Late on a Friday night in April 2020, Lexi Walls was alone in her laboratory at the University of Washington, waiting nervously for the results of the most important experiment of her life. Walls, a young structural biologist with expertise in coronaviruses, had spent the past three months working day and night to develop a new kind of vaccine against the pathogen ravaging the world. She hoped that her approach, if successful, might not only tame COVID but also revolutionize the field of vaccinology, putting us on a path to defeat infectious diseases from flu to HIV. Unlike any vaccine used before, the vaccine Walls was developing was not derived from components found in nature. It consisted of artificial microscopic proteins drawn up on a computer, and their creation marked the beginning of an extraordinary leap in our ability to redesign biology.
Proteins are intricate nanomachines that perform most tasks in living things by constantly interacting with one another. They digest food, fight invaders, repair damage, sense their surroundings, carry signals, exert force, help create thoughts, and replicate. They are made of long strings of simpler molecules called amino acids, and they twist and fold into enormously complex 3-D structures. Their origamilike shapes are governed by the order and number of the different aminos used to build them, which have distinct attractive and repellent forces. The complexity of those interactions is so great and the scale so small (the average cell contains 42 million proteins) that we have never been able to figure out the rules governing how they spontaneously and dependably contort from strings to things. Many experts assumed we never would.
But new insights and breakthroughs in artificial intelligence are coaxing, or forcing, proteins to give up their secrets. Scientists are now forging biochemical tools that could transform our world. With these tools, we can use proteins to build nanobots that can engage infectious diseases in single-particle combat, or send signals throughout the body, or dismantle toxic molecules like tiny repo units, or harvest light. We can create biology with purpose.
Walls is at the forefront of this research. She completed her doctorate in coronavirus structure in December 2019, making her a member of what was at the time a very small club. “For five years I’d been trying to convince people that coronaviruses were important,” she says. “At my Ph.D. defense, I began by saying, ‘I’m about to tell you why this family of viruses has the potential to cause a pandemic, and we are not prepared for that pandemic.’ Unfortunately, that ended up coming true.”
As soon as word of a mysterious new pneumonia trickled out of Wuhan, China, in late December 2019, Walls suspected a coronavirus. On January 10, 2020, the genetic sequence for SARS-CoV-2 was released to the world. Walls and biochemist David Veesler, the head of her lab at the University of Washington, stayed up all night analyzing it. Walls says she felt an overwhelming sense of focus: “It was like, ‘Okay, we know what to do,’” she says. “‘Let’s go do it.’”
Like other coronaviruses, SARS-CoV-2 resembles a ball covered in protein “spikes.” Each spike ends in a cluster of amino acids—a section of the protein known as the receptor-binding domain, or RBD—whose alignment and atomic charges pair perfectly with a protein on the surface of human cells. The viral protein docks at the receptor like a spacecraft, and the virus uses this connection to slip inside the cell and replicate.
Because of its dangerous role, the RBD is the primary target of the immune system’s antibodies. They, too, are proteins, created by the body to bind to the RBD and take it out of commission. But it takes a while for specialized cells to manufacture enough effective antibodies, and by that time the virus has often done considerable damage.
The first-generation COVID vaccines, including the mRNA vaccines that have been such lifesavers, work by introducing the virus’s spike into the body, without a functional coronavirus attached, so the immune system can learn to recognize the RBD and rally its troops. But the RBD is periodically hidden by other parts of the spike protein, shielding the domain from antibodies looking to bind to it. This blunts the immune response. In addition, a free-floating spike protein does not resemble a natural virus and does not always trigger a strong reaction unless a large dose of vaccine is used. That big dose increases costs and can trigger strong side effects.
As successful as the COVID vaccines have been, many experts see inoculations based on natural proteins as an interim technology. “It’s becoming clear that just delivering natural or stabilized proteins is not sufficient,” says Rino Rappuoli, chief scientist and head of vaccine development at U.K.-based pharmaceutical giant GlaxoSmithKline. Most current vaccines, from childhood inoculations to adult flu shots, involve such natural proteins, which vaccinologists call immunogens; GSK makes a lot of them. “We need to design immunogens that are better than natural molecules,” Rappuoli says.
Walls and Veesler had an idea. What if, instead of a whole spike, the immune system were presented with just the RBD tip, which would not have any shield to hide behind? “We wanted to put the key component on display,” Walls says, “to say, ‘Hey, immune system, this is where you want to react!’
The immediate trouble with that notion was that biology does not make isolated RBDs, and the segment on its own would be too small and unfamiliar to get the immune system’s attention. But Walls and Veesler knew some people who could help them solve that problem. Just up the street from them was the Bell Labs of protein invention, the University of Washington’s Institute for Protein Design (IPD). The institute had learned enough about protein folding to design and build a few hundred very simple, small proteins—unlike any that have ever been found in a living organism—that would fold into consistent shapes with predictable functions.
In 2019 a group in the IPD led by biochemist Neil King had designed two tiny proteins with complementary interfaces that, when mixed together in solution, would snap together and self-assemble into nanoparticles. These balls were about the size of a virus and were completely customizable through a simple change to their genetic code. When the scientists festooned the particles with 20 protein spikes from the respiratory syncytial virus, the second-leading cause of infant mortality worldwide, they triggered an impressive immune response in early tests.
Why not try a similar nanoparticle core for a SARS-CoV-2 vaccine, Walls and Veesler thought, using just the RBD instead of an entire spike? As a bonus, the protein-based nanoparticle would be cheap and fast to produce compared with vaccines that use killed or weakened virus. It would also be stable at room temperature and easy to deliver to people, unlike fragile mRNA vaccines that must be kept in a deep freeze.
Walls reached out to the IPD and collaborated with nanoparticle specialist Brooke Fiala, who worked with King, on a prototype—a nanoparticle sphere displaying 60 copies of the RBD. The scientists also tried something radical: Instead of fusing the RBDs directly to the surface of the nanoparticle, they tethered them with short strings of amino acids, like kites. Giving the RBDs a little bit of play could allow the immune system to get a better look at every angle and produce antibodies that would attack many different spots.