All of the interns had the incredible opportunity to talk with the President of ISB, Dr. Jim R. Heath. It was amazing to hear about Dr. Heath’s insightful and outstanding journey as well as gain helpful advice. Below is the interview transcript:
Could you tell us about the research you did at Rice University that led to the work winning the Nobel Prize in Chemistry?
When winning the Nobel Prize, it was the C60 buckyballs, and that was certainly a very exciting thesis. It was during my second year and first month of graduate school when I made that discovery. It was a radical discovery because everybody thought that carbon had two forms: graphite and diamond plus a morpheus carbon. To come up with a whole class of carbon molecules, because other structures like nanotubes and fullerenes came out of that, was really heavily criticized at the time because when we discovered we were using this massive machine- a huge vacuum chamber- about the size of a two car garage. We were looking at maybe 100-200 C60 molecules at a time and so we had to have a sensitive place to understand what this molecule was. And then, of course, we had to make a leap of faith on what the structure was, but we had a lot of evidence. But it was still controversial, and in fact, when I was a graduate student I went to a conference with all these elite leaders in the field and they all were sort of making fun of me because of this project. And then a year later they were all working on it. For about five years it was the hottest thing in all of science once people figured out how to put it into a bottle. But what that taught us was that, when you think about chemistry, you think about the periodic table and the different elements that you mix and match to make different chemical properties; C60 taught us that size and shape were equally important. So that was really the launch of the fields of nanoscience and nanotechnology. And, still if you see nanoscience and nanotechnology, you’ll see that the fullerenes were the ‘poster children’ of that field.
I spent the next part of my career really trying to understand some of the physics of size and shape. We did some very cool experiments- you could take little, tiny, and round particles of metal, say silver, maybe containing 300-400 atoms and you can’t treat them as if they were atoms and you could make a crystal of these little nanocrystals. One thing that we did is that if you take these little particles and you make a crystal out of them, they’re pretty isolated; but if you squeeze that crystal, they start quantum mechanical interactions. If you squeeze it just enough, it turns into a bulk metal; but if you release the pressure, it goes back to being an insulator. You could bring it up to where it was almost a metal, and we sent sound waves through it, and you could see these waves of metal by eye passing through as the pressure of the sound waves causes it to become a metal. All sorts of cool things one could do. Really trying to work at that physics and chemistry of size and shape took up the first years of my scientific career. Nanoscience, in many ways, was thought to be a manufacturing approach that really started at atoms and you built up as opposed to sort of top-down (like taking a piece of wood and whittling it down). Most manufacturers did top-down manufacturing. I thought if you were going to make something, you should use nanoscience to do so. We ended up trying to build a computer with molecular switches, nanowires, and all that. And we did, in fact, we built a computer that is actually still a world record, we made a 160,000 bit-memory circuit that is actually as small as a white blood cell. We used that type of manufacturing that we did for that to show that we could make very novel materials. Since we were making these circuits the size of single cells that were pretty complicated, I thought we were able to build interfaces into biology at the single cell level. I tried to learn about biology, since I never took a course in it, I had someone teach me biology over Christmas one year and basic cancer. That was a very instructive process.
For those of you going into any biological field, take some computer science, hone up on your math skills. It’s important to have the domain knowledge that comes with knowing biology, but it’s also important to figure out how to use that with the data you get.Jim R. Heath, PhD
If you are trying to learn a new field, and you are in science, there’s a big language barrier. It’s not like science is that different if you are a physicist or a biologist or engineer or chemist, you have a problem you are trying to solve. But the language and the skill set to solve those are different. For example, when we were building the computer, I talked to a computer architect. Also, you don’t make everything perfectly, there’s always a yield. We had to have an architecture that was organized like a crystal but the computer could still work even if it had defects. So, each of the little chips on the computer were laid out in a periodic array like a crystal- and they’re defective. We did not crush the bad chips. We used software to wire the computer together. So in other words, the computer was like a chameleon, and we could download software that turned it into a Mac or a PC, any computer that you wanted to. When we finished, it was actually, for a while, the fastest computer in the world. It wasn’t very energy efficient, but it was a pretty spectacular computer. But it also provided a framework for what we could build on a molecular nanoscale. Without knowing what to build, we never would have been able to do it. When we first started doing this, I met with a computer architect and we would sit in a room for 4 hours, and the very first day– after 4 hours of talking– we walked out with a noun that we both agreed upon. Our backgrounds and languages were so different that he would talk to me and tell me what he was thinking about and I had no idea what he was talking about. And I would talk to him; he had no idea what I was talking about. But eventually, with a word a word and enough frustration we had a noun. And the next day we had a few nouns, and then after that it just built.
