The Four R's

Teams at each of New York City's leading universities are making important research advances. Their overarching goal is to understand the molecular underpinnings of disease and then rapidly translate the information to the clinic. Using a combination of advanced imaging technologies, biophotonics, immunology, translational research and other areas of basic science, they work to achieve this goal. ON THE SHORES OF THE EAST RIVER Although the building itself is still under construction, New York University School of Medicine's Smilow Biomedical Research Center already sees itself as an integral part of New York's medical and research community, according to Vicki Match-Suna, associate dean and vice president of real estate and strategic capital initiatives at NYU Medical Center. The facility, adjoining the medical school's East River campus, is part of a growth agenda established by the school's dean Robert Glickman in 1998. "We're looking at our research, our educational programs, and our clinical programs, and together ... we are targeting specific areas that we're interested in growing, and building the necessary facilities and doing the necessary recruitment in order to do that," explains Match-Suna. Recruitment is underway to hire more than 80 new principal investigators, staff scientists, and administrative personnel who will be split between the new 13-story building, which is scheduled for completion in late 2005, and the older adjacent medical sciences building that is currently being renovated. The project will cost an estimated $150 million. When completed, the Smilow Center's 230,000 square feet will house conference rooms, classrooms, and laboratory space for nine concentrated research areas including dermatology, cancer, neuroscience, genetics and genomics, renal diseases, cardiovascular biology, and infectious diseases. "It was essential for us to build new facilities to attract individuals that we would like to [come and work in] these areas," says Match-Suna. "It's essential for medical schools and medical centers to build modern, state-of-the-art facilities in order to be able to do the kind of research that's important and to grow in the ways we would like to grow." - Maria W. Anderson BIOTECH ACROSS THE BROOKLYN BRIDGE New York City apartment hunters know that Brooklyn offers more space and what seem like bargain rents compared with the island of Manhattan to the northwest. Now it's hoped that biotech firms will catch on. This summer, the State University of New York at Downstate opened the first phase of its Advanced Biotechnology Incubator, the city's second, after Columbia's Audubon Ballroom which opened in 1995 (see related sidebar). The completed 11,000 square foot facility is part of a multi-phase project to turn warehouses adjacent to SUNY Downstate into enough space for 20 to 30 biotech companies. It's part of a larger biotech park of which Imclone Systems is the anchor tenant. Though one of the goals is to provide affordable space to start-ups, Eva Cramer, who is in charge of the project, foresees a mix of tenants, with some more-established companies serving as "role models for the babies." So far, two ventures by Downstate researchers, including Randall Barbour's company NIRx (see main story), have signed on as tenants. A Long Island orthotics/prosthetics maker decided to take space to be near one of its target patient-clinician populations, as the surrounding community has a high rate of diabetes. Cramer says that as incubator tenants outgrow their space, they will have a chance to expand into some of the vast industrial space that dots Brooklyn, in areas designated Empire Zones where the state offers tax breaks and other incentives. - Amy Norton Oded Gonen is among a group of New York University researchers using magnetic resonance imaging to delve into the brain. His work focuses on understanding the biochemistry of multiple sclerosis by using MR spectroscopy, and he found that dips in levels of N-acetylaspartate (NAA) happen early on in the disease. Moreover, there is a steady NAA decline that correlates with disease duration. The hope, Gonen says, is that MR spectroscopy can help answer two key questions: 'What will be the course of a patient's disease?' and 'Is an individual's drug regimen working?' "Right now, we have no answers for these questions," he notes. A few miles away, in Brooklyn, researchers at State University of New York, Downstate, see a potential role for near-infrared optical tomography in everything from cancer to ADHD (Attention Deficit Hyperactivity Disorder). With its ability to capture the interaction between tissue and its blood supply, the technology may catch cancer, particularly breast cancer, in its initial stages, according to Randall L. Barbour, SUNY Downstate pathology professor. The optical tomography imaging system he developed – and markets through his startup, NIRx Medical Technologies – is now in clinical trials for breast cancer, an application based on the fact that burgeoning tumors rely on the disorganized vascular network produced by neo-angiogenesis. Barbour also sees a "big neuroscience application" for near-infrared optical tomography which could, he says, serve as an inexpensive, portable, alternative to functional MRI in research on disorders such as Alzheimer's disease and ADHD. Columbia University and the NYU Child Study Center are among the first centers to pruchase the system for use in brain imaging research. BRINGING IN BIOPHOTONICS Images of single cells and single molecules are what's on view at the new Innovation Laboratory at Albert Einstein College of Medicine at Yeshiva University. The lab, headed by John Condeelis and Robert Singer, will be the hub of a biophotonics center being constructed as part of a facility for genetic and translational medicine. Singer's own lab has been using green fluorescence protein tagging and new in situ hybridization-based microscopy techniques to follow the travels of RNA in living cells, from the point of transcription onward. The researchers recently described how messenger RNA migrates from the nucleus through simple diffusion, and not directed movement (Science 304:1797-1800, 2004). Singer says work at the new biophotonics center will aim to develop the next generation of tools that can reveal even more complex subcellular goings on, such as RNA-protein interactions. Such capabilities should have important implications for cancer treatment, according