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."

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.


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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.

Explore Further

C. Janeway, “How the Immune System Recognizes Invaders,” Scientific American, September 1993.

Pam Walker and Elaine Wood, The Immune System: Understanding the Human Body, Lucent Books, 2002.

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