By the late 1980s, you had switched from studying T-cell receptor and activation to doing knockout mice. What prompted this change?

Mak: You could say that my yearning for genetics, or my respect for the power of genetics to assess biological roles, came back to me. In 1988, several things happened simultaneously. Mario Capecchi and Oliver Smithies had shown that one could induce homologous recombination in mammalian cells. They and others then postulated that if it was possible to do that, it was possible to get homologous recombination to occur in embryonic stem cells. Embryologists had already shown that one could inject embryonic stem cells into mouse blastocysts and generate a new mouse. Combining those two techniques would essentially give you knockout mice. So, in 1988, I got together with Oliver Smithies, who was a friend from my Madison days, and tried to learn the general concept from him. Then I met with Klaus Rajewsky, a B-cell immunologist in Cologne, and we agreed that we would both work to establish the technology to obtain knockout mice. He would concentrate on B-cell genes and I would concentrate on T-cell genes. In 1990, just as we planned, we were first to make knockout mice in the field of immunology; Rajewsky's lab in B cells and my lab in T cells. Since then we’ve probably made nearly 100 different kinds of knockout mice.

  And now you’re moving into Drosophila genetics?

Mak: Yes, because we want to sort out intracellular signal transduction pathways like those involved in a tumor suppressor called PTEN, among others. I thought that the easiest way to decipher these pathways would be to use some kind of a genetic screen. The publication of the Drosophila sequence this past spring in Science (287[5461]:2181, 24 March 2000) makes Drosophila genetics relatively easy. In anticipation of that publication, we set up to do Drosophila genetics in our lab.

  Before turning to Drosophila, however, in the mid-1990s, you switched to apoptosis and cell survival pathways. What was your motivation?

Mak: I wanted to understand apoptosis and survival pathways, and felt that using the genetic approach of deriving mutant mice might be very successful. We first got involved in generating mice mutated in the genes for the TNF receptors, and by this kind of study found out how complex apoptosis is and how some genes are essential for cellular suicide while others are redundant. I also returned to studying tumor suppressor genes, something I was interested in during the early 1980s. It was our lab that made the knockouts of the breast cancer-associated genes BRCA1 and BRCA2 genes, and also helped uncover the signaling pathway downstream of PTEN, which is still a major focus in our lab.

  Last year you had a breakthrough in Hodgkin’s lymphoma. Are you excited about that?

Mak: Hopefully, this is going to turn out to be one of the things I will remember in the last hour of my life, and I dream that it will lead to a very, very important adjunctive treament for Hodgkin's lymphoma. Right now the disease is treated with radiation and chemotherapy, and patients have an approximately 70 to 80 percent chance of "long-term remission." But the treatment is very harsh, and is often associated with a high rate of sterility and secondary tumors, What we discovered was that Hodgkin's lymphoma may be autocrine disease, in that cells called Reed-Sternberg cells produce the growth factor interleukin 13, which then acts back on its own receptor to promote further tumor-cell growth. Amazingly, when we deprived the Hodgkin lymphoma cells of IL13 by adding neutralizing antibodies against some cell lines, the tumor cells stopped growing. We speculate that this anti-IL13 may represent a useful treatment for the disease. Even better, since IL13 is not a cytokine that our bodies absolutely need, we might have a treatment that will make some impact on the disease yet be totally free of side effects.

  How far along is the work?

Mak: It’s still at the theoretical state but the basic results have since been confirmed. The problem now is that Hodgkin's lymphoma is not a very common disease, so the big biotech and pharmaceutical companies consider the commercial market too small to interest them. So far, the interest in mounting a clinical trial based on our findings is mainly coming from academic and non-profit organizations. I think it eventually will happen, but it’s too early to say how or when. Keep watching the literature!