One of the great puzzles of modern medicine is the cancer cell--what causes it to grow and what can destroy it. For more than 20 years Dr. Robert Bittman, Distinguished Professor of Chemistry and Biochemistry, Queens College and The Graduate Center, CUNY, has contributed significantly to critical investigation of the structural properties of cell membranes at the molecular level, particularly with regard to how properties of biomembranes are controlled by their constituent lipids. Lipids and proteins constitute the principal structural components of living cells. One focus of his research has been the naturally occurring sphingosine-based lipid, ceramide, which is generated in response to various cellular stresses, including chemotherapy and radiation. If cells allow it to act freely, ceramide induces the death of cancer cells. Unfortunately, the cells' enzymes quickly learn to recognize ceramide, and they modify its structure, either by adding a sugar molecule, thus turning ceramide into a cell-growth enhancer rather than a cancer-cell suppressor, or by removing a long chain from ceramide, thus making it less effective. To inhibit the modification of ceramide by the cells' enzymes, Dr. Bittman uses chemical synthesis to create unnatural analogs of ceramide. By taking out one atom and putting in another, for example, or by relocating some of the chemical groups within the molecule, he and his colleagues have created ceramide-like compounds that more effectively destroy cancer cells in cell cultures and escape recognition by the enzymes that would normally metabolize to wipe out normal ceramide.
Two other areas of his laboratory work are lipid rafts and anti-tumor ether lipids. Lipid rafts--they are called rafts because the lipids float on top of a tube containing different densities--are transient, specialized microdomains in biological membranes that contain cholesterol and various sphingolipids. Many scientists believe that lipid rafts are the platforms by which various viruses, including HIV, gain entry into the cells. Knowing whether or not lipid rafts are required, in general, for viral binding to cell membranes will have an important effect on the development of various drugs. In pursuing research on this question, Dr. Bittman and his co-workers analyzed the lipids required in the cell entry of two alphaviruses called Semliki Forest virus and Sindbis virus (both carried by mosquitoes but neither dangerous to humans), then they created an unnatural compound by synthesizing analogs of a phospholipid called sphingomyelin; these analogs do not form rafts because of their different structure. The team discovered that the alphaviruses were able to bind to the cell without rafts, thus proving that some viruses do not need lipid-rafts to bind with cell membranes.
Anti-tumor ether lipids, which are among the newest experimental anticancer agents, have two strong points. First, being unnatural compounds, they are highly resistant to the normal metabolic reactions that degrade most naturally occurring molecules in cells. Second, they differ from conventional cancer chemotherapeutic agents because they do not interact directly with the cell's DNA, which means that instead of giving rise to mutations, they block the growth of different types of cancer cells through a variety of mechanisms involving interactions with proteins. Through research on the mechanisms by which anti-tumor ether lipids promote cancer cell death, Dr. Bittman found that ET-18-OCH3, the most promising compound in this lipid family, acts by causing a protein called cytochome c to leak out of the mitochondria. Since mitochondria are the powerhouses of the cell, this leakage causes the cell itself to die. However, there is a price to pay: the naturally occurring ET-18-OCH3 has hemolytic properties so that patients can develop thrombosis. By changing the structure to put a sugar in the place of another group of atoms, Dr. Bittman's team made a new lipid compound that has no hemolytic properties but retains its anti-tumor properties. He is now trying to understand the way in which the anti-tumor ether lipid interacts with various proteins in the cell.
Other projects being studied by Dr. Bittman and his co-workers involve interactions between lipids and proteins in model membranes and movement of lipids within biological cells.
Dr. Bittman is the winner of the 2003 Avanti Lipid Award from the American Society for Biochemistry and Molecular Biology (ASBMB), and in 1985, he was among the first to receive the NIH Merit Award, a 10-year research award for which candidates may not apply, but are selected by the NIH staff. His research, which involves the participation of doctoral students in the Ph.D. Programs in Biochemistry and Chemistry and postdoctoral research associates, has been funded by the National Heart, Blood, and Lung Institute of NIH without interruption for 30 years, and the total of grant funds during this period is more than $5,000,000.
http://qcpages.qc.edu/~bittman/rb.html