Sue Merrilees, Science Philanthropy Alliance
Remarks have been edited and condensed for clarity and brevity
Recently, I spoke with Nobel laureate Tom Cech, an External Science Advisor to the Science Philanthropy Alliance, about the publication of The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets, his first work written for a general audience to help them understand the importance and role of RNA, its relationship to DNA and its potential in curing or treating diseases.
Merrilees: Your intention was to write a book for the educated lay public, not for scientists. To that end, you are prolific in your use of metaphors. I note spaghetti, a record player, bridge traffic in New York City, garden gnomes, and more garden gnomes. How did you come up with these or have you always used metaphors to help explain your work?
Especially when working on the frontiers of knowledge–there’s always stuff you don’t understand, with fits and starts and false leads, but that’s the way you move forward.“
Cech: Not so much in the laboratory because we use a lot of jargon. I can walk into the lab and say maybe we should just CRISPR this allele into the genome of HEK 293 T cells, and my student knows immediately what I’m talking about. It would take three days for me to even begin to explain that sentence to a non-scientist. However, if you’re talking to the neighbor over the fence, the same technical language becomes a barrier, which prevents communication. Of course, metaphors and analogies are less precise, but you gain a larger audience.
When I’ve given talks about the book to a public audience, many scientists have also attended. My pitch to them is that while it’s hard to explain our research to the general public, we must do it, or we are digging our own graves.
We have to do it because we have a voting population that needs to be somewhat scientifically literate, so they can understand how science-based decisions are made while also comprehending the limitations of science– that science doesn’t know all the answers and sometimes gets it wrong.
That’s not to say scientists are incompetent; but rather science is an ongoing process, and we try to get better all the time. Especially when working on the frontiers of knowledge–there’s always stuff you don’t understand, with fits and starts and false leads, but that’s the way you move forward.
It’s the moments of exhilaration that keep the scientists going, “Ah, ha!”
Merrilees: One moment of exhilaration no doubt was when you won your Nobel Prize in Chemistry (shared with Sidney Altman in 1989) for the discovery that RNA could be catalytic. Can you describe your shift from DNA to RNA guy?
The research was not being done to cure a disease; it was being done to understand how nature works.“
Cech: All my graduate work and my post-doctoral work involved DNA, which I thought was so much more important than RNA. When I set up my own lab at the University of Colorado, I had every intention to study DNA. I wanted to understand how DNA was regulated to produce whichever RNA molecules were needed. The DNA seemed paramount with RNA being just the expression of the gene.
Much to my surprise, we found that the RNA that was being made was rearranging its own internal structure. This process had been discovered just a few years earlier by Phil Sharp at MIT and by a group of scientists at Cold Spring Harbor Laboratory (Long Island); it was called RNA splicing. It was clear that this was an essential step in the expression of genes– especially in humans– but nobody knew how it worked. They didn’t know the nuts and bolts of how particular sites along an RNA molecule were chosen, cut and rejoined to remove these interruptions in the code–these so-called introns–to restore the continuity of the RNA.
Here, we had a system that was amplifying or exaggerating this phenomenon, and it just drew us in like a magnetic attraction. It became even more intriguing when we found that the RNA didn’t appear to need any external help in doing the splicing. Eventually, we were able to show that the RNA was, by itself, catalyzing its own rearrangement.
Merrilees: You are a strong believer in the value of basic science. Other than the world’s most recent example of the development of mRNA vaccines to counter COVID-19, what other basic science discoveries have stood out to you as especially foundational?
Cech: Much of the work that we now consider “translational,” having medical applications, came from an initial discovery that was curiosity based. The research was not being done to cure a disease; it was being done to understand how nature works. One great example is a phenomenon discovered in a tiny transparent roundworm, C. elegans, which has the scientific name RNA interference (RNAi).
