Interview with the 2019 Nobel Laureate in Physiology or Medicine William G. Kaelin on 8 December 2019 during the Nobel Week in Stockholm, Sweden.

Was it your dream to be a Nobel Laureate?

Was this my dream to become a Nobel Laureate when I was a child? To be honest, when I was a child, I had heard of this prize and I think like many people, it quickly takes on sort of this mythological proportion. Like a lot of children growing up in the sixties, I had an interest in science and engineering because of the space race. I had a lot of toys that fostered an interest in science, one of which I’m going to donate to the museum today. I remember hearing a scientist speak for the first time, who visited my elementary school when I was in the fifth grade. I think there was a little part of my brain that imagined I might eventually become a scientist. I think I did have a little part of my brain that dreamt maybe what would it be like to win a Nobel Prize one day.

How did you decide to pursue medical research?

As a young boy, my favourite subject was mathematics, because mathematics to me was a subject where you didn’t have to study very much. If you understood the concept, you understood the concept and it stayed with you. I didn’t particularly like courses where you had to take the books home and memorise lots of facts and information. I loved mathematics initially, and then later when computers came along, I became interested in computer science because I thought that was a way of applying math in everyday life. But I’m embarrassed to say, I wasn’t Bill Gates and I wasn’t Steve Jobs, I didn’t see the personal computer revolution that was going to eventually come. I didn’t imagine smartphones. I couldn’t imagine a career in computer science, and I frankly didn’t think I was quite gifted enough in mathematics to be an academic mathematician. So, I started to look for other ways I could use a mathematical mindset, if you will, and still make a living.

I started to gravitate a little bit more towards science and medicine. Medicine it seemed to me was a way that I could have science and math in my life and use that hopefully for the betterment of mankind. My father growing up was a lawyer, so maybe I was slightly inclined to follow a profession. Now, from watching him, I had decided I didn’t necessarily want to become a lawyer, but I knew there were some benefits to following a profession, and so I decided to pursue medicine.

How do you deal with failure?

I think failure comes in different flavours. For example, the first time I attempted to work in a laboratory to do research, I was an undergraduate in college. In hindsight, I now appreciate the project that was given was simply undoable, unimportant and uninteresting, which is a very bad combination for a young person trying to become a scientist. Then during the last month in the laboratory, I correctly told my professor that by doing a little reading, I had determined that this project would never be completed because it was all based on a mistake of one of my predecessors, a so-called artifact. Of course, he rewarded me by giving me a bad grade and telling me I should never work in the laboratory again. That’s one type of failure. The lesson I took from that is, sometimes if you’re struggling in a laboratory the problem might be you, but it might also be the laboratory. But then there’s another type of failure where perhaps you’re having a challenge mastering a particularly sophisticated technique. I think any scientist knows that’s part of the territory. Sometimes you muddle through and you master the technique, or perhaps instead, you identify a collaborator who’s already good at the technique, who can help you get over that barrier.

But the final type of frustration, which I think is the most important one for any young scientist to consider, is that, as you say many times, our guesses and hunches are simply wrong. Sometimes we obtain results that are frankly disappointing given our perhaps prior expectations. But I try to remind especially young scientists that if every time you do an experiment, you get the expected results, you’re probably doing engineering, but you’re not really doing science, and frankly, science would be terribly boring if every time you did an experiment, you got exactly the results you thought you were going to get. In fact, I’ve even gone one step further and said that a good scientist should actually live for unexpected results. Because as you probably well know, there are many, many major discoveries that actually began with a completely unexpected result, where fortunately, there was someone with a receptive mind who decided that they would perhaps pursue this further, even though initially perhaps they couldn’t comprehend the significance of what they were seeing.

In fact, I’ve heard one Nobel Laureate say that many results that might have led to a Nobel Prize probably wind up in the waste paper bin because someone refused to actually look objectively at the data simply because it didn’t conform to their prior expectations. I think what any type of frustration that we’ve talked about, persistence is key. Whether it’s having the persistence to overcome various forms of rejection whether it’s a mentor who doesn’t have confidence in you, as was the case with my first mentor. Whether it’s reviewers and editors telling you your papers are not worthy of publication. Whether it’s a study section rejecting one of your grants. This just goes with the territory, and you have to be persistent, perhaps even a little thick-skinned. But likewise in the laboratory, you have to be persistent because as you know, in science, seldom are things straightforward and linear. There are going to be obstacles to overcome, and occasionally your data will take you off the path you thought you were traveling on into a different area. I think you just have to be persistent and to live for those occasional moments where you do have those ‘eureka moments’ where you suddenly have the privilege of seeing something and understanding something that’s never been seen or understood before. I think knowing that if you’re lucky, you will occasionally have those ‘eureka moments’ that provides you the fuel to get through the frustrating periods.

What would you advise a young person starting a career in science?

I would have several pieces of advice. The first thing I would tell them is everything else being equal. I’m a big advocate of focusing on studies that teach you how to think rigorously and clearly and logically, because those things never go out of fashion. You can study and memorise facts and factoids, but sometimes those facts and factoids eventually turn out to be wrong or irrelevant, and they’re often quite specific to various disciplines. Whereas if you take courses that really train you to think clearly, that will serve you well, no matter what you do. For example, I actually didn’t like biology as a young person because at the time biology was quite descriptive and wasn’t particularly mechanistic. I found that terribly boring, whereas I thought courses like mathematics, computer science, and physics were very good for helping me to think clearly and to arrive at answers that were objectively true. I tended to steer away, for example, from some of the subjects that I found overly subjective.

