Tak Mak (Canton, China, 77 years old) is the author of two great discoveries, one theoretical and one technical, which made immunotherapy possible and turned it into the great revolution in cancer treatment in recent decades. Although he did not win the Nobel Prize for these transcendental contributions – the prize went to those who put them into practice: James Allison and Tasuku Honjo – he is a world-renowned figure in the field of basic research in oncology and immunology.
Mak defends the idea of the scientist as a solitary thinker, motivated only by discovering the whys, regardless of the awards or recognition that may come later. His latest work studies the relationship between the brain and the immune system, which Mak hopes will open a new path in the fight against cancer. The veteran Chinese-Canadian researcher believes that this scientific war may be somewhat stagnant and that is why he has dedicated the last years of his career to looking for different solutions, as he told EL PAÍS in A Coruña in the hours before his opening conference at the 46th congress of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), in which he participated thanks to a collaboration between the BBVA Foundation and this scientific society.
Ask. Has immunotherapy been the biggest recent advance in the war on cancer?
Answer. By far. Today, it is without a doubt the fourth pillar of cancer treatment. First came surgery, then radiotherapy and chemotherapy. But at the turn of the 20th century, there were only 10 generic types of chemotherapy agents and no more have come out, the last one was approved in 2004. Then we moved on to targeted chemotherapies, but that wellspring has also dried up. Now that the genes of more than half a million cancer patients worldwide have been sequenced, there are very few prominent new oncogenes left to target. So, in a way, we were stuck.
P. How did your discoveries that led to immunotherapy resolve that bottleneck?
R. Well, actually, our lab published in 1995 in the journal Science The immune system has a brake, the CTLA-4 gene, without which T cells begin to divide and proliferate uncontrollably. We blocked that gene in mice and saw that they died within two weeks and that 10% of their weight were T cells. However, it was James Allison – who has been one of my closest friends for 40 years – who discovered that if you block the CTLA-4 receptor with an antibody, you can cure certain types of cancer in mice. And finally, in 2010, researchers at Memorial Sloan Kettering in New York (USA) used an antibody against CTLA-4 in patients with advanced melanoma: they saw that 20% survived and, hopefully, were cured. That was what basically opened the field of immunotherapy.
We must also not forget that Tasuku Honjo discovered another brake called PD-1. And that brake works even better. Instead of 20% of advanced melanomas, it cured 40%. Similarly, non-small cell lung cancer, kidney cancer or Hodgkin lymphoma have responded spectacularly to this immunotherapy. For these achievements, both Allison and Honjo received the Nobel Prize in 2018.
P. In a recent interview, Spanish oncologist Joan Massagué — scientific director of the Sloan Kettering Institute — told EL PAÍS that thanks to these advances, metastasis is no longer a death sentence. Do you agree?
R. There is an extension of life, of course, due to immunotherapy treatments. And we can remember cases like that of the president [de EE UU] Jimmy Carter, who had melanoma metastases in the brain and received immunotherapy and is now cured [Carter cumplirá 100 años el próximo 1 de octubre]I know Massagué well, but I cannot fully agree with his statement. We have made enough progress in some cancers to say so; for example, Hodgkin’s lymphoma, which no longer matters if it is metastatic: it is cured. On the other hand, in metastatic non-small cell lung cancer, from which everyone used to die, immunotherapy has now achieved that 5% live five or even 10 years without a recurrence. So my answer to your question cannot be yes or no.
P. What do we need to do to stop metastasis with immunotherapy?
R. In the 2010s, it was thought that it was going to be fairly easy to combine anti-PD-1 with other drugs. But unfortunately, in the last dozen years, 2,000 clinical trials have failed. There have only been small improvements by combining anti-CTLA-4 and anti-PD-1, but with the problem of associated toxicity, because by doing so we are provoking an unleashed response of the immune system, a kind of explosion. So, again, we are stuck.
