Interview with Professor Thomas R. Cech by science writer Peter Sylwan, October 2004.
Thomas Cech discusses why studying RNA catalysis in the ‘curious pond animal’ Tetrahymena thermophila safeguarded his research from early censure, why the discovery of only 35,000 genes through the human genome project invites further research in RNA coding (9:08), why recapitulating the steps for the origin of life falls to scientists (14:20), why the United States education system needs improvement (15:57), why the Howard Hughes Medical Institute holds promise (20:58), and, finally, why there is value in exploring the unknown (26:50).
Who or what come first, the chicken or the egg? Welcome to meet Tom Cech, the Nobel Laureate of 1989, when he got the Prize together with Sidney Altman to solve just this question. Before Tom Cech and Sidney Altman, everyone was firmly convinced that the genetic machinery needed a protein to run around. The genetic material holds all the information and all the templates and all the tools to churn out new proteins, but who is in charge of the genetic machinery? That is the proteins. It all went round in a circle. And where on Earth can you find the beginning of a circle? So how on Earth could life arise on Earth if such a complicated event should occur? To have one complicated molecule to meet another complicated molecule, to rise spontaneously and simultaneously and meet at the same time and the same place. It was totally impossible.
Then came Tom Cech on the scene and showed that one of the crucial molecules in the genetic machinery, and maybe it was also the only molecule that existed when life originated on Earth, and showed that this molecule could do perfectly well without the protein, it was outer catalytic, it could stimulate itself to churn out new molecules. So now I wonder, Tom Cech, how on Earth did you feel and what did you think about when you sat there in the lab and saw all these results coming out that could only be explained in mechanism that no-one would believe in?
Thomas R. Cech: We ourselves did not believe it for more than one year and I was working very hard and encouraging the people in the laboratory to work very hard to find a protein that we were sure must be responsible for the RNA splicing and …
It wasn’t there?
Thomas R. Cech: It wasn’t there and we kept getting evidence really that it wasn’t there. For example, we would take the RNA preparation and we would subject it to detergent, which is very bad for proteins, and the splicing reaction continued unabated and we would boil the solution, which normally denatures and unravels protein chains and again, the splicing reaction continued after that treatment. So the system kept trying to tell us that there was not a protein but for a long time I refused to listen and kept urging people to look harder for that evidence for the protein.
It looks like a really good detective story.
Thomas R. Cech: Yes, it was and had I, you know … Eventually we got to the point where we said, well, we cannot show the presence of a protein. Maybe we’d better change the hypothesis and now the hypothesis should be there isn’t a protein. How could we go about proving that? And then of course you’re subject to thinking Oh, everyone’s going to say you have a very small amount that you cannot detect of a protein, how can you ever show that there’s no protein in the solution? So then we switched on to recombinant DNA technology and made a very artificial RNA that had never seen the inside of a cell and only then could we demonstrate to our satisfaction that there was no protein.
But you must have thought of the risk of being ridiculed when you came out on the stage, in the open air, with all those results. Were you, by the way?
Thomas R. Cech: Not immediately. The world was sort of waiting for this result because Francis Crick and Leslie Orgel and others had speculated about such a possibility in the mid-1960s. I’m embarrassed to say I had not read those, I was too young, I had not read those papers and I was unaware of this, but others, who were more senior, were still thinking that maybe RNA could tell us this would be perhaps important for the origins of life and that the fact that the ribosome was composed of partially RNA seemed to many people to be a hint that RNA had a very primordial role in catalysis.
Now, since there were no examples, that had sort of faded away in the meantime but once we provided this evidence, there was really great excitement. I think the fact that we did the experiments in this obscure organism, this pond animal Tetrahymena thermophile allowed many people to think of this as a curiosity rather than something that would be central to biology, so that perhaps also prevented us from being ridiculed. We said Oh this is a weird organism, it does weird things, it’s interesting but we don’t have to incorporate it into the centre of our thoughts.
But there is a very exciting mechanism that I want to know something about inside now. I mean, how do you really break down a paradigm? Because that was what you did. I mean, how do you function as a scientist to be able to do that in the first place?
Thomas R. Cech: You have to, of course, have an open mind and you have to have very rigorous experiments and you have to be your own worst critic. You have to be so demanding to get very sharp proof yourself, in your own laboratory, that by the time you announce it to others; they have to accept it because you’ve done things so carefully.
