reason“ we search for longevity genes.

for my research grants. But since the research has shown that the offspring “Centenarians live longer because goal of our work is to keep people of centenarians are healthier than they tend not to get illnesses like can- healthy, having older people feeling their control peers—and more likely to cer and heart disease, or else they well enough to work longer might possess longevity genes. develop these diseases far later in actually help to curb Social Security All told, the four longevity stud- life,” Dr. Barzilai explains. “When they payouts.” ies at Einstein’s Institute for Aging eventually do get sick, it is with a ter- ” Fortunately, another part of Research occupy 17 co-investigators, minal illness. With their very advanced government—the NIH—is highly sup- primarily from Einstein, with expertise age, illness rapidly overtakes them, portive of Dr. Barzilai’s research. In in gerontology, endocrinology, neu- and the end of life comes relatively August of 2007, the National Institutes rology, genetics, statistical genetics, quickly. This so-called compression of

of Health (NIH) awarded Dr. Barzilai advanced statistical analysis, bioin- morbidity translates into lower use of © Veer and his colleagues a five-year, formatics, nutrition, and metabolism. health care resources. These savings $9.25-million grant to further explore “This work could not be accom- in Medicare and other health costs Inc./Corbis © RCWW, the biological factors that underlie plished by any single investigator,” would very likely exceed any possible longevity. longevity. This project is led by Dr. emphasizes Dr. Barzilai. “I think of increase in Social Security payouts to The study comprises four inte- Barzilai and Dr. Yousin Suh, associate myself as the promoter, the one bring- Americans living longer.” grated projects. The first study, led professor of medicine and molecular ing the best researchers together to Dr. Barzilai cites data from the by Aviv Bergman, Ph.D., professor of genetics at Einstein. accomplish the goals we have set Centers for Disease Control and pathology, will continue the search The remaining two projects are for ourselves.” Prevention (CDC) to support his case: for additional genes, and genetic long-term longitudinal studies. One, In addition, Dr. Barzilai has In 1993, the CDC found that, for a

© DiMaggio/Kalish/CORBIS variations within genes, that are led by Richard B. Lipton, M.D., profes- assembled a separate multidisci- person who died between the age of associated with longevity. A second sor of neurology and principal inves- plinary research team for a second 60 and 70, the average health-care protection against age-related project will focus on the growth hor- tigator of the Einstein Aging Study, NIH-funded program to investigate expense for the final months of life diseases—not cause and effect. mone/insulin-like growth factor (IGF) will determine if people who possess environmental factors that may con- was about $24,000. However, the That would require other research signaling pathway, which plays a role longevity genes are less likely to expe- tribute to successful aging. The proj- health care expense for individuals methodologies, including long-term in the growth and function of almost rience cognitive decline as they age. ect is now focusing on resveratrol, the who died at age 100 was two-thirds studies of individuals with and with- every organ in the body. Genetic The other study, directed by Clyde ingredient in red wine that has been less, or about $8,000. out the putative longevity genes, variations in the IGF pathway have Schechter, M.D., associate professor shown to extend the lives of mice and plus various laboratory tests and been associated with exceptional of family and social medicine, will other animal models. Adding new life to years © Corbis statistical analyses aimed at under- determine whether the three longev- Decades ago, President Kennedy standing what is happening at the ity genes that are already identified What about health care costs? sent a special message to Congress molecular and genetic levels. confer protection against cardiovas- Dr. Barzilai doesn’t believe that about seniors, noting, “It’s not enough Nonetheless, the very idea of cular disease. spending on health care will neces- for a great nation to have added longevity drugs was enough to But how can long-term studies sarily rise as the lifespans of Americans new years to life; our objective must energize baby boomers—and be conducted on centenarians, increase. He notes that the average be to add new life to those years.” cause managers of pension who presumably don’t have too senior citizen lives approximately Dr. Barzilai echoes this sentiment. funds and the Social Security many more years to live? And who three to six years after developing “It is not the extension of life per se Administration to lose sleep. would serve as the control group? a fatal illness and, during that time, that compels us; we seek to increase “From the Federal government’s (The logical controls would have there is a greater need for health health span along with life span,” perspective, the best thing that died decades ago—and would, of care and related services. In contrast, he says. “If we are healthier, we will could happen is that you work until course, be among the centenar- centenarians generally pass away just naturally live longer. But more impor- you’re 65, retire, and die the next ians if they had lived.) Dr. Barzilai three to eight months after falling tantly, the length of our days will be day—this is the most economical has sidestepped these problems by terminally ill. enhanced by good physical and outcome,” he says with a laugh. matching the offspring of centenar- mental functioning. This is the reason “I’m just thankful that I don’t have ians (constituting the test group) with we search for longevity genes.” E to rely on the folks at Social Security the offspring of parents who lived usual lifespans (the controls). His © Heide Benser/Solus-Veer/Corbis

