Anne-Marie Green
Anne-Marie Green
Communication Manager, Wiley

Next Friday, April 17th, the Wiley Prize in Biomedical Sciences will be awarded to Evelyn Witkin and Stephen Elledge for their studies of the DNA Damage Response. At that time, they will be giving an honorary lecture at The Rockefeller University, which will be live-streamed as a part of the free Current Protocols webinar series. We spoke to them recently about their contributions to their field and what the Wiley Prize means to them.

Q. How and why did you enter this area of research?

 

 

Source: Evelyn Witkin
Source: Evelyn Witkin

Evelyn Witkin: Early in my graduate work at Columbia, I read two articles that determined my decision to study induced mutations in bacteria. The first was by Hermann J. Muller, the Nobel laureate who discovered that X-rays induce mutations in fruit flies. Muller believed that one way to understand the nature of the gene (which was totally unknown in the early 1940s) was to study the mechanism of mutagenesis. I decided to focus on ultraviolet light-induced mutations in Drosophila.

Then I read the 1943 paper by Luria and Delbruck, which essentially proved, unexpectedly, that bacteria have genes like other organisms. It seemed to me that bacteria would be ideal material for the study of genetics, as they divide every 20 minutes and produce a billion individuals overnight in a single test tube. With the approval of my advisor at Columbia, I chose to investigate ultraviolet light–induced mutations in Escherichia coli.

 

Source: Stephen Elledge
Source: Stephen Elledge

Stephen Elledge: I was trained as a chemist as an undergraduate but became fascinated, like so many others, with DNA, so I enrolled in the biology department at MIT for grad school. After MIT, I did post-doctoral work at Stanford in 1984 where I initially intended to work on plants, but eventually I decided to work on gene targeting in human cells. My plan was to clone the key recombination enzymes from mammals and use them to coat recombinant DNA and reintroduce them into cells to allow them to disrupt the chromosomal gene by homologous recombination. This would allow us to perform genetics in mammalian cells, a lifelong goal of mine. To find the recombinase I first decided to isolate it from a model eukaryote using knowledge about the pathway from bacteria and then use this gene to identify the homolog from human cells. I thought that I had isolated the yeast gene but it turned out to instead be a gene for making dNTPS, ribonucleotide reductase. This was a disappointment. However, before I dropped the project completely, I noticed this gene was turned on very strongly if I interfered with DNA replication. While I wasn’t intending to work on this area, I realized there must be a pathway that sensed the replication problem and transmitted that information to my gene. This gave me the idea that a signal transduction pathway exists for reporting information about the status of DNA to the cell to coordinate a response and I decided to work on this area as part of my research program.

Q. What has been the most challenging aspect of your research?

EW: The lack of direct biochemical approaches to the study of mutagenesis at the time I was doing most of my experiments, between the 1940s and 1980s, was the biggest challenge. We had to infer the molecular events that took place between the exposure to the radiation and the establishment of a mutation during the first postirradiation DNA replication. It was difficult, but very satisfying when our indirect methods succeeded in illuminating that particular black box.

SE: While I thoroughly enjoy working in new fields, it is a challenge to keep up. In addition to working on the DNA damage response, my group has worked on developing genetic technology, yeast and human cell cycle research, cancer research, virology and now immunology. Sometimes I think not knowing exactly what everyone thinks is actually a good thing, because it encourages independent and creative thought.

Q. What has been the most rewarding part of your research?

EW: Without doubt, the most rewarding part was the joy of being part of a community of scientists who shared my passion for understanding the gene, and who regarded science as a cooperative, rather than a competitive, venture. The small international field of mutagenesis and DNA repair was a close-knit group of researchers who freely exchanged information, ideas, and mutant stocks; who cheered each other’s successes and who often became close friends.

SE: My answer to that is three-fold. First, it is a great pleasure to try to solve biological puzzles. And when the right idea appears and all the disparate pieces fall into place and everything makes sense, it is an incredible feeling. The second truly rewarding part of my work is the ability to interact with bright young scientists and to help them develop critical thinking skills. I watch them grow both scientifically and personally and it is a great source of pride to watch them go on to develop their careers. Finally, I find rewarding the fact that our work might help others.

Q. What are the biomedical implications of your findings?

EW: Although we worked with bacteria, I often told my students that we were actually doing cancer research. Cancer often starts with DNA damage and the mutations that may follow. The understanding we achieved in bacterial genetics has certainly informed our current understanding of carcinogenesis. Higher organisms have evolved their own ways of coping with DNA damage, yet we still share with E. coli some of the same genes, enzymes, and strategies that were first revealed in bacteria.

SE: In addition to its significance in cancer research, our work also has implications for aging. Not only do mutations in the genes I have discovered cause cancer, but these same pathways help chemotherapies cure cancers. One gene I discovered, Chk1, has been a drug target for pharmaceutical companies and is in clinical trials.

Q. What are you currently working on?

EW: I retired from active research in genetics in 1991, and haven’t done any laboratory work since then. However, I am doing active research in a new (for me) field: Victorian literature. I am looking for (and finding) connections between my two favorite Victorians, poet Robert Browning and his contemporary Charles Darwin. At the same time, I am trying to keep up with the break-neck pace of advances in genetics. You never fall out of love with genes.

SE: I am now working on the physiological significance of activation of the DNA damage response pathway. Activation of our pathway can result in cellular senescence which is another tumor suppressor pathway. However, senescent cells also accumulate in our bodies as we age and contribute to an overall inflammatory environment which promotes age-related diseases including cancer, it is a two edged sword. We are currently working out how this inflammatory state is activated in response to DNA damage. We are also working on understanding how aneuploidy promotes cancer and we’ve developed a new theory to explain this and show that aneuploidy is a strong predictor of survival in cancer patients. On the immunology side of my lab, we have developed new methods to identify autoantigens in autoimmune diseases and an assay that can detect antibodies to all human viruses.

Q. What does winning the Wiley Prize mean to you?

EW: Winning the Wiley Prize is a great surprise, as well as a great pleasure. It is also a welcome excuse to look back on some of my nearly forgotten papers, and to relive the excitement of discovery after nearly forty years. It is gratifying to have one’s work recognized, although any temptation toward self-congratulation is tempered by thinking of all those I could mention who deserve it more.

SE: It is a great honor, especially to win it with Evelyn Witkin, who has done so much to first bring this field to the attention of science. She is a true pioneer to whom we all owe a debt of gratitude. This prize is also a testament to the great people I have worked with over the years. To have your work honored like this is very fulfilling and is an honor for all of these great students and post-docs who have made it all possible.

Thanks to you both and congratulations!