What are the solutions? I think the key to avoiding these uncontrolled responses — which kill patients receiving immunotherapy — is to better understand how T cells work, which are the detectives of the immune system and are the ones that tell the antibodies, which are the policemen inside our body, which cells to arrest and which not to. And we have also encountered this underlying problem with Covid: Why do some patients get very sick and die? Why are others asymptomatic? And it turns out that one in 200,000 lose all their hair: Why?
P. Knowledge of immunology is relatively recent in the history of science. Are there still basic discoveries to be made in order to find the answers to the questions you raise?
R. I think that, in general, the foundations are already laid. But a large part of the reason that this puzzle is still unsolved is due to the fact that T cells are very difficult to study. In the case of Covid, we have come to know that the T cell genes that you have inherited from your parents make the difference between whether you have a bad Covid or whether you are asymptomatic.
When I am asked what the fifth or sixth pillar is going to be for treating cancer [tras el último gran avance que ha supuesto la inmunoterapia]I actually have no idea. But I think whatever it is, it will come from a continuation of our understanding of the immune system. As I am Chinese, I will allow myself to quote Confucius here: “We all have two lives. The second begins when we realize that we only have one.” And I, half-jokingly, as an immunologist, often say: “Medical researchers have two lives. The second begins when they realize that the immune system is the orchestra of almost all of life’s symphonies.”
P. What do you mean by such a poetic statement?
R. On the one hand, immunology helps us to better understand, of course, the fight against infections. Then there are transplants and autoimmune diseases. And now we have cancers that are either caused by the immune system itself, or are being treated by involving those bodily defenses of ours. I can also imagine that neurodegenerative diseases are going to have an element of the immune system causing them in some way; and perhaps one day we will be able to turn that around and use it to treat these diseases, as we have done with cancer.
In fact, I think that the connection between the immune system and the nervous system will be the next important discipline. Studying how these two very complex and very important systems communicate, I think, is going to be a great new field of research, which is going to flourish in the next five to 10 years. Perhaps my opinion is biased, because Our laboratory is already working on it: in 2019 we published an article in Science that demonstrates that if you remove the ability of T lymphocytes to produce acetylcholine [un neurotransmisor]they lose their ability to completely kill a viral infection. And that is genetic proof that our brain is talking to our immune system.
P. Wow, if I were a young researcher I would dive headlong into researching in that field that you recommend. Because your discoveries, starting with the T-cell receptor in 1984, which was considered the Holy Grail of immunologyhave laid the foundations for immunotherapy. And the advances of others who made it a reality were awarded with a Nobel Prize.
R. I am not allowed to compliment myself. And there is one thing I would like to say to those who come. We are not in science for the recognition, for the Nobel Prize. We are here for one reason only: to ask ourselves why. As an author called Simon Sinek says: “Everything should start with a ‘Why’, and then a ‘How?’ and finally a ‘What?’ That is what we recommend in my group to our colleagues and to our disciples.”
And then there’s one more thing. I think scientists should be solitary. If you’re part of a crowd, you end up following in other people’s footsteps unnecessarily; and if you continue to follow in their footsteps, you’ll never find your own way. I’m very much against crowds. I need to learn from my colleagues, from students, from technicians, from anyone who has ideas – I need to hear them. But then I need to retreat and use my own solitary thinking, with my prejudices, to evaluate things so that I can come up with a new angle to look at them.
P. Have you always been a solitary thinker since you were a child and have you been wondering why?
R. No way, I don’t believe it. In fact, I went to a Jesuit Catholic school in China, and my childhood dream was to become a priest.
P. And how did that boy who wanted to be a priest end up being a scientist?
R. My parents emigrated first to the US, and there I lost contact with the Catholic Church. Later, it was the need for money that led me to research. I had a job cleaning test tubes in a laboratory, but it was not very well paid. It was only a dollar an hour, and that money was not enough. When I finished and asked for more things to clean, the boss would tell me there was no more. But if I wanted, I could do experiments, which were better paid, and then I would have more material to clean. That is how I came to science, first as a scientist. hobbyand then it became my profession.
You can follow SUBJECT in Facebook, X and Instagramor sign up here to receive our weekly newsletter.
#Tak #Mak #immunologist #immune #system #orchestra #lifes #symphonies