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Disease and treatment

A revolution in the code of life

Jason Chin has accomplished in a few years what many researchers have been anticipating for decades. His research group has restructured the production system of cells so that they can use completely new building blocks. The goal is to transform living cells into advanced factories that can produce new and improved types of polymers, which might include new materials and medicines.

This is the most robust and infallible machine known to humanity. We all have it, and even though we have known for a long time how it worked, we have not been able to discover how it could be used – until now. British researcher Jason Chin is not only the first to discover how to alter the ribosome, part of the cell’s translational apparatus, for producing the usual proteins. He has built a totally new and improved version of the ribosome for this purpose.

“Ribosomes are incredible machines inside cells that make proteins. We wondered if ribosomes could be adapted from merely producing the proteins they create in the body so that they could be used to produce new types of proteins and possibly other types of polymeric substances. We therefore decided to learn how to alter or even restructure the ribosome. Now that we have achieved this, we can potentially produce new types of materials and medicines, which may ultimately benefit people,” explains Jason Chin, Head of the Centre for Chemical and Synthetic Biology at the Medical Research Council Laboratory of Molecular Biology, and Professor of Chemistry & Chemical Biology, Department of Chemistry, University of Cambridge.

REPROGRAMMING RIBOSOMES

However, reaching this goal required that the researchers change a key to living organisms: the ribosome. This synthesizes proteins based on the genetic code. Ribosomes are so crucial in cells that an organism will die if ribosomes are altered or disabled. So, researchers created an extra ribosome alongside the existing one, and altered the extra ribosome to better produce new polymers.

Another major obstacle was to reprogramme ribosomes to both learn to read and new genetic codes. A normal code comprises four base pairs represented by the letters A, C, G and U. The AAA codon, for example, deposits the amino acid lysine into the developing protein; the AAU codon deposits asparagine. A ribosome deposits a specific amino acid for each combination.

“A ribosome normally reads three letters at a time, but because the existing 64 combinations (4 times 4 times 4) were already used up, we had to create a new code to get a ribosome to deposit other amino acids. We therefore got a ribosome to read four base pairs at a time instead of the usual three. This provided upto four times the number of possible codon combinations and allowed us to produce new types of proteins.”

CELLULAR FACTORIES FOR MAKING MATERIALS AND MEDICINES

The new code can revolutionize the development of protein-based pharmaceuticals such as antibodies, insulin and growth hormones. Since the 1970s, researchers have successfully modified antibodies to make them more effective and with fewer side effects for people. The new production system will enable these modifications to be manufactured and tested more rapidly and easily.

“California-based Ambrx, Inc. is already conducting a clinical trial of a growth hormone that contains synthetic amino acids. They hope that this will make the drug more stable in the bloodstream so the users can reduce the dose. Other scientists use the synthetic amino acids to bind antibodies to toxic molecules so that they target cancer cells, leaving the healthy cells undamaged.”

In October 2016, the researchers announced that they had been able to put unnatural amino acids into proteins in the mouse brain.

BEING ENGAGED IN LIFE

Jason Chin is cautious in drawing conclusions about the consequences of the discovery by his group even though he knows that the discovery has fundamental importance. He emphasizes that their work relies on decades of basic research by fellow scientists. He similarly believes that his group’s research will have multiple effects on future research.

“As a researcher, you need to be willing to explore new horizons to make breakthroughs. This is when you start to see the connections between many things because you absorb things from different fields. The task is therefore being able to synthesize them in a way that is uniquely yours.”

Although Jason Chin believes that creativity is merely being engaged in life, it is creativity that has brought him to where he is today. As a student, Chin found teaching and research to be extremely traditional. A word of advice from his professor of biological chemistry, John Sutherland, was a game-changer. He told Jason Chin that he should never be constrained by what he had learned in the classroom.

“He said: If you look at the periphery, you will see the best opportunities for discovery. When I solve a problem, there are two options: either you can continue to solve the same problems over and over again or you can find new problems to solve. I clearly prefer the latter,” concludes Jason Chin.

Jason Chin gave a presentation at the October 2016 Copenhagen Bioscience Conference: Protein signaling – from pathways to networks. The Copenhagen Bioscience Conferences are a Novo Nordisk Foundation initiative. “Defining synonymous codon compression schemes by genome recoding.” appeared in Nature in November 2016. “Genetic code expansion in the mouse brain” appeared in the October 2016 issue of Nature Chemical Biology.