Tak Wah Mak Microbiology and Immunology

Discovered the T-Cell receptor, a key to the human immune system

"Don’t be afraid to tackle science if you enjoy it."

The Story

Tak Mak is a very imaginative fellow. When asked to describe his work as an immunologist, instead of telling a story about himself he came up with the following tale concerning the life of an imaginary T-cell.

Tommy T-Cell is a biodetective. His job is to patrol the human body, investigating suspicious characters. Think of the cells in the human body as shops on a city street. Billions and trillions of police detectives like Tommy T-Cell are driving by all the time, looking in all the shop windows for something unusual going on. Each T-cell is trained to find one — and only one — type of criminal. There are several different kinds of T-cells. Tommy is known as a helper T-cell, part of the body’s immune system, but you can think of him as a cop.

As Tommy cruises through blood and tissue he meets a macrophage, a specialized cell that’s a combination reconnaissance and disposal unit in the body. Macrophages go around collecting bits of your own living and dead cells. They find parts of invading viruses and bacteria, dust, pollen and any junk that’s floating around. They stick pieces of this garbage on their outside surfaces in special places where detectives like Tommy can see them. Tommy has unique Y-shaped spikes called receptor sites all over his surface, and they recognize one kind of garbage. (In 1983 Tak Mak discovered these T-cell receptors.) Tommy’s got about 5,000 receptor sites and each one is exactly the same. No other T-cell has spikes like Tommy’s. His are specially designed to collect a tiny bit of protein from a virus that causes colds. Tommy tries his receptors on the macrophage, but nothing happens, so he moves on. The whole thing takes less than a second.

As Tommy floats along, he remembers his days years ago at the body’s police academy, the thymus, where he learned how to tell foreign invaders from good cells that belong to the body. The T in T-cell is for “thymus,” because that’s where T-cells come from. The thymus is a fist-sized gland located just above the heart. It’s bigger and more active in babies than in adults. In the first years of life, the thymus gives all the T-cell detectives in the body their lifelong assignments. T-cells start out in the thymus as police cadets. They are trained by special macrophages that show new T-cells every possible little bit of garbage that a normal healthy body produces. These bits are called “self.” T-cells whose receptors recognize “self” are killed in the thymus before they can leave; if they ever got out, they would become bad cops that attack good cells instead of invaders.

Tommy finally cruises up to a macrophage that shows him a piece of a cold virus. He checks it with his receptors. It’s a match. The virus has been in the body for only five minutes, but Tommy leaps into action. First he sends out chemicals that signal regular police officers in the body — B-cells — to make antibodies. Antibodies are like heat-seeking missiles that zero in on a particular virus and kill it. Tommy, the helper T-cell, also calls in a SWAT team of killer T-cells and together they go out in search of the invader. They start dividing rapidly, doubling in number about every six hours. It takes four days before millions of T-cells, B-cells and killer T-cells are mobilized to kill all the virus in the body. Immune-system cells are some of the fastest-dividing cells we have inside us.

One day, Tommy is cruising the body on his usual rounds when he meets a thug in a black leather jacket, an AIDS virus. He decides to check him out with his receptors, but before he can do anything the little creep gets right inside Tommy through a tiny hole near the handle that Tommy uses when he visits macrophages. Viruses don’t usually attack T-cells, but AIDS does. That’s what makes AIDS so bad. Now that Tommy has the AIDS virus, little bits of AIDS proteins will appear on his surface. This makes him look very bad to other cells in the immune system. Tommy sees a killer T-cell coming and says his prayers: he knows that a killer T-cell is trained to kill anything that looks foreign. The killer T-cell sees that bit of AIDS on Tommy and, without a second thought, kills his boss. That’s the end of Tommy.

The tragedy of AIDS is that T-cells are the mastermind detectives of the body’s defence system, the ones that organize the other cops. Once AIDS is inside a T-cell, those T-cells look like spies to the rest of the immune system. So the body kills off its best cops, which then makes it harder to fight AIDS and any other infection. Most people with AIDS actually die of a common disease, such as a chest infection that would never kill some-one with a healthy immune system.

