One on one with…Tony Hunter
For the Kinase King and River Rat, the challenges aren't just in the lab
In an office filled nearly floor to ceiling with journals, books and papers from a four-decade career, it's easy to imagine you're visiting with a wizard—especially when you see Tony Hunter's flowing white beard and the strange map of a watery kingdom on his wall. It seems to show a river delta spreading in all directions, with tributaries of various colors that look like elongated runes.
In fact, what has been so meticulously mapped out is a cellular landscape that Hunter began exploring decades ago—a quest that prompted the Journal of Cell Biology to dub him "The Kinase King." The map depicts the "kinome," the collection of enzymes known as kinases, which are crucial to life and play a role in cancer.
Louis Pasteur once said, "Fortune favors the prepared mind," and it aptly describes the discovery that Tony Hunter made in 1979. Hunter ran an experiment on tumor viruses and then ran it again, expecting the same result. Yet the results didn't match. Someone else might have dismissed this as just an annoying glitch, but Hunter's biochemistry background alerted him that an extremely subtle difference in the ingredients had exposed a significant finding. He discovered that a certain enzyme — known as a "kinase"— specifically targeted the amino acid tyrosine, which among other essential functions, regulates cellular growth, and thus, the spread of certain cancers. Two decades later, the drug Gleevec, which is highly effective against two cancers, was developed based in part on Hunter's keen observation.
His research has led to a cancer drug and caused textbooks to be rewritten, but what Tony Hunter is equally proud to show off is a video of a whitewater rafting trip he took in the summer of 2010, his ninth through the Grand Canyon. He's in a raft on the Colorado River with his two sons, steering through the Lava Falls rapid, a whirling pit of bucking water so technically challenging that the Colorado's premier explorer, John Wesley Powell, opted to walk. As they run it, their raft plunges in and out of colliding waves and arcing froth that hits with the force of fastballs. They swerve into a huge claw of water, and Hunter is swept overboard.
But fortune, it seems, favors the prepared body as well. A few frames later, Hunter can be seen back inside the raft, enjoying the rest of the ride. After all, how else would you spend your vacation when you're 67 years old?
Did anyone at the Institute ever suggest you might consider a safer hobby?
No one told me that, but one summer in 1975, just after I got back from spending a month river rafting, Walter Eckhart, a faculty colleague at Salk, said, "Tony, I think you should spend more time in the lab!"
Many scientists seem to have extreme outdoor hobbies, like mountain climbing….
Well, they're crazy! I think river running is safer than mountain climbing. The rush you get running through a big rapid is tremendous—and the relief when you get out the other side. If you're concerned, you can take a trip on big tourist rafts that are almost bullet-proof safe. However you do it, a trip through the Grand Canyon by raft is an amazing experience. Seeing it from the bottom is very different from seeing it from the top.
Speaking of safety, we hear that early in your career you burned down a lab.
Yes, when I was back in Cambridge. The picture's right there on the wall. [He casually points to a framed black-and-white photograph of charred ruins.] I've still got some of the lab notebooks. We're not sure what started the fire, but because the notebooks were so tightly stacked against one another, the fire had no oxygen to burn them.
But wouldn't most people have seen those ruins and given up in despair?
Well, we were young—nothing was going to deter us! We were lucky there was extra lab space in a building next to the famous Laboratory of Molecular Biology where Francis Crick worked in Cambridge. We were given dining rights there, which produced a silver lining to the fire. Because the unwritten rule was that you were supposed to sit at a table with people other than your lab mates, we started discussions with a group there working on tobacco mosaic virus and set up a collaboration. This resulted in a very nice paper that came out in Nature, so that was a totally new direction that came out of a disastrous event.
What are "kinases" and why are they important?
Let me take it back a step. Most processes in the cell occur because proteins signal to each other in a relay chain. But protein signaling is as restrictive as dominoes—the ends must match exactly. Kinases are enzymes that add chemical components known as phosphate groups onto proteins, a process called phosphorylation. Phosphates are very versatile— it's analogous to putting on a blank domino—so through phosphorylation, you vastly increase the number of links a protein can have.
