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Synthetic biology gets a second wind

Image credit: The North Face

The Covid-19 pandemic has put the spotlight back on synthetic biology, a technology that is beginning to make it out of labs.

It’s just over a decade since the J Craig Venter Institute replaced the entire genome of a small bacterium with one the scientists had synthesised chemically. To try to demonstrate they had not simply cloned an existing organism and used its 1.1-million-base-long DNA, they included watermarks and a sequence that spelt out an email address in the initials of the nucleic acids.

The experiment was effective in that it demonstrated that an entirely synthetic genome could restart a cell that had been stripped of its original DNA. At the same time, the incredibly costly synthetic genome seemed an unnecessary step in a field where it’s far easier and cheaper to simply edit an existing genome to make what you want. The early promise of synthetic biology a decade ago was that re-engineered crops, bacteria and yeasts could make fuels, plastics and pharmaceuticals far cheaper to produce, simply by making edits to genomes.

As is normal for such an uncharted area of technology, progress has been slow but it has taken place. And one area where directly synthesising genomes makes sense has been propelled into the spotlight by the Covid-19 pandemic. Vaccines have already benefited from the technology, as pointed out in a September commentary in the journal Nature Research. In that piece, Elie Dolgin points out how Novartis turned to the Venter Institute, while it was engaged in the bacterial genome projects, and its commercial offshoot Synthetic Genomes to make what amounted to a fake virus that could be used as a vaccine candidate. The outer protein coat was designed to trigger antibody production but the particles the DNA created inside a cell would not build a working virus. In principle, it is a safer route to vaccines because it does not rely on the use of weakened natural viruses that could still prove infectious.

The first attempt was a dry run. In 2013, bird flu arrived and the technique was applied to an actual outbreak. Though that strain of flu did not become a pandemic, the vaccine proved safe enough to make in volume. More recent work has dug into whether you need a virus at all: using the same production techniques to make virus-like particles that are all antibody-triggering coating and no payload. Naturally, as Covid-19 took hold, researchers around the world were keen to use whatever means they had at their disposal to try to get a vaccine into trials quickly and then into production.

As an example, one team led by workers at the Vaccine Research Center in Bethesda, Maryland took the DNA sequence published on 10 January for SARS-CoV2 virus and modified the part for the key spike protein with a change found in work on the MERS virus to make it more immunogenic before synthesising the genetic sequence that would make a cell produce it. Sixty days later the vaccine went into early trials with human subjects.

At the Synbitech conference last week (26 October) organised by a group at Imperial College, London, Global Helix CEO Rick Johnson said: “Covid has in many ways provided the first pressure test for synthetic biology. It has proven to be very valuable for speeding up new solutions, such as new vaccines: how they are being designed and for biomanufacturing.

“This is becoming a breakout moment for synthetic biology, because of its scope, speed, sustainability and scale,” Johnson claimed.

Also chair of policy and international relations at the California-based Engineering Biology Research Consortium (EBRC), Johnson said: “We are learning two lessons, at least in the US. We are recognising that synthetic biology has huge potential for addressing other grand challenges.”

The other is a recognition that many technologies are coming together. “Convergence has become a major factor in reshaping the economy. A key driver for 21st-Century science would be the convergence of biology with engineering and physical sciences, supplemented by what I would call Convergence 2.0: a tools revolution.”

In the US, the feeling that R&D-led technologies are where the future lies has led to a succession of bills that favour synthetic biology as well as other areas that policymakers see as important for moving industry back onshore, although some may fall by the wayside if the Senate decides against spending. For example, though it has sponsors from both main parties the Endless Frontier Act has come in for criticism from right-wing “small government” think tanks that dislike the kind of spending it proposes. In what may turn out to be a suddenly more deficit-conscious Senate, it may make an easy target.

However, governments around the world have decided synthetic biology is a solid long-term bet. Mary Maxon, associate laboratory director for biosciences at Lawrence Berkeley National Laboratory, said some 40 countries have now created formal strategies for promoting “bioeconomies”.

According to Yoshi Fujishima, senior analyst at Japan’s government funding agency the New Energy and Industrial Technology Development Organization (NEDO), the country has put roughly $100m into a project for manipulating plants and microbes with the aim of using them to make pharmaceuticals, materials and fuels.

The products of synthetic biology are beginning to trickle through into production. For example, taking spider silk as the starting point, Spiber created a protein-based artificial fibre that is now being used in in padded jackets made by The North Face.

But it is difficult work. The concepts are attractive: re-engineer microbes to make chemicals and materials you want. After all, cells are good at making all kinds of stuff using just food and light. Why not stuff you want? But the details are incredibly subtle.

In her keynote at Synbitech, Christina Smolke, CEO and co-founder of Antheia and a professor at Stanford University, described the many obstacles to making the many subtle and complex changes needed to have a reworked baker’s yeast produce a drug that today needs to be extracted from plants like deadly nightshade. The tropanes these plants produce are needed for treating conditions such as heart functions for patients on ventilators as well as acting as anaesthetics. Plant production takes place in few locations, making it hard to obtain enough chemical in times of need. Biomanufacturing in vats filled with yeast and sugar would make it easier to scale production when necessary.

“The Covid-19 pandemic has exposed a lot of failures in global supply chains. If you have spikes in demand, the supply chains can’t react quickly enough,” Smolke said.

However, moving production from plants to microbes comes with major challenges. “For tropane production there is a very large number of reactions that have to be engineered and optimised. There are 30-plus enzymes that we have to move in. And if you look at plant biochemistry, it’s fairly unique. That can be challenging to reconstruct when you move into a microbial host.

“If you look at illustrations of plants and all the different cell and tissue types they have, they can evolve to present special conditions for certain reactions to take place. Often biosynthesis will occur in a particular tissue. If you think about moving that chemistry into a baker’s yeast, you lose all of that spatialisation,” she explained.

However, even something apparently as simple as baker’s yeast does provide some opportunities for separating out chemical reactions. It is far from being one tiny bag of undifferentiated, enzyme- and DNA-filled soup. “It has internal compartmentalisation. They do provide chemical micro-environments, so we can recapitulate and mimic what occurs in plants to allow these reactions to occur.”

Getting to a point where yeast can produce tropanes has been a difficult process that has involved numerous tools as well as a large degree of trial and error. Some synthesis pathways can look promising only to turn out when tried in a re-engineered yeast to be too slow and inefficient to use.

The work has underlined how important cell structure is to the manufacturing process: you cannot just pop a bunch of enzymes in and expect things to work. Sometimes even just making sure an intermediate is moved to the right chamber is not enough: it has to be embedded in a membrane for the next stage to take place properly. “If you want to use a microorganism like yeast, you need to think of different ways to access the different microchemical environments it has,” Smolke said.

Even scaling up production has challenges. Things that work at the small scale fail to work when you need vat-level production. So it becomes easy to see why, a decade or more since many of the R&D forays into synthetic biology began, industrial production is at the beginning. In principle, turning cells into micro-factories should easily out-compete chemical synthesis, but the knowledge needed to get there remains patchy. Synthetic biology has a long future ahead of it but it’s a future that may take somewhat longer to realise.

 

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