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Tom Cech leads RNA splicing dance as part of BioFrontiers Institute Professor John Rinn’s biochemistry class in April 2018. Photo by Glenn Asakawa / ���񱦵�

It’s been 30 years since ���񱦵� Distinguished Professor Tom Cech received the 1989 Nobel Prize in chemistry for his findings that RNA in living cells is not only a molecule that encodes information but can also function as a catalyst. His discovery laid the foundation for advances in molecular genetics and gave rise to an expanding appreciation of the roles of RNA in biology. 

Among his many awards and recognitions, Cech was selected as a Howard Hughes Medical Institute (HHMI) investigator in 1988 and served as president of the Chevy Chase, Maryland-based HHMI—the nation’s largest private supporter of basic biomedical research—from 2000 to 2009, while retaining his ���񱦵� faculty positions and lab. He is an HHMI investigator and the director of the ���񱦵� BioFrontiers Institute and also has a faculty appointment at the . 

Cech came to ���񱦵� as a faculty member in 1978, and his work has had a significant impact on students, faculty and colleagues.

 

When students come into the university, they’re excited and easy to engage...If you tap into and reinforce the enthusiasm, it can make it a life-changing experience for them.”

 

On the 30th anniversary of being awarded the Nobel Prize, Cech shares his thoughts on a distinguished career.

What were you doing 30 years ago when you got the phone call?

I was in Boston at Harvard receiving an award they give every three years called the Warren Triennial Prize (recognizing scientists who are seekers of and contributors to new knowledge in the service of medicine), which I shared with John Steitz from Yale University, who’s a good friend. During the speeches at the dinner the night before, they said many of the previous winners of the Warren Triennial Prize had won the Nobel Prize within 10 years. So, the next morning I got the phone call. I didn’t have to wait 10 years.

I was pretty much a “deer in the headlights.” Speechless. It was amazing. They put a Swedish friend on the phone to assure me it wasn’t a crank call. The minute I put the phone down it started ringing, and it was reporters. They had heard the news and were contacting me. 

What was biochemistry like 30 years ago compared to today? 

The big difference is the Human Genome Project and the other genome projects that have completely changed the way we do biological science now. Computation has become a much more important part of it. The techniques we were using 30 years ago seem very primitive by today’s standards.

The actual Nobel Prize work was published in 1982, so that was going on 40 years ago at this point. Certainly, the science is very different in this postgenomic era. Experiments can be done much more precisely. Some things can be done much more quickly. As a result, the expectations for a good experiment are much higher now. When I look back at some of the papers from that earlier era, they seem so simple compared to what we have to do to publish a paper today. Students have to go through many more hoops than we did back then.

BioFrontiers, as an academic institution, has a philosophy of interdisciplinary collaboration. Why is that important? It’s a passion for you.

It is, because I think if you want to answer a biological or biomedical question at a deep level, you want to bring together whatever talents, training, resources, equipment, theories, from wherever you can to answer the question. This has always been my way of thinking. I was trained as a chemist originally, but I never felt constrained by chemistry. We’ve done structural biology, X-ray crystallography, cryo-electron microscopy. We use whatever techniques are required to really delve into questions about how nature works. 

Interdisciplinary science does rock a lot of people’s boats in a way they find to be uncomfortable, because a lot of scientists, as they get more ensconced in their topic, get narrower and narrower in their thinking. You end up being more and more of an expert in things that fewer and fewer people care about. We try to fight that by embracing multiple disciplines and encouraging our students to do the same. 

How did you choose this path?

Research is always two steps forward and one step to the side, one step back. It’s always a circuitous pathway. Often just keeping our eyes open and ears peeled has allowed us to make discoveries that we really didn’t set out to make. And then those lead us in new directions. To some extent we’re being led by the science rather than us leading the science, although it’s always a bit of a mixture of the two. Personally, I found studying chemistry, working the problem sets and solving the equations to be very exciting as a student.

But the research didn’t fit my personality. I found the chemistry lab work to be too slow and to give too infrequent a return to the scientist. You didn’t get an answer very quickly, and I wanted something where you could think of an idea, ask a question, get an answer the next day or at least the next week. Then use that answer to design the next experiment. Molecular biology is much more of that tempo. 

What are some of the most effective ways to convey the importance of this research to the public?