32 Einstein I winter 2008 winter 2008 I Einstein 33 The bravery of the diplomat who saved A JOURNEY WELL-TRAVELED Sylvia and her family was eventually The Amazing Odyssey of Sylvia Smoller recognized, and he became known as the “Japanese Schindler.” USHMM, courtesy of Hiroki Sugihara Chiune Sugihara

Dr. Smoller’s peregrinations ended Sugihara’s list British and the French would defeat Squeezed between the Germans in New York in 1941. But in many There was nothing good around the Germany in two weeks, and it would to the east and the Russians to the ways, her odyssey had just begun. corner for Europe in the 1930s. By late all be back to normal,” says Dr. west, the Hafftkas had no place to She would buck the social trends by 1938, Austria and Czechoslovakia Smoller. “They really believed that.” go. Few countries were accepting working at IBM in the late fifties, and had fallen to the Germans, and One couldn’t leave Warsaw very Jewish refugees. Their only hope was then lose her first husband to cancer, Poland was next. Jews everywhere easily, however. The hostilities had Lithuania, where a Japanese consul raise a child alone, earn a Ph.D., and were being targeted by the Nazis or idled the trains and the army had by the name of Chiune Sugihara, in become the first statistician on the their sympathizers. Dr. Smoller’s father, commandeered most of the vehicles. defiance of his own government, was Einstein faculty—all in the sixties. Later, Aleksander Hafftka, a civil servant in Hafftka went to a nearby police issuing transit visas to refugees, giving she would play key roles in nation- Poland’s Interior Ministry and the high- station to demand a car and driver, them an avenue for escape. As the wide studies that changed treatment est ranking Jew in the government, bluffing that he had been ordered Germans bore down on Lithuania, for people with mild hypertension and was no exception. Hafftka’s troubles to join the government in Pozna, a most diplomats fled. Sugihara and for postmenopausal women, lose her began when he alerted a Jewish city to the west. The gambit worked. his wife remained, feverishly writ- y the time Sylvia Smoller entered second husband to cancer, and write organization about a proposed law Within a half-hour, the family began ing visas for thousands of Jews. The grade school, she had experienced a novel. Today, at an age when most that would ban Kosher slaughter, a their escape to temporary safety in brave consul also convinced Russian people are well into retirement, the thinly veiled attempt to put Jewish the countryside. (Readers interested authorities to let the refugees cross more turmoil than most people indefatigable professor is a leader of butchers out of business, driven by in this unique period of European and the continent to Japan via the the largest-ever study of the health growing anti-Semitism. Government Jewish history might want to pick up trans-Siberian railroad. Sugihara was do in a lifetime. Born in Poland status of Hispanics in the U.S. and an officials accused him of high crimes a copy of Dr. Smoller’s new novel, eventually dismissed, his diplomatic Bbetween the two world wars, she was just six invaluable mentor to a new genera- and abolished his post. Undaunted, Rachel and Aleks, a fictionalized career ruined. Years later, his heroism tion of epidemiologists. Hafftka became a leader of a com- account of her parents’ lives and was acknowledged, and he became when the Nazis invaded, driving her family Dr. Smoller cannot help but look mittee helping to resettle German times from 1918 to 1945.) known as the “Japanese Schindler.” ahead, a legacy of her mother’s Jewish refugees in Poland. “I was very fortunate because The Hafftkas were among the into exile. Thus began an 18-month-long enduring optimism. After suffering a Even after the Nazis invaded both my parents were with me,” says lucky ones to make it onto Sugihara’s journey that would take them to Lithuania, heart attack at age 73, her mother, Poland in 1939, Hafftka was reluctant Dr. Smoller. “The only time I remember list. After about a year, the family, Ola, earned a college degree and to leave, knowing from his refugee being scared was en route to Pinsk, surviving on assistance from refugee Russia, Japan, and, finally, the United States. then remarried. “Her motto was, ‘You work the hardships of exile. When a I think. We were approaching a organizations and proceeds from never know what’s around the cor- former colleague tipped him off that railroad track and a German plane the sale of Ola’s jewelry, left for ner,’” she says. “There’s no question government leaders themselves had came sweeping down very low, so Moscow, where they obtained visas Sylvia Wassertheil-Smoller, Ph.D. is Professor of Epidemiology and that my mother’s spirit affected me.” fled, he decided it was time to go. low that we could see the Swastika. for America. Eleven days later, they Population Health and heads the Division of Epidemiology at the “But the expectation was that the The driver yelled, ‘Get out, get out, Albert Einstein College of Medicine. hide under the bushes!’”

34 Einstein I winter 2008 winter 2008 I Einstein 35 All the while, Aleksander and Ola encouraged their daughter to learn as much as possible, and to be as independent as possible.

