It's vacation time. You and your family visit a country where you've never been and, in fact, your parents or grandparents had never been. You find yourself hiking beside a beautiful lake. It's a gorgeous day. You dive in. You are not alone.
How can your T cells and B cells react to a pathogen they've never seen?
In the water swim parasites, perhaps a parasite called giardia. The invader slips in through your mouth or your urinary tract. This bug is entirely new to you, and there's more. It might be new to everyone you've ever met or come into contact with. The parasite may have evolved in this setting for hundreds of thousands of years so that it's different from any giardia bug you've ever come into contact with before or that thrives in the region where you live.
How can your T cells and B cells react to a pathogen they've never seen, never knew existed, and were never inoculated against, and that you, or your doctors, in all their wisdom, could never have foreseen?
This is the infinity problem.
For years, this was the greatest mystery in immunology.
As I reported An Elegant Defense -- my book about the science of the immune system told through the lives of scientists and medical patients -- I was repeatedly struck by the profundity of this question. It is hard to overstate: how can we survive in a world with such myriad possible threats?
Matt Richtel's new book about the science of the immune system, An Elegant Defense, was published this month.
To further underscore the quandary, the immune system has to neutralize threats without killing the rest of the body. If the immune system could just kill the rest of the body too, the solution to the problem would be easy. Nuke the whole party. That obviously won't work if we are to survive. So the immune system has to be specific to the threat while also leaving most of our organism largely alone.
"God had two options," Dr. Mark Brunvand told me. "He could turn us into ten-foot-tall pimples, or he could give us the power to fight 10 to the 12th power different pathogens." That's a trillion potential bad actors. Why pimples? Pimples are filled with white blood cells, which are rich with immune system cells. In short, you could be a gigantic immune system and nothing else, or you could have some kind of secret power that allowed you to have all the other attributes of a human being—brain, heart, organs, limbs—and still somehow magically be able to fight infinite pathogens.
Dr. Brunvand is a retired Denver oncologist, one of the many medical authorities in the book – from wizened T-cell innovator Dr. Jacques Miller, to the finder of fever, Dr. Charles Dinarello, to his eminence Dr. Anthony Fauci at the National Institutes of Health to newly minted Nobel-Prize winner Jim Allison.
In the case of Dr. Brunvand, the oncologist also is integral to one of the book's narratives, a remarkable story of a friend of mine named Jason. Four years ago, he suffered late, late stage cancer, with 15 pounds of lymphoma growing in his back, and his oncologist put him into hospice. Then Jason became one of the first people ever to take an immunotherapy drug for lymphoma and his tumors disappeared. Through Jason's story, and a handful of other fascinating tales, I showcase how the immune system works.
There are two options for creating such a powerful immune system: we could be pimples or have some other magical power.
Dr. Brunvand had posited to me that there were two options for creating such a powerful and multifaceted immune system: we could be pimples or have some other magical power. You're not a pimple. So what was the ultimate solution?
Over the years, there were a handful of well-intentioned, thoughtful theories, but they strained to account for the inexplicable ability of the body to respond to virtually anything. The theories were complex and suffered from that peculiar side effect of having terrible names—like "side-chain theory" and "template-instructive hypothesis."
This was the background when along came Susumu Tonegawa.
Tonegawa was born in 1939, in the Japanese port city of Nagoya, and was reared during the war. Lucky for him, his father was moved around in his job, and so Tonegawa grew up in smaller towns. Otherwise, he might've been in Nagoya on May 14,1944, when the United States sent nearly 550 B-29 bombers to take out key industrial sites there and destroyed huge swaths of the city.
Fifteen years later, in 1959, Tonegawa was a promising student when a professor in Kyoto told him that he should go to the United States because Japan lacked adequate graduate training in molecular biology. A clear, noteworthy phenomenon was taking shape: Immunology and its greatest discoveries were an international affair, discoveries made through cooperation among the world's best brains, national boundaries be damned.
Tonegawa wound up at the University of California at San Diego, at a lab in La Jolla, "the beautiful Southern California town near the Mexican border." There, in multicultural paradise, he received his PhD, studying in the lab of Masaki Hayashi and then moved to the lab of Renato Dulbecco. Dr. Dulbecco was born in Italy, got a medical degree, was recruited to serve in World War II, where he fought the French and then, when Italian fascism collapsed, joined the resistance and fought the Germans. (Eventually, he came to the United States and in 1975 won a Nobel Prize for using molecular biology to show how viruses can lead, in some cases, to tumor creation.)
In 1970, Tonegawa—now armed with a PhD—faced his own immigration conundrum. His visa was set to expire by the end of 1970, and he was forced to leave the country for two years before he could return. He found a job in Switzerland at the Basel Institute for Immunology.
Around this time, new technology had emerged that allowed scientists to isolate different segments of an organism's genetic material. The technology allowed segments to be "cut" and then compared to one another. A truism emerged: If a researcher took one organism's genome and cut precisely the same segment over and over again, the resulting fragment of genetic material would match each time.
When you jump in that lake in a foreign land, filled with alien bugs, your body, astonishingly, well might have a defender that recognizes the creature.
This might sound obvious, but it was key to defining the consistency of an organism's genetic structure.
Then Tonegawa found the anomaly.
He was cutting segments of genetic material from within B cells. He began by comparing the segments from immature B cells, meaning, immune system cells that were still developing. When he compared identical segments in these cells, they yielded, predictably, identical fragments of genetic material. That was consistent with all previous knowledge.
But when he compared the segments to identical regions in mature B cells, the result was entirely different. This was new, distinct from any other cell or organism that had been studied. The underlying genetic material had changed.
"It was a big revelation," said Ruslan Medzhitov, a Yale scholar. "What he found, and is currently known, is that the antibody-encoding genes are unlike all other normal genes."
The antibody-encoding genes are unlike all other normal genes.
Yes, I used italics. Your immune system's incredible capabilities begin from a remarkable twist of genetics. When your immune system takes shape, it scrambles itself into millions of different combinations, random mixtures and blends. It is a kind of genetic Big Bang that creates inside your body all kinds of defenders aimed at recognizing all kinds of alien life forms.
So when you jump in that lake in a foreign land, filled with alien bugs, your body, astonishingly, well might have a defender that recognizes the creature.
Light the fireworks and send down the streamers!
As Tonegawa explored further, he discovered a pattern that described the differences between immature B cells and mature ones. Each of them shared key genetic material with one major variance: In the immature B cell, that crucial genetic material was mixed in with, and separated by, a whole array of other genetic material.
As the B cell matured into a fully functioning immune system cell, much of the genetic material dropped out. And not just that: In each maturing B cell, different material dropped out. What had begun as