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Crispr, the gene-editing technology whose inventors won a Nobel Prize last year, has received far more attention, but the rise of gene synthesis promises to be an equally powerful development. If the first phase of the genomics revolution focused on reading genes through gene sequencing, the second phase is about writing genes. Now companies and scientists look toward a post-Covid future when gene synthesis will be deployed to tackle a variety of other problems.
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We had vaccine prototypes within weeks and shots in arms within the year. But technical advances in the last few years allowed the vaccine developers to synthesize much longer pieces of DNA and RNA at much lower cost, more rapidly.
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It would have been challenging for researchers to synthesize a DNA sequence long enough to encode the full spike protein. This meant that their vaccines - unlike traditional analogues, which teach the immune system to recognize a virus by introducing a weakened version of it - could deliver genetic instructions prompting the body to create just the spike protein, so it will be recognized and attacked during an actual viral infection.Īs recently as 10 years ago, this would have been barely feasible. first released the genomic sequence of SARS-CoV-2 to public databases in January 2020, the two pharmaceutical companies were able to synthesize the DNA that corresponds to a particular antigen on the virus, called the spike protein. Gene synthesis is behind two of the biggest “products” of the past year: the mRNA vaccines from Pfizer and Moderna. Twist is one of a number of companies selling synthetic genes, betting on a future filled with bioengineered products with DNA as their building blocks. These molecules eventually become the basis for new drugs, food flavorings, fake meat, next-gen fertilizers, industrial products for the petroleum industry. At that point, you can insert the synthetic DNA into cells and get them to begin making - hopefully - the target molecules that the DNA is coded to produce. After a few days, the DNA is delivered to your laboratory door. As a customer, you can visit the Twist website, upload a spreadsheet with the DNA sequence that you want, select a quantity and pay for it with a credit card. Today Twist charges nine cents a base pair for DNA, a nearly tenfold decrease from the industry standard a decade ago. Called oligos, they can then be joined together to form genes. Twist Bioscience, the company that Leproust and the Bills founded, currently synthesizes the longest DNA snippets in the industry, up to 300 base pairs. In general, the longer your strand of DNA, the greater the likelihood of errors. A’s and T’s bond together more weakly than G’s and C’s, so DNA sequences with large numbers of consecutive A’s and T’s are often unstable. The concept was simple, but, Leproust says, “the engineering was hard.” When you synthesize DNA, she explains, the yield, or success rate, goes down with every base added. The Bills proposed to put this same process on a silicon chip that, with the same footprint as a 96-well plate, would be able to hold a million tiny wells, each with a volume of 10 picoliters, or less than one-millionth the size of a 50-microliter well.
“In a 96-well plate, conceptually what you have to do is you put liquid in, you mix, you wait, maybe you apply some heat and then take the liquid out,” Leproust says. The reagents - those famous bases (A’s, T’s, C’s and G’s) that make up DNA - were pipetted onto a plastic plate with 96 pits, or wells, each of which held roughly 50 microliters, equivalent to one eyedropper drop of liquid. The Bills, who met when Banyai hired Peck to work on a genomics project, realized that there was an opportunity to do something analogous for writing DNA - to make the process of making synthetic genes more scalable and cost-effective.Īt the time, DNA synthesis was a slow and difficult process. When the chemistry was miniaturized and put on a silicon chip, reading DNA became fast, cheap and widespread. Peck was a mechanical engineer by training with a specialty in fluid mechanics Banyai was a semiconductor expert who had worked in genomics since the mid-2000s, facilitating the transition from old-school Sanger sequencing, which processes a single DNA fragment at a time, to next-generation sequencing, which works through millions of fragments simultaneously. The Bills, as they were later dubbed, were biotech veterans. Ten years ago, when Emily Leproust was a director of research at the life-sciences giant Agilent, a pair of scientist-engineers in their 50s - Bill Banyai and Bill Peck - came to her with an idea for a company.