As A Young Scientist...

Tak Mak was the son of a successful businessman in southern China. After the Communists took power in 1949, Mak’s father moved the family to Hong Kong to escape the turmoil of political revolution. They were very well off and lived in a predominantly white, upper-middle-class district made up mainly of Dutch, Danish, Swedish, Norwegian and British families. They lived next door to the consulates of Norway and Denmark. “It was a rich neighbourhood,” says Mak. He was the only Asian kid on his street, but like all the other boys he liked to play marbles in the dirt and kick soccer balls around.

Mak wasn’t particularly interested in school, but his mother insisted that he do well and study hard. It helped that at school he was in a very bright group of about 20 kids. Most of them went to universities all over the world. Mak went to the University of Wisconsin in Madison.

In the early 1970s, after he had received his doctorate (PhD) from the University of Alberta, Mak began his research at the Ontario Cancer Institute in Toronto. He is still a senior scientist there today. After his discovery of the T-cell receptor he became a professor at the University of Toronto, and in 1993 he also became director of the Amgen Research Institute in Toronto, which develops, patents and markets transgenic mice — animals that carry immune-system genes transferred from human beings. During his years at Amgen, Mak led a team that produced 20 patented molecular discoveries for use in drug development. In 2004 Mak left Amgen to become director of a new Institute for Breast Cancer Research.

The Science

As an immunologist and molecular biologist, Mak examines the structure and function of molecules and cells in the human immune system, which protects the body from microscopic dirt and disease. His immune-system research may lead to cures for many autoimmune diseases in which the body’s immune system malfunctions — diseases such as diabetes, multiple sclerosis, rheumatoid arthritis, lupus, myasthenia gravis and others. His current cancer research is aimed at finding a cure for breast cancer.

After Mak discovered the genes for the T-cell receptor, he began using this knowledge to create “knock-out” mice. These are mice with missing DNA instructions for making just one protein in the immune system. Mak’s group was one of the first labs in the world to make knock-out mice and they made about 100 kinds throughout the 1990s.

A “knock-out” mouse

To Mak, the immune system is like a huge company that’s so big and complicated you can’t easily tell how it functions. But there is a systematic way to find out. One day you take “John Smith” out of the company building, and see what stops functioning. Maybe the mailroom grinds to a halt. Now you know what John Smith does. Then you put John Smith back and you try the same thing with another person. Eventually you find out how the whole company works. Along with many other researchers around the world, Mak is using a similar process to understand the immune system. They “knock out” certain genes in mice and then they see what part is missing in the immune systems of those mice.

The human immune system is very complicated and the following is just a very simple explanation of one major part.

1. Macrophages are like combination reconnaissance and disposal units. They get bits of molecules from invaders and present them to T-cells for identification. They can also surround and digest dead cells and foreign substances in the blood.

2. Helper T-cells (Th) are the “masterminds” of the immune system. They use their receptors to identify invaders and send signals to B-Cells (B) and killer T-cells (Tk) to start the attack. Each T-cell receptor recognizes one short piece of a protein molecule, about eight amino acids long. There are trillions of unique T-cells in a healthy person, enough to recognize any foreign molecule that enters the body.

3. Killer T-cells (Tk) are best at killing viruses. They can recognize a virus and then release a toxin, or poison, that kills it and any others in the vicinity.

4. B-cells are particularly good at destroying bacteria. They make antibodies (G) that glom onto bacteria and make them easy to kill. B-cells can also trigger mast cells that act as a kind of long-term memory for the immune system, so a defence can be mounted faster the next time the body is attacked.

