"Some time ago, DNA synthesis was a slow and difficult process.
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. “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 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.
Because the wells were so small, they couldn’t simply
pipette liquids into them. Instead, they used what was essentially an inkjet
printer to fill them, distributing A’s, T’s, C’s and G’s rather than pigmented
inks. A catalyst called tetrazole was added to bind bases into a single-strand
sequence of DNA; advanced optics made perfect alignment possible. The upshot
was that instead of producing 96 pieces of DNA at the same time, they could now
print millions.
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. 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. In general, the longer your strand of DNA, the greater the
likelihood of errors. Twist Bioscience, the company that Leproust and the Bills
founded, currently synthesizes the longest DNA snippets in the industry, up to
300 base pairs. Called oligos, they can then be joined together to form genes.
Today Twist charges nine cents a base pair for DNA, a nearly
tenfold decrease from the industry standard a decade ago. 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. After a few
days, the DNA is delivered to your laboratory door. 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.
These molecules
eventually become the basis for new drugs, food flavorings, fake meat, next-gen
fertilizers, industrial products for the petroleum industry. 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.
In a way, that future has arrived. Gene synthesis is behind
two of the biggest “products” of the past year: the mRNA vaccines from Pfizer and Moderna.
Almost as soon as the Chinese C.D.C. 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. 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.
As recently as 10 years ago, this would have been barely
feasible. It would have been challenging for researchers to synthesize a DNA
sequence long enough to encode the full spike protein. 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. We had vaccine
prototypes within weeks and shots in arms within the year."
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