“As synthetic biologists our goal is to develop gene circuits that will enable us to harness mircoorganisms for a wide range of applications.”
Researchers at US-based University of California San Diego have developed a method to significantly extend the life of gene circuits used to instruct microbes to do things such as produce and deliver drugs, break down chemicals and serve as environmental sensors.
Most of the circuits that synthetic biologists insert into microbes break or vanish entirely from the microbes after a certain period of time – typically days to weeks – because of various mutations. However, UC San Diego researchers demonstrated that they can keep genetic circuits going for much longer.
The researchers published this study in the 6 September edition of journal Science.
According to the bioengineers, the key to this approach was the “researchers’ ability to completely replace one genetic-circuit-carrying sub-population with another, in order to rest the mutation clock, while keeping the circuit running.
“We’ve shown that we can stabilise genetic circuits without getting into the business fighting evolution,” said UC San Diego bioengineering and biology professor Jeff Hasty, the corresponding author on the study. “Once we stopped fighting evolution at the level of individual cells, we showed we could keep a metabolically-expensive genetic circuit going as long as we want.”
The circuit the UC San Diego researchers used in the Science study is one that this team, and others, are actively using to develop new kinds of cancer therapies.
“As synthetic biologists our goal is to develop gene circuits that will enable us to harness mircoorganisms for a wide range of applications. However, the reality today is that the gene circuits we insert into microbes are prone to fail due to evolution,” said Michael Liao, a UC San Diego bioengineering PhD student and the first author on the Science paper.
Liao added: “Our work shows there is another path forward, not just in theory, but in practice. We’ve shown that it’s possible to keep circuit-busting mutations at bay. We found a way to keep hitting reset on the mutation clock.”
According to UC Dan Diego, if the team’s method can be optimised for living systems, the implications could be significant for many fields, including cancer therapy, bioremediation, and bioproduction of useful proteins and chemical components.
In 2016 in Nature, UC San Diego researchers led by Hasty, along with colleagues at MIT, described a “synchronised lysis circuit” that could be used to deliver cancer-killing drugs that are produced by bacteria that accumulate in and around tumours. This led the UC San Diego group to focus on the synchronised lysis platform for the experiments published in Science.
These coordinated explosions only occur once a predetermined density of cells has been reached, thanks to “quorum sensing” functionality also baked into the genetic circuitry. After the explosion, the approximately 10% of the bacterial population that did not explode starts growing again. When the population density once again reaches the predetermined density (more “quorum sensing”), another drug-delivering explosion is triggered and the process encoded by the researchers’ synchronised lysis circuit restarts.
The challenge, however, is that this cancer-killing genetic circuit – and other genetic circuits created by synthetic biologists – eventually stop working in the bacteria. The culprit. Mutations driven by the process of evolution.
“The fact that some bugs naturally grow in tumours and we can engineer them to produce and deliver therapies in the body is a game-changer for synthetic biology,” said Hasty. “But we have to find ways to keep the genetic circuits running. There is still work to do, but we’re showing that we can swap populations and keep the circuit running. This is a big step forward for synthetic biology.”
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