The scientists studying the worm were trying to understand how double-stranded RNA was inhibiting the activity of certain genes. What is true for the worm is often also true for the human, and that turned out to be the case with RNAi. The same process exists in all the cells in our bodies, and now companies have been able to make pharmaceutical therapies based on RNAi. These therapies were first developed to treat several rare diseases and are now being repurposed to attack neurodegenerative disease.
Another example is telomerase, often called the immortality enzyme, because it is responsible for the ability of our stem cells to regenerate. On one hand, telomerase is good to keep stem cells dividing; on the other, it’s responsible for the reproduction of cancer cells.
Telomerase is an RNA-directed little machine that extends the DNA at the ends of our chromosomes. It was first discovered by Elizabeth Blackburn and Carol Greider in the pond scum organism Tetrahymena.
Like C. elegans, Tetrahymena shares a lot of fundamental biology with human cells, but it’s as cheap and easy to grow as bacteria, giving you a shortcut into exploring a lot of fundamental biology questions. By studying telomerase in Tetrahymena, scientists Blackburn and Greider were examining the mechanism of how chromosome ends get maintained and kept from getting frayed and damaged during cell division. This turned out to be key to understanding cancer.
The third most mutated gene in all of cancer is the telomerase protein gene, which was discovered in my lab by a Swiss postdoctoral fellow, Joachim Lingner. He did this via basic science involving a different pond scum organism called Euplotes. Again, it wasn’t cancer therapeutics that was driving our experimentation, but rather curiosity about how life works.
Merrilees: You mentioned in your book the existence of dark matter of the human genome, which is sometimes pejoratively referred to as dust or junk. Yet, you see promise in identifying and learning more about it. Can you speak more about that potential?
Cech: It turns out that only a small percent of the DNA in our cells is destined to be copied into messenger RNA to encode particular proteins. That’s very important, but it leads to the question, what’s the other 97 percent of our DNA doing?
For example, if you look at skin cells, you see very little of this so-called dark matter of the genome being transcribed into RNA. If you look at neurons, you see a different part of it transcribed, likewise in liver and reproductive cells. However, if you integrate all human cell types, most of this dark matter is in fact being used to specify RNA.
The fact that this dark-matter RNA is so specific to tissue and cell type makes it seem like it’s not going to be junk but does actually have a function.
Scientists are starting to unravel some of those functions. Many of them seem to be regulatory in that these non-coding RNAs are reaching back and influencing which part of the human genome is specifying proteins in a particular cell type. Different tissues need to express different genes. If they only expressed the same part of the genome, rather than having a brain, a heart and skin, we would be all skin and no brain or heart.
These non-coding RNAs are involved in regulating that process, sometimes called Epigenetics because it’s a level of regulation beyond what the code of the DNA specifies. It’s above the level of Genetics, which is just reading out the order of A’s, G’s, C’s and T’s on the DNA backbone.
Merrilees: What would be the focus or purpose of that regulation?
Cech: It takes 20,000 different genes to make a human. That’s a pretty small number of genes, but RNA may provide the secret sauce that allows so much diversity from a limited set of genes. In each type of cell, only a particular set of genes is turned on. It’s the non-coding RNAs that help make the master regulatory networks to
These RNAs may also help explain why humans can be exponentially more complex than yeast or fruit flies even though the numbers of genes these organisms have are not vastly different. Yeast has 6,000, 7,000 genes; we have 20,000. Yet, yeast has only one kind of cell, and we have hundreds of kinds of cells. How can you possibly get so much complexity just by tripling the amount of genetic material that you have? RNA regulation may help explain how we get more bang for the buck, so to speak, from a limited number of genes.
Merrilees: I always found those statistics somewhat humbling, similar to the C. elegans’s gene count versus the human count.
Cech: Yes, I can’t remember the exact count for C. elegans, but it’s approximately 20,000. It’s very similar to the number in humans.
Merrilees: Maybe we will think twice about routinely using “lowly” to describe worms.