And the same thing happened when I went to learn about oncology. There is a famous protein in oncology called mTOR which is a signal molecule that is important in many cancer cells. But mTorr also means millitorr, which is one millionth of an atmosphere. And this guy I was talking to, Charles Sawyers, a famous oncologist, was giving me a lecture on oncology and I had no idea why he was talking about a millionth of an atmosphere. It was the most confusing conversation I’ve ever had. But then, after we beat each other up for 3 hours on mTOR/mTorr, we both understood what it meant in each other’s worlds, and after a while we were able to make progress on that. When we started doing biology, initially I thought that these nanoversions of technology would be the kind of things that we could build that would be powerful tools for looking at biological systems. It turned out that if you wanted to publish papers it was a great idea, but if you wanted to make progress it was a bad idea. When it came to biology, every cell was different, and you actually had to measure a statistical number of cells. We developed technology that allowed us to measure many different things in single cells (to stay fundamental), and some of that stuff is now a company and broadly used by many people. As we began to learn more biology, we began to think about biology in novel ways. Biology is rapidly beginning to become a data science. If you can get large levels of data, then you can really begin understanding human disease and hopefully make a difference. But it eventually becomes a computational challenge. For those of you going into any biological field, take some computer science, hone up on your math skills. It’s important to have the domain knowledge that comes with knowing biology, but it’s also important to figure out how to use that with the data you get.
I saw in your bio that you have co-founded many other companies (including PACT Pharma, Isoplexis, and NanoSys), what did you see in your own life, the world around you, or the scientific community that motivated you to do so?
A lot of times you can take a certain idea in your lab, a certain distance, and then you can’t take it further. Let’s take the company Isoplexis, that’s the company that pushed forward the single cell technologies. To take what had been done in my lab, which could be successfully done by Caltech graduate students at one experiment a week. We needed to turn it into something where someone of minimal technological training could do a hundred times a day for it to have a high impact. So that’s what role the company plays. We’ve continued to feed ideas and inventions into that company, but it’s not my lab’s business to make it something robust and put it into a box to ship it to customers. That’s what a company has to do. With PACT, a pharmaceutical company, it was a pretty cool idea.
For some background, t-cells and antibodies have the ability to recognize very specific pieces of proteins or antigens, they are part of the adaptive immune system. So it turns out that there are certain parts of a cancer that will look different than healthy tissue. Some of those differences have to do with the fact that cancer has genetic mutations that drive it. If you look at a cancer cell, it’s generally replicating quickly, which is why cancer is so bad. If you look at the healthy tissue where it came from, it’s basically doing nothing. A fragment of one of those genetically mutated proteins is going to be a sequence of amino acids that does not look like something your body naturally makes. You can develop an immune response against that antigen, the part of the protein that contains the mutation. So we showed in my lab at Caltech that not only could you do that, but you could identify the t-cells that recognize that antigen. If you sequenced those individual t-cells, cloned them and put them back into a creature, say a mouse, it would kill the tumor. That was about as far as we could take it. You could turn that into a therapy, but for each patient you treat, since it is such a high tech approach, it’s going to cost a million dollars. And you’re going to have to take that therapy and drop it down to the price of a normal cancer treatment. You’ve also got to really show that it works in a clinical trial. So, I and two of my colleagues formed PACT, which is a cell based therapy company, to do that. That is actually in the clinic and being used to treat patients right now. It’s sort of a rapidly developing area. The idea of using the power of the immune system to attack cancer is something people pursued for a long time. In fact, it was something that I got into during my start in biology. But it did not really start working until about 7-8 years ago, but when it started working, it really transformed oncology. So when people talk about the fact that new cancer treatments are developing all the time, they actually mean it, and they are really different because they are designed to harness the power of the immune system. Basically, you take something in your lab, you can only take it so far, and then you put it in a company. And you’ve got to raise a ton of money, so it’s not a casual thing to do. But if it works, it’s great! It’s not a get-rich-quick scheme, it’s about taking scientific innovation and making a difference in the public.