Yes, but how come that your mind is starting to think of something that no-one else thought of?
Thomas R. Cech: Well, as I said, we were a bit slow to come to that realisation. It took a full year and you just … As a scientist, you get hooked on these questions and you’re thinking about it all the time, you think about it in the shower in the morning; you think about it in the middle of the night, you think about it when you’re riding your bicycle and you just keep turning over the possibilities and the important thing is to recognise that there could be other explanations.
And then all of a sudden there is this eureka moment where you say Ah!
Thomas R. Cech: There were some eureka moments, mostly by the time we got to the final evidence. We knew that it had to be the case. We had no other ideas left and so then, if it had not been that the RNA was self-splicing, I don’t know where we would’ve gone next.
So now this is 15 years ago, so there must have been happening a lot since then. What is going on in the field now?
Thomas R. Cech: The important thing for what we called ribozymes which means ribonucleic acid that has catalytic activity, and I think this was key to the Nobel Prize, was other people finding more examples because if it had only been the one example in this pond animal, I’m not sure the interest would have been so sustained. But within, well the next year, there was another example and then the year after that several more examples and then literally hundreds of examples of RNA catalysis in nature and that helped not only sustain the interest but increase the interest so that there actually started to be conferences on catalytic RNA. There was enough of a community that hundreds of people around the world were working on this and they would get together and talk and compare their results, so that was one development that we had no way of predicting but that was of course very exciting, for us and for the field.
But what is actually now and what do you see in the future? Will there be any new surprises coming up on this molecule, the RNA molecule? It will do a lot of things we never thought of before.
Thomas R. Cech: Yes, absolutely, in fact many of these have been found just in the last three years that when the genome was sequenced, the human genome, people said 35,000 genes, this is surprising that there are only 35,000, only twice the number that it takes to make a fruit fly to make a human, surprisingly compact but those were just the protein coding chains. We don’t even know yet how many genes there are that function only by making an RNA molecule and then the RNA’s not a message to make a protein but the RNA functions as an RNA molecule and some of these have been found recently, that regulate expression of genes, they regulate chromatin structure, the way that the chromosome packs together or unravels. They regulate rearrangements of the genomes, so already we’re seeing that RNA has many more activities than anyone would have guessed.
This must mean that all this talk about junk DNA and DNA that is not working or RNA that you don’t know any use of, it will totally change in the coming five or six years? There will be no junk left?
Thomas R. Cech: I don’t know. I think there still could be some junk. Much of the junk appears to be almost parasitic transposable elements which inhabit chromosomes and then have a strategy for copying themselves without damaging the ability of the host organism to function properly, so there could still be some junk but I think buried, you’re correct, that buried within what now appears to be junk may be some RNA transcripts which have activities that are not yet imagined.
How come that we call things we don’t understand, don’t know anything about, junk? History shows that it always comes up to be more useful. Have a better meaning?
Thomas R. Cech: Yes, I think often it’s just ignorance of what it could be, of what the function could be.
Ok, this science is part of bioscience and if you look back, the 20th century was a century of physics and understanding matter. Now the knowledge and the technology that came out of that totally turned society upside down and changed our minds. Is there an equivalent perspective on the biosciences and the 21st century?
Thomas R. Cech: Absolutely yes. I think it’s already starting to happen. The completion of the human genome project was a wonderful event, but it was not an end in itself. It provides a tool which will allow the medical sciences to understand both healthy human life and also disease in a much different way than they were able to do before and we, as we learn more and more, we will learn that particular variations of genes that each of us, one person to the next has thousands of differences, some of which may be inconsequential but some of which may give us a resistance to a virus or a susceptibility to heart disease and as these are, the meaning of these differences is unravelled, then medical science will be able to use these to better diagnose and treat disease.
But how will it affect our lives? Will there be eternal life or will agriculture be something totally different?
Thomas R. Cech: I hope not in terms of the eternal life because if you remember the gods on Mount Olympus from Ancient Greek mythology, who had eternal life, they were wasting time and drinking and partying all the time. They did nothing useful with their lives because there was no time pressure, so I think that having, I think the fact that life is finite is what makes it so valuable and what gives us incentive to make the best use of every day.
But surely it will affect the way on our route to the final end? I mean, what will the journey look like when bioscience is ripe?
