The technology of "Nature Methods" to accelerate the directed evolution of molecules is here

Natural evolution is a slow process that relies on the gradual accumulation of genetic mutations

This widely used technology, called directed evolution, has produced new antibodies to treat cancer and other diseases, enzymes used in biofuel production, and imaging agents for magnetic resonance imaging (MRI)

Researchers at the Massachusetts Institute of Technology have now developed a robotic platform that can perform 100-fold directed evolution experiments at the same time, giving more people the opportunity to propose solutions while monitoring their progress in real time

Kevin Esvelt, assistant professor of the MIT Media Lab and the senior author of this new study, said: "Traditionally, directed evolution is more of an art than a science.

MIT graduate student Erika DeBenedictis and postdoc Emma Chory are the lead authors of this paper, which was published in today's "Nature Methods" magazine

Rapid evolution

Directed evolution works by accelerating the accumulation and selection of new mutations

Then, the scientists introduced random mutations into the antibody sequence and screened these new proteins again

About 10 years ago, as a graduate student at Harvard University, Esvelt invented a method to accelerate directed evolution

Using this method called phage-assisted continuous evolution (PACE), directed evolution can be 1 billion times faster than traditional directed evolution experiments

This technique is described in a paper newly published in the journal Nature Methods, and the researchers named it phage and robot-assisted near-continuous evolution (PRANCE), which can evolve in parallel under different conditions 100 times the population

In the new PRANCE system, the phage population (which can only infect specific bacterial strains) is grown in the wells of a 96-well plate, rather than in a single bioreactor

DeBenedictis said: "The robot can take care of these viral populations by measuring this reading.

If the virus is struggling to survive, it means that the target protein is not evolving in the expected way, and robots can help them avoid extinction by replacing the bacteria they infect with a different strain, making it easier for the virus to replicate

"We can adjust these evolutions in real time and directly respond to the occurrence of these evolutions," Chory said

Novel molecule

In this study, the researchers used their new platform to design a molecule that allows viruses to encode their genes in a new way

In another experiment, they evolved a molecule that allows viruses to integrate a synthetic amino acid into the protein they make

Researchers are now using PRANCE to try to create new types of small molecule drugs
.
The researchers say that other possible applications of this large-scale directed evolution include trying to evolve enzymes that degrade plastic more effectively, or molecules that can edit the epigenome, similar to how CRISPR edits the genome
.

With this system, scientists can also better understand the step-by-step processes leading to specific evolutionary outcomes
.
Because they can study so many populations at the same time, they can adjust factors such as mutation rate, the size of the original population, and environmental conditions, and then analyze how these variations affect the results
.
This kind of large-scale, controlled experiment allows them to potentially answer basic questions about how evolution occurs naturally
.

"Our system allows us to actually perform these evolutions and have more understanding of what is happening in the system," Chory said
.
"We can understand the history of evolution, not just the end
.
"

Systematic molecular evolution enables robust biomolecule discovery