For Dr. Tak Mak, there are only two constants: the Ontario Cancer Institute and change

Posted: January 1, 2008 In: Portal Newsletter

Dr.

Dr. Tak Mak discovered in the T cell receptor in 1984. Since then he has conducted research on transgenic knockout mice, breast cancer and lymphoma.

In 1983, a 36-year-old scientist named Dr. Tak Mak attracted international attention for his breakthrough discovery of the T cell receptor. Mak is still a leading researcher with the Ontario Cancer Institute, but there are few other things that haven’t changed at least once over the past 30 years.

When Mak began his career, scientists had known for many years that a class of white blood cells, called T cells because they are produced by the thymus gland, protect the body against many types of infection. T cells recognize “foreign invaders” – substances that should not be in the body and could cause it harm. When they detect an invader, T cells signal B cells (the “B” stands for bone marrow, where B cells are generated) to produce antibodies that kill the invader, such as a virus, in the bloodstream. Because each T cell and antibody affects only one invader, the body is capable of producing millions of variations.

When antibodies fail to flush invaders out of the bloodstream, viruses can infect cells and grow inside them. Researchers had hypothesized that at this stage, T cells kill the cell after identifying that it has been invaded. However, research in this area was limited because nobody could find the receptor molecule on the T cell surface that identifies foreign invaders.

In 1983, Mak and Stanford University immunologist Dr. Mark Davis independently discovered T cell receptors and the gene that produces them. The breakthrough marked a major contribution to the understanding of immunological diseases ranging from AIDS to the common cold, as well as cancer.

In an interview with CBC Radio shortly after the discovery, Mak said that identifying the receptor was the “first step” to understanding the T cell. With his characteristic flair for explaining abstract science in concrete terms, he described the T cell as a “hit man” that goes around the body asking cells for passwords. If a cell presents the correct password, the hit man recognizes the cell is not his intended target and moves on. If it presents an incorrect password, however, it can also act like a weapon and kill the cell.

“If a T cell goes around to your lung cell and gives the password but the T cell has forgotten this is the right password, your body ‘shoots’ the cell,” he explained. “You slowly eat yourself up.” This is the basis of autoimmune disease.

“On the other hand, if the T cell goes around and sees a cancer cell or a virus-infected cell, and they give a password and the T cell says ‘Oh, maybe this is one of my own,’ then that guy is going to be allowed to take over,” leading to growth and spread of the disease.

Like many cancer patients, people with AIDS do not have a sufficient immune response to recognize and kill foreign invaders. This is why many people who die “from AIDS” in fact die from common diseases that would only cause minimal symptoms for a patient who does not have AIDS.

The discovery greatly accelerated many areas of research on vaccines and cancer. Although research on the T cell receptor continues to this day, Mak moved on to an entirely different area of in the late 1980s. He and his team dropped their ongoing research to re-focus on making transgenic knockout mice, with the hope of improving knowledge of cellular pathways.

Knockout mice have had a specific gene intentionally “knocked out” of their genetic makeup. The premise is that scientists can uncover a gene’s function by observing how a mouse without it is different from a normal mouse.

The first knockout mice were produced by Mario R. Capecchi, Martin Evans and Oliver Smithies in the 1980s, for which they were awarded the Nobel Prize for Medicine in 2007. However, the international scientific community was at first sceptical that knockout technology would be a practical way to conduct research.

In less than half a decade, Mak’s team had made significant advances in proving the technology was workable and attracted $100 million in funding from pharmaceutical company Amgen to continue his work.

“By the time he received the Amgen contract in 1993, it had become clear that Dr. Mak had made some excellent choices early on about which genes he wanted to study and had assembled a team that was capable of achieving his goals,” says his colleague Dr. Bob Phillips, who was director of immunology and cancer research at The Hospital for Sick Children at the time and is now deputy director of the Ontario Institute for Cancer Research. “Fifteen years later, knockout mice are one of the most valuable tools we have for assessing the role of gene functions.”

Less than a decade later, a combination of factors in Mak’s personal and professional life led him into another field of research. In 2002, funding for his laboratory was reduced. Mak used the remaining funds to establish the Advanced Medical Discovery Institute and shifted his interests to breast cancer.

In 2004, Mak was appointed Director of the new Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital. The Institute is involved in a range of studies, some of which are funded by OICR (go to story).

A year before the appointment, Mak told the journal Nature Medicine he had chosen to dedicate the remainder of his life to searching for cures for cancer. “Before I was like a kid on a beach turning over rocks looking for anything interesting. Now I am very focused.”

In a somewhat unique twist of fate, by making the move toward breast cancer research, Mak has followed in his daughter’s footsteps – she is a medical geneticist who works with breast cancer patients.

Unlike his daughter, Mak did not grow up with scientists as role models. Born to a wealthy merchant family in southern China, Mak moved with his parents to a predominantly European district of Hong Kong to escape from China where the communists took over the government in 1949. As a child, Mak took a greater interest in playing soccer and marbles than in schoolwork. After he graduated from high-school, Mak, whose family was Catholic, began training for the priesthood before deciding his interest was in science.

After earning his undergraduate degree from the University of Wisconsin (and after making another slight change in focus, from chemical engineering to biochemistry) Mak moved to Alberta to complete a PhD, then to Toronto for postdoctoral work at the Ontario Cancer Institute.

Since then, Mak has been invested as a member of the Order of Canada and earned scores of awards, including the Gairdner International Award. He was the first Canadian to win the prestigious Alfred P. Sloan Prize in the U.S. and has also received Germany’s top scientific award, the Paul Ehrlich and Ludwig Darmstaedter Prize.

Along with the awards have come offers to work elsewhere, but Mak has chosen instead to build his entire career at the Ontario Cancer Institute. “The whole world is contributing to medical research, and there is a sense that we should do our part. We are proud of what we can contribute to the world,” Mak says.