Prior to your work at ISB, what interested you most about systems thinking and how did that inspire you to serve as a president at ISB?
Systems thinking means that you are attacking a problem from all different directions at once. When we built the computer, we were developing the molecular switching, the wires, everything at the same time so that we can have a self consistent solution at the end. That was a systems approach to building a computer. We were just doing it, and I did not have a term for it until I heard Lee Hood talk (I was still at UCLA when he started systems biology thinking, and a friend of mine was invited to his talk). Lee Hood talked about systems biology, and I had no idea what he was talking about, but I understood that he was also taking a systems approach to a problem. After I knew how effective that systems approach could be, it made the most sense to take a systems approach in biology. We were already doing systems type work, so when we got to biology that was just a natural extension of how we thought about things. In terms of coming to ISB, Caltech was a pretty good place, but what we were finding our work was more and more dependent upon patients. You can do lots of experiments on cell lines and things like that, but the real test is if it works on patients. Caltech did not have a medical school, it did not have any capability to access patients, which is why I had my position at UCLA. However, when you look at Caltech and UCLA on a map, they are really close together, but when you get in a car and drive, they are not very close anymore. Right before I came here, ISB partnered with The Providence health care system that gave us access to 51 hospitals, which gave us a mission to do translational medicine, that was what I was looking for. The next stage of ISB was going to be to take systems biology and translate it to patients, that was something that I wanted to build, so that is why I came.
Could you tell us more about your roles as a Professor of Molecular and Medical Pharmacology at UCLA and director of the NSB Cancer Center?
That professorship gave me lab space, but it didn’t really pay anything because I was a full-time professor at Caltech. But, it gave me lab space and access to patients in the medical school. My role as director of the NSB Cancer Center was to bring in the new technologies we were developing to make a quantitative difference in patient health, and there was a lot of science to be done. So, I went with a couple of my friends, including Lee, and we talked to the director of the NIH at the time and the director of NCI and convinced them to launch a big program in nanomedicine, which they did. One of the flagships of that program was to launch these cancer centers, which was a type of grant. We applied for one of those cancer centers that allowed us to bring in physicists and engineers and oncologists all into one environment to work on some of these problems. That was very successful: the company PACT came out of that, the company Isoplexis came out of that, and so a lot of things that have made a meaningful difference came out of that. I ran the cancer center for 15 years, but it’s no longer a program now. The NCI makes these programs for 10 years and they send it for 5 more years but that’s it. So now we have to do the next thing. I still have a faculty position at University of Washington and the main advantage of that is that it allows me to get graduate students. And so, I have a lot of graduate students in my lab.
What has been the hardest part of your journey thus far?
