The rockefeller university

As Pamela Björkman walks her life’s path, unlikely destinations sparkle through the brush. She repeatedly veers, unconstrained by the absence of a well-trodden route or the certainty of clear passage. Guided by a robust internal compass, her pilgrimages have opened new personal and scientific vistas.

Throughout her career, Björkman has wielded structural biology to crack strategies by which the body fends off microbial invaders. Her tour-de-force graduate work unveiled key information about how T cells distinguish foreign from self molecules and thus discern whether the immune system should launch an attack. This advance yielded immediate revelations about autoimmune disease and laid the groundwork for mechanistic insights into how the body protects itself from intracellular pathogens. She has wrestled with destructive viral foes, probing HIV’s notorious ability to elude eradication, for instance, and exposing details about antibody interactions with SARS-CoV-2 that promise to enhance vaccine design.

But before all of that, Björkman had a different vision. In grade school, she drew pictures of her brother and herself. “He can play ball,” she wrote. “She can help her mother.” Björkman and her female friends in their hometown of Parkrose, Oregon, “were trained that a girl is going to do well in school, go to college, meet a nice man, get married, and have children,” she says.

Furthermore, science numbed young Björkman’s mind. “We were supposed to read books and memorize facts,” she says. “If I didn’t understand something, I didn’t enjoy it.” Finally, in 8th grade, her teacher asked the students to dream up questions and devise experiments to answer them. The creativity, logic, and exploratory nature of the enterprise sparked Björkman’s imagination. “Maybe that’s when I decided that this could be really interesting, even if you get the ‘wrong’ answer,” she says.

By the end of high school, Björkman had rejected her pre-ordained future as only a wife and mother and resolved to pursue a career. “At a certain point, I thought, ‘I’m not doing this,’” she recalls. “I didn’t tell anyone.” She set her sights on biomedical research because the prospect of improving human health appealed to her. “I wanted to make a difference in the world.”

Björkman attended a private college for a year, but her parents’ financial support came with expectations and restrictions. “To do what I wanted,” she says, she had to pay for her own education. She transferred to the University of Oregon, Eugene, and majored in chemistry.

In 1978, Björkman went to Harvard for her Ph.D. There, a talk by X-ray crystallographer Don Wiley riveted her: A molecule’s structure, she suddenly grasped, unlocked boundless intellectual and practical realms. It offered interpretations for previously gathered information and could steer drug and vaccine development. The possibility of harnessing structural biology to advance medicine bewitched her.

She joined Wiley’s lab and proposed a wildly ambitious thesis project. At the time, immunologists knew that T cells detect viral molecules only if they simultaneously “see” a host protein that is encoded within the so-called MHC region of the genome and called HLA in humans. The molecular basis of this dual recognition baffled scientists.

“I figured the only way to answer that question would be to look at the structure of HLA,” she says.

This project would have tested an aficionado crystallographer, never mind a neophyte. But this glittering goal seized Björkman. To justify her swerve from “the professional wife/mother thing,” she says, “I wanted to do something amazing, something really worthwhile. I didn’t want just a Ph.D.; I wanted this structure. It was a sacred quest.”

Ideas abounded to explain why T cells require a host and a microbial molecule. One theory posited that separate receptors on a T cell interact with each element, and only occupation of both receptors triggers an immune response. Another view held that a single T-cell receptor recognizes a conglomeration of the two elements; in that scenario, neither member of the pair could, on its own, spur T cells into action. Björkman could not imagine how any given HLA protein could bind to a vast number of different viral molecules, each of which has a distinct three-dimensional shape and chemical properties, so she initially favored the two-receptor model.

She wrangled with an irksome portion of the emerging structure, which seemed to contain extra material. Sometimes she and her colleagues floated the ridiculous idea that the mysterious signal represented a chunk of foreign protein, a peptide or mixture of peptides. Then they’d chuckle. This could not be, as the HLA protein they were studying came from cells that were not infected by a virus.

After seven years, she triumphed. “This was not a fun time,” she says, “I just beat on this thing until we finally got it to work.”

