By Jessica Aguirre, C&EN BrandLab
How Robert A. Welch left a legacy that shapes science in Texas and reverberates worldwide
A structure of the respiratory syncytial virus (RSV) F protein bound to antibody D25. This fusion protein helps viruses bind to cellular membranes and enter the cell.Source: Jason McLellan
B efore the pandemic, Jason McLellan’s field was considered obscure. A structural biologist, McLellan was interested in emerging pathogens—potential threats to human health that haven’t yet gained a foothold in large sections of the population. In 2017, he applied for a grant to study what it would take to create a universal vaccine for a family of viruses that weren’t very well known. His application was rejected; its reviewers thought his work in the area wouldn’t have much of an impact. He had proposed research on how to protect against coronaviruses.
McLellan continued his studies in related fields, though, supported in part by the Welch Foundation, one of the largest private funding organizations that contributes to advancing chemical science. He looked at the structure of viral fusion proteins—he was initially drawn to respiratory syncytial virus (RSV), a common illness causing mild, cold-like symptoms in most people, but can be dangerous for babies and older adults. As chemistry is fundamental to so many branches of science, the foundation ends up supporting a wide range of research, including structural biology, neuroscience, materials science, catalysis, and everything in between.
Viral membrane-fusion proteins let viruses like coronaviruses get into cells by penetrating their membranes, but these proteins are highly unstable in their prefusion state. After they fuse into the cell, they shift shape, which helps them evade the immune system’s defenses. A notorious example of a membrane-fusion protein is the spike protein that dots the surface of the SARS-CoV-2 virus and allows the pathogen to gain entry into human cells. McLellan wanted to understand the structure of viral membrane-fusion proteins and figure out a way to stabilize their prefusion state. His breakthrough in understanding and genetically altering RSV membrane-fusion proteins paved the way for vaccines that prompt an antibody response to prefusion versions of coronaviruses’ spike protein—technology that proved critical in vaccine development to address COVID-19, the disease caused by SARS-CoV-2.
Funding the future
“We’re thinking about the next pathogens,” McLellan says. “It’s hard sometimes to get the money for those.” McLellan is now the Robert A. Welch Chair in Chemistry at the University of Texas at Austin. The Welch Foundation was created at the behest of Robert Alonzo Welch, an entrepreneur who arrived, penniless, in Texas in 1886 and built a fortune in oil and minerals. It awards tens of millions of dollars in research funding every year and underpins a broad swath of science across Texas. Since its focus is on basic science, the foundation often supports work that goes on to provide the basis for important breakthroughs.
Welch, who was convinced that chemistry would pave the way to improved conditions for all humankind, left $25 million in 1952 to endow his foundation. With its careful fiduciary stewardship, the foundation has grown to play a critical part in scientific research that has impacts worldwide. In addition to funding research through its grant program, the foundation has helped endow 48 chairs in Texas. It hosts an annual conference of global renown and confers a $500,000 lifetime achievement recognition, the Welch Award, to an eminent scientist. In addition, the foundation bestows a smaller prize, the Norman Hackerman Award in Chemical Research, to a promising early-career scientist in Texas. It also supports scientifically minded precollege students through a summer scholar program.
Before becoming an endowed professor, McLellan had received funding from the Welch Foundation in the form of a research grant. Through its grant program, the foundation is able to advance research that might not otherwise take place by focusing most of its support on fundamental science. During the pandemic, the importance of helping build a basic understanding across a multitude of scientific fields came into stark relief. “It was 100,000 person-years of people working on viruses, on virology, epidemiology, immunology, biophysics—not with the goal of solving a pandemic in 2020 but just because they were curious and they wanted to know how proteins work and how the spike protein allows the virus to enter the cell,” Welch Foundation president Adam Kuspa says. “Because they were curious and it’s exciting to discover new things. So that’s the importance of basic research.”
Risk and reward
Steve McKnight, a professor and the former chair of the biochemistry department at the University of Texas Southwestern Medical Center, has seen firsthand the effects of the Welch Foundation and its willingness to fund research that may not otherwise receive support. As the chair of a department, McKnight headed up a team of chemists, biochemists, and biologists studying a transcriptional regulation pathway related to kidney cancer. With the help of the foundation and his university, McKnight and his colleagues built a library of chemicals and screened for ones that could act as inhibitors. “Historically, it’s been nearly impossible to discover chemicals that can inhibit transcription factors; in fact, it had never been done,” McKnight says. “If you’re doing very risky research, the tendency is the [National Institutes of Health] will not support you. On the other hand, the Welch Foundation really likes risky research as long as it’s being done by high-quality scientists.” They did identify an inhibitor that blocked transcription of the kidney cancer–promoting genes, which was clinically developed by Dallas-based Peloton Therapeutics and later by Merck. The therapy, named belzutifan, was approved by the US Food and Drug Administration in August.
McKnight received the Welch Award last year for his contributions to the field of gene transcription, but he credits the foundation for providing funding for nearly 2 decades to his colleagues in the department. “Without that reliable, substantial support, this drug would never have seen the light of day,” McKnight says.
Preliminary, but promising
McLellan, who used his award to look at the structures of the polymerase complex of a group of pathogens called pneumoviruses, says the foundation is open to research questions that are still in their preliminary stages. Its support can catalyze those first critical steps, he says, and scientists can use that initial data in applying for other grants. “One of the benefits of the money is that it allows us to be bold and go after creating interventions for pathogens that maybe haven’t been on the radar of different funding agencies but are important and need to have interventions in place now,” McLellan says. Coronaviruses may be on the minds of many funding agencies, but he is already looking at what may come next.
To Kuspa, the pandemic underscored the relevance and boldness of Robert A. Welch’s vision and the need to provide continuous support for progress in scientific understanding. Helping researchers move forward on basic questions while enabling them to shift their focus as novel challenges appear is one of the ways that Welch Foundation support is unique. “The pandemic has been an object lesson for every citizen around the world that this is actually important,” Kuspa says. While the applied value of McLellan’s work may not have been clear at the time he proposed it, the steps he took in furthering basic comprehension proved to be a critical element in the most important vaccine development in modern history. As the Welch Foundation continues its work and expands into new areas, like advanced materials, the scientists it supports have their eyes on the future.
Brain: The final frontier
It’s hard to imagine what the interior of our brains looks like, but Xiaowei Zhuang has helped pull back the veil, revealing structures previously unknown. Her novel imaging techniques have allowed for a clearer picture of the molecular networks in the human brain. Zhuang has also started building a tool kit that could help develop an understanding of when dysfunction leads to disease.
But Zhuang can’t solve all the mysteries of the brain on her own. As scientific adviser for the Welch Foundation and program chair of the 2021 Welch Conference on Chemical Research, Zhuang decided to focus this year’s meeting on brain science and medicine. Researchers from around the world will convene virtually to discuss the most complex organ in the known universe.