Fishing expeditions are often frowned upon when one writes grant proposals. This is because one never knows what one will find and thus one can't expect to be funded for theoretical possibilities in biological sciences. I learned that it is a great thrill to actually go fishing for genes and to stumble upon something truly novel, a clue to an important regulatory pathway or mechanism of importance to human health. I also learned that few people care unless the findings have biological relevance. My mentors in the MD/PhD program at the University of Miami School of Medicine gave me the tools I needed to go into any field of medical research.

As I completed my medical internship at Johns Hopkins Hospital, a paper came out in the September 1, 1988 issue of the New England Journal of Medicine (the only journal I subscribed to at the time) on genetic alterations in colorectal tumorigenesis. When I read that elegant paper I knew I wanted to learn from Bert Vogelstein. I actually worked with Steve Baylin during my medical residency at Hopkins where I was exposed to the field of DNA methylation and the techniques of molecular biology. With persistence and a strong desire to work with Bert, I eventually joined his lab as a Medical Oncology fellow. Being in that environment was without a doubt critical for what followed. P53 seemed like a good choice to work on because not much was known about how it functions as a tumor suppressor.

On one snowy day during the blizzard of 1993, I came to the lab and obtained the first Northern blot result that showed that a transcript I had pulled out from a subtractive hybridization screen is in fact upregulated by p53. I called this transcript WAF1 (Wild-type p53-Activated Fragment #1) and kept on trying to find out what it does and how it was regulated. Maybe it was fortuitous that the abundance of the transcript was over 1% in the p53 "on" state, and so I kept recloning it over and over as a differentially expressed gene. It was definitely fortuitous that it’s a small gene and that most of my clones were full length.

As might be expected, others in the lab were skeptical about this target. I also wasn’t sure if it would turn out to be important. I did learn at that time that in science one has to take the quickest path to deciding whether what one is working on is a worthwhile activity. During the next several months of 1993, the evidence accumulated that p21 suppresses growth of cancer cells and that it is a conserved direct target of p53. It became obvious that it was a big story, bigger than the sum of its parts, when in the same issue of Cell in November 1993 the WAF1 gene was also cloned by Wade Harper and Steve Elledge as a CDK2-interacting protein which they called CIP1. I certainly think the timing of those discoveries was unbelievably coincidental and I am totally convinced that it really was an incredible coincidence.

Those pieces of the puzzle, provided from different fields asking different questions and using different approaches, immediately suggested a biochemical pathway that now seems so fundamental. For the first time, it became clear that when cells experience DNA damage, such as is caused by gamma-irradiation or exposure to chemotherapeutic drugs, activation of the p53 protein leads to direct transcriptional activation of a gene called WAF1/CIP1. This gene encodes a protein known as p21, which is a potent cyclin-dependent kinase inhibitor and mediator of cell cycle arrest. Cell cycle arrest of course allows time for repair of damage in order to enhance survival. I have spent the last few years trying to understand how p53 causes apoptosis, which is another piece of the tumor suppression puzzle and important for chemo- and radio-sensitivity in cancer therapy.

  What role did practical support (facilities, funding, etc.) play?

The environment and funding are very important for success in research. One needs to have equipment and resources and a set-up to answer the questions. One needs to have colleagues to talk to.

  What are the implications of your work for the future of your field in terms of clinical/therapeutic applications/products?

The implications are broad. Understanding the targets of p53 provides molecular markers that are being developed for diagnostic applications. The targets or effectors of p53 have opened up their own fields of trying to understand their physiological functions and to develop them as drugs or find drugs that activate them or their targets. There is a lot of activity along these fronts in the biotech industry. Small molecule CDK inhibitors are a good example of agents that are in clinical trials, which function in part similar to p21 through inhibition of cyclin-dependent kinases. Mediators of p53-dependent apoptosis are a hot item because of their relevance for cancer therapy. It does take years to screen and develop drugs for cancer but at least the connections to p53 are providing a rational way of doing so.

  What would you rate as your most difficult or trying professional moment?

There are many, as this career is often not a picnic. One has been to restrict my clinical responsibilities in order to focus on research. So rather than doing clinical work every week on an ongoing open-ended basis and dealing with whatever comes up, it has become clear that a much more protected practice is necessary to remain competitive in research. This is an important choice that all physician scientists face at some point. Another difficult moment came with a realization that funding runs out even if one carefully spends money for research. It would be nice if that never happened, but it has and I know it will happen again.

  Which of your professional achievements brings you the most satisfaction?

I would have to say serving on Grant Review panels and on Editorial Boards. Being able to play a part in making sure that the best science is funded and published is gratifying. I do enjoy teaching students more one-on-one in the lab, because that’s when you really get to know them well.

  Aside from your scientific career, what is your greatest or most compelling ambition in life?

I would like to be a good husband to my wife Evelyn, to raise a family, and to make sure they have a good life in the future.

Dr. Wafik S. El-Deiry
Howard Hughes Medical Institute
University of Pennsylvania
Hematology/Oncology Division
Philadelphia, PA, USA