Thomas R. Cech: Of course, the dream is that people will live a healthy productive life, as many people are now, but even more people will be able to look forward to having a life that lasts for perhaps 100 years in a productive healthy manner.
What about the greatest riddle of them all, how life originated?
Thomas R. Cech: Yes. That one is fascinating to think about and one wonders if it will ever be solved because if you think about it, it’s not so much just as scientific question, it’s for historians to talk about, but how do historians normally ask questions about things that are that ancient? That are almost, you know, over three billion, perhaps close to four billion, years ago? You look for fossil evidence if you are a paleontologist and single molecules, such as RNA, do not leave a fossil imprint, so it’s very difficult to ask the historical question. Instead, as scientists, we try to recapitulate steps in what might have been a plausible scenario for the origin of life.
But if you managed to make a self-replicating molecule with the RNA type in the lab, then you at least would show how it could happen.
Thomas R. Cech: I think that’s perhaps the best we can do, is to say this is a plausible mechanism, that self-replicating RNA, since it would be both the genotype, the gene part, the information part, and the activity to do the replication, would simplify how one would think about the origins of life.
But to get these answers, if they are impossible to get, you need people coming into science. Are there enough people coming into science in United States and also in Europe?
Thomas R. Cech: Well, certainly in the developed countries, we see a discouraging decrease in interest in sciences. In the United States, the only thing that is sustaining our biomedical sciences is an influx of very talented students from Eastern Europe, from Russia, from Asia, especially China, some from South America, from countries where people are hungry for opportunity and I’m afraid many of the American students have an easy life and this seems very difficult, to have to think about the scientific concepts, so we see a declining interest. It worries us a great deal.
What are the consequences?
Thomas R. Cech: Well, the consequences are that, for the United States, the consequence is that as the opportunities get better, for example in China, and the Chinese students don’t come to the United States any more, we will lose our ability to have a very strong scientific establishment. It won’t happen overnight but it’s a trend that is worrisome.
So there’s a brain drain instead of a brain rain? Going that way instead, brain draining the Western countries instead of the brain draining on the other way round, that we talked of before.
Thomas R. Cech: I mean, the United States has benefited greatly from being the recipient of the brain drain from other countries and that source of talent is not going to continue forever.
Where do you put the blame? That the young people of the United States and Europe just don’t feel attracted to a scientific endeavour.
Thomas R. Cech: It is difficult to know all of the reasons, but I think one factor is that we are not doing as good of a job with science education as we should be, that we are teaching our students in very old fashioned ways and although the scientific research of today is completely different from even 10 years ago, the education is the same as 20 years ago, as 40 years ago. We have not made the science seem vital and exciting and interesting to many students. They spend too much time reading about it in text books and not enough time being allowed to explore the science with their own hands and to try to understand the excitement of discovery.
And after all, what does the practising scientist do? Do we go into our offices and open a text book and work problems? Which is what we ask the students to do. We don’t spend any of our time doing that. We’re doing discovery research, we’re extending the frontiers of knowledge. If we could only give our students a sense of that, I think that many of them would get very turned on by it.
But don’t you think that also the scientists are a little to blame because the idea of putting scientific knowledge in peer reviews or in scientific papers is to rip off all the emotions, to limit it to the pure knowledge and nothing of the excitement should be left in the paper when it’s in nature or science, so how can you ask people to walk along a street that lies in darkness when not even the people are walking there are illuminated?
Thomas R. Cech: Of course there are some museums which now do quite a good job of, I think, communicating the excitement of science and also allowing the public to play around with various experiments and have an interplay with an experimental system. There are some television shows and some web based activities. Now you can do virtual laboratories on the web where you’re actually mixing things together in a test tube and seeing what happens, so I think that there are quite a number of points of light around the world where people are doing some innovative things, but the overall picture is still that we’re not doing enough and that only a small part of the general public really gets exposed to these ideas.
The Howard Hughes Medical Institute is investing 500 million dollars in a new campus?
Thomas R. Cech: Yes. In fact, that’s just the cost of building the campus. The total investment is about a billion dollars over the next 10 years, including the cost of running the campus.
What do you hope to get out of that?
Thomas R. Cech: We recognise that biology has changed over the last decade and that technology, both computer technology but also instruments for peering into the function of cells, what we call imaging, to be able to see how molecules move and combine with each other and perform reactions in a living cell, that it’s very difficult to explore those areas in the best way in a university setting, because in universities, the biologists are in a separate building away from the physicists, who are separate from the engineers and the chemists are yet somewhere else.
