Three of the most important papers on the nature of genes that participate in the crucial decision-making process of cell death or cell survival come out of the laboratory of Tak Wah Mak, director of the Amgen Institute at the Princess Margaret Hospital in Toronto and the University of Toronto. Mak, however, has also recently published two other papers on genes that participate in the equally interesting area of bone formation. Collectively, these five highly cited reports gave Mak a prominent place in this publication's latest roundup of the hottest researchers in science (see Science Watch, 11[2]:1-2, March/April 2000).

   Mak’s resume demonstrates the remarkable range of his research career, from cloning the human T-cell receptor in 1984–an achievement documented in a Nature article that has garnered over 1,100 citations since then–to creating nearly 100 different gene-targeted "knockout mice" in the early 1990s, to his latest work on apoptosis and tumor suppressor genes. "I’ve been accused of being all over the place," says Mak with some pride.

   Mak, now 53, obtained his bachelor’s degree in biochemistry in 1967 and a master’s in biophysics two years later, both at the University of Wisconsin at Madison. He obtained his doctorate at the University of Alberta in Edmonton in 1972. He then moved on to a post-doctoral fellowship at the Ontario Cancer Institute in Toronto, where he’s been a member of the senior scientific staff ever since. In 1974, Mak joined the faculty of the University of Toronto, where he is now a University Professor. In 1993, he became the founding Director of the Amgen Institute at the Ontario Cancer Institute.

  You say your research interests have been "all over the place." Can you give us a brief summary of your career path?

Mak: I started off with retroviruses and then worked with the Friend leukemia virus, which causes erythroleukemia. I next worked with Howard Temin and cloned a gene called v-rel, a member of what is now recognized as one of the most important gene families in the immune system. kB, for instance, is part of the rel family. My group and I then shifted into immunology and were lucky enough to have cloned the human T-cell receptor genes. This basically opened up T-cell molecular site-recognition studies. Then, to look at the physiological functions of some of the genes that we and others discovered, my group learned how to make knockout mice. In fact, we were one of the first labs in the world to make a knockout mouse. We stayed in immunology for a while, making mutant mice to define cellular and molecular pathways of immune-system development and activation. Cellular and embryonic development require apoptosis, which is how we got into studying genes involved in programmed cell death. We started looking at tumor suppressor genes because defects in cell death and survival pathways can contribute to cancer. We're now shifting to Drosophila genetics because many of the pathways uncovered in mammalian cells are conserved in the fly. The Drosophila genome has just been sequenced, and the reproduction time of these animals is short, making it easier and fast for us to do our work.

  What’s the connection in your five hot papers–between the genes involved with apoptosis and genes involved with bone formation?

Mak: Apoptosis occurs in response to balancing of the triggering of survival and death receptors, and many genes in very complex signaling pathways lie downstream of these receptors. What we want to do is define the biological roles of these genes in different situations: whether they are participating in certain pathways but not others, in certain tissues but not others, or in response to only certain death stimuli. This has long been an area of intense research interest. Biochemistry was originally promising as an approach but has sometimes led to confusion in defining, once and for all, the requirement for a gene and the proteins it encodes. Our approach is genetic, and the advantage of the genetic approach is that once you obtain a mutant and it behaves in a certain way, you can deduce the gene's function and basically get a solid answer. After such a definition people don’t usually have to go over it again, and so these sorts of papers tend to get more attention than others.

To answer your question, we got into the bone work as part of our immunology program. There is a molecule called OPGL, which is part of the tumor necrosis factor (TNF) family. Dr. Josef Penninger and his colleagues had imagined that OPGL would be involved in the development and activation of T and B cells. It was found, to our surprise, that OPGL also has a critical role in bone formation because it is the primary differentiation factor for osteoclasts. OPGL is going to be one of those factors that pharmaceutical companies will explore as a possible treatment for bone diseases. In addition, we found that a TNF receptor family downstream effector molecule called TRAF-6, which was thought to be only in signaling for inflammation, is also involved in osteoclasts differentiation.

  Your most highly cited paper was the cloning of the T-cell receptor. How did that come about?