Robert Kirchdoerfer knew he wanted to be a scientist as far back as the early 1990s, when he was a student at Netherwood Elementary School.
But he did not envision those ambitions would play a role in helping to end a deadly pandemic.
The Oregon native, now an assistant professor at the University of Wisconsin-Madison, conducted research on coronaviruses five years ago that has since found its way into two of the leading vaccines against SARS-CoV-2 – the virus that causes COVID-19. It has killed more than 290,000 people in the United States and 1.5 million worldwide as of Friday, Dec. 11.
Kirchdoerfer’s contribution to the two vaccines comes from imaging coronaviruses, and figuring out how they infect their hosts.
One of the vaccines, made by pharmaceutical giant Moderna, is on the cusp of receiving the federal Food and Drug Administration’s emergency authorization. The FDA approved the other vaccine, made by Pfizer, Friday, Dec. 11. Both companies reported last month their respective vaccines have demonstrated 95% efficacy rates in building immunity to the illness, respectively, according to a Nov. 30 Washington Post story. And last week, Britain started administering the Pfizer vaccine to its public, with Canada also approving its use.
Knowing how far vaccine trials have come within the last year, Kirchdoerfer said he’s thrilled to be part of that global race to bring the health crisis to a standstill.
He gave credit to his parents, Tom and Diana, who had always taught him to roll with the punches and try his best. And their work with various organizations in the Oregon community demonstrated for Kirchdoerfer what it means to help others, he said.
“Those lessons have served me really well,” Kirchdoerfer said. “Nothing in life turns out to be easy if you want to be good at it.”
A love for ‘discovery’
Kirchdoerfer’s career began when he was just a fourth grader, he said.
“I definitely held onto a view that I wanted to study genetics all the way through high school,” he said. “I loved science. I loved discovery. I loved biology and living organisms and figuring out how they work.”
The 2002 Oregon High School graduate carried those loves all the way through his time studying genetics and biochemistry at UW-Madison, where he earned his bachelor’s degree in 2006.
After graduating, Kirchdoerfer soon moved to the Scripps Research Institute in La Jolla, California until 2012, to pursue his Ph.D. in biophysics and influenza replication.
It was there where he spent three years researching how Ebola, a deadly virus that causes internal bleeding, replicates its genome.
Kirchdoerfer then felt himself gravitating toward coronaviruses, since the Scripps campus already “has one of the strongest virology communities in the country.”
Little did he know, he and his team would make discoveries that would later have major implications for a pandemic that no one anticipated would reach the scale of infection and death it has, he said.
“While it was reasonable to expect this would emerge, the idea that you have a coronavirus pandemic is unprecedented,” Kirchdoerfer said.
Imaging the spike
The first discovery Kirchdoerfer and his team made was in imaging coronaviruses, particularly its spike protein.
That protein is what allows the virus to enter an organism’s cells, he said, causing the host to contract an infection and eventually display symptoms. Nobody knew what it looked like, even in 2015, he said.
Scripps had just finished the installation of an electron microscopy center, giving Robert and his team the opportunity to remedy that problem.
They started to work with a collaborator, molecular biologist Jason McClellan from University of Texas at Austin, to use “cryo-electron microscopy” to view the spike’s three dimensional structure at a higher resolution than ever before.
The team first studied and imaged the virus that causes the common cold, HKU1, and later moved on to the deadly Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome.
SARS appeared in 2002 in China, quickly spreading worldwide, but was quickly contained, with no known transmission since 2004. MERS spread around the Middle East in 2012, also rapidly contained.
SARS-CoV-2 shares the same structure and spike characteristics with those viruses, Kirchdoerfer said.
Once the team imaged the coronaviruses, he said the next step was to study the exact process through which they enter and infect their hosts.
‘Prefusion’ and ‘postfusion’
Coronaviruses exist in two states, Kirchdoerfer said of his team’s second finding during his time in California.
It was a discovery that Moderna and Pfizer would examine as early as 2017 – which became the precursor to the 2020 vaccines.
Those two states include prefusion, when the coronavirus enters the body, and postfusion, when it enters a cell to replicate itself and multiply, Kirchdoerfer said. The spike protein of the coronavirus helps it bind to the cells and carry out that process, called “a membrane fusion event.”
The goal of identifying and studying this “event” was to create mutations that render the coronavirus incapable of entering the postfusion phase. Kirchdoerfer said antibodies best target the coronavirus in its prefusion form — a finding that would have significant meaning when SARS-CoV-2 would emerge in Wuhan, China, for the first time in November 2019.
So where the spike protein of the HKU1 virus was “well-behaved,” the structures of the SARS and MERS virus were “unstable,” spontaneously undergoing shape changes.
The Scripps team and its collaborators had the challenge of “stabilizing” the SARS and MERS viruses, creating two mutations that kept both in their prefusion form.
“These mutations have now been incorporated into the spike vaccines that are being used by both Pfizer and Moderna,” Kirchdoerfer said.