Merrilees: You advocate a need for caution when using CRISPR technology to alter genes of plants and animals in the environment. Yet, you do endorse its application to counter climate change through the creation of new biofuels. Can you talk a bit more about your concerns and hopes in these areas?
Learning from other people and reproducing their results and extending their results in new directions is something that scientists not only appreciate but enjoy.”
Cech: I’m looking out of my window right now and the ozone level is high; there’s smoke from Canadian wildfires, a thousand miles away, which is putting a thick, soupy haze over the town carried by the jet stream. There’s no question that the planet is warming, and it’s destroying itself; there are more fires, more devastating hurricanes and tornadoes.
The food supply is endangered. With the bleaching of the coral reefs, marine life, which accounts for 30% of all the protein consumed on the planet, is at risk.
We need to imbue heat and drought resistance in various plants and animals that we depend on. As much as people are suspicious of genetically engineered organisms, I think the planet is on a pathway where genetic engineering may be the only way to survive.
As for CRISPR, with its incredible RNA-driven accuracy, which could arguably also be a savior of humanity why am I generally enthusiastic but also want to put on a bit of a brake?
Our history of introducing new species into the environment has been fraught with numerous examples where the introduction of plants and animals has backfired. More research is needed to prepare ourselves for the time when we’re going to introduce these CRISPR-modified organisms into the environment.
Merrilees: Tom, you were careful to credit the many, many scientists who have been involved in this field of research. Like Newton, do you believe you are standing on the shoulders of giants? If so, any shoulders in particular?
Cech: Oh, absolutely. When I decided that it would be more fun to be an RNA guy instead of a DNA guy, I really needed some mentorship,
If you don’t stand on the shoulders of giants, you won’t be able to see the horizon, you won’t know where you were headed. Learning from other people and reproducing their results and extending their results in new directions is something that scientists not only appreciate but enjoy.
Merrilees: Most people picture a scientist as an individual in a white coat, in a lab, surrounded only by test tubes. In The Catalyst, you recount many interactions and sharing of insights with others throughout your career. Either you have a fantastic memory, or you keep a very detailed journal, or both. Do you think research has become more collaborative?
Cech: Yes, absolutely, although I think it’s always been collaborative within a so-called research group. Each Principal Investigator has his/her own laboratory, and we bring in students and technicians and postdoctoral fellows and they typically each have their own project, but they also play off each other, especially when running into a problem. You go to your friend in the lab and say, “Hey, I’m stuck, can you help me out of this hole?”
That kind of collaboration has been going on ever since research groups existed.
What’s happened more recently is that research has become very interdisciplinary. Scientists want to do some computation, or structural or cellular analysis. They might want to do a mouse experiment. All of these areas are so technologically demanding that you can make a lot more progress if you find good collaborators outside of the lab, as well as inside.
Maybe not all of these funding experiments are going to work, but there are some real home runs when people cut across traditional funding modalities and tackle problems in new ways.“
Merrilees: Speaking of good collaborators, can you describe the role that philanthropy has played in your success?
Cech: Well, it’s just been an enormous help because the Howard Hughes Medical Institute (HHMI) has a philosophy of supporting science that is very different from and complementary to the way that the federal government supports science.
The federal government is very project-oriented and wants to know exactly what you plan to do, how you plan to do it, and what results you will deliver. There’s value in that sort of organization of science funding. In contrast, HHMI, a private funder, believes in people not projects.
They choose people who have made discoveries in the past and say, ‘we’re just going to trust you, do whatever you want for the next seven years. Oh, and by the way, we’re going to call you back after seven years, and you better have a good story to tell about something you’ve done.’
Since HHMI puts the money into people rather than into projects, it means tremendous freedom to study pond scum, for example. You don’t have to justify that pond scum is going to cure cancer at some point. You just have to say, ‘I’m interested in understanding fundamental biology, and this pond scum exaggerates the phenomenon that I’m interested in, so it’ll make it easier for me to figure it out.’
