♪ >> Welcome to Canada Files.

I'm Valerie Pringle.

My guest today is Dr. Tak Mak, Senior Scientist at Princess Margaret Cancer Centre.

And Professor of Immunology at the University of Toronto.

At the age of 30, Dr Mak discovered the T-cell receptor.

And paved the way for modern immunotherapy drugs that have cured certain forms of cancer.

His work is made more poignant by the fact that he lost his wife to cancer.

Because of the exceptional nature of his discoveries and the continuity of his research-- he's now in his late 70s, he ranks among the greatest scientists.

>> Valerie: Dr. Mak, hello.

>> Mak: Hi.

>> Your work has been groundbreaking.

You're the most-cited Canadian scientist.

When you discovered and cloned the T-cell receptor in 1983, did you realize at that moment, how monumental it was?

>> Mak: I have to say I didn't.

Although everybody around me was telling me that.

I guess I wasn't really in the field of immunology.

I had no idea that it was that big.

It turned out to be much more than I had thought.

>> It was called the holy grail .

How many people at that time do you figure were looking and trying to find the T-cell receptor?

>> I can only tell you one statistic.

I gave a talk December 1983 at Harvard.

Professor Phil Leder, who was the chairman of genetics, told me there are 18 labs in the department of genetics alone, looking for it.

>> Why do you think you were the one who managed to find the T-cell receptor.

>> Luck... By the way, two laboratories-- Mark Davis at Stanford, and us here in Toronto.

He's actually younger than me by two years.

These two innocent reckless people just took a different approach.

At that time, the idea was that antibody was already discovered.

Antibody is so complicated.

Because the amount of antibodies made is unlimited.

Because you need to be able to accommodate or be prepared for any pathogens of any kind.

Bacteria, viruses, COVID, you know, influenza--whatever.

So when there is a T-cell receptor which is actually the beginning.

In a very simplistic way, maybe antibodies are policemen.

T-cell receptors are detectives.

But the detectives also have a branch of identifying a particular substance in your body.

Is it yourself?

Please don't touch.

Otherwise, you will get an auto-immune disease like lupus, rheumatoid arthritis, multiple sclerosis, and 90 other ones.

Or if you are bacteria or virus, they have to tell the difference.

These are the T-cells.

They tell it by the T-cell receptor.

It takes them four seconds to tell whether this is a virus, bacteria, parasite or yourself.

If it's yourself, you move on.

If it's one of those guys, then you call up your other T-cell receptors who are killer T-cells to come in.

Then they call up eventually the antibodies-- the B-cells who make the antibodies.

Together, everybody goes to remove the virus.

So that was the T-cell receptor-- the one that can tell-- yes, this is foreign, kill!

No, this is self, don't touch.

>> Do you remember that day in July, I think it was in 1983?

>> I remember July on a Sunday afternoon.

I walked in the lab.

At that time it was at 500 Sherbourne, Princess Margaret.

It used to be called the Ontario Cancer Institute.

But now the Prince Margaret Cancer Centre.

It was a beautiful Sunday afternoon and I was there.

I walked in and then the number of pages was piled all the way up to here and I went one after the other... After two hours, I was seeing something a little bit crazy.

That there were a couple of genes that looked so different.

That was my first hunch.

>> You saw it then and it was really the needle in a haystack.

>> It was.

>> ..insane... can't possibly be there.

>> Because nobody even knew what they should be looking for.

>> You say you didn't take in all the huge implications of this.

For what it would do for immunology-- that it might treat cancer.

>> That we didn't know.

We, the world, didn't know until 2010.

Which is 26 years later.

We didn't know that until Jim Allison showed it.

That it can go after cancer too.

I had no idea.

I was in the cancer centre and my boss was always asking me, "Tak, you work in the cancer centre.

You've gotta do something about cancer.

I know you work on auto-immune diseases.

Nice but you've got to do something about cancer!"

No way the T-cells can tell cancer cell apart.

I was wrong.

>> Well, I love the story.

You were born in China.

Grew up in Hong Kong, then moved to America.

Went to university, first to study chemical engineering.

And you were a total failure.

>> I hated it.

>> Well, this was a lucky thing that you were not good at this.

Then the story continues that you were... you needed money as a student.

You were washing test tubes.

They said, "You can even make more if you do research."