The thing that people always fall back on are the medical advances that can come from the research. But the truth is, that isn’t what we care about from day to day working in the lab. It’s more just the joy of understanding how nature works, how biological systems operate, how biology is regulated, and how cells and organisms go about responding to their environment and reproducing. What is life? Very fundamental. That’s what really drives our experiments. We do keep our eyes open for possible medical relevance. 

The greatest medical discoveries typically come from basic scientists who didn’t care about medicine. People don’t understand that in the community.

There are two kinds of medical advances, which are both very important: One is the clinical research, which is applying basic science knowledge to human health. That’s the kind of stuff Anschutz Medical Campus is really expert at, and is very important. To some extent you aren’t allowed to be very creative. It’s illegal and unethical to do novel experiments on people as your subject matter! If you’re doing a human clinical trial, you have to do it exactly the way it’s designed. You’re not allowed to deviate from that.

The kind of basic science we do is the opposite of that, since we’re not constrained by working with people as the experimental organism. We’re just interested in how things work. We come up with a basic principle of biology, which then has tremendous medical relevance. But we didn’t know that would be the case at the beginning.

What has surprised you? 

I’m surprised all the time. I’d say several times a year in our lab something really breathtaking happens. It’s usually a student or a postdoctoral fellow who has made the breakthrough—not me. I’m more the conductor of the orchestra. I’m helping the students think about what’s the best experiment to do, helping them interpret their findings, but I’m not the one who’s in the lab making these findings.

We have been using cryo-electron microscopy to determine molecular structure, and the postdoctoral fellow, who’s from Singapore, just had another big break over the weekend. This is what we live for. It energizes everybody in the lab when these things happen. It’s what students live for. In a research lab, I said it happens fairly often, but for any individual student it might be something that happens only once or two or three times during their five-year PhD career, but perhaps not every year. 

What are your thoughts on the current state of bioscience education—what are some key factors that correlate to student success?

It’s important to give young students the opportunity to explore science. This is best done in a hands-on, inquiry-based way rather than by reading books or lecturing. You have to let them actually work with their hands on a scientific project. We’re lucky enough at ���񱦵� to have students coming in from all over the world who are hungry to try their hands at working in the laboratory. We take in as many as we can. I have three undergraduates in my lab now. That is typical of many of our labs. 

These students enjoy doing something that is so much at the frontier of knowledge that the answer is not known. They get good mentorship about how to go about asking the question, how to do the experiments, but they take ownership of a project and start asking their own questions and getting answers. This is great preparation for their future careers.

At the PhD student level, this is what it’s all about. We minimize the coursework, and there’s not much actual classroom learning, except during the first year. After that it’s all about participating in the process of designing their own project and carrying it out and presenting it to the world. That’s the process we enjoy being part of. 

You have taught undergraduate chemistry classes many times. Why is it important to you to teach those undergraduate classes? 

When students come into the university, they’re excited and easy to engage. They’re expecting things to be different from high school. And to the extent that you give them a bunch of boring lectures, sitting in straight rows, they can be talked out of that enthusiasm rather quickly. If you instead tap into and reinforce the enthusiasm, it can make it a life-changing experience for them. I think the freshman year is particularly important for that. 

BioFrontiers is a leader in Colorado and national biotech. What changes have you observed in how the state attracts, funds and retains bioscience talent? How has BioFrontiers contributed to that?

Most of the biotech industry in Colorado has spun out of science that’s done on one of the university campuses, one of the academic institutions. It’s usually a project that comes to the point where a discovery has been made and now needs to be developed into something useful for medicine or society. It’s no longer a good project for graduate students because it’s become sort of repetitious and very much has to be done in a way that will pass all the regulatory and legal requirements. 

Many of us in BioFrontiers have been involved in technology transfer from the laboratory into a company. Many of the labs at Anschutz have been very successful in starting companies based on their research and technologies, as well. There can be many pathways to this. I think the one thing we do that is different in BioFrontiers, and we think is powerful, is that we don’t hide the biotech career opportunities from our students. We talk them up. We have seven small companies in our building that students can interact with. That’s quite unusual. Around the country you’ll find very few examples of that.

We have speakers from companies come talk to our students to network with them.  We think these are valuable connections and career opportunities for our students to have and that can serve society in a very positive way. We celebrate the connection of science with industry.