Because the immune system kills invading cells to protect the body, Mak’s research eventually led to the study of how cells die and how cell death is regulated within the body. Scientists had discovered that one way T-cells rid the body of a virus is by inducing virus-infected cells to commit suicide. This process of programmed cell death is called apoptosis and is a normal part of life. Damaged cells in living things sometimes need to die to protect the rest of the organism from potential harm. For instance, the thymus “police academy” in the story above kills self-attacking T-cells by apoptosis. (Mak had to learn all about this process of orderly, controlled cell death to better understand T-cells and disease.) In the process of building up an army of police to attack the intruders, the T-cells make billions of copies of themselves so they can have enough troops to fight. After the battle is over, most of these T-cells also have to “commit suicide”; otherwise, they might upset the balance of different kinds of blood cells in the body. However, too much apoptosis causes cell-loss disorders, and too little results in uncontrolled cell proliferation, as in cancerous tumours. Through much of the 1990s Mak was working on cancer, which is really about cells that won’t die.

In 2004 Mak’s research took a new direction when he became director of the Campbell Family Institute for Breast Cancer at Toronto’s Princess Margaret Hospital. He wants to devote his time to breast cancer, the second-most-common cancer in women (after lung cancer).

According to the U.S. National Cancer Foundation, more than 200,000 American women are diagnosed with breast cancer each year and nearly 40,000 die because of it. In Canada, with its smaller population, an estimated 23,000 women will develop breast cancer this year, and 5,300 will die from it. “It’s the number one cause of death for young women,” says Mak. “That’s a lot of mothers, a lot of children, a lot of daughters, a lot of wives. A lot of reasons to do breast cancer research.”

Mak’s research now focuses on apoptosis and the many biochemical processes that regulate cell death in cancers. “We found out how complex apoptosis is when we were making knock-out mice, and how some genes are essential for cellular suicide while others are redundant.” His team is following many avenues of research; for instance, it has started breeding fruit flies to gain a deeper understanding of fundamental biological systems that may have an impact on human diseases. The genome of the fruit fly was completely decoded in 2000, and much of the genetics and biochemistry of apoptosis is the same in fruit flies as in humans, making it relatively easy to identify which genes are involved in turning apoptosis on and off. Fruit flies have a much shorter lifespan than mice, so results can be obtained faster since more experiments can be done in a shorter period of time. The goal is to use the technique of knocking out certain genes to identify specific biochemical factors that stop the growth of various kinds of tumours.

Mak is also active in developing what are called targeted therapeutics — special drugs that attack only diseased cells. In 1999 he and his team found a specific growth factor that appears to fuel the growth of Hodgkin’s lymphoma, a type of cancer. “Right now the disease is treated with radiation and chemotherapy and patients have a 70- to 80-percent chance of long-term remission, but the treatment is very harsh and often results in a high rate of sterility and secondary tumours.” In test tube experiments and in mice, when Mak added a chemical that blocked the fuel supply to Hodgkin’s lymphoma cells, the tumour cells stopped growing and died by apoptosis. The growth factor he blocked is not something our bodies absolutely need most of the time, as it functions mainly to fight parasites, so Mak is hopeful that it will stop the disease and yet be mostly free of side effects.

Mystery

Mak believes that in the future scientists will use the immune system to clean out leftover cancer cells after tumours are surgically removed or killed with chemotherapy. He also believes that much better vaccines can be developed for malaria and other diseases that are currently difficult to control. He thinks a cure will be found for juvenile diabetes. But for him the biggest unsolved mystery of all is the way the immune system distinguishes between foreign invaders and “self.” He says the thymus is only half the story, because many new antigens (or foreign molecules) attack our bodies long after the thymus has finished the bulk of its work training T-cells.

Professor Howard Temin at the University of Wisconsin; Ernest McCulloch, Director, Ontario Cancer Institute 1983-92; Roland R. Ruekert, Director, Virology, University of Wisconsin. The Professor who introduced me to science was Roland Rueckert from the university of Wisconsin. All the above individuals taught me to think of hypotheses, test them experimentally, and formulate new concepts based on them.