Early last year, Jimmy Gollihar was deep into building a unique facility on the Forty Acres, what he calls "the biological foundry" – a turbo-charged, biotech playground with a focus on rapid scientific discovery. The foundry was to be a key element of a partnership in synthetic biology research between The University of Texas at Austin and the U.S. military. Then, as fate would have it, COVID-19 would change everything.
Fighting biological threats is a high priority of the U.S. military. It's one of four main focus areas in a partnership in synthetic biology research that began when the Army Research Laboratory South was established in 2017. About 10 UT Austin researchers, including Gollihar, Jason McLellan, Ilya Finkelstein, Andy Ellington and Hal Alper, conduct a range of research projects through the partnership.
When the pandemic began, there was no time to waste for UT Austin collaborators. Gollihar had been designing and building the foundry for over a year and some key pieces of equipment still hadn't arrived, but UT researchers aimed to identify as quickly as possible the antibodies in patients that were highly effective at wiping out the novel coronavirus, information that could lead to the development of possible treatments.
"My first thought was, we need to get samples from infected individuals," says Gollihar.
Collecting and analyzing blood samples from local COVID patients and through a collaboration with Houston Methodist Hospital, the researchers started analyzing the samples manually; then as more of the missing pieces to the foundry puzzle fell into place, they moved work over to automated systems. Within months, that work led to a potential new treatment for COVID-19 that's currently under development – the product of an emerging and important partnership.
Leveraging Collaboration
The U.S. Combat Capabilities Development Command Army Research Laboratory (ARL) is the Army's national research laboratory; it focuses on fundamental research, cutting-edge scientific discovery and technological innovation. ARL South is one of several regional hubs within ARL, which also includes ARL West, ARL Central and ARL Northeast.
"ARL extended our research presence throughout the country by establishing regional partnerships like the one we have with UT Austin," says Heidi Maupin, ARL South's regional lead. "This enabled Army researchers to work side by side with esteemed university researchers. Our collaboration leverages access to cutting edge facilities, data and elite subject matter experts to solve unique Army problems in an accelerated manner."
ARL South and the other regional labs address a key challenge facing the military: there is a painfully slow lag between fundamental research happening at universities across the country and the application of the new knowledge and experimental approaches they create within the Army.
Establishing research teams with regional partners can potentially lead to new technology directions, new perspectives on Army problems, new industry collaborators and, ultimately, new discoveries that will help the Army solve current and future challenges in preparedness.
"In many cases, the solutions we reach through our strategically designed partnerships are suitable for Army technologies as well as other government agency and commercial applications, often benefiting society as a whole, as in the case of the successful COVID-19 collaborative research," Maupin says.
ARL South is headquartered on UT Austin's Pickle Research campus in north Austin. There are 17 academic institutions involved around the south-central region of the U.S., many in Texas, which engage roughly 110 Army researchers. At UT Austin, more than 10 leading researchers in synthetic biology interact on cutting edge innovation with ARL South, while across campus there are over 40 in areas such as networking, robotics, artificial intelligence and materials development.
"While there are many premier institutions in Texas, UT Austin was selected as the location to plant our ARL South flag because of the proximity to Austin's broad tech start-up community," Maupin says. "There's a definite advantage to being in the heart of the entrepreneurial culture that is home to Austin, motivating our own researchers to take risks and embrace innovation as we strive for transformational technical capabilities that will protect our nation."
Another key benefit of these kinds of partnerships is that students and postdocs can gain skills and experience working on real world problems and explore career opportunities outside of academia.
Putting Biology to Work
Besides countering biological threats (natural or otherwise), synthetic biologists working in the partnership between ARL South and UT Austin are exploring ways to adapt the natural machinery of life to make advanced materials with useful properties, protect plants and animals, and foster sustainability.
For example, one project involves developing toolkits that allow for controlling gene expression in microbes and plants so they produce materials needed at industrial scale, such as for lighter, stronger or more camouflaged armor for soldiers. The project also might yield sensitive biosensors that can detect the presence of biological or chemical weapons in the field, or it may lead to more sustainable production of materials and better ways to handle manufacturing waste.