Dr. Smoller (l) was a leader of the international effort to recognize the heroic deeds of the Japanese diplomat, Chiune Sugihara.

reached Vladivostok and boarded decided he had to make money, so returned home from the Korean per company policy. It should have Mr. Wassertheil passed away in schools and hospitals, were mobilized a boat to Japan. It was another four he went into the import-export busi- War. Soon, they both landed jobs been a joyous time for the couple, 1968, leaving Dr. Smoller to raise to address the serious problems of months until they set sail for Seattle. ness. Unfortunately, he was anything with IBM, he in Poughkeepsie, N.Y., but Mr. Wassertheil was diagnosed six-year-old Jordan on her own. “A poverty in urban ghettoes and in rural This was followed by another trans- but a businessman. So he struggled she in nearby Kingston, in a branch with Hodgkin’s disease. In a conspir- year after he died, I moved to New areas of the nation.” Also, the focus continental rail journey, to their new all his life. But he was a great patriot. of the company dedicated to acy of silence between her mother York City. All of a sudden, it seemed of epidemiology shifted from infec- home in New York. He loved America, he revered defense research. Dr. Smoller’s and her father-in-law, Dr. Smoller impossible to live in Poughkeepsie. tious diseases to chronic diseases like Sugihara remains in sharp relief, Roosevelt. He was so proud when he task was to design radar displays wasn’t informed until after she That’s when I came to Einstein.” cancer and heart disease. however. Over the years, Dr. Smoller was made the block air-raid warden, for a Cold War-era early-warning delivered, for which she is eternally Dr. Smoller contributed to several has delivered numerous lectures on knowing that he was serving his new system, guarding the nation’s grateful. “I might have gotten tha- Is it relevant? studies during those first years at the consul and his heroic deeds, country.” Her mother fared better borders against enemy aircraft. “It lidomide,” she says, referring to the The next year, Dr. Smoller joined Einstein, including one with significant most recently last November at the in commerce, as the proprietor of a was human information process- sedative and anti-emetic commonly the Department of Community sociological and political implica- Auschwitz Peace Museum and the shop selling custom-made lingerie, ing, a combination of psychology, prescribed to pregnant women until Health (now the Department of tions. “Around that time, New York International Peace Museum of whose clients included Eleanor physics, and mathematics,” she it was found to cause horrific birth Epidemiology and Population State passed the first law in the nation Ritsumeikan University, both located Roosevelt and Judy Holiday. explains. “It was a wonderful defects. Her son, Jordan, is now an Health), becoming the first statistician allowing abortion,” she writes. “It in Japan. About a decade ago, she All the while, Aleksander and experience. IBM was a remarkable associate professor of psychiatry at on the Einstein faculty. It was not was widely thought that it would be established a Sugihara-inspired essay Ola encouraged their daughter company. I learned so much,” Harvard Medical School and director exactly the highest of honors, she de facto useless since most doc- contest on moral choices and respon- to learn as much as possible and she says. of the Psychiatric Genetic Program admits. tors would not perform abortions.” sibility for high school students in New to be independent. The lessons At the time, few other women in Mood and Anxiety Disorders at the “Teaching was an interesting and However, the study showed just the York City. Now known as the “Tribute stuck. Dr. Smoller earned bachelor’s worked at IBM. “My husband got Massachusetts General Hospital. difficult experience in those days opposite, that the vast majority of to the Rescuers Essay Contest,” the and master’s degrees at Syracuse the flak from that,” she remembers. Not content to be a stay-at-home —when students mounted strikes of the physicians would either perform program was subsequently expanded University, the latter in psychology. “What was he doing having his mom, Dr. Smoller joined the faculty classes they didn’t like, held sit-ins at the procedures themselves or refer to other cities and is run under the aus- “The courses that most appealed to wife work? I always wanted to at SUNY-New Paltz, where she deans’ offices...” she writes in a brief a patient to a clinician who would. pices of the Anti-Defamation League. me were in quantitative methods,” work. I knew it wasn’t considered taught mathematics and statistics history of the department. “The big Furthermore, six months after the law she says. “There was something entirely normal in those days, but and developed the first computer- word was ‘relevance’—and most went into effect, a repeat survey Education and independence reassuring about being able to get I couldn’t imagine not doing it. assisted statistics learning program, students (and faculty) thought bio- showed that doctors now held more The Hafftkas settled on the Upper answers to things.” Work has gotten me through some with support from her old employer, statistics and epidemiology were not liberal views, showing that legislation West Side, finding freedom if not She had met her first husband, very tough times. Freud said love IBM. She also began doctoral studies relevant to the problems of society, can change attitudes. prosperity. “I remember weeks when David Wassertheil, when she was 16 and work are the cornerstones of in operations research and statistics so my own specialty was held in “We sent the report of that study to we didn’t have enough to pay the and he was 20. They married after he our humanness.” at New York University. rather low regard.” Albany, and we liked to think that we grocer,” Dr. Smoller recalls. “My father, Not long after, Dr. Smoller But that would soon change, she had some role in helping that law to who was an intellectual, a historian, became pregnant, remaining continues. “This was the time ... when succeed,” she says. on the job until her sixth month, major institutions, including medical

