Directing Evolution

Andy Ellington uses evolution to create new therapeutics, train the next generation and ask questions about the origin of life.

When Andy Ellington looks at the living world, he sees what most of us do: giant trees of green, birds chirping, dogs walking and people smiling. He also, however, sees the world from the bottom up, as collections of millions of cells, made of billions of molecules and gazillions of atoms. Mostly, he focuses his attention on the miraculous double-stranded molecule buried within all of these cells, capable of replicating itself and ultimately responsible for cranking out all of the living matter we see today.

“There is nothing else in the entire universe like DNA. It’s a marvelous material,” says Ellington, a research professor in biochemistry. Marvelous, because it’s through DNA that the world has inheritance, variation and, ultimately, evolution.

Ellington and his students—from graduate students all the way down to first-year students fresh off of the High School Musical boat—harvest the power of evolution to engineer new molecules that can do things as diverse as locate tumor cells or reveal the presence of ricin, a toxin used for biological warfare.

Associate Director, Evolution

The technique Ellington uses to engineer new molecules in his lab at the Institute for Cellular and Molecular Biology is known as “directed evolution,” but this is actually somewhat of a misnomer. Ellington will be the first to tell you that he likes to think of himself as the “director of nothing and the associate director of everything.” And so it is with the process of directed evolution.

He doesn’t direct each detailed step in the engineering of a molecule, but rather determines what he’d like a molecule to do—say, bind with a protein sitting on the surface of a tumor cell—and then lets evolution do the work for him.

The molecules evolved in the Ellington lab are bits of RNA. RNA, you may recall from Biology 101, is the molecular middleman that directs the making of proteins from the code residing within DNA. Here’s how it works in a nutshell: double-stranded DNA is transcribed into single-stranded RNA. RNA is then translated into proteins, and proteins make most things in life possible.

Beyond building proteins, researchers are finding that RNA is also a bit of a “jack-of-all-trades;” it can catalyze chemical reactions and bind to other molecules to activate or deactivate them. It’s these properties of RNA that Ellington exploits in the lab.

Ellington builds small, customized pieces of RNA called aptamers. To do this, specialized robotic machines first synthesize billions of random DNA sequences, and those sequences are used as patterns to create RNA aptamers. The population of aptamers is then tested in solution with a target molecule. Those that bind best with the target are kept and the others are removed. This selection process is repeated many times until an almost perfect population of RNA aptamers has evolved that interacts best with the target.

“Biological materials have achieved function through the process of evolution,” says Ellington. “I basically use evolution as a tool for engineering. I like the notion that it’s not evolutionary science, it’s evolution for application.”

The Ellington lab has its eyes on aptamers that, among many things, act as decoys for HIV proteins, bind to tumor cells to detect cancer, and deliver chemotherapy directly to cancerous cells.

With ICMB research associate Dr. Matt Levy, Ellington recently developed an aptamer complex that delivered gene-disrupting siRNAs to prostate tumor cells. siRNAs interfere with the expression of specific genes and have great potential for use in therapeutics. The researchers envision that, since aptamers can be selected to bind to a wide variety of cells, they could develop aptamers to deliver siRNAs or other therapies to almost any cell type.

Experiential Education

There’s no shortage in this world of drugs to be discovered and viruses to vanquish, which means there exists great opportunity and necessity for more hands and minds working on the science.

Thankfully for Ellington, cadres of natural sciences undergraduates are being enlisted as evolutionary engineers through the Freshman Research Initiative (FRI).

In the FRI, first-year students enter one of 14 research streams and begin doing real science. In Ellington’s stream, “Aptamer Selection,” students learn the techniques of directed evolution and apply them to biomedically relevant protein and cell targets. The stream is led by Brad Hall, an FRI research educator and graduate student in Ellington’s lab.

“One of the things that the directed evolution techniques are being used for is to train students about the importance of evolution for biotechnology,” says Ellington.

Often, the targets the students use in the FRI lab come directly from other universities and companies.

“These are targets that people have given to us because they are important. They’re not just throwaways for a cookbook lab,” explains Ellington. “I always tell the students, ‘If you get something out of this, I’m happy to patent it. I’m happy to promote you to this company, to this university.’

“They are learning science through practice, and they’re getting contacts to industry. They’re learning relevant research and getting the opportunity to do translations or applications themselves.”

Beyond their first year, Ellington imagines that some of the students completing the FRI will—as sophomores, juniors and seniors—feed into one of the new facilities that are part of the Texas Institute for Drug and Diagnostic Development (TI-3D), of which Ellington’s research program is a major component.

He wants to see undergraduates staffing the new high throughput screening facility, which is used to test lots of drugs against molecules and cells, and future protein and gene expression facilities. He wants them to learn, in a direct way, how to operate a business.

“These students can get a range of skills that will put them in a fluid job system,” he says.

Muck and Buck

Though a lot of Ellington’s research focuses on using evolution as a tool for engineering, with a particular focus on therapeutics, he still maintains a major interest in an intellectual problem with grand implications: the origins of life itself.

“Origins of life and how to make a molecule for profit are the same problem,” says Ellington. “How do I make a molecule function so it can climb out of the muck? Or how do you make it function so it can make a buck? Muck and buck; it’s exactly the same problem.”

Without reproduction and inheritance, life as we know it would not exist. This is true of larger organisms—bacteria, beavers and brontosaurs—and of the simple molecules that inhabited shallow pools on early Earth. Many scientists believe that RNA could have been the first self-replicating molecule to appear in those pools, the first molecule to experience natural selection, and the molecule that led to the complexity of life as we know it today. Eventually, of course, DNA took the reigns from RNA as the primary source of the genetic code.

Ellington says that the nucleotide building blocks for DNA and RNA (the Gs, Cs, Ts, As and Us) aren’t particularly interesting alone, but that strung together they are “exquisitely adaptable.”

“What I’ve learned about origin of life is that I think it’s a much easier problem than anyone anticipated, in the sense that there are probably multiple functional optima,” he says, reflecting a concept promoted by the late evolutionary biologist Stephen Jay Gould. “If you were to ask for a given function, there are many different ways for a molecule to achieve that function [through evolution].

“The miracle, as it were, is in front of us all of the time.”