You can also follow an unexpected discovery that takes you in an entirely new direction as we did when we wanted to solve the structure of large catalytic RNA molecules. How do these RNA molecules look in three-dimensional space? How do they fold up? That’s what we wanted to know but we needed x-ray crystallography, instrumentation, and computational resources that were not present at the university. There would have been no chance of getting federal funding for someone who had no track record in an area–we would have been laughed at if we had asked for what in today’s dollars might be five million dollars. This was when Jennifer Doudna (now also an HHMI Investigator) was a postdoctoral fellow in my laboratory. The head of research at HHMI visited my laboratory, talked to Jennifer and the next week the million dollars arrived.
Basically, philanthropic support allows researchers to examine a problem in a novel way; it can bring diverse disciplines together creating new areas for exploration. Maybe not all of these funding experiments are going to work, but there are some real home runs when people cut across traditional funding modalities and tackle problems in new ways.
Merrilees: Kind of like a venture capital funding model. Tom, RNA science certainly has promise for curing disease, but you also note its implications for exploring the origins of life, however, inconclusive that research may be. Have the origins of life research sparked any new insights for you?
Cech: It’s one of the most fundamentally fascinating questions that people have asked since ancient times: how did any living thing first come to be?
It took hundreds of millions of years, and many failed experiments because life forms that weren’t robust enough to survive can no longer provide any evidence of their existence.
But how did it all start at the very beginning? We think that this happened almost four billion years ago, when the planet was cool enough to finally support life. During a period of time, perhaps as short as a hundred million years ago–short relative to the age of the Earth–the first life form was established.
What do I mean by life form? Not something with arms and legs and a brain, but the simplest life form–something that could reproduce itself to give the next generation of entities.
This has always been a chicken and egg problem, because if you need some kind of informational molecule to pass down to the next generation that could be DNA, but a little scrap of DNA doesn’t do anything by itself, it just sits there. It needs protein enzymes to copy the mother DNA into daughter DNA molecules. It isn’t very plausible that at the beginning, from random chemical processes, there was a DNA molecule and a protein that could copy it, both coexisting in a little drop of water on some rock. Now we know that RNA can be both the informational molecule and the catalyst that copies the information. Maybe in the beginning there was just RNA copying itself, and the proteins came along later, and DNA is a much more recent invention, necessary to stabilize the genetic information for long-lived organisms.
The reason we know DNA is not so central to life is that many viruses have only RNA genomes; an example is SARS-CoV-2, which doesn’t even use DNA. Maybe at the beginning, it was solely an RNA world. It’s hard to prove but plausible.
If there were no mistakes made in copying the human genome, we would all look exactly the same. And, as soon as the first virus infected one of us, we would all die.“
Merrilees: So, chicken or egg?
Cech: The chicken and the egg are one and the same.
Merrilees: You note in the book, “viruses are so adaptable because of their replication errors,” which I find somewhat counterintuitive.
Although Silicon Valley is famous for its culture of acceptance–or even encouragement–of failure, errors and mistakes are not generally regarded as positive. But errors allowed viruses to evolve and survive.
Cech: Genetic errors are important for all healthy organisms to evolve. If there were no mistakes made in copying the human genome, we would all look exactly the same. And, as soon as the first virus infected one of us, we would all die.
Replication errors lead to diversity, and diversity is the way you produce positive traits that can make a species more robust. However, these errors are a double-edged sword since mistakes in copying the DNA can result in genetic diseases.
Viruses play this game to the hilt because they don’t care if 90% of their progeny die out. They make so many at a time, not one, but 100,000! All they need is for a few to be robust. By being sloppy copiers, they introduce enough diversity allowing some to survive, no matter what drug you throw at a viral population.
This is something viruses are famous for: making just enough errors for diversity, but not so many errors that they hit what’s called the error catastrophe, which prevents their ability to copy themselves.
Merrilees: Tom, this has been a thought-provoking exchange. Thank you so much for your time, insights and your book, The Catalyst.