In addition to manufacturing biomaterials, the approach can be used to protect important agricultural crops and pollinators. For example, a group of UT Austin engineers and molecular biologists engineered microbes that naturally live in the guts of honeybees to produce substances beneficial to these essential agricultural workhorses. In one project, the microbes produced a substance that helped improve the bees' memory and learning. In another project, the microbes pumped out medicines protecting the bees against deadly viruses and mites.
The team includes molecular bioscientists Andy Ellington, Bryan Davies and Jeffrey Barrick, as well as chemical engineer Hal Alper. They collaborated with Nancy Moran, a professor of integrative biology, and members of her lab to apply the new tools to bees. While the Defense Advanced Research Projects Agency initially funded development of the tools to engineer these microbes, the scientists are now exploring potential new applications such as coaxing microbes to produce protective or conductive coatings through the partnership with ARL South.
Ellington and Alper are also partnering with ARL South to develop processes that can convert waste into useful products.
"The Army always has interests in bioremediation," Ellington says. "The Army wants to be able to both clean up after themselves and 'live off the land.'"
The researchers are also using machine learning to make waste-degrading enzymes more stable and work in real world conditions. These advances will be especially important when moving biology outside the lab and into the real environment.
"We are excited to combine the research strength here at UT Austin with the biological foundry being established by ARL-South," Alper says. "These facilities will certainly elevate the level of training we can provide to students. Through these collaborations we hope to realize the promise of synthetic biology for improving our lives and environment."
Antibodies to the Rescue?
Not long ago, Gollihar was a graduate student at UT Austin working with Ellington and others on synthetic biology research. He left for a time to work in the biotechnology industry, learning the tools of automation. He returned to UT Austin in 2018 as the synthetic biology lead for ARL South; Chief Technology Officer of an ARL Essential Research Program focusing on synthetic biology; and head of the biological foundry. By then, Gollihar had a new goal: combining automation with an approach called directed evolution—an iterative process that starts with generating a host of mutated versions of a molecule or organism, selecting ones that best fit certain criteria, and then repeating—to accelerate scientific discovery.
At this point, the biological foundry is a facility of 2,500 square feet with state-of-the-art equipment capable of high-throughput screening and directed evolution of molecules and organisms needed to manufacture materials with unique properties. It houses capabilities typically dispersed across multiple university labs: sequencing and synthesizing DNA, sorting individual cells, sorting and analyzing the chemical constituents of materials and editing the genetic code of plants and microbes.
But the special sauce is the ability to do a lot of work quickly. For example, in terms of automation, the foundry deploys liquid-handling robots. In the time it takes a graduate student to use a pipette to transfer a sample from one tube to another, a liquid-handling robot can transfer 384 samples. In terms of directed evolution, Gollihar is developing methods that will allow him to analyze a billion unique variants of an enzyme in one single tube simultaneously and then in one fell swoop, select the best 10,000 versions. Through successive iterations, he can converge on the best enzyme much more rapidly than with traditional methods.
"Biology is messy and noisy, and designing things doesn't always work out," Gollihar says. "With high-throughput automation, you can take more shots on goal. And so something that once took you years to do now can take you weeks or months."
Thanks to the long-range vision of the ARL South partnership with UT Austin, the tools and personnel were already coming together when the pandemic struck. The team—led by Gollihar, Jason McLellan and Daniel Boutz; and also includes George Georgiou, Ilya Finkelstein and Edward Marcotte, among others—found an antibody produced naturally by an infected COVID-19 patient that robustly neutralizes the virus in cell cultures. The researchers are currently testing in animals and if all goes well, clinical trials in humans could begin within a few months.
"This wasn't the original plan," Gollihar says of the COVID-19 research at the foundry. "I wanted to build a platform that was agnostic to application, and was just about biological engineering. And it just so happened that it all came together during the worst biological event in our lifetime."
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