Much to my satisfaction, the 1996 review of the Lab's the DNA Tumor Virus Program Project Grant resulted in renewal of this funding for the fifth time. As the term of the grant is five years, we enter our 26th year with this Program Project Grant, good through the year 2001.

This grant was established 25 years ago by Jim Watson and Joe Sambrook to use DNA tumor viruses to study cancer. In 1968, the Lab changed direction toward the study of DNA viruses that infect mammalian cells. Jim recruited Joe Sambrook, among others, to pursue these studies and in 1971 the first application was made for a large ($1 million) program project grant. This program project continues to be a cornerstone of cancer research at the Lab to this day. Over the years this grant has supported the studies of Joe Sambrook, Richard Roberts, Robert Tjian, Michael Botchan, Phillip Sharp, Louise Chow, Earl Ruley, Ed Harlow, Terri Grodzicker, Michael Mathews, Yakov Gluzman, and myself, as well as many others. It was this grant that supported Richard Roberts' studies on split genes that resulted in his winning the Nobel Prize in 1993 with Phillip Sharp.

The Program Project continues to use DNA tumor viruses to probe how normal cells become cancer cells and now includes Winship Herr, Arne Stenlund, Adrian Krainer, Ryuji Kobayashi, and myself. Additional components of cancer research recently added to the grant are studies by Carol Greider into the involvement of telomerase in tumor progression and a multifaceted approach aimed at understanding the mechanisms and regulation of programed cell death (apoptosis) in cancer cells by Scott Lowe (a former Cold Spring Harbor Fellow), and Yuri Lazebnik. Apoptosis involves a mechanism--built into every cell--that will cause the cell to self-destruct when it is triggered. This process is vital to development, ridding organisms of unnecessary cells (i.e., webs from human embryo fingers and toes, and tails from tadpoles as they become frogs) and also by destroying damaged or diseased cells. Most conventional cancer therapies work by triggering apoptosis, and Scott and Yuri each study different aspects of this process.

Scott Lowe reported, early in the year, the discovery of an important characteristic of the p53 gene--a known tumor suppressor. Cells at the center of solid tumors usually die from hypoxia, a lack of oxygen that results from the dense cellular overcrowding caused by the rampant cell division that is characteristic of cancer. Some cells, however, survive in these hypoxic conditions, and Scott, with Tom Graeber and colleagues at Stanford University School of Medicine, has shown that it is the cells with a p53 mutation that survive. Scott had shown previously that cells with a p53 mutation are immune to the effects of conventional cancer therapies. Together these studies provide a link between tumor growth and resistance to cancer therapy; tumor cells which acquire p53 mutations would survive hypoxic conditions and simultaneously become less susceptible to cancer therapy.

Yuri Lazebnik, who studies the mechanisms involved in the execution of programed cell death, has also focused on drug resistance in cancer cells, and is looking for ways to by-pass this therapeutic obstacle. Because conventional cancer therapy typically triggers apoptosis by damaging the cell to the point that it self-destructs, Yuri is trying to understand why this machinery is not active in some tumor cells despite the presence of the cell death signal. In addition, he is trying to discover how the latent signal in tumor cells can be activated.

Yuri uses an experimental cell-free system that he developed by mixing cytoplasmic extract from a cell with purified nuclei. Howard Fearnhead of Yuri's lab made an interesting observation in the cell-free system. When he used an extract from normal cells there were no changes to the nuclei, but the addition of an extract from untreated, drug-resistant tumor cells caused apoptotic changes in the nuclei--they began to fragment in the same way as nuclei in dying cells. This indicated that drug-resistant cells have the apoptotic machinery, but they cannot sense the triggering signal that is present. In collaboration with Scott Lowe, Yuri's lab traced the origin of this signal and found that it is generated by the very same oncogene that transformed the cell to become drug-resistant. Yuri's lab is now working to further identify the oncogene-generated activity. The hope is that this knowledge could be used to find a way to selectively activate apoptosis in cancer cells.