You’ve probably heard that the first two vaccines approved for
battling COVID-19 in the United States use a relatively new
approach—injections of simple packets containing mRNA, a genetic
material that instructs our cells to make coronavirus spike
proteins. But the technology for generating sufficient amounts of
those mRNA packets dates back to the 1980s, when F. William
Studier, then a senior biophysicist at the U.S. Department of
Energy’s Brookhaven National Laboratory, developed a way to harness
the molecular machinery of a very different virus.
“The fact that scientific knowledge and tools developed decades
ago are now being used to produce today’s lifesaving mRNA vaccines
for COVID-19 is a great example of how the Department of Energy’s
long-term investments in fundamental research at our National
Laboratories can improve American lives today and into the future,”
said Dr. Steve Binkley, Acting Director of DOE’s Office of
Science.
In the 1980s, Studier, the late John Dunn, and their group in
Brookhaven Lab’s Biology Department completed sequencing and
annotating the genome of the T7 bacteriophage. T7 is a virus that
infects E. coli bacteria and commandeers those cells to
make copies of the virus. Having the complete genome sequence
helped the scientists understand how T7 genes and other elements
work together to reproduce many copies of the virus.
Shortly thereafter, Studier and his team found a way to direct
T7’s prolific copying capability toward making things other than
more T7s. They cloned the T7 RNA polymerase—the enzyme that
transcribes DNA genes into messenger RNA (mRNA), which instructs
cells which amino acids to link up to build a particular protein.
The team then used this T7 RNA polymerase along with a powerful T7
promoter (a genetic element that serves as a “start” signal for
gene transcription) to produce large amounts of RNA from almost any
gene. These RNAs could be used directly, such as in mRNA-based
vaccines, or delivered to ribosomes (cells’ protein-making
factories) to be translated into proteins, as in the T7 expression
system.
“Scientists around the world have used Bill’s ‘T7 expression
system’ to make large quantities of proteins or RNA of interest for
the past four decades,” said Venki Ramakrishnan,
a Nobel-Prize-winning structural biologist from the
Medical Research Council Laboratory of Molecular Biology, in
Cambridge, UK. “The new mRNA COVID-19 vaccines use precisely this
system,” he said.
At manufacturing plants run by Pfizer/BioNTech and Moderna,
T7-derived promoters and enzymes crank out kilograms of
spike-protein mRNA at a time—leaving our own cells to do the
protein-making part after a dose of instructions is injected into
our arms.
“Bill’s fundamental work made the lifesaving mRNA vaccines
possible,” Ramakrishnan said.
Back to basics
William Studier had no visions of making vaccines when he began
his fundamental research on the T7 virus as a graduate student in
biophysics at the California Institute of Technology, nor while
continuing this research after joining Brookhaven Lab.
“T7 was not a well-studied bacteriophage when I came to
Brookhaven in 1964,” he said. “I was using it to study properties
of DNA and decided also to study its molecular genetics and
physiology. My goal, of course, was to understand as much as
possible about T7 and how it works.”
Cloning the gene for T7 RNA polymerase in 1983 was
particularly difficult, Studier noted.
“Others had tried and failed. Companies had asked me if we had
it,” he said. “We had the DNA sequence then and I thought that I
understood why the cloning had failed and how to remedy the
problem.”
Studier worked with Parichehre Davanloo, then a postdoctoral
fellow, and Alan Rosenberg, a senior lab member, to tackle the
challenge. John Dunn purified the T7 RNA polymerase and showed that
it produces large amounts of RNA. Barbara Moffatt, then a graduate
student, worked with Studier to turn these discoveries into
the T7 expression system.
“The Brookhaven Lab patent attorney knew what we were doing and
we filed what I think was the first patent at Brookhaven under the
Bayh-Dole Act”—a law passed by Congress in 1980 that allowed
institutions and grant recipients to patent and license rights to
inventions stemming from government-funded research, Studier
explained.
The rest is history. The T7 expression system went on to become
Brookhaven Lab’s most successful technology, with research
labs around the world using it and hundreds of companies licensing
the technology to make products. And although the patents have now
expired, T7 is still the go-to system for biochemists
everywhere.
“T7 RNA polymerase can synthesize large amounts of RNA from any
DNA adjacent to a strong T7 promoter. I don’t know whether there is
anything comparable,” Studier said.
John Shanklin, chair of Brookhaven Lab’s Biology Department,
agrees. “The T7 polymerase and promoter are so efficient, they make
it possible to produce enough mRNA for millions of vaccine doses at
a time. Bill’s discoveries played a huge role in making it possible
to rapidly scale up production to protect people around the world
from COVID-19.”
Two of those recently vaccinated people are Bill Studier and his
wife Sue.
“I had wondered casually if T7 RNA polymerase might be involved
in making the RNA vaccines,” mused Studier, now a senior
biophysicist Emeritus. “Basic research is almost always useful, and
I’m pleased that my work has been helpful in obtaining powerful
vaccines against this pandemic.”
F. William Studier earned a B.S. in biophysics from Yale in
1958, followed by a Ph.D. from the California Institute of
Technology in 1963. He worked as a postdoctoral fellow in the
Department of Biochemistry at Stanford University School of
Medicine, and then joined Brookhaven Lab’s Biology Department in
1964 as an assistant biophysicist. Over the years, Studier rose
through the department’s ranks, receiving tenure in 1971 and
becoming a tenured senior biophysicist in 1974. He served as chair
of the Biology Department from 1990 to 1999 and then returned to
research. He also served as an Adjunct Professor of Biochemistry at
Stony Brook University. His achievements have been recognized by
election to the American Academy of Arts and Sciences in 1990, the
National Academy of Sciences in 1992, and as a Fellow of the
American Association for the Advancement of Science in 2007. In
2015 he was named Senior Scientist Emeritus at Brookhaven Lab, and
was elected as a Fellow of the National Academy of Inventors in
2018. He holds 15 patents of which 9 have been licensed and
commercialized, including those on the T7 system.
Studier’s research at Brookhaven Lab was supported by the DOE
Office of Science (BER).
Brookhaven National Laboratory is supported by the U.S.
Department of Energy’s Office of Science. The Office of Science is
the single largest supporter of basic research in the physical
sciences in the United States and is working to address some of the
most pressing challenges of our time. For more information,
visit https://www.energy.gov/science/ [https://www.energy.gov/science/].
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Pete Genzer
Brookhaven National Laboratory
6313443174
genzer@bnl.gov