And so technology and biology really need to be working more shoulder to shoulder and the university puts people in separate places who need to really talk to each other, so we decided to build a place where there was a single building with great horizontal spaces so that physicists, chemists, engineers, computer scientists could be working shoulder to shoulder with biologists and learning about what kind of technology was really required to drive biomedicine to the next step.
And also, when you see the plans, the research groups will be rather small, only 10 to 15 persons.
Thomas R. Cech: No, even smaller. We decided more like six persons and the reason is that we have noticed, we did an analysis of the sociology of science and how scientists interact. What we found is that as soon as research groups become large, there are some negative things that happen. First of all, the students quit talking to people from other laboratories; they only talk to people within their very large single laboratory, so you don’t get so much cross fertilisation of ideas.
Secondly, the professor is so busy organising things and writing grants – the professor spends all their time in their office rather than working with the students and post-doctorate fellows in the laboratory – so we think that by restricting the groups to very small, that we will then, when they want to do a bit project, they will have to interact with other groups and talk more to come together to do a bigger project.
So small groups, a lot of money and people coming from all different sort of disciplines, putting them together in one place and make them talk, that is the recipe?
Thomas R. Cech: That’s part of the recipe. The other part is that we are very close to Dulles International Airport in the Washington DC area, and so we hope to have visitors from all over the world who come, because we want to share the things that we create. We don’t want to just hold them to ourselves. We want to make them accessible to the world, so we have built a hotel for 100 people and we have built 48 apartments so that people can come and stay for a month or six months or a year, and then the proximity to the airport should make it very easy for scientists to come from all over the world to join us there, to bring their ideas or maybe bring their problems, bring their samples to put in a microscope or to learn a new bioinformatics algorithm, so we want to have a very active visitors programme as well.
And also to bring that passion, because that is people you’re looking for, passionate people who want to solve difficult problems. That is in your ad.
Thomas R. Cech: That is our goal. We want people who really care about these questions and the reason we want housing right on campus is because we think they will be working through the night and then they will need a place close by in order to catch a few hours of sleep before returning to the laboratory.
So what will this laboratory have explained to us in 10 years from now? The secrets of consciousness?
Thomas R. Cech: Maybe the secrets of consciousness will be more 100 year goal, but one step towards that will be to unravel the network of neurons that are responsible for behaviour and we don’t want to, we’re ultimately interested in human behaviour but the human central nervous system, the human brain, is too complicated, so we will work with simpler organisms such as the fruit fly, the zebra fish and the mouse, that are genetically tractable organisms and also ones that are smaller so that we can apply this imaging technology, this advanced microscopy to visualise these neurons in action.
Finally, then, do you think that all the possibilities that will come up with science will come to a societal use? Is there a fruitful ground in the general audience that can accept the knowledge of science? I mean, it seems to be more and more complicated and more and more difficult to understand and also more and more scaring.
Thomas R. Cech: Well, that’s a big question Peter, and I’m not quite sure where to start. I think the biomedical sciences have had the advantage that we can justify much of the work that we do, that it has an opportunity to provide better health, to rid the world of infectious agents and of course it’s proven its ability to do this. Not in every case, but many infectious agents that ravaged mankind are now under control; diseases such as polio and smallpox are largely eradicated in much of the world; AIDS, although still a terrible epidemic, at least the science has allowed us to find pharmaceuticals that can be very effective in preventing HIV infected individuals from coming down with the AIDS disease.
The problem now, of course, is how does one get these drugs to places such as sub-Saharan Africa that are so terribly ravaged by this problem. And that’s not so much a scientific problem, that’s more of a political and economic problem and a problem of poverty but the other side of the coin is that, you know, it’s not just the medical benefit that drives us as biological scientists to do this work. It’s the pure excitement of understanding the secret of life and how nature works and I hope we don’t lose sight of that either. I think there is value in humankind exploring the unknown and I hope that we don’t quit funding the physics and the mathematics and the chemistry and the other sciences that don’t have, you know, so much ability to justify their work on the basis of medicine because there’s great value in those sciences as well.
Thank you so much for sharing your time and all your exciting ideas and knowledge with us. Thank you.
Thomas R. Cech: It’s been a real pleasure, thank you.
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