Thus, kinases are important for continuing—or breaking—the chain. In a cancer cell, you want to say to a kinase, "Stop! Don't make the link that lets that cell divide."
You discovered a previously unknown kinase that acted on a building block of proteins called tyrosine. Was the reaction in your field, "Of course, it's only logical," or "Oh my God!"?
I think it was more of the latter, although surprisingly, there wasn't any skepticism. Often when you make an unexpected discovery, people say, "Oh, that can't be right; they must've done something wrong." Instead, it was very quickly adopted. Within a year of our beginning to talk about it, there were four or five papers from other groups reporting that their kinases were also tyrosine kinases.
There is a lesson here: however logical you are, the experiment doesn't always give you the expected results, and once you rule out the obvious, you've got to spend some time investigating what the new result means.
What is the kinome, and what does it tell you?
Once we realized protein phosphorylation was such a prominent cellular mechanism and that there were going to be such a large number of protein kinases, it clearly became important to try to determine exactly how many there really were, so we could understand the extent of the landscape.
Using the complete sequence of the human genome, Gerard Manning, a former staff scientist here at Salk, did most of the work to find out how many genes coded for protein kinases. Originally, we came up with the number of 518, but this is about to be revised upward to about 540.
It's been very useful because mapping the kinome does suggest that certain kinases will have similar properties. Knowing this gives you a starting point for developing drugs that can target processes involved in diseases like cancer.
If we can land a robot on Mars, why can't we cure cancer?
First, cancer is not a single disease. Each cancer undergoes genetic changes that are unique to that cancer. Because of those differences, we actually have had success with certain cancers, such as chronic myeloid leukemia, but not with others, such as pancreatic cancer, which remains especially challenging because the cancer develops a peculiar vasculature that makes it very difficult to deliver drugs.
As for putting a robot on Mars, it turns out biology is much more complicated than physics. The human body has evolved over billions of years to be very robust—you push on one thing, and another one changes in ways that you couldn't necessarily know. Particularly with cancer cells, if you target one thing you know that a cancer cell needs to grow, what you find is that something else pops up to take its place.
We're all hoping that if we understand the pathways that are switched on in cancer cells by genetic mutation and could block two or three of them simultaneously, then we would stand a much better chance. If you only block one, then the cell finds a way around it. If you can also take out its backup strategies as well, then treatment is more likely to be successful.
You're a senior editor of the new journal eLife. Why is it important to you?
It's a journal for scientists, run by scientists. The decisions are made by scientists in the field instead of professional editors, who increasingly rely on the referees to make the decisions instead of making t heir own decisions.
In addition, the whole reviewing process is made easier for authors; there's just a single round of revision allowed. You receive one letter back, which outlines what needs to be done, rather than the current practice of having to answer multiple suggestions and objections from several separate reviewers. We're hoping it will become the new model for how scientific journals are run. It's going to be a lot of work, obviously.
You not only work at Salk but also support the Institute financially. Why do you choose to contribute to Salk?
I owe an enormous debt to the Salk for having been the place that enabled me to establish my career and that gave me the environment to do the best science. When I was appointed an assistant professor in 1975, I joined a group of young faculty members in the Tumor Virology Laboratory, which was created in the early '70s, and it was a fantastic place to work. I give money to the Salk because I think science is still fascinating, and there is lots more to do. Salk is a really important biomedical research institution, and I want to see it survive and succeed because we know the Institute can't survive on federal funding alone.
How does funding change the way science is done?
Your research can be restricted if the grant money is dedicated only to a specific purpose. But sometimes this can also open up opportunities. In fact, the reason I'm a cancer biologist is because I came to the Salk to do a postdoc with Walter Eckhart, who had money from the Special Virus Cancer Program at the National Cancer Institute. That program brought a lot of very talented people into the cancer field because the money was available. Nowadays, private donors are very important to provide that kind of support.