In 1987, her data showed unequivocally that the perplexing portion was not part of the HLA molecule and suggested that it was indeed a peptide or a mixture of peptides. Björkman had solved the puzzle: A particular groove of the HLA molecule holds a peptide. “The structure explained so much,” she says.

Indeed, it crystallized for the entire field how HLA does its job and illuminated crucial features of T-cell function. HLA molecules need not recognize a multitude of shapes after all. “You take the 3D out of [a folded viral protein] and just stretch out a small piece of it,” she says. Because the peptide is seen only in the context of the HLA molecule, the results argued for the existence of a single T-cell receptor that “doesn’t know that these are two separate molecules,” she says.

The presence of a peptide of the HLA groove in a non-infected cell also implied that, in the absence of a pathogen, the groove holds a protein fragment from the host’s own body. “The immune system asks, “is it me or is it foreign?” says Björkman. “If it’s me, leave it alone.” This observation explained connections between HLA, immunological tolerance, and autoimmune disease.

Björkman moved to Mark Davis’s lab at Stanford as a postdoctoral fellow. By drawing on comparisons between antibody and T-cell receptor subunits, they conceived a model for how the T-cell receptor recognizes bound peptides on MHC molecules.

In 1989, she joined the faculty at Caltech, where she has been ever since. She has continued to gravitate toward problems of momentous difficulty and impact.

She probed how a protein that resembles MHC molecules transports antibodies in newborn mice from maternal milk to the bloodstream, thus protecting the babies from harmful microbes. This process was inherently confounding, as MHC molecules were known by this time to bind peptides, not complete proteins such as antibodies.

For more than a decade, Björkman has been tackling a challenge that has foiled biologists since HIV appeared in the 1980s. This virus excels at evading the human body’s attempt to quash it with antibodies in large part because HIV mutates within an individual’s body, so the relevant immune target is constantly morphing. “Antibodies work but then they no longer work,” says Björkman.

She has undertaken an HIV vaccine crusade. “It is really hard, but I won’t give up on this,” she says. “HIV is devastating the world, it’s just that we don’t see it in the US.” On a visit to India in 2012, she met with HIV-infected sex workers, who felt that they had no other way to make enough money to send their children to school, Björkman says. Once infected, they could receive antiretroviral drugs from the government, but customers would find out and business would fizzle. So the women wouldn’t take the medication. “With a vaccine,” she says, “there would be no issue.”

After Björkman noticed that HIV’s envelope displays relatively few spike proteins, the entities that antibodies grab, she began thinking about how this dearth might contribute to the feeble antibody response. Antibodies have two appendages, and they can bind to most of their targets with both. If mutation within the target renders it slippery, she reasoned, an antibody can still hang on with the other arm. The sparse arrangement of HIV spike proteins, however, creates a situation in which each antibody can reach only one. In this view, loss of the single grip would release the antibody entirely. Björkman’s model has provided the framework for pursuing antibody- and vaccine-design schemes that address this dilemma.

She and the Rockefeller’s Michel Nussenzweig are collaborating to study the subset of patient antibodies that do manage to subdue a broad range of HIV strains. They hope that lessons from these natural “elite neutralizers” will enable them to train the immune system to obliterate the body’s first encounter with the virus and thus sidestep HIV’s inclination to mutate. Bjorkman and Nussenzweig have coauthored dozens of papers and they share a close partnership.

This and other work positioned her and Nussenzweig to respond swiftly to the Covid-19 pandemic. They are studying the structures of the coronavirus’s spike proteins in complexes with antibodies to discern rules for how these molecules bind each other. The researchers’ results have provided insights that hold implications for vaccine effectiveness against the variant strains that are emerging.

Björkman is also trying to develop vaccines that will protect humans from multiple viruses simultaneously—those we know about and even those that have not yet surfaced. Toward that end, she is creating so-called mosaic nanoparticles that display components from SARS-CoV-2 and other coronaviruses that attach to host cells.

Bold as ever, Björkman is continuing to delve into uncharted territory as she combats viral scourges and aims to enhance human health across the globe.

Authored by Evelyn Strauss, Ph.D.