Ask a friend what DNA is and, chances are, they have a general idea.
Seventy years after scientists discovered the two-stranded helix, DNA (deoxyribonucleic acid) is widely understood as the keeper of our genetic information and a window into our ancestry. It has become a household word.
Not so with RNA.
"RNA was never the star of the show," writes Tom Cech, a distinguished professor of biochemistry at CU Boulder who won the Nobel Prize in Chemistry in 1989 for his research on RNA. "It was like a biochemical backup singer slaving away in the shadows of the diva."
As Cech reveals in his new book The Catalyst: RNA and the Quest to Unlock Life's Deepest Secrets, RNA (ribonucleic acid) is having its moment, with research surging globally and more than 400 RNA-based drugs in development.
One variety, known as messenger RNA, could ultimately lead to a one-shot immunization that renders seasonal flu shots obsolete. Another guides CRISPR, a molecular set of scissors that can edit out mutations in the genetic code to prevent or cure deadly diseases. An RNA-powered enzyme called telomerase can also - for better or worse - forestall aging in human cells, a tantalizing but misunderstood idea for those seeking the Fountain of Youth.
CU Boulder Today sat down with Cech to discuss CU Boulder's rich heritage of RNA research and the oft-overlooked molecule he has dedicated his career to.
What prompted you to write this book?
During the pandemic, my lab was shut down but my subject was suddenly on the tip of everyone's tongue. People started hearing more about what RNA was and what messenger RNA might be able to do. Some were excited; some were hesitant. I thought that more information is always a good thing, so I decided to reach out to the non-scientific public and try to explain it.In a nutshell, what is RNA?
RNA is a copy of one of the two strands in DNA. It is best known as a messenger that carries the information from DNA out of the cell nucleus to orchestrate the synthesis of proteins. It is tiny: If you stacked molecules of RNA side by side, you could fit 50,000 of them within the breadth of a single human hair. What it lacks in size it makes up for in versatility. Because it is a single strand, RNA can fold itself in myriad different ways that give it a huge list of roles beyond just being a messenger.
What did your Nobel-winning team discover in 1989?
We revealed that RNA could also be a catalyst. That means it could cut and join biochemical bonds, speeding up reactions necessary for life to exist. There are dozens of other equally thrilling things that RNA is capable of. But it was one of the moments in science when people woke up to thinking they had underestimated RNA, and they should keep their eyes open for new things it could do. They found them. Since 2000, RNA-related breakthroughs have led to 11 Nobel prizes (including the 2020 prize to Jennifer Doudna, who did her postdoctoral work at CU Boulder, for the co-development of CRISPR).
What's the connection between COVID and RNA?
The coronavirus itself is an RNA virus. It doesn't have a genome made of DNA like we do. Instead, it uses RNA both to store its genetic information (yes RNA can do that, too) and as a messenger to make the proteins it needs to continue its infectious cycle. Ebola, polio and influenza are also RNA viruses.
What was so revolutionary about the "mRNA" COVID vaccines?
To vaccinate against a virus, we typically inject a person with a disabled form of a virus. That can be a little frightening to think about. mRNA vaccines take that concern away because they are not made of virus. Instead, they are made of messenger RNA that instructs the body itself to make a protein - the spike protein in the case of COVID. It gives the immune system a heads up and says, 'If you ever see anything that looks like this, it's gonna be bad, so you need to mount a cellular response to kill it.'
Cech, left, with Jennifer Doudna, who won the Nobel Prize in chemistry in 2020 for co-designing the RNA-guided gene-editing tool CRISPR.
Could this improve vaccines in general?
That is the hope. For instance, believe it or not, we currently inject about a million chicken eggs annually with the flu virus to make the seasonal flu vaccine. It takes so long that we have to guess what strain will be prominent during the next flu season and sometimes we are wrong. That's why it's only between 30% and 60% efficacious. With mRNA vaccines, the process is so simple, someone could design the vaccine in about a week. The hope is that vaccine manufacturers could wait until they know what strain was going around and then design a much more effective vaccine or design a one-and-done and the seasonal shot would become a thing of the past.
Telomerase has become a darling of the biotech and supplement industries. Is it really an anti-aging miracle?
Chromosomes are like little strings of DNA pearls. In the absence of telomerase, the pearl at the end is lost each time a cell divides, and the string becomes shorter and shorter. Telomerase is a collaboration between RNA and a protein called telomerase reverse transcriptase which was discovered at CU Boulder. It continually adds pearls to the end of the necklace (known as the telomere) rendering cells forever young. Multiple diseases have been traced to low levels of telomerase. These individuals would greatly benefit from a way to lengthen the telomerese of their stem cells. On the other hand, what is a tumor cell? Well, it's immortal. So an anti-telomerase therapy could be useful in treating cancer. The fact that telomerase can immortalize human cells is a scientific fact, but to suggest that an increase in the level of telomerase could extend human life span generally is overly simplistic.
Can you provide a few examples of RNA-based medications in use today?
Spinal muscular atrophy (SMA) is a reasonably common and deadly childhood disease that has been treated successfully with an RNA therapy. The first CRISPR therapy was approved late last year for sickle cell disease. CU Boulder scientists have developed RNA-based therapies for macular degeneration, and some are trying to tackle Alzheimer's disease.