36 Einstein I winter 2008 winter 2008 I Einstein 37 The 1990s brought what is perhaps the At an age when most people are well into defining study of Dr. Smoller's career, the retirement, the indefatigable professor is a Women's Health Initiative. leader of the largest-ever study of the health status of Hispanics in the U.S., and an invaluable mentor to a new generation of epidemiologists

significantly raises the risk of these Hispanic health cardiovascular illnesses. The paper, Today, the relevance of biostatistics which drew worldwide media cover- and epidemiology is beyond age, also confirmed that hormone question, thanks in no small part to replacement therapy increases one’s Dr. Smoller. risk of breast cancer — long sus- “She is a giant in the field, one of (l) Dr. Smoller with the first enrollee in pected but never so clearly demon- the most distinguished practitioners Einstein’s landmark Women's Health strated. “You should not be taking this of clinical trials in the world,” says Dr. Initiative. (r) the opening ceremony for for the prevention of heart disease, Alderman. “Her early studies were the Hispanic Community Health study. or for the prevention of cancer,” among the first to answer big clinical Dr. Smoller remarked on NBC’s questions, such as, should you treat “Today” show. all these millions of people who have Over time, Dr. Smoller gained con- While there were triumphs, there quality of life in postmenopausal The following year, WHI released modestly elevated blood pressure?,” Dr. Smoller, the principal inves- siderable experience running large, was also tragedy. In 1980, after nine women. WHI still ranks as the largest another startling finding in JAMA says Dr. Alderman. “That you could tigator at Einstein says the study multicenter clinical trials, which were years of marriage, her second hus- study of women’s health ever under- about hormone replacement therapy reliably answer these questions dem- will address such questions as why quickly gaining favor in the scientific band, Saul Smoller, a pediatrician and taken. and dementia, again influencing onstrated the value of large clinical Hispanics experience increased community. Several of these trials adjunct faculty member at Einstein, “Women today spend as much medical practice. Many believed it trials, which led to further studies, like rates of obesity and diabetes and focused on cardiovascular disease, died of lung cancer. Her stepson, of a percentage of their lives in their would help prevent cognitive decline, WHI. When she first came to Einstein, yet have fewer deaths from heart such as the 1970s Hypertension Scott Smoller, graduated from Einstein menopausal years as in their repro- but WHI proved otherwise. “We epidemiology was not looked upon disease than non-Hispanics, and why Detection and Follow-Up Program, and is now is a nephrologist practic- ductive years,” said Dr. Smoller, the found that, indeed, to our enormous as an important part of medical asthma is more common in certain sponsored by National Health, Lung, ing in Florida. principal investigator for the WHI at surprise and dismay, that there was education and medical practice. Hispanic subgroups than in others. and Blood Institute (NHLBI) of the She remarried in 1984, to Walter Einstein. “Yet, very little was known a doubling of the risk of dementia,” Now, partly because of her work, About 16,000 people will be enrolled, National Institutes of Health. “That Austerer, a graphics designer and about how to keep women healthy explained Dr. Smoller on PBS’s we in health care live a world called including 4,000 at Einstein. study demonstrated for the first artist, with whom she shares a similar as they advance in age.” “Charlie Rose.” evidence-based medicine, and to a “I love these multicenter stud- time the value of treating people childhood history. A native of Austria, At Einstein, Dr. Smoller and her The influence of the WHI continues, large extent what we mean by ‘evi- ies,” says Dr. Smoller, showing off a with moderately elevated blood he was saved from the Nazis by the colleagues established a clinic and sparking numerous secondary studies dence’ is clinical trials results.” memory book from the WHI study pressure,” says longtime colleague Kindertransport, the British-led mission recruited 5,000 women in New York of postmenopausal health, including Over the course of her career, compiled by one of her staffers. “It’s Michael Alderman, M.D., professor of that rescued thousands of Jewish chil- for the WHI. Nationwide, the landmark a half-dozen or so at Einstein. One of Dr. Smoller has attracted more than exhilarating to work with people from epidemiology and public health and dren in Europe just before the war. study enrolled 160,000 women. these is Dr. Smoller’s own current study $45 million in research funding to all over the country and many differ- of medicine and the Atran Professor Along the way, she wrote For more than a decade, WHI of biomarkers of stroke. “The oppor- Einstein. That sum includes $10 million ent disciplines.” of Social Medicine at Einstein. “It Biostatistics and Epidemiology: A researchers produced paper after tunities go on and on. The WHI data for yet another long-term clinical Dr. Smoller does not linger over the mobilized the medical community to Primer for Health and Biomedical paper, yielding key insights into post- are a great resource for our junior trial, this one focusing on the health past, however fond the memories, address an unrecognized problem Professionals, a well-received text on menopausal health and persuading faculty,” says Dr. Smoller, a mentor to of Hispanics in the United States. preferring instead to talk about stud- in a huge chunk of the American the scientific method, probability, and physicians to rethink treatment for many of these investigators. Surprisingly little is known about the ies to come, about what is around population.” clinical trials, now in its third edition. millions of postmenopausal women. “This has been critical for the health status and health risks of this the corner. E Dr. Smoller also led or co-led In 2002, for example, WHI reported in growth of the department,” adds minority group, the nation’s largest. numerous clinical studies of cancer, Focus on women’s health The Journal of the American Medical Thomas Rohan, M.D., Ph.D., chairman To learn more about this population, several of which addressed the role The 1990s brought what is perhaps Association (JAMA) that long-term of epidemiology and population NHLBI has launched the Hispanic of nutrition in various forms of the the defining study of Dr. Smoller’s use of estrogen and progestin, once health. “We are among the most suc- Community Health Study, which is to disease, earning plaudits for her career, the Women’s Health Initiative thought to prevent heart attacks and cessful of the 40 WHI centers in terms be conducted at five sites around the managerial skills as well as her scien- (WHI), a nationwide investigation of strokes in women after menopause, of generating ancillary studies.” country, including Einstein, over a six- tific acumen. the effects of hormone therapy and and-a-half-year period. of diet on heart disease and cancer and of death, disability, and impaired

