RNA

Paige Gruenke #IAmScience

Paige Gruenke

Paige Gruenke, a Ph.D candidate in Dr. Donald Burke’s lab in Bond LSC. | Photo by Mary Jane Rogers, Bond LSC

By Mary Jane Rogers | Bond LSC

“#IAmScience because I am fascinated by life on a molecular level and inspired that my research could positively impact medicine.”

As a graduate student in Donald Burke’s lab at Bond LSC, Paige Gruenke explores the role of ribonucleic acid, or RNA. That means her work involves a lot of test tubes. She looks at how specialized RNA molecules, called aptamers, bind tightly and specifically to proteins from HIV to prevent the virus from replicating. Her job is to locate the aptamers that bind to HIV proteins from a very large starting pool of RNA sequences by doing repeated cycles of removing the sequences that don’t bind and keeping the ones that do, until the strong binders dominate the population.

“A lot of the things I do don’t sound very exciting,” said Gruenke. “It’s throwing components into tubes and waiting for things to happen. It might sound mundane, but it’s all for the greater good.”

Gruenke hopes that her research will give scientists a better understanding of HIV, because understanding the virus will lead to better drug treatments and eventually, a cure. She is finishing up her second year as a Ph.D candidate in biochemistry, and plans to graduate by summer 2020. Gruenke has always been interested in the area of molecular medicine, but she has some advice for students who are just getting started.

“On a day to day basis, many experiments fail,” said Gruenke. “You’re always going to be learning something you didn’t know before. So, don’t be disheartened because something didn’t work out — just keep trying. Because whenever you have an ‘Aha!’ moment, it makes it all worthwhile.”

Building blocks of life in the lab could revolutionize life for us all

NASA, NIH-funded work seeks to understand bio-chemical mechanisms of life on Earth, and among the stars
By Phillip Sitter | Bond LSC

Donald Burke-Agüero

Donald Burke-Agüero stands in his office in Bond LSC, holding a model of an RNA protein structure. Burke-Agüero studies the bio-chemical functions of RNA, and how those functions might be able to be artificially designed or replicated. | Phillip Sitter, Bond LSC

Any child obsessed with Legos knows the fun of creation bound only by imagination and the size or variety of the blocks within their pile.

For some scientists, that spirit extends into adulthood, but instead of plastic parts they think about arranging blocks of nucleic acids.

Scientists may not be able to create dinosaurs, dragons or mythical sea creatures the way kids with Legos can. Through the manipulation of nucleic acid building blocks though, they may be better able to understand how the processes of life on Earth work, as well as out among the stars.

“I have a lot of fun asking what is possible,” said Donald Burke, a Bond Life Sciences Center investigator who spends his time researching the building blocks of life.

Burke said he has been interested in the origins of life for 40 years, and he has been associated with NASA for about 20 years.

NASA’s interest in understanding the origins of life is pretty straightforward. It wants to know what clues to look for on other worlds to figure out if those planets also support life.

Many of Burke’s previous discoveries at Bond LSC are funded by NASA’s exobiology and evolutionary biology program.

“No, I have not thought of an excuse to fly anything up there. I’ve tried to think ‘which of my experiments would make sense to do in a micro-gravity or zero gravity environment?’” he explained of the prospect of sending some of his work into orbit, with a wry smile.

But, there’s even more to understanding the building blocks of life than looking for bio-chemical signatures out among the stars. Knowing how these parts are put together allows scientists like Burke to understand the origins and processes of Earth’s biology, and, conceivably create chemical and biological processes or even organisms not found in nature in the near future.

 

A quadrillion arrangements of blocks, one arrangement at a time

“Many of the molecules of life are built from strings of amino acids, or nucleotides or other building blocks,” Burke explained. He also noted that these buildings blocks are not just strings, but fold up into three dimensional shapes.

RNA, or ribonucleic acid, stands out as an essential building blocks in the bio-chemical processes of life.

Put simply, RNA is a kind of molecular structure of nucleic acids similar to DNA (deoxyribonucleic acid) that comes in many combinations. These combinations are at the core of every cell, and play a role in coding, decoding, regulating and expressing the basic operating instructions for each cell — its genes.

The molecules we’re talking about are almost unimaginably small. In one test tube, Burke said there can be one quadrillion of them — that’s a one with 15 zeroes after it. Put another way, that’s roughly equivalent to the estimated number of ants that live on Earth.

Burke’s work focuses on the end goal of being able to artificially create original RNA combinations. In what’s known as experimental evolution, “the population of molecules in the tube is evolving as a result of us imposing experimental constraints upon it.”

This artificial synthesis of RNA molecules looks to create random sequences or variations on natural RNA to create new ones non-existent in nature. A second route aims to selectively choose molecules with certain properties, and use them to build altogether new combinations.

“Their string-like properties allow us to copy them, and make more copies, and make more copies, and make more copies. Their shape-like properties allow us to observe the bio-chemical behaviors they may have,” Burke explained how he and other scientists interact with RNA’s structure in the lab.

“I don’t think we know what those limitations are yet,” he said of the capabilities of RNA.

The motivation for wanting to be able to intentionally design RNA molecules is so that it “can do the things we want it to do under the conditions where we want it to do those things,” he explained of the process of the process of selecting RNA sequences for specific properties.

“I want the ones that will bind a tumor cell. I want the ones that will bind a viral protein. I want the ones that will catalyze useful chemical reactions.”

 

RNA’s path to the future following in biology’s footsteps

The National Institutes of Health and other organizations recognize that engineered forms of RNA have the potential to fight diseases, and they have funded Burke’s work.

He has studied RNA that instructs human cells on how to defend themselves from HIV and is now looking at other RNA that interferes with the proteins of the Ebola virus.

The expectation is that such therapeutics would work in conjunction with other treatments. In the future, they could be expanded to help fight other viruses, cancers and other diseases.

RNA could also be used to start, or catalyze, chemical reactions. As Burke explained, catalysts remove barriers to chemical reactions — “they don’t make things happen that wouldn’t otherwise happen, but they speed up the process.”

Synthetic RNA could be used to accelerate removal of toxins from soil or to get the bacteria in our guts to recognize cancerous tumor cells and kick-start an immune response.

But, the future of RNA research may soon reveal a few different Holy Grail moments on its horizon.

One such Holy Grail that Burke said will definitely happen will be observations consistent with the presence of life on other worlds, based on evidence like an atmosphere having certain chemical compositions.

Another likelihood could involve construction of a self-replicating, fully-artificial organism, either created from scratch or reverse-engineered from other organisms.

For those of you already anticipating the plot of a low-budget sci-fi thriller, Burke offered to assuage your fears.

“The notion of it escaping out in the world and taking over Los Angeles is [only] good 1950’s B-movie” material, because the conditions under which this artificial organism would survive would probably be difficult to maintain even in the controlled environment of lab, he said.

Instead of B-movie science, Burke explained that “really, I’m thinking about what kinds of chemistries we want to see take place, and then building the enzymes that would make it possible.”

“Biology has had a few billion years to work on this, but we’re just starting to figure it out.”

Donald Burke-Agüero is a professor of molecular microbiology and immunology and joint professor of biochemistry and biological engineering.