Profile of Tak Wah

PROFILE Profile of Tak Wah Mak ays after Tak Mak and col- for the same pay rate. Mak accepted leagues (1) revealed a way that the challenge. “That was the beginning of Dcancer cells adapt to environ- my scientific career,” he says. mental stress, the immunologist At the time, Rueckert was studying the and his team announced the discovery replication and assembly of RNA viruses, of a protein that may cause heart failure particularly picornaviruses. In 1974, (2). The two breakthroughs were all in a Mak coauthored a Rueckert paper pub- week’s work for Mak, director of The lished in Intervirology (4). The meticu- Campbell Family Institute for Breast lousness of this study, which involved the Cancer Research at the Princess Margaret use of sodium metaperiodate in micro- Hospital in Toronto, Ontario, Canada. molar concentrations, exemplified Throughout the course of his career, Mak Rueckert’s approach to science and has contributed to over 700 papers, re- made a strong impression on Mak. “Ev- ceived more than 65,000 citations in erything Roland did was very systematic, fi leading scienti c journals, and garnered thorough, and precise,” Mak recalls. numerous prestigious international “Through Rueckert, I learned discipline awards. In 2002, he became a foreign asso- and how to organize experiments.” ciate of the National Academy of Sciences. After earning his doctorate, Mak Mak’s discoveries have made enormous ’ accepted a postdoctoral fellowship at contributions to researchers under- the Ontario Cancer Institute (OCI) in standing of immunity, particularly as it Toronto, where he remains a member of relates to cancer, arthritis, autoimmune the senior scientific staff. In the mid- disorders, heart disease, and HIV/AIDS. 1970s, Mak worked in the OCI laborat- In 1984, working against all odds, in- ories of Ernest McCulloch and James cluding a rejected research grant, Mak and Till, the codiscoverers of hematopoi- colleagues (3) identified a cornerstone Tak Wah Mak. etic stem cells (5). “McCulloch was an of modern immunology: the first gene encoding a subunit of the human T-cell original thinker and not at all a conventional person,” Mak says. “He taught me receptor (TCR). Mak, who is also a pro- about to enter university. “I wanted to go to challenge dogma and not to believe fessor in the Departments of Medical to the University of California, Berkeley, ” Biophysics and Immunology at the Uni- but my mother and her friends said, everything I read. If the young Mak versity of Toronto, achieved this success, ‘ ’ ’ broached a theory, McCulloch would Don t go to Berkeley. It s a hotbed of fi in part, because he challenged conven- antiwar activities, and you will never be ask for ve different speculations based “ tional scientific thought and forged fresh able to concentrate on your studies,’” he on that single theory. For me, it was research paths. Many of his peers have recalls. “I wound up at the University of like a new door opened. McCulloch fi predicted that these qualities will allow Wisconsin, Madison, which had one of taught me the bene ts of combining a Mak, a visionary and prolific researcher, to the top chemistry and biochemistry de- careful and methodical approach with solve some of the world’s most perplexing partments in the nation. Ironically, it also thinking freely and beyond the usual scientific problems. had even more radical antiwar activities boundaries.” than Berkeley.” In 1980, Mak returned to the University Unusual Beginning Mak initially pursued chemical engi- of Wisconsin to learn molecular biology Mak’s journey could never be called neering at the University of Wisconsin techniques from Howard Temin, who later conventional. As he says, “The classic but soon realized his interests lay else- won the Nobel Prize in Physiology or profile of a scientist begins with someone where. He switched his major to bio- Medicine for his discovery of reverse tran- at the age of 4 finding a frog in the woods chemistry, earning his bachelor of science scriptase (6). “That was a very important and then becoming in tune with nature. degree in 1967 and his master of science year for me,” Mak says. “Ilearnedtobe My story was nothing like that.” degree in biophysics 2 years later. He humble because, after working with Born in southern China and raised in then moved to Canada and obtained his McCulloch, I believed I could think freely Hong Kong, Mak was educated at a re- doctorate from the University of Alberta and make my own hypotheses in an un- ligious school deemed among the best in in Edmonton in 1972. restricted way. Howard Temin taught me the then-British colony. His high school, that my free thoughts also needed to be directed by Jesuit priests, was extremely Three Wise Men deep and insightful.” Like Mak, Temin was well regarded, with parents competing to During his studies at the University of interested in