Why RNA Could Answer Biology’s Greatest Mysteries
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Why RNA Could Answer Biology’s Greatest Mysteries

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Why RNA Could Answer Biology’s Greatest Mysteries

Thomas Cech is a professor of biochemistry at the University of Colorado Boulder. He was awarded the 1989 Nobel Prize in Chemistry and the National Medal of Science in 1995. He is also an investigator at the Howard Hughes Medical Institute.

Below, Thomas shares five key insights from his new book, The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets. Listen to the audio version—read by Thomas himself—in the Next Big Idea App.

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1. Fundamental research into how biology works—not aiming for a practical outcome—often gives rise to the most transformative medical innovations.

About 15 years ago, scientists studying bacteria noticed that they were taking bits and pieces of DNA from their viral parasites and storing them in their own DNA. What could this mean? Driven by curiosity, they determined that the bacteria were keeping track of past encounters with these “bad guys” in a sort of a Rolodex file, so they could quickly recognize and destroy them if they saw them again.

Initially, no one imagined that this bacterial defense system (later known as CRISPR) would start a medical revolution. Two researchers—Emmanuelle Charpentier of Umeå Centre for Microbial Research in Sweden and Jennifer Doudna of the University of California, Berkeley—figured out RNA was key to how this bacterial self-defense worked. The CRISPR machine carried a guide RNA, and only when the code of the guide matched a stretch of code in the DNA did it go to work. The guide RNA gave CRISPR its exquisite specificity, which allowed Doudna and Charpentier to repurpose it into a gene-editing machine. They won a Nobel Prize in 2020 for their discovery, which has already been developed into a therapy for sickle cell disease, with more therapies for genetic diseases on the way.

2. Big breakthroughs in understanding human biology often come from unlikely critters.

Common sense might lead you to believe that if you wanted to understand human health and disease, you should study humans. Or at least other mammals, like apes and mice, because they are more related to humans. But remarkably, many of the biggest discoveries in human biology have come from studying distantly related organisms that provide a special advantage to the researcher.

The “immortality enzyme” telomerase is a good example. Studying a one-celled pond animal named Tetrahymena, Carol Greider and Liz Blackburn discovered the little cellular machine that maintained the DNA at the ends of Tetrahymena chromosomes, and they named it telomerase. It was a little RNA machine, with the RNA serving to template or specify the DNA building blocks added at the chromosome ends. The Tetrahymena telomerase allowed scientists to identify the corresponding human enzyme which turned out to be the key to the immortality of cells (not entire people). Building out the DNA at chromosome ends allows cells to keep dividing, whereas in its absence, telomeres shrink, and cells enter a state called senescence, meaning gradual loss of functionality due to age-related deterioration.

“The Tetrahymena telomerase allowed scientists to identify the corresponding human enzyme which turned out to be the key to the immortality of cells (not entire people).”

This immortality enzyme is essential for our reproductive cells and stem cells. But it’s also necessary for cancer growth, so if you wish for longer telomeres, be careful what you wish for!

3. If at first you don’t succeed, attack the problem from a different angle.

This is a well-known strategy in science research. An example from the world of RNA involves the ribosome, the conglomerate of multiple proteins and RNAs that forms a little machine that reads out messenger RNA’s code to make thousands of different proteins (such as the enzymes that digest food in our stomach, allow our muscles to flex, or that keep our hearts beating).

When the saxophone-playing, Ferrari-driving scientist Harry Noller started his professor position at the University of California, Santa Cruz, he wanted to figure out which protein in the ribosome was doing the key job of linking amino acids together to form protein chains. He removed ribosomal proteins one at a time, but the ribosome seemed unfazed—it still did its job. This was weird because every scientific textbook proclaimed that “all enzymes are proteins,” so where was the key ribosomal enzyme hiding? So, even though at the time it seemed like a long shot, Harry turned the idea on its head: maybe it was the RNA part of the ribosome that was doing the heavy lifting, and the protein parts were just a supporting cast? That approach hit paydirt. RNA was indeed the heart and soul of the protein-making machine.

4. Don’t believe everything the textbooks say.

Harry Noller’s ribosome work already provides one great example, but there are tons more. When I set up my lab at the University of Colorado Boulder, my students and I quickly stumbled on an example of a process called RNA splicing. Just as a sailor might cut out a frayed portion of a rope and splice the good ends together, RNA molecules often need to cut out interruptions in the code called introns. We did not discover introns, but no one knew how the critical job of RNA splicing worked.

“We were stuck for a while in the textbook dogma that ‘all enzymes are proteins.'”

We set up test-tube experiments to find out, adding proteins from the cell to provide what we thought would be necessary splicing enzymes. However, the RNA splicing worked just fine without adding any source of protein enzymes. We were stuck for a while in the textbook dogma that “all enzymes are proteins,” so what could be powering the splicing of our RNA? We eventually showed that pure RNA catalyzed its own splicing reaction, and unlike the ribosome, no assistance by proteins was required. As the Nobel Prize Committee said a few years later, “Many chapters in our textbooks have to be revised.”

5. RNA appears to have been the molecule that started life on the primordial Earth.

There are many definitions of “life,” but all of them require that information is passed down from one generation to the next. So, arguably, the initial life form consisted of just information being copied into more of the same information. In modern cells, information is DNA, and copying DNA into more DNA requires protein enzymes. Scientists faced a daunting chicken-and-egg problem: which came first, the DNA information or the protein that could reproduce it?

It seemed so unlikely that information and function could arise by random chemical reactions in the same place at the same time to kick-start life. Once the catalytic activity of RNA was found, however, an enormous simplification could be envisioned: maybe life began with RNA copying itself into daughter RNA molecules, and proteins and DNA came later. In short, maybe the chicken and the egg were one and the same. Most scientists now think it’s plausible that RNA kick-started all life on our planet almost four billion years ago.

DNA is like a one-trick pony, with an admittedly important trick: it is the storehouse of all our genetic information. RNA, on the other hand, has an enormous number of tricks up its sleeve. It can carry information, which it does quite well as a messenger RNA. It can also catalyze biochemical transformations, assemble all the proteins on all organisms on Earth, extend our chromosome ends to keep our cells dividing, direct the CRISPR machinery to edit DNA and correct the mistakes that drive genetic diseases, and explain how life got started on our planet. It is indeed The Catalyst.

To listen to the audio version read by author Thomas Cech, download the Next Big Idea App today:

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