Erica Ollman Saphire self-identifies as a “do what needs to be done” kind of person. A professor at La Jolla Institute for Immunology, she is more than an immunologist or a structural biologist: she is a leader.
Some of her colleagues thought it was impossible to convince nearly fifty competing labs across the world to combine forces and find the perfect antibody treatment for infectious diseases such as Ebola virus disease and Marburg hemorrhagic fever. She did it anyway when she spearheaded the Viral Hemorrhagic Fever Immunotherapeutic Consortium, which she now leads.
She now applies what she learned to lead a new consortium dubbed the Coronavirus Immunotherapy Consortium (CoVIC), where members search for the most effective antibody therapeutic for COVID-19. The researchers involved conduct side-by-side analyses of nearly 300 promising therapeutics using high resolution cryo-electron microscopy.
“What do antibodies do against COVID-19? When they hit different places, do they have different functions? Which sites are and are not susceptible to which mutation?” Ollman Saphire wondered.
The answers to these questions will provide critical insight into how to fight COVID-19.
“We have the opportunity to come up with cocktails that no one could alone and build the largest, most lasting database to help us understand a future variant,” she said.
We recently chatted with Ollman Saphire to find out how her personal and scientific philosophies fuel her passion for developing collaborations between different, and sometimes competing, researchers, and why she thinks this is a good strategy for finding the best antibody therapeutics for infectious diseases. She also discussed how she will use what she learned from these consortiums to run the La Jolla Institute for Immunology when she becomes their new CEO in September.
How did you choose your research focus?
I became fascinated with structural biology during my undergraduate years at Rice University. I double majored in ecology and biochemistry because I was interested in what happened at the molecular and environmental level and how these two things fit together. All the biochemistry students had to take a biophysics class to graduate. I was convinced that I would flunk it, so I saved it for the last semester of my senior year so the bad grade would not go on my transcript. (I had already accepted an offer to a PhD program in marine biology at Stanford University.)
But I loved the class! I remember the exact day, the chair that I sat in, and the lecture hall where the professor explained how to use scattered x-rays to mathematically calculate the topographical map for protein structure. We could understand the XYZ coordinates in space of every atom in a protein, how atoms move, and how they interact to fold. The clouds parted, the light came down, and I decided that this was what I wanted to do! This was the most powerful way to understand biology that I had ever seen. From that moment, I planned to be a structural biologist.
I changed plans and went to Scripps Research Institute to learn X-ray crystallography, which was the best way to get a high resolution structure at the time. I really wanted to understand how molecules work. How does a change at the amino acid level become a change at the organism level?
Those questions made viruses fascinating to me. A mutation that changes a single amino acid in the virus can change how it attaches to its receptor, the species it infects, and its transmission. It was intellectually satisfying and incredibly practical to try to combine cryo-EM and virology.
What inspired you to organize a consortium to study COVID-19?
I gave a talk on the Viral Hemorrhagic Fever Immunotherapeutic consortium I organized in 2013, and the Gates Foundation liked the model. The Gates Foundation is dedicated to finding new treatments for malaria, HIV, and tuberculosis. But when COVID emerged, they wanted to make a difference there as well.
They knew that scientists needed to do unbiased side-by-side comparisons of all the developing antibody therapeutics for COVID to find the differences. They wanted to understand what the landscape of potential therapeutics was, and to make sure that these therapies could save lives in low- and middle-income countries. To do that, a therapeutic must be safe and potent enough to work in small doses. So they funded us to rebuild the Viral Hemorrhagic Fever Immunotherapeutic consortium study for COVID. It’s a framework and muscle we already have; we are just applying it to a new virus. Since we have done this once before, we know what did and didn’t work and can do it better this time.
How did the initial Viral Hemorrhagic Fever Immunotherapeutic consortium study work?
In 2013, researchers with the Viral Hemorrhagic Fever Immunotherapeutic Consortium had antibodies against Ebola virus that looked wonderful in test tubes, but failed to protect non-human primates. We had other antibodies that protected non-human primates but didn’t look interesting at all in testing. That was a humbling moment for the field. We weren’t asking the right questions.
We each tested our antibodies with our own tools. Some research labs had a hammer and were looking for nails. Others had a screwdriver and were looking for screws. We inadvertently put blinders on ourselves. The solution was to pool everyone’s samples and expertise, do a big broad study, and see what shook out in the end.
We galvanized an international study of nearly 50 previous competitors across five continents where everyone sent their antibodies to one place. We gave more than 200 antibodies codenames to keep everything fair, and divided them up. Each team used their own tool or approach to understand the antibodies. Some people studied what sugars attached to an antibody. Some looked at the structure. Together, we generated a massive data set and answered questions like what correlates with in vivo protection? What experiments are most predictive?
We understood that the best antibody cocktail could be one antibody from Washington and another from Paris, for example. But we never could determine the optimal combinations unless we had the antibodies in the same room at the same time. Ultimately, there is a place for collaboration that celebrates and builds upon competition.
How did you find balance between collaboration and competition?
Neither collaboration nor competition is better than the other; there's a time and a place for each. As scientists, we need to step in and out of each box depending on the problem we’re trying to solve. It’s especially important to be friendly about it the whole time.
For years, researchers in another lab and I repeatedly published nearly identical papers two weeks apart. At some point, we realized that there was a better way. We made a deal to let each other know when we solved a structure so that we could pull our postdoctoral fellows off repetitive projects.
To do this, I had to have the humility to make my work about the biology, not my ego. What we learn with different approaches is better than what we learn alone. The kinds of scientists who build up the field and other people around them lead to more opportunities.
When is competition beneficial?
Competition helps in all times and places where speed is important. Nobody likes to lose. It’s not just a personal loss when we get scooped, but the world doesn’t gain the information if we don’t write it down in some digestible and publishable way. Any time someone innovates a better technique that helps people get things done faster, better, or more completely, that lifts the entire field.
How will your experience organizing these large collaborative projects affect how you lead the La Jolla institute for Immunology when you become the CEO in September?
I got a crash course when trying to figure out how to get those fifty competitors to work together to get the data we needed. I spent a lot of years analyzing how to propel science using the resources available and how to get the most out of people. I learned not to tell a scientist what to do. Just enable them, or get out of their way.
I have the honor and privilege of working in one of the best places in the world for understanding and conquering human disease. Enabling and propelling the scientists around me will not be leading them, but following where they want to go and understanding the gap between where they want to go and how to get them there.