38 Einstein I winter 2008 winter 2008 I Einstein 39 News from the Labs

Study of Breast Cancer Einstein Researchers Use Novel says Dr. Aviv Bergman, a professor in in the same way that a Sunday strategy. So we’ve started with viru- the August 16 issue of Nature. The Patients Is First to Evaluate Approach to Uncover Genetic the departments of pathology and driver on a narrow road slows down lent Mycobacterium tuberculosis—the new strategy could be a powerful Yoga’s Benefits In An Components of Aging neuroscience at Einstein and senior all traffic behind him. organism that actually causes TB tool for determining how key enzymes Ethnically Diverse Population author of the study, which appeared in humans—and are knocking out work in the body and for deciphering People who live to 100 or more have in the August 31 issue of PLoS • In the absence of pausing, elon- certain genes to yield a live, attenu- the activity of enzymes of unknown Einstein researchers have shown that just as many—and sometimes even Computational Biology. Other Einstein gation proceeded much faster ated M. tuberculosis strain that still function. yoga can benefit ethnic minority more—harmful gene variants com- researchers involved in the study —about 70 nucleotides synthesized produces a strong immunological “Many of the proteins being breast cancer survivors (primarily pared with younger people. Now, were Gil Atzmon, Kenny Ye, Thomas per second—than has previously response that protects people.” revealed by ongoing genome African-Americans and Hispanics) as Einstein scientists have discovered McCarthy and Nir Barzilai. been reported. In designing their TB vaccine, the sequencing projects are not charac- well as women living in underserved the secret behind this paradox: favor- Einstein researchers discovered a terized in terms of function, or their communities. The study corroborates able “longevity” genes that protect These phenomena of pausing and gene in M. tuberculosis, known as functions have been mis-annotated,” previous research among largely very old people from the bad genes’ In a Scientific First, Einstein rapid RNA synthesis during elongation secA2, that the TB bacteria rely on to notes Dr. Almo. “So as genomes Caucasian populations showing that harmful effects. The researchers Scientists Discover the may be crucial for regulating gene prevent apoptosis of the cells they accumulate, the type of interdisciplin- yoga can maintain or improve quality hypothesized that people living to Dynamics of Transcription in expression, Dr. Singer speculates infect and thereby evade a person’s ary approach used by our team will of life in a variety of ways for women 100 and beyond must be buffered by Living Mammalian Cells The other Einstein researchers immune response. The researchers become increasingly important for with breast cancer. The findings genes that interact with disease-caus- involved in the study were lead knocked out secA2 and injected discovering the functions of enzymes appear in the September issue of the ing genes to negate their effects. To Transcription—the transfer of DNA’s author, Xavier Darzacq (now the mutant TB strain into laboratory and other proteins.” Journal of Clinical Oncology. test this hypothesis, they examined genetic information to messenger at Laboratoire de Génétique animals. The infected cells underwent Crucial to the team’s success was The 12-week study examined the individuals enrolled in Einstein’s RNA—forms the basis of all cellular Moléculaire, Centre National de apoptosis, eliciting protective immu- computer simulation of candidate impact of yoga on overall quality of Longevity Genes Project, initiated in activities, yet little is known about la Recherche Scientifique, Paris), nity that was measurably superior substrates that mimicked the short- life (including fatigue, psychologi- 1998 to investigate longevity genes its dynamics. In the August issue of Yaron Shav-Tal (now at The Mina to the standard BCG vaccine The lived and unstable molecules that cal distress, and spiritual well-being) in a selected population: Ashkenazi Nature Structural & Molecular Biology, & Everard Goodman Facility of researchers hope that initial human initially bind to the active site of an among an ethnically diverse sample (Eastern European) Jews. researchers led by Dr. Robert Singer, Life Sciences, Bar-Ilan University, trials of the secA2 mutant TB vaccine enzyme (the so-called transition of breast cancer patients from the All participants were grouped into co-chair of anatomy & structural biol- Ramat Gan, Israel), Valeria de could begin within two to three years. state), after which the enzyme-cata- underserved urban community of cohorts representing each decade ogy at Einstein, have measured the Turris and Shailesh M. Shenoy. Besides Dr. Jacobs, other Einstein lyst turns the substrate into a new Bronx, NY. The women in general had of lifespan from the 50’s on up. Using stages of transcription in real time. researchers involved in the study molecule. Once the researchers had lower-than-average levels of qual- DNA samples, the researchers deter- The study focused on RNA polymerase were co-senior author Steven A. predicted the substrate, the predic- ity of life at the outset of the study. mined the prevalence in each cohort II—the enzyme responsible for tran- Einstein Researchers Develop Porcelli, Joseph Hinchey, Sunhee Lee, tion was tested and confirmed experi- “Overall, we saw that yoga had its of 66 genetic markers present in 36 scription. Growing numbers of RNA Prototype Vaccine That Could Manjunatha M. Venkataswamy, Bing mentally. Dr. Almo further confirmed greatest effect on the social function- genes associated with aging. Two key polymerase II molecules assemble Provide Improved Protection Chen and John Chan. the findings by using x-ray crystal- ing of these women,” says the study’s predictions were borne out: Some on DNA and then synthesize RNA by Against Tuberculosis lography to determine the substrate’s lead author, Dr. Alyson Moadel, an disease-related gene variants were as sequentially recruiting complemen- atomic structure. Then, having used assistant professor of epidemiology prevalent or even more prevalent in tary RNA nucleotides. Einstein researchers have developed Predicting Enzyme Function the enzyme’s structure to divine the and population health at Einstein. the oldest cohorts of Ashkenazi Jews Some unexpected and surprising a prototype vaccine against tuber- from Form natural molecule that triggers the She and her colleagues (Drs. Chirag than in the younger ones. And genes findings were reported: culosis (TB) that works better in animal enzyme into action, the research- Shah, Joseph Sparano, Judith Wylie- associated with longevity became models than Bacille Calmette-Guérin The ability to predict an enzyme’s ers were able to establish that the Rosett, Melanie Harris, Sapana Patel, more common in each succeeding • The transcription process is quite (BCG), the only available vaccine. function from its structure has long enzyme works in a previously unchar- and Charles Hall) are now looking at cohort. inefficient. Only one percent of poly- Their study appears in the August issue eluded scientists. Now it has been acterized metabolic pathway in the yoga’s impact on patients with can- “These results indicate that the merases that bind to the gene actu- of the Journal of Clinical Investigation. done. Dr. Steven Almo, professor bacteria. Other Einstein scientists cers of the breast, colon, and lung, frequency of deleterious genotypes ally remain on to help in synthesizing “Virtually all efforts to develop of biochemistry and physiology & involved in the study were Alexander and on survivors of those cancers. may increase among people who an RNA molecule. a better TB vaccine have focused biophysics at Einstein, was a key A. Fedorov and Elena Fedorov. live to extremely old ages because on ‘boosting’ BCG—modifying it to member of a multi-institutional team (Continued on next page) their protective genes allow these dis- • While the binding phase of transcrip- elicit a stronger immune response in that developed the ground-break- ease-related genes to accumulate,” tion lasted six seconds and initiation people,” says Dr. William Jacobs, Jr., ing strategy responsible. The team’s took 54 seconds, the final stage— co-senior author of the paper and accomplishment, involving an elongation of the RNA molecule a Howard Hughes Medical Institute enzyme extracted from a bacterium —took a lengthy eight minutes, investigator at Einstein as well as pro- that lives at very high temperatures possibly because the “lead” poly- fessor of microbiology & immunology near ocean vents, was described in merase on the growing polymerase and molecular genetics. “But we feel II enzyme sometimes “paused” for that tweaking the marginally useful long periods, retarding transcription BCG vaccine is the wrong