Then you've got more test tubes to wash. >> Yeah, I do my thing I tell you what totally wasn't my cup of tea.

I got a problem set.

In chemical engineering, University of Wisconsin up to today, is still one of the top, if not the top, chemical engineering school in the world.

So it's very prestigious.

I got in, I was quite happy.

Then I discovered that there was one problem set.

It takes me about 5 minutes to finish one.

But they had 100 sets of numbers.

So I did three.

And I wrote on it if these three are right.

I do not understand why I have do the rest of the 97.

The next thing I knew, I was summoned to see the dean.

And she said I don't think you belong here.

>> Well, this is a win for mankind, you can say.

How great that the test tube cleaning turned you into a scientist, and a researcher.

Understanding how science works!

Dealing with failure, intuition, patience, time and curiousity.

>> And luck.

And lots and lots of amazing trainees.

I mean I am just so proud.

>> You came to Toronto because of Ernest McCulloch.

He brought you here.

The co-discoverer of the stem cell.

What did you learn from him?

>> Ah, I love and miss him in so many ways.

He was very eclectic.

He's so special.

He's all by himself.

He and James Till-- it was a perfect pair.

Because McCulloch was a clinician.

He was a leukemia doctor.

He's very open-minded.

He thinks not just broadly but kind of out-of-the-box.

Jim Till is a physicist.

As a physicist, everything has to be correct.

Down to the last decimal place.

The two of them are awesome!

One goes off thinking about things that nobody's ever thought of.

The other says, "Hold on a minute.

Before you go too far, let me measure this and that."

So from this very rigid thinking--just get it done to someone who looks out into space and says, "What is missing and how can we bring it to earth?"

That's fantastic.

>> One of McCulloch's lines you say he said to you is, "The goal is not to live forever but to create something that will."

So he was a huge influence on you.

>> Totally.

I was really really lucky.

Because first I was very disciplined with Roland Rueckert, the virologist.

Everything has to be titrated-- everything has to be like this.

Then McCulloch, then Howard Temin.

Also...he has to be one of the smartest persons I have ever ever met.

So I was really lucky.

>> All these wonderful influences.

You lost your wife to cancer, 1998.

Obviously it was personally devastating.

What effect did it have on your work?

>> Well, I think for the first year or two, it grounded to a halt.

I couldn't do anything.

I had my daughters with me.

Then my daughters went off to college.

I got together a group of friends who were really top-- not just scientists in the world but top drug developers.

These people know how to make drugs.

And why wouldn't I take advantage of that?

Why wouldn't I take that opportunity to try to do something.

If I can't make it, I tried.

If I can make it because of the help and everybody else, I stand a chance of making a small difference.

>> You've said, especially working in cancer centres, "I've seen so much pain.

If I have one life to live, I'll try and make a small dint."

>> I think we all do.

We have to.

We can't really walk in and out of a hospital filled with patients and not feel that we want to do a little bit more.

>> Do you see a huge difference in the number of cancers that we can cure now even with the immunotherapy?

>> Enormous difference.

I mean in certain cancer--testicular.

In this short career, I have been in the cancer field, testicular cancer is now almost cured.

Hodgkins lymphoma is now almost cured.

Chronic myeloid leukemia is now almost cured.

So there are-- and with immunotherapy, gosh, I would say 20-30% of the melanoma patients which had five years and everybody, maybe 5% survival.

Now there are 30% of the patients are out 10 years!

Certain kinds of lung, bladder, kidney cancer-- with immunotherapy, they have a much better chance of living longer and doing well.

But we still have a long way to go.

Pancreatic cancer, brain tumours.

Ovarian cancer-- I hate ovarian cancer!

It's nasty.

Breast cancer of course.

One in 6 Canadians are going to get breast cancer.

Right?

>> You must always think of your wife in that regard.

Even now, the treatments that she would have had would be different.

>> Unfortunately her breast cancer-- breast cancer is not one kind.

They've got about five - six kinds.

And within those five - six, there are a lot of variables.

Her kind is called basel triple-negative.

It is still tough.

But we're trying.

>> Will immunotherapy, do you think surpass ultimately the other pillars of cancer treatment-- surgery, radiation, chemotherapy?

>> Confucius said, "We all have two lives.

The second one begins when we realize we only have one."

Cancer biologists have two careers.

The second one begins when they realize immunology is the orchestra of most lives' symphonies.

