While you’re probably pretty familiar with DNA, it’s likely that RNA only made it onto your radar during the pandemic, thanks to Covid-19 vaccines such as the ones from Moderna and Pfizer.
DNA is “the storehouse of genetic information,” says chemist Thomas R. Cech. It contains the genes that encode all of the proteins that a living thing needs — making it possible for our muscles to move or our hearts to beat, or creating the circuits in our brains. “Proteins are the key to life, and DNA tells the body how to make each of them, but it doesn’t do it directly, it has a messenger that acts as an intermediary.”
That’s where RNA comes in. As a messenger, it takes the instructions from our DNA to the area where the protein is created.
“We saw that with the mRNA (messenger RNA) vaccines that it can be a good messenger,” says Cech. “But it can do so much more than just act as a message.”
Cech would know. In 1989, he won the Nobel Prize in Chemistry alongside Sidney Altman for their discovery that RNA “is not only a molecule of heredity, but also can function as a biocatalyst,” or enzyme — basically a kind of spark that can facilitate a chemical reaction.
For many years, Cech has researched RNA and taught chemistry to undergrads at the University of Colorado, Boulder. Now, he’s released a book titled “The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets” to share his knowledge — and what it could mean for the future — with everyone.
This interview has been edited for length and clarity.
You mentioned in “The Catalyst” that research on RNA has been around since the ‘50s. What made you decide to write a book about it now?
Although scientists have been well aware of the wonders of RNA for over half a century, the general public has really been focused on DNA.
That’s understandable, because DNA allows us to understand if our family might be carrying a genetic disease, it allows us to trace our ancestry, it solves crimes. We even use phrases like, “It’s in our DNA” if something is really fundamental to us. So everyone is comfortable with DNA.
But RNA, which some of us think is much more versatile and interesting, has been the purview really, of just the scientists. And I thought that the non-scientist population might be interested in hearing about it.
What is something that most people get wrong about mRNA vaccines, such as the Covid-19 ones?
They were developed so rapidly that people were understandably suspicious that maybe some corners were cut — and that this was a newfangled drug that they should be suspicious of.
But in fact, we have understood how mRNA works in great detail since the 1960s. It’s in every living organism on Earth. It’s in all of the food we eat, independent of whether we’re a vegetarian or a meat lover. So mRNA is not a strange drug. It’s actually a very natural molecule. In Boulder, Colorado, we might even say that it’s organic.
All of the technologies that were needed to make the vaccine had been painstakingly developed by scientists over decades, and well-proven and understood.
So when the brave scientist in China put out on the internet the bits and pieces of the so-called sequence of the SARS-CoV-2 genome (the virus that causes Covid-19) — and it’s an RNA, by the way … this virus doesn’t even mess around with DNA at all. It’s just an RNA virus because RNA, like DNA, can store information — it took only weeks for scientists to identify what must be the protein on the outside of the virus — that would be the first thing that our immune system would see — and, therefore, the protein that we needed to introduce into the human body to give our immune system a heads up and have it be on the lookout for the virus.
How could mRNA impact future health crises?
We’re at this fascinating moment in time, where the opportunities seem almost unlimited, but we don’t know how many of them will pan out. So we have all the ideas, but we don’t know which will turn out to be practical.
So let me start with the low-hanging fruit, which would be other vaccines. I think that, given the success rate of the Covid-19 vaccine — even though respiratory viruses are a terrible tar, they’re really hard for any vaccine technology to be very good — for other viruses, the mRNA vaccines may work much better.
What we’re looking forward to is the opportunity for a flu vaccine that might work against all the strains instead of just what we think will be the predominant strain in the next flu season.
So the flu vaccines are pretty marginal, as we all know. Depending on the year, they might be 60% efficacious, they might only be 40%. Well, it’s still worth getting the shot. But you know, that’s sort of like 50/50 that it’ll really help you.
If we could use the mRNA vaccines to speed up that process, and perhaps even get a vaccine against multiple strains, we might be able to increase that value of the vaccine by a huge amount.
Then there’s the even more speculative area of genetic diseases in which a protein that we need for a healthy life is missing. Cystic fibrosis is a genetic disease, we know which protein is missing, but we don’t know how to put it back. Muscular dystrophy, we know which protein is missing in those kids’ muscles, we do not know how to put it back. Could mRNA be the code that could be introduced to replace that protein? In theory, yes. Practically, we don’t know whether we could make enough of the protein in the right tissue to be therapeutic. But it’s exciting enough that scientists are working on it.