40 Einstein I winter 2008 winter 2008 I Einstein 41 News from the Labs The Compleat Physician (continued from previous page) (continued from page 27) In Memoriam A Commonly Found that these sessions provide opportuni- “The session on behavior change Contaminant May Harm ties for students to develop their sense ... contributed much to my interview- Nursing Infants of professionalism and reflect on the ing skills, reminding me especially of humanistic nature of their work, both the importance of being non-judg- Perchlorate, an industrial pollutant worthy goals. Hopefully, after PDC mental.” linked to thyroid ailments, is actively becomes more of the norm, students “Students are enjoying the oppor- concentrated in breast milk, Einstein will come to appreciate it.” tunity to get away from the clinical researchers have reported. Their “We have tried to better balance environment and reflect on it,” Dr. finding suggests that perchlorate the needs of the students with the Marantz notes. “Our course is very Dr. Salome G. Waelsch Jews were being fired in universities contamination of drinking water may needs of the course,” adds Eric H. much connected to what they are Pioneer Woman Scientist Dies at 100 throughout Germany. pose a greater risk to nursing infants Green M.D., assistant professor of seeing or doing in the wards. We Dr. Waelsch and her husband than previously realized. Dr. Nancy medicine, who took the helm of PDC don’t create paper cases.” Dr. Salome Gluecksohn-Waelsch, Rudolf Schoenheimer, himself a young Carrasco, professor of molecular starting with the 2007-08 academic Distinguished University Professor Jewish biochemist of great promise, pharmacology, was the senior author year. “To wit, we have reduced More to come Emerita of Molecular Genetics at fled Germany for careers in the United of the study, which appeared in the both the number of sessions and the The Division of Education has modest Einstein, and one of the pioneering States. After the untimely death of December 3-7 advance online issue amount of content in each session expectations for PDC. As Dr. Marantz women scientists of the 20th century, Schoenheimer, she later married of the Proceedings of the National Although this meant sacrificing learn- points out, “Third-year students spend died November 7th at her home in Heinrich Waelsch, a neurochemist. Academy of Sciences. ing objectives we consider important, about 2,500 hours on the wards, but Manhattan. She was 100 years old. In the United States, in the 1930s, Perchlorate is known to interfere it allows more time for unstructured only 30 hours in PDC. We’re looking Dr. Waelsch, a founder of the Dr. Waelsch again faced discrimina- with the ability of the thyroid, mam- discussion during which students relay for incremental changes.” fundamental field of biological tion—this time as a woman seeking mary glands and certain other tissues issues that challenge their professional More curriculum reforms are afoot, science known today as develop- work in a field wholly dominated to absorb iodide from the blood- identity, and the group, both students however. PDC is one part of a sweep- mental genetics, received worldwide by men. She began her scientific Dr. Waelsch receives the National stream. The thyroid requires iodide to and faculty, discusses the issues and ing curriculum overhaul now under- recognition for her contributions to career at Columbia University in the Medal of Science from President synthesize the hormones T3 and T4 brainstorms for solutions.” way at the College. In 2006, Einstein our understanding of the way genes laboratory of L. C. Dunn, a well-known Bill Clinton, September 30, 1993. that are essential for normal devel- By the same token, Dr. Marantz won one of nine “K07 awards” from determine how an embryo forms. At scientist in the field of mammalian opment of babies’ central nervous has little patience for those who the National Institutes of Health a time when many geneticists did genetics. She was offered laboratory Dr. Waelsch its “golden doctoral systems. Iodide is relatively scarce would prefer to do away with PDC. that are designed to enhance the not believe that genes, studied up space in which she could study the diploma,” in recognition of her life- in the diet, and tissues that need “Medical students are coming teaching of prevention, ethics, pro- to that time extensively in the fruit development of the mouse—albeit time of distinguished achievements. to accumulate it—the breast and through a prolonged adolescence, fessionalism, population health, com- fly, controlled the complex events without a salary. Ironically, 1982 also marked the 50th thyroid in particular—are equipped where they still don’t have a clue munication, and similar disciplines in of embryogenesis, Dr. Waelsch was In 1938, Dr. Waelsch made a major anniversary of Hitler’s rise to power. with a cell-surface protein called what it means to be a doctor, espe- undergraduate medical education. the first to demonstrate that classical breakthrough in the field of genetics, Therefore, while she accepted the NIS (sodium/iodide