How Tak Mak connects the dots to make medical breakthroughs

Shelley White
Special to The Globe and Mail
Published Friday, Aug. 22 2014

When it comes to scientific discovery, Tak Wah Mak is an undisputed rock star.

The world-renowned Canadian scientist and researcher has devoted his life to unravelling medical mysteries in the areas of virology, immunology and cancer metabolism. His brilliant career has been punctuated by breakthroughs, including the discovery of the Holy Grail of immunology – the T-cell receptor – in 1984.

At 67, Dr. Mak is co-director of the Campbell Family Cancer Research Institute at the Princess Margaret Cancer Centre in Toronto. He thrilled the medical community last year when he and his team developed an exciting new drug that could revolutionize cancer treatment.

Called a “sharpshooter” drug, CFI-400945 is a totally new way of approaching cancer treatment. The drug targets a key enzyme called PLK4, which plays a critical role in cancer cell division, and unlike chemotherapy, doesn’t affect healthy cells.

The drug has been in clinical trials for several months, blinded to everyone except two doctors who are sworn to secrecy. (Dr. Mak is not one of them.) The trials are scheduled to continue until 2016, but he says, “If [results are] spectacular, I think we will know early next year.” Meanwhile, Dr. Mak and his team have continued to search for more targets, and are developing another promising cancer drug from a second target enzyme.

Dr. Mak stepped out of the lab to discuss his innovative process, why Canada needs more clinician-scientists and how scientific discovery can be like listening to Mozart:

Where does the spark of innovation come from?

I don’t know! (Laughing.) I think it’s important that one is curious. Curiosity is a very important part. There are theories that this is genetically inherited – the ability to make connections. But I think it is so very important for those of us who try to make new intuitions that we are very, very curious about different things.

Read and try to understand a wide variety of disciplines and try to make connections, because the universe in science is all connected, whether it’s at the level of chemistry or physics or biology. There are principles you can cross-reference and I think that to me is a very important part of being able to make new observations.

What is your innovative process? Do you work better alone or in a team?

I work extensively in teams. I have two dozen or so very close friends who are scientists who I constantly engage with, whether it’s in a meeting or when we try to relax and play a round of golf.

My quest for knowledge is very high, and what turns me on is to be able to listen to a presentation that someone is making and all of a sudden, in my mind, I say, ‘Oh my gosh, this is connected to something else I know.’ And I think this process is extremely important.

You have made brilliant discoveries in your career. How do you allow your mind to let go of what you know and think outside the box?

I am on a dozen scientific advisory boards … so I am constantly being exposed to lots of data and ideas from everybody. So it’s almost like you keep feeding information into a computer and the computer keeps cranking away, trying to make connections.

I just came back from Japan … and a very prominent cancer doctor presented his work and his views. I was going nuts. It’s like listening to Mozart and making connections. Like, this tune comes from Mozart’s Piano Sonata K. 331, and these particular three notes are shared with one of Bach’s cello concertos. And at the end, the talk stops and you come up with a question, and you say, ‘I think that this particular string of notes can be found in these different pieces of music.’ But it’s not just music you listen to and forget, you make demands on yourself to try to make patterns out of all the music you listen to, and try to come up with some unifying concept that transfers right through a string of melodies.

Even talking to you I get excited. Nature works like that, and nature is even more fundamentally rational than music because everything from the primordial soup to a human being is driven by selection.

How much of scientific discovery is luck?

I’d say 50 per cent – 50 per cent is luck and serendipity.

When it comes to scientific and medical discovery, what stifles innovation?

What stifles innovation are cultures where they demand that students only regurgitate knowledge. There are countries where I am on scientific advisory boards and the students work very hard and they memorize everything. Unfortunately medical school is like that. It’s about regurgitating what you know. Mind you, different medical schools have different approaches.

About seven years ago, the two top graduates at the University of Toronto with the highest GPAs [grade point averages] came to my lab. As a requirement for one of them to get into Stanford medical school, they would only accept her if she spent one year in my lab to do research. That’s Stanford, because it’s one of the top medical schools in the world. There are very creative minds there.

Did you know that 97 per cent of Stanford medical school grads have some connection to academia? So when they graduated and went on to a career, they didn’t just set up a private practice, they also remained connected to a university. 97 per cent! So that says very clearly that is a medical school that is training doctors to be innovators.

Would that be your advice to medical students who want to innovate? Spend time doing research?

The 20th century was a great century for science. It was a century where fundamental paradigms of biology were discovered. But we basically have discovered 99 per cent of the biological paradigms. I think the only discipline where there will be new fundamental paradigms that we have not yet discovered would be neurobiology, how the brain works.

But the 21st century will be about applying that fundamental knowledge – the paradigms and principles of biology – into medicine. And the only group of people who can translate that well will be the physicians. So to me, in the 21st century, the great principles of new insight into physiology will come from brilliant people who are trained in both fields: the clinician-scientists.

I constantly have in my lab five clinician-scientists, who are with me but are also qualified doctors. I have a medical oncologist, a nephrologist, I just had a cardiologist. They are actually seeing patients one day a week and spending six days in my lab, because they work seven days a week. These people, if they see something one day in the clinic and then can connect it to something in the lab, that kind of translation will be above and beyond just listening to music. It’s like learning how to play the violin and then integrating all that knowledge to compose a symphony.

I think that is the most important convergence needed – clinician-scientists – and Canada has very, very few.

Why don’t we have more?

It has to be something you want to do, because when you graduate from medical school and you’ve done your residency and you are now a specialist in a particular discipline, you can make $300,000 or $400,000 a year. You want two cars, a house with three garages. That is fundamentally in conflict with deciding to go into research.

One of the clinician-scientists in my lab makes a salary of $23,000. He has a wife and two kids at home. So I applied to have special permission to pay him more. Is that person not pressured to give it up and go into practice? Who is going to be a fully trained physician and go into research? But there are some people like that.

These are the people of the future.

Is part of the motivation to innovate about wanting to do something good for the world? To help sick people?

I think that is probably to some extent flawed. If you are like, oh, I feel so bad because every day I come to work I see these patients, some are very young and they are dying of cancer, I’ve got to help them, that is not enough.

If you’re doing it just for the patients, it doesn’t work as well as if you are just driven by the curiosity of finding new scientific and medical connections. A brilliant scientist could do it all out of the curiosity, and not care about the patients, and whatever happens that is good for the patients is just a bonus.

So taking the emotion out of the process is a good thing?

As Aesop said about emotion, ‘It is with our passions as it is with fire and water, they are good servants, but bad masters.’ When we use water to shower or fire to

cook, it’s a servant. But when it is a master, it’s a building burning down or you drowning.

So emotion should be used as a servant. You use your emotion because you care and therefore you try to make that scientific discovery. But if your emotion is your master, when your experiment doesn’t work, you will break down. And that doesn’t help, because you have to keep on trying.