The next thing I would tell them is I think one of the keys to happiness in life is to find something you find so rewarding and so fulfilling, you would do it even if you didn’t need the money, right? Most people go to work every day because they need a roof over their head, and they need food on their table and clothes on their back. I fully understand that, but what a great privilege it is to do a job that you would do even if you didn’t need the money. One of the great joys of my life has been … I discovered I enjoyed science so much I would do it even if I wasn’t getting paid. In fact, there are many times I feel guilty I’m getting paid to do this because it feels like I’m playing rather than working. I think if you can find such a thing, I think that’s priceless. If you have any interest in science whatsoever, I would give it a chance and find out whether you really enjoy it. Because I think it is such a great privilege to do something where you come to work every day, you’re surrounded by bright people, and you get to follow your curiosity, and if you’re lucky, occasionally actually discover something useful.

How did you react when you heard you had been awarded the Nobel Prize?

The night before, someone asked me whether I would be able to sleep knowing that the following morning would be the announcement of the Nobel Prize. I told them that I thought I would sleep quite well, because I thought that the chance of winning was no greater than one or two percent, maybe even that was optimistic. I said, at one to two percent, I’ll be able to sleep tonight, but at one to two percent, I will leave my phone ringer on, on my bedside table, which I don’t normally do. I went to bed at the normal hour, and I had a very vivid dream where I looked at the alarm clock, and the time had already passed when I would’ve gotten the phone call. In my dream, I was already rationalising why this might even be a good thing. I was happy before, I’ll be happy now, and now I can go back to my work without this distraction. Then I unfortunately woke up from my dream and saw that the alarm clock said 2:00 a.m. and I said to myself, I have to do this all over again and go back to sleep. Then the phone rang at 4:40 a.m. and at that point, first of all, I was again wondering, is this now a dream? Or is this now reality? It was almost, I’ve described it as almost like an out-of-body experience, because I’m listening to this lovely gentleman with a Swedish accent telling me I’ve won the Nobel Prize. It was like overwhelming emotions of just gratitude and the overwhelming sense of what a privileged life I’ve had because so much luck goes into this. Clearly this is a dream for so many scientists. To think I now have the privilege of being a Nobel Laureate, it was just quite overwhelming. My next thought was how wonderful it was going to be to share this with all the important people in my life who’ve made it possible.

Can you explain your Nobel Prize-awarded discovery?

I think most people are aware that you need oxygen to live, but less appreciated is the fact that too much oxygen would also be quite toxic and potentially lethal. All of the animals on the planet, including us, had to evolve a system that would allow the cells and tissues to know whether they were getting enough oxygen and to respond accordingly. So just as you might have a thermostat in your room to adjust the temperature properly, your cells need a system to adjust how much oxygen they’re being exposed to. It turns out precisely because oxygen is important, there are many human diseases where part of the problem is inadequate oxygen delivery to a tissue, such as in a heart attack or a stroke. Those two diseases are caused because the heart or the brain are not getting enough blood and hence are not getting enough oxygen. We also know that cancers, in order to grow, have to obtain oxygen. We now understand how in some cases they’ve hijacked the system that we use to sense and adapt to oxygen for their own evil purposes, so that they can trick the body into providing them with an oxygen supply.

Where are we today in understanding cancer?

It started to become clear in the middle to the late part of the last century that cancers arose because of alterations, or scientists called them mutations in specific genes. But frankly, until the year 2000, we didn’t have the complete list of human genes, and we didn’t even know what the normal sequences of those genes were. It had always occurred to me back in the 1980s, when I was still a doctor taking care of cancer patients, that treating cancer was a little bit like trying to fix the engine of your car with a hammer. We really needed to understand this disease much better. Fortunately, in the year 2000, we finally obtained the complete list of human genes and their normal sequences that allowed us for the first time to start to understand which genes are altered or again, mutated in specific cancers, and then to start to use that information to develop better, more targeted, more precise drugs. I think we’re in a phase now where things are starting to accelerate, because we’re starting to reap the harvest of that knowledge that started to emerge in the year 2000.

More and more now we have new treatments for cancer that are helping many, many patients. But along the way, we’ve learned that no two types of cancer are genetically identical. Even within a given type of cancer, such as breast cancer, the cancer for one patient might be genetically dissimilar from another breast cancer. That’s why progress is sometimes frustratingly slow. I don’t think there’s going to be a single magic bullet that will cure all cancers. I think we have to continue to methodically make progress on all of the different cancers because as I said, sometimes the treatment for one cancer might not be applicable at all to another because of their different genetic makeup.

What are your thoughts on how science is perceived today?

One source of great sadness and concern for me is this trend in certain quarters to disparage science and to disparage expertise. I was born in 1957, which was the year of Sputnik, so when I grew up as a young boy in the sixties in the New York area, the scientists and engineers, they were the heroes. I can remember going to ticker-tape parades for the returning astronauts. Like a lot of young children at the time, especially, unfortunately it was mostly young boys at the time, I had a chemistry set and a microscope and electric cars and a rock collection and a number of things that I think indirectly or directly were fostering an interest in science and engineering. I think for most of my adult life there was great support for investments in science because I think it was held as indisputable that creating new knowledge was intrinsically good, and that this was a gift we gave to ourselves and to future generations.

Now increasingly, at least again, in certain quarters, you hear people disparage science, especially when they don’t like the conclusions of the scientist. For example, I think about the current debate, and it’s sad that I even have to use the word debate because it’s no longer debatable, but when you hear a certain climate change, deniers make comments about science as though you get to pick and choose what the data tells you. You simply can ignore if it’s expedient to do so, what the best minds in the world are telling you you should be doing. I think we do this at great peril, and I think this is simply a road to the dark ages. If the pendulum shifts to the point where expertise is a bad thing, and we no longer celebrate science and engineering.

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