symporter) that cially not in the third year. So, the The overall goal of Einstein’s five- Mendelian genetics directed the making it possible to trace the effects honor, she felt compelled to send the actively pulls iodide from the blood- suggestion that this is not what they year grant, with Dr. Marantz as the development of a mouse. For her of genes on development from the University a poignant letter, in which stream into the cells. NIS was first iden- need is not something we can take principal investigator, is “to graduate work she was awarded the presti- embryo to the mature mammal. This she wrote, in part: tified and cloned by Dr. Carrasco’s all that seriously,” he says. physicians with the knowledge, gious National Medal of Science by research laid the foundation for all “…My feelings of appreciation laboratory in 1996. The Class of 2008’s reactions to attitudes, and skills ... required to be President Clinton in 1993, the nation’s future advances in developmental and gratefulness… are tempered by In the current study, Dr. Carrasco PDC are not entirely negative, judg- outstanding practitioners of the heal- highest scientific honor. She received genetics. It proved vital to improving feelings of bitterness. I cannot accept and her colleagues injected female ing from a mid-year student survey ers’ art.” Major themes to be covered the Thomas Hunt Morgan medal of the understanding of birth defects, the recognition of this anniversary rats with perchlorate and then and from faculty feedback. In the include doctor-patient communica- the Genetics Society of America and particularly in finding the cause of as though the 50 years since the extracted the animals’ breast milk survey, at least half the students rated tion, professionalism, ethics, mind- the first Lifetime Achievement Award mistakes in the development process date of my promotion had passed and tested it on cells that express NIS. PDC adequate or better, which is body medicine, behavioral medicine, of the American Cancer Society. that result in defects. smoothly, and without remembering The milk inhibited iodide transport in fairly effusive praise from the hard-to- social and cultural issues in health, She was elected to the US National Dr. Waelsch joined the founding the Holocaust and its impact. I regret NIS-expressing cells, indicating that please student body. and health economics and policy. Academy of Sciences, the American faculty of Einstein when the medical the tendency to forget and deny perchlorate had become concen- One student noted, “I am better Academy of Arts and Sciences, and school opened in 1955. Starting as the tremendous human and political trated in the milk. E able to evaluate how my residents The compleat surgeon was a foreign member of the Royal an associate professor of anatomy upheavals of the past half century deal with different situations (e.g., After my off-putting encounter with Society of London. She also received in 1955, she was named professor and to celebrate anniversaries as end-of-life issues) and decide which that orthopedic surgeon, I found an honorary doctorate degree in 1958 and was appointed acting though nothing had happened. To aspects I would like to adopt for myself.” another—one who listened instead of from Yeshiva University, a Spirit of chair of genetics when the new give expression to this regret is my Other students commented: lectured. Together, we decided that Achievement Award from the Albert department was created in 1963. In duty towards all of those who suffered “It reminds me to think about what surgery was the best solution. Two Einstein National Women’s Division, 1973, Dr. Waelsch was named chair of under the Nazi regime, among them type of physician I want to be and weeks later, he performed the opera- and an honorary doctorate of sci- genetics and served in that capacity the man whose name our medi- how to apply that in everyday work.” tion. It went perfectly. His assistant ence from Columbia University. through 1976. In 1978, she was named cal school carries with the greatest The session on ethics “helped me surgeon called that evening to follow Born in Danzig, Germany, in 1907, professor emerita, yet she continued pride…” relay some bad news to a patient.” up, and he called the next morning, Dr. Waelsch earned a Ph.D. in biol- to carry on her research, coming in to The letter from Dr. Waelsch was “The health beliefs session helped even though I had undergone the ogy at the University of Freiberg, in her laboratory daily and maintaining read at the University’s commence- me asked certain questions in a par- most minor of procedures. I hope Germany, in 1932. She served as her mouse colony until her mid-90s. ment ceremony, in its entirety. E ticularly difficult [clinical] situation that PDC turns out more doctors like a research assistant in cell biology In 1982, nearly 50 years after fleeing that no one else in the room thought him. E –Gary Goldenberg at the University of Berlin for a year Germany, her college alma mater, to ask.” but, as Adolf Hitler came to power, the University of Freiberg, awarded