The companies that are in the E-Wing are all aware they have a fixed lease, and at some point the space will be needed for academic purposes. In the meantime, it’s a win-win situation that we are able to accommodate these companies. It provides the companies with an easy way to get set up because they have access to all of our core facilities, some of which have been paid for by state funding and are available to the companies at a similar price we would have to pay to use our own core facilities. So they help contribute to the upkeep of these facilities, and they can attend the seminars held in the building because they’re open to the public. They can interact with scientists informally, as well.

Any reflections on your time at the helm?

We’ve tried to be fairly broad so students from multiple backgrounds could find exciting things to do in the institute. It’s an interesting discussion. To what extent should you concentrate your resources? To what extent should you be as diverse as possible? It’s an ongoing discussion.

What are some of the opportunities and growth areas for BioFrontiers over the next five to 10 years?

You can talk about it in terms of human disease or you can talk about it in terms of interdisciplinary scientific opportunities. In terms of human diseases, the areas we’re particularly strong in are cancer, cardiovascular research, virology, infectious diseases and neurodegenerative diseases. Added to that would be tissue engineering. The idea of intervening with body parts that are falling apart by creating artificial ones that can be used to restore good health. We have had some astounding discoveries, made in our building. 

The other way of talking about it is to talk about what are the scientific opportunities just in a basic, fundamental sense. One is at the interface of physics and biology. We want to be able to image molecules within cells at unprecedented resolution. We’ve even been able to watch single molecules move around a cancer cell in real time using microscopes we have in this building and technology that was developed around the world that has been made available to researchers. So that’s one area.

Second area that’s really exciting is the interface of computer science and biology. This used to be a dream that one could sit down at your desk and compute things rather than going into the lab and doing experiments, and now our students are often spending half of the day in front of a computer doing calculations and computation with all of the human genome and other genomic databases. You can find a lot of data on the internet that’s good quality to use to try to answer your question. You don’t necessarily have to go into the lab and develop your own data. So, we want to be a leader in that area, too, and we’ve succeeded in hiring some spectacular junior faculty members and a couple of senior faculty members who are really experts in that area.

I would say the third area of real excitement to me is the biomaterials area—the ability to go into the lab and, using stem cells for example, to actually grow new tissues using a combination of chemistry, material science and regenerative medicine. That’s facilitated by the fact we have all these engineers in the building. Because the building is not just BioFrontiers. It’s shared with the Department of Chemical and Biological Engineering and the Department of Biochemistry. The walls are low between these groups. A lot of conversations are taking place.

Do these cross-disciplinary interactions expand the possibilities?

Absolutely. Through productive collisions between people who are in different disciplines—sparks fly, new ideas spin off. People have different training and different expertise, and they bring those together in exciting new ways.

What research questions are you pursuing now in your own lab that excite you?

We’ve become hooked on this fairly new field of epigenetics. It used to be thought that differences between individuals, either the way they look or the way they behave were due to different genes. Different mutations in genes could cause different behaviors. Mutations could also cause disease. That’s still true. Darwin was correct, but as is often true in science, it was true but incomplete. 

The other half is that there is a layer of regulation of the genome that does not depend on differences in the As, Ts, Gs and Cs marching down the chromosomal DNA sequence but instead is superimposed on top of that. For example, the way certain genes can be condensed and balled up so that they’re not active, or the same gene can be expanded in the nucleus of the cell so that it can be read out and can be active, all without any change in the DNA sequence. These “epigenetic” changes can be heritable, and this is thought to be very important for once a stem cell differentiates and becomes part of the brain or part of the heart or skin. How does it then remember what it’s supposed to be? How does it keep this identity going—that a contractile cardiac myosyte in our heart doesn’t become a neuron? That would not be good.

Almost all of this is due to epigenetic type of regulation. RNA is involved in this process, and because our laboratory had expertise in ribonucleic acid, we thought, well, let’s apply that to this new area of epigenetics and see how the RNA might be controlling this epigenetic programing of human cells.

In closing

I’d like to say it’s really been a great ride. I’ve tremendously enjoyed my colleagues here at the university. The quality of the science is breathtaking. The students have been so energized about performing this research. Because they are energized, that energizes me. The great thing about being a professor is the people you work with are always the same age. Thirty years ago, they were all in their 20s. They’re still in their 20s. As you get older, they stay young, because they move on. That’s one of the great joys of working at a university. 

The university leadership, the administration, has been so supportive of our work, and that has made it an extremely pleasant experience and certainly contributed to our success.