You mention in the book that there are more than 400 RNA-based drugs that are in some stage of development. Can you talk about that?
Because RNA is so central to biology, if there’s a disease-causing RNA, we might want to snip it up or otherwise inactivate it. There are multiple categories of these, but a fascinating one — that is a chapter in the book — are the small interfering RNAs. These are, again, natural products.
We can repurpose this compound to attack disease-causing RNAs in our cells. And this is the work of a company called Alnylam in Cambridge, Massachusetts, and they now have five of these drugs that have been approved, and they’re against rare diseases.
That’s sort of the beauty of this. The RNA technology is so quick to repurpose to a new disease that you don’t have to just target diseases that have an enormous patient population — where you can recoup the large cost of drug development by selling the drug — you can actually target fairly rare diseases and make a real impact on that population of patients.
How does CRISPR factor into all of this?
CRISPR technology is a way to correct mistakes that crop up in our chromosomes in our DNA. And this little tiny machine that scoots around the body has two components. It has a protein, which is like a little pair of scissors, that can snip the DNA and make corrections in the DNA code.
So many human diseases are genetic or have a genetic component. One example is sickle cell anemia, an incredibly painful and debilitating blood disease that is caused by a single change in the gene for the blood carrying protein hemoglobin.
Just a few months ago, a CRISPR-based therapy for sickle cell — the first ever therapy — was approved for use in the United States. And we’re going to see many more of these.
RNA is the real secret sauce here. RNA is the component that allows the CRISPR machinery to be so specific and to edit one gene in the human genome while leaving all of the other genes intact.
What are some potential uses of CRISPR that people aren’t even thinking about?
The other really major opportunity has to do with the plants and animals that we rely on for our food and shelter. They are under stress because of the warming planet and the oceans are under stress.
We get about a third of the protein in the world from the marine environment. The bleaching of the coral reefs, a huge part of the marine ecosystem, is going to be a real challenge for food production for fish and shellfish and other marine organisms in the future.
So what can CRISPR do? Well, just let’s just use coral for an example. There’s no real biology of coral — it’s a hard shell thing. Compared to research on mice and humans and other organisms with a backbone, almost no one is studying coral.
Now, with CRISPR, we can actually change the coral genome — and we might be able to do what in nature would take hundreds of years of evolution before coral could adapt to rising sea temperatures — we might be able to do this quite quickly, and reintroduce heat-resistant coral back into the ocean.
Scientists talk about the ethics of what we could do versus what we should do. The public also has been thinking a lot more lately about how ethical it is to change some of these things — to edit our DNA. How does this apply to DNA, RNA, mRNA and CRISPR?
I think we need to start explaining these things. So we have to start in the schools, but also in other places where people gather — in churches, in Rotary Clubs, in Lions Clubs and book clubs and other venues, and engage the public.
The scientists, though, in the meantime, have been meeting and talking about the ethical implications. And one thing they have decided is that it would be premature to allow CRISPR genome editing of the human germline so that the changes would be inherited.
You might ask, “Well, why wouldn’t you want to do that if you can? Cure sickle cell disease in a patient? Why wouldn’t you want to change the inheritance of that and wipe it out completely?”
Well, there might be a time when we’re ready to do that. But right now we don’t know 100% the safety of this technology — it could be that, in addition to changing the code of the target gene that we’re trying to fix, that it inadvertently makes other changes here and there in the human genome.
Another concern is what are called enhancements — could this technology be used to make your children larger, stronger, choose their hair color and eye color, and give them other traits to make them a superior race? And wow, we think that sounds a lot like Nazi Germany — a lot like eugenics. And we think that’s not an appropriate use of this technology. But we have to discuss it.
You had to cut some things from the book for brevity’s sake, is there anything that you weren’t able to include that you want people to know about?
One area that is fascinating has to do with evolving RNAs in the laboratory to do novel things that natural RNAs don’t do. You can make RNAs that do remarkable things that you have never seen in nature, which could be either just intellectually exciting or could be actually useful for technology. So that’s an area that I only mentioned very briefly because of my wanting to get the book out.
What would be some practical uses for evolving RNAs in labs?
I think there could be medical uses. Of course, much of this was happening before CRISPR and gene editing. Now that we have CRISPR, that’s a pretty high bar to do better than that. Some of them can be used as biosensors, and so RNA can be evolved so that it glows when it sees a particular toxic compound. Could we have such RNAs in our water system on the lookout for new coronaviruses? I think, again, the answer is yes. We probably have the technology to do that. Is it practical? Is it cheap? Enough to employ that, broadly? Those are the challenges with these things now.