many different disciplines. gain their children entrance. Mak’s family Wisconsin, Mak met the first of three Temin took great advantage of his exten- urged him to become a doctor, but the men who he says shaped his life’s work. sive knowledge to make unconventional intellectual young man had other ideas, Virologist Roland Rueckert was new to scientific connections. Mak explains that “ ’ and a lot of them. I was very interested the university s biochemistry department the process is “like turning over a rock in “ in history, but there were no jobs in his- and looking for staff. Roland had a job Australia and having it remind you of an- ” “ ” tory, he says. I was also interested in opening in his lab for a dish washer, other rock on a beach in Hong Kong.” For math, biology, and chemistry but not so Mak says. The job paid $1.25 an hour. Mak, it is a matter of thinking in an much physics. Basically, I graduated from After scrubbing test tubes and beakers for high school with the goal of avoiding a day, Mak inquired if more such work ” medical school. was available. Rueckert replied that there fi ’ This is a Pro le of a member of the National Academy of During the mid-1960s, Mak s family were no more dishes to wash but invited Sciences to accompany the member’s Inaugural Article on moved to the United States just as he was Mak to help with research experiments page 13984 in issue 32 of volume 107. www.pnas.org/cgi/doi/10.1073/pnas.1116912108 PNAS Early Edition | 1of3 Downloaded by guest on October 2, 2021 unconstructed manner while drawing on traction work until, on one memorable a leading biotechnology company based a wealth of remembered data. weekend, the Eureka moment happened. in California. That company established Although Mak also credits his students “It was a sunny Sunday afternoon in the a research institute in Toronto where and postdoctoral fellows with teaching summer of 1983,” Mak recalls. “I walked Mak and others could expand their stud- him a great deal over the years, it was into the lab, and there was a stack about 2 ies of genetic diseases, cancer, and auto- these three men—Roland Rueckert, ft high of computer sheets comparing the immune disorders. With the generous Ernest McCulloch, and Howard Temin— sequences of our T cell-specific genes to funding provided by Amgen, Inc., Mak who most strongly influenced Mak everything in the gene bank.” About was able to double the size of his team. during the years preceding his own 5,000–6,000 known sequences had been scientific breakthroughs. compared at that time. “After scanning Changing Course through hundreds of pages, I held up one Like many others, Mak and colleagues Beating the Odds sheet, looked at it from an angle, and have used genetically modified mice After wrapping up his work with Temin, there it was—YT35, a clone whose pre- and related approaches to achieve im- Mak returned to Toronto to establish dicted protein sequence was similar, but portant advances in cancer research. his own laboratory at OCI. Mak’s original not too similar, to an Ig’s variable, join- However, Mak has been frustrated by the team, consisting of postdoctoral fellow ing, and constant regions. I stared at it lack of targeted therapies for this deadly Kohei Nagasawa and three other indi- for a long time and finally said to myself, disease. “The FDA has not approved viduals, focused on two separate areas: ‘I can’t believe it. This could be the a drug for a new major anticancer target oncogenic retroviruses and human T-cell human TCR.’” between 2007 and 2010,” he points out, leukemia. Their initial goals were to un- Subsequent experiments proved that even though billions of dollars have been derstand precisely how retroviruses can Mak’s suspicion was correct. Also in the poured into this field, along with the ef- transform cells and to elucidate the mech- summer of 1983, Mark Davis at Stanford forts of thousands of scientists. anisms underlying T-cell differentiation. University was independently using a re- Popular targets for new anticancer drugs At the time, the genes encoding the lated approach to clone a mouse TCR are oncogenes, which are mutated or TCR had proved so difficult to clone that gene (8). The Davis and Mak teams amplified forms of normal cellular genes. the task was nicknamed “the holy grail of published back-to-back papers in Nature In the 1970s and 1980s, the general sci- immunology” (7). Laboratories world- in March 1984, announcing their seminal entific belief was that a few oncogenes wide were pouring millions of research findings. The first line of Mak’s abstract were the major drivers of most cancers; dollars into solving the mystery of how understates the tremendous power of the thus, these genes became the focus of T lymphocytes recognized their targets achievement: “We have cloned and se- much basic research.

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