The Four R's

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.