The hardest part of my journey so far… Well, everything you work on has its bumps along the road. For someone like myself who has changed fields substantially a large number of times there’s always steep learning curves that can be challenging. I’d say in general I’ve always had the perspective that you can have fun doing science because otherwise it’s too hard, so I don’t think I’ve had anything difficult out of that. Now it turns out that when I was finishing my postdoc and I was applying for jobs I was already a pretty famous guy because of C60, because the Nobel prize hadn’t been awarded for that yet and it was the hottest thing in the science community. I decided that I had done the experiment in that field and I was not going to stay in that field. In fact, I was going to run away from it as far as I possibly could and find another set of problems to work on because I think if you’ve done the key discovery, everything else is downhill after that. So I went out looking for a job and I was proposing to develop this new field of nanoscience, which wasn’t a field at the time. Because I was pretty well known, I got interviewed by every single school in the country. But because I was proposing to change fields and do something different, I didn’t get a single job offer. That was actually very frustrating, I almost decided I was going to leave science.
My post-doctoral advisor convinced me to stay in science, and so I decided to give it one more year, and it all worked out. The only and best job offer I got leaving my post-doctoral fellow was to work at IBM (International Business Machines Corporation) in their basic science lab in New York. They gave me a big start-up package in a lab, so that means they give you a lab, a million dollars, and ask you to do something interesting. About two months after I got there, in the early 90s, IBM almost went broke. So my 1 million dollars reduced down to 20,000 dollars, which is a small amount of money to build a lab. And it pushed me to really be creative in terms of how I spent that money and how I used the resources that already existed at IBM to get something done. Especially to begin developing this new field of nanoscience and nanotechnology. I did that. Once I got a couple papers out, I got job offers from everybody. But it was not so bad, being starved, and being forced to be clever rather than just spending money. I think if I had all that money and built a lab, I would not have done nearly as creative science as I ended up doing with no money. I wouldn’t suggest people try to do science with no money, that’s not my lesson here. My lesson is that sometimes lemons turn into lemonade.
What would your biggest piece of advice be for anyone wishing to pursue STEM, medicine, or science in general?
I think you should get in a lab or get in an environment where you are actually doing science and trying to solve a problem. At some point you are going to find something that really peaks your interest and is worth pursuing. You’ve got a lot to offer so don’t sell yourself short. Work on a problem that really gets you excited because basically, if you don’t have a problem that gets you excited, you better have good hobbies. You’ll learn a lot in the classroom, but the best thing you can do is try to work in a lab or an environment that’s working on a problem you think is important. There’s synergy, environment, human health, economic and health disparities, whatever you get excited about. Jump in and make something happen. The best way to predict the future is to make it and be an active participant in what happens. Also women are going to take over the world and I think you know that! When I first started at Caltech it was only 30% women, but there are big changes being made in that ratio. Women are stepping up to solve some of the world’s biggest problems.
From the beginning of your science career to now how has science changed in your eyes? And what change would you like to see?
We need many levels of expertise to solve the biggest problems we face today. I would like to see the hard and soft sciences partnering together to solve some of those problems.Jim R. Heath, PhD
I think almost all of science has changed and has become much more of a data science. I think it’s become much more quantitative. Biology used to be very descriptive. One is more focused on measuring how many molecules are in a cell rather than just if the protein is up or down. And also trying to capture the views of biology in many different ways which becomes now a computational problem as well as a measurement problem. So, I think the issue of quantitation has really transformed many areas of science, especially biology, it really opens up science in ways that weren’t there before. That’s the big change that happened. Before the pandemic, there was a real split in science. I think people should worry about technical solutions to resolving issues. I would like to see fundamental work happen in those areas and I think it’s more than just a technical solution, I think it’s universal. We need many levels of expertise to solve the biggest problems we face today. I would like to see the hard and soft sciences partnering together to solve some of those problems.
What practices help you to maintain a healthy work/life balance?
I went to school as a music major, and I still play music! I play lots of different instruments. I fish a lot as well. I do not take that much time off, to be honest, but when I do I take advantage of the outdoors. I also ride my bike back and forth to work everyday which is 10 miles each way, and so that gives me exercise as well as an hour before and after work where you are not on Zoom or not in meetings working on stuff. I do try to be balanced, but I am fun! As a scientist, you get to do science which is actually fun.
Link to ISB Profile: James R. Heath, PhD · Institute for Systems Biology (isbscience.org)