>> So the future of this is... >> Immunology combined with another drug.

And we'll go to another step.

>> And eventually cure all cancers?

>> No, I'm not that crazy.

Today in Canada, 65% of all cancer patients can be considered cured.

It was 5% 30 years ago and the numbers are rising.

As we all grow older, we all are either going to get cancer or Alzheimers .

>> And you're still at it!

You've had great success with companies you've been part of-- creating drugs, knock-out mice.

You could have happily retired but you're in the lab because you're curious, you can make a difference.

Because it makes you happy.

>> It's all those things but I think one thing you left out, are the young people.

All the seeds of all the flowers of all the tomorrows.

They need a pot of soil & that's what we're trying to provide.

Yes because I can retire but what am I going to do?

How do I tell them that I can't be there for them?

Young people always ask me what are the elements of success?

I think the first is yourself--your own initiative.

Your own thinking.

The second is you have to have good collaborators-- good trainees that work together.

The third is you have to have money.

Because you can have a crazy idea--you need the money to support these people, to go that extra step.

And the last 25% is luck.

>> Now what interests you to study is the connection between the brain and the immune system.

>> Yeah, that's fascinating.

I think it's the tip of the iceberg.

It's so crazy.

There's so much we don't know.

For example, one of my graduate students, Sean Kublee, in his master's degree, he showed that if you take a male songbird and suppress the immune system at birth.

That male songbird, when he grows up, can only sing 3 songs instead of 50.

So what does the immune system have to do with your brain, right?

But it only happens in male songbirds.

It doesn't happen in female songbirds.

That's another dimension of complexity we don't understand.

We just published the paper in a journal called Major Cancer, very prestigious.

That if your immune cells cannot make neurotransmitters, the tumour grows back faster and kills them much faster.

And proved beyond doubt, our immune system is controlled by our brains.

>> But then so much still to learn.

There's a painting I've heard you cite.

That is sort of emblematic of how you think in your career called Two Swallows .

Tell me about that.

>> Yeah, you should look at it.

The Two Swallows is a painter, Wu Guanzhong.

He was actually trained in Sorbonne in Paris in the 1940s.

There is this one picture where there is a river and a house in a village.

Then the title is Two Swallows .

You look at it and you say what?

All of a sudden you go to the top-right corner, there are 2 swallows.

To me, that's so reflective of my whole career.

That sometimes when it's something so small is part of it but we often do not know that the two swallows was meant to be the subject.

The rest was just part of it.

>> Is discovering the T-cell receptor the greatest thing you did?

Or do you think of that as a great thing but part of your body of work?

>> I don't look at it that way.

I certainly under no circumstances has it ever crossed my mind that Mark Davis and I, in our early 30s, cloned the T-cell receptor.

And I could just sit back and enjoy.

>> Collect honourary degrees and science awards.

You should have a Nobel, btw.

But who am I?

>> ...I never think of it this way.

I just try to enjoy whatever is in front of me.

Whether it's five steps, five thousand steps or five thousand miles.

You know, you go where the light is.

>> The final question we always ask is what does being Canadian mean to you?

>> Being Canadian is, the word is-- if I have to use one word, comfort.

Because we are a nation that is very comfortable with ourselves.

We like to, in a comfortable way, contribute to the world.

That's one word I would say.

It may not be the same word for everybody.

>> Because you've chosen to have your career here, keep working here.

>> Yes, I have left Canada one day for a job in an American university.

I started at 9 and at 5 o'clock I called my secretary.

I said, "I'm finished of being outside of Canada.

I'm coming home."

That night I went to see my boss.

I knocked on the door at 10 o'clock-- McCulloch.

He knew I'd left this morning.

It was on the front page of The Globe and Mail .

He opened the door.

He looked at me and said, "Tak, would you want to come in and have a scotch?"

That is the kind of person, I just was forever grateful.

>> So out of loyalty to him and various other things, you stayed always in Canada.

>> Yes, I have never looked at another job.

That's not true.

I looked at a job at University of Hawaii.

More as kind of like--okay, because I was told let's come on over and have a look.

Where else would I want to be?

>> Well, it's been wonderful talking to you.

I'm delighted you're here.

>> Thank you very much.

>> Thank you, Dr. Mak.

We'll be back next week with another episode of Canada Files .

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