42 Einstein I winter 2008 winter 2008 I Einstein 43 In Memoriam (continued from previous page)

Edmund H. Sonnenblick, M.D. M. Henry Williams, M.D.

Dr. Edmund H. Dr. M. Henry Sonnenblick, Williams, Distinguished Professor University Professor Emeritus of and Safra Professor Medicine, and of Cardiovascular a pulmonolo- Medicine, who gist renowned was renowned for his work in for pioneering respiratory ail- research that helped establish modern ments, particularly asthma, died on treatment of heart failure, died on September 16, at the age of 83. September 22, at the age of 74. Dr. Williams developed an out- Dr. Sonnenblick’s findings concern- standing Chest Service at the Bronx ing the structure and function of heart Municipal Hospital Center (now muscle cells and how the heart muscle Jacobi Medicial Center), where contracts and relaxes contributed to he served as the Service’s director the development, by others, of ACE for 35 years. He came to Einstein in inhibitors, commonly used to treat 1955 as a visiting assistant professor patients with heart failure. He and of physiology, and was appointed other researchers also adapted beta associate professor of medicine and blockers for use in heart failure. Both of of physiology in 1959. In 1981 he was these treatment developments have also named director of the pulmonary extended the lives of millions of people division in the department of medi- worldwide. cine, a position he held until 1994. During the 1960s, when Dr. Sonnenblick During his distinguished career, Dr. was still a young physician-scientist, Williams trained legions of pulmonary there was much yet unknown about physicians, residents and students. the best ways to treat a failing heart. He was highly respected as both a Dr. Sonnenblick is credited as the first to clinician and clinical investigator, and use the electron microscope to image revered as an outstanding teacher. heart muscles under scientifically con- He received his bachelor’s degree trolled conditions. Using this powerful from Yale University in 1944, and his new technology, he correlated mea- medical degree from Yale Medical surements of heart muscle structure and School in 1947. He then trained at the force of its contractions. He was Presbyterian Hospital in New York and able to demonstrate how heart muscle at New Haven Hospital. Following mil- contractions were dependent on the itary service, where he was a first lieu- alignment of certain molecules in tenant and then a captain in the U.S. the cells. Army, he was stationed at the Walter Dr. Sonnenblick was a Phi Beta Reed Army Medical Center, where he Kappa graduate of Wesleyan University began his medical career. He served and received his medical degree as chief of the respiratory section in from Harvard in 1958. Among his many the medical center’s Department of honors, he received the Distinguished Cardiorespiratory Diseases. Scientist Award of the American Dr. Williams’ eldest son, Stuart, is an College of Cardiology in 1985, and alumnus of Einstein, a member of the in 2007, he was the recipient of the class of ’75. E American Heart Association’s presti- gious Research Achievement Award. E

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