to Condeelis. A unique aspect of the work at Einstein is its focus on gene expression specifically in the tumors' invasive cells. The goal, Condeelis says, is to provide molecular markers that reveal what a tumor will do, similar to "predicting the path of a hurricane." FROM BENCH TO BEDSIDE According to Mount Sinai School of Medicine dean for research Dennis Charney, the "seamless relationship" between his school and its medical center provides a good foundation for translational medicine. Examples can be seen, he says, in the schools' "pillars" of research, such as gene and cell medicine, and neuroscience. In neurology, Charney points to Mt. Sinai's work on Parkinson's disease. Several years ago, the institution set up a center designed specifically to translate lab discoveries on PD into new treatments. Mount Sinai scientists were the first to show that transplanted dopaminergic neurons can re-enervate patients' brains http://www.mountsinai.org/msh/whatsnew_0616_neuro.jsp, and though the tactic of using fetal cells against Parkinson's has so far failed, it's an approach researchers there continue to refine. Other research, focusing on the role of apoptosis in Parkinson neuronal death, has yielded a potentially neuroprotective drug now in Phase II testing. At Columbia University, as well, there is much emphasis on the "continuum from discovery to delivery," says Eric Rose, associate dean for translational research at Columbia University. Two prime areas he cites are cardiology and neuroscience. Last spring, Columbia researchers reported on a new compound – a derivative of 1,4-benzothiazepine, called JTV519 – that may prevent fatal arrhythmias in heart failure (Science, 304:292-6, 2004). Building on their past work showing that heart failure patients have "leaky" calcium channels, the researchers found that a small-molecule drug that enhances the binding of two proteins governing calcium-channel function prevented arrhythmias in mice http://www.cumc.columbia.edu/news/in-vivo/Vol3_Iss06_may_04/index.html. They want to get the drug into clinical trials within the next two years. USING DNA VACCINES At Memorial Sloan-Kettering Cancer Center, translational research that merges gene transfer and immunology has resulted in DNA vaccines that are in clinical trials for melanoma and prostate cancer. Michel Sadelain, who heads the gene transfer and gene expression laboratory, is investigating a number of immunotherapy approaches. One is to genetically engineer artificial antigen-presenting cells that can be used to stimulate, ex vivo, the T cells of any patient with a given HLA type. Another approach bypasses antigen-presenting cells altogether by introducing tumor-antigen receptors into T cells drawn from the peripheral blood. Sadelain and his colleagues have found that human T cells armed with a CD19-specific receptor were able to eradicate human B-cell tumors in mice (Nat Med, 9:279-86, 2003). In addition, transduced T cells taken from patients with chronic lymphocytic leukemia were capable of destroying the patients' own tumor cells. EPIGENETICS INCORPORATED Getting at the genesis of cancer and other diseases is a central goal of epigenetics research, a relatively new field in which C. David Allis at Rockefeller University is among the leaders. With the sequenced human genome now in hand, Allis and his colleagues are looking to unravel the histone code. Epigenetic regulation sways gene expression without altering the DNA sequence, and Rockefeller researchers are gathering evidence that enzyme modification of the histone proteins that help form chromatin is vital to whether genes get switched on or off. Most recently, Allis's team and collaborators at Weill Cornell Medical College found that a poorly characterized enzyme, peptidylarginine deiminase 4, silences certain genes via histone demethylation – the removal of the "marks" that methylation makes on histone proteins (Science, 306:279-83, 2004). Joanna Wysocka, a postdoc in Allis' lab, theorizes that knowing how epigenetic marks are erased could eventually serve regenerative medicine by allowing scientists to reprogram a patient's differentiated cells to become replacements for other, diseased cells. Regenerative medicine will be the focus at Weill's new Ansary Center for Stem Cell Therapeutics, now under construction. Shahin Rafii, who will direct the center, is working to understand how stem cells self-renew, differentiate, and mobilize. His team has found that under normal conditions, bone marrow stem cells reside in the "safe haven" of the osteoblastic niche, and that from there, they must travel to another microenvironment (dubbed the vascular niche) to get instructions to differentiate (Nat Med, 10:64-71, 2004) The researchers identified the two chemokines, stromal derived factor-1 and fibroblast growth factor-4, that direct this trip. DANCING WITH BIOTECH AT THE AUDUBON BALLROOM For researchers with a marketable idea, having office space to start a company right across the street from the lab where they generated the idea, and where they're still working, is invaluable, says Mitch Gipson, the executive director of the Audubon Business and Technology Center, a bioincubator adjacent to the Columbia-Presbyterian Medical Center. The center is on the site of the Audubon Ballroom, where Malcolm X was killed in 1965; part of the ballroom has been reconstructed and is now maintained as an historical site. Although the Audubon Center is no longer the only bioincubator in the metropolitan area – the State University of New York now has an Advanced Biotechnology Park at its Brooklyn campus – it is still the largest. The 100,000 square foot facility, part of the Audubon Biomedical Science and Technology Park in Washington Heights, has provided space for more than 45 companies since its opening in 1996. It currently houses 22 companies, including Acceptys, which aims to develop human antibody therapies for cancer and infectious diseases; GliaMed Inc., which is designing compounds to treat neurodegenerative diseases; and Ortec International Inc., a tissue engineering company that has developed a type of artificial skin for burn victims. The Park also includes two academic buildings: the Russ Berrie Medical Science Pavilion and the Irving Cancer Research Center. A second commercial facility and a third academic building will be built in the next several years. - Maria W. Anderson

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