NOV 10, 2018 5:09 AM PST

Scientists Engineer a Better Way to Direct Evolution

WRITTEN BY: Carmen Leitch

Earlier this year, three researchers shared the Nobel Prize in Chemistry for pioneering a process called directed evolution, in which diversity is introduced into a genome with the aim of creating a new biomolecule. Those new biomolecules have a wide array of potential applications, especially in drug development. The process was considered painstaking and laborious; however, scientists at the University of California, Irvine have now streamlined the process. In work reported in Cell, they have used live yeast cells as a conduit to accelerate genetic mutations, which can be introduced stably as the yeast reproduces and evolves.

An artist's depiction of a bacterial enzyme derived from directed evolution, and the high-energy carbon ring it can create. / Credit:Caltech

“By moving high rates of diversification into cells in a targeted manner, we can grow and pressure those cells to evolve into something new from any genes of our choosing,” explained first author Arjun Ravikumar, a recent recipient of a biomedical engineering Ph.D. at UCI. "Our work has reduced evolution to be an extremely rapid, straightforward and scalable process."

Introducing changes into a genome can be a challenging prospect. In this work, the researchers created a molecular system that could introduce errors in live yeast cells. Called OrthoRep, the "DNA polymerase-plasmid pair" creates mutations in a host cell's genome about 100,000 times faster than the natural rate. Their method also allows for researchers to see what is happening in the genome as evolution happens.

The number of evolutionary cycles the genome goes through is very important when using directed evolution, noted the senior author of this study, Chang Liu, UCI assistant professor of biomedical engineering. Every one of those cycles may add a new function or improve an existing one. “But if each cycle requires repetitious test-tube DNA molecular biology processing, you can only reasonably go through a few iterations,” he said.

"In contrast, natural evolution runs cycles continuously, essentially by culturing cells over time in an environment that pressures them to develop some new function; the problem from a biomolecular engineering standpoint is that the process is very slow," Liu added. "We have figured out a genetic architecture that allows biomolecular evolution to be very fast."

Credit: Graphical abstract from Ravikumar et al Cell 2018

Liu suggested that this new work will help investigators with experiments that were previously very challenging to perform. In their report, the UCI team did 90 replicates of an enzyme evolution experiment to look for all of the changes it made, in this case, to develop drug resistance.

"There are many ways of solving a particular evolutionary challenge such as drug resistance, so the ability to run evolution experiments at the scale that we have allows us to capture and understand more of those possibilities, giving us therapeutically relevant insights into how resistance arises," Liu said.

The team plans to continue their studies; Liu wants to use the new technique to create antibodies that can constantly evolve to fight disease, or to make enzymes that engineer better drugs.

"Instead of having to inject an antigen into an animal in order to isolate an antibody, imagine just putting it into a culture of yeast cells and having it come out as a specific antibody," he said. "That could revolutionize how these and other protein drugs are discovered and developed."

One of this year’s Nobel Prize winners, Frances Arnold commented, "Directed evolution is a powerful way to build new proteins, but it can certainly benefit from technological innovations. The technique that Professor Liu and Dr. Ravikumar have developed will stimulate new applications and new avenues of investigation which will continue to expand our ability to compose new DNA."

Arnold is featured in the video above, discussing directed evolution.

Sources: AAAS/Eurekalert! via University of California, Irvine, I & EC Research, Cell

About the Author
  • Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
FEB 18, 2021
Genetics & Genomics
'Dancing' DNA is Caught on Video
FEB 18, 2021
'Dancing' DNA is Caught on Video
For the first time, researchers have used high resolution images to generate video footage of DNA as it 'dances' inside ...
MAR 21, 2021
Cell & Molecular Biology
A Model of Early Human Development is Created
MAR 21, 2021
A Model of Early Human Development is Created
Scientists now have a new way to investigate the processes underlying human development, diseases that may arise during ...
APR 08, 2021
Immunology
It's Not Just Cholesterol That Clogs Arteries
APR 08, 2021
It's Not Just Cholesterol That Clogs Arteries
Researchers have discovered a gene that is directly linked to the development of cardiovascular diseases, such as high b ...
APR 20, 2021
Genetics & Genomics
The History of Lettuce Domestication Told Through DNA
APR 20, 2021
The History of Lettuce Domestication Told Through DNA
The more we know about the genetic history of food crops, the more prepared we'll be to maintain their growth through en ...
APR 27, 2021
Genetics & Genomics
A Genetic Path Forward For Endangered Sumatran Rhinos
APR 27, 2021
A Genetic Path Forward For Endangered Sumatran Rhinos
There are fewer than 100 Sumatran rhinoceroses remaining in the world, making this animal one of the world's most endang ...
MAY 04, 2021
Genetics & Genomics
The Weird World of Flatfish
MAY 04, 2021
The Weird World of Flatfish
Many of us have wondered how fish like sole and flounder ended up with two eyes on one side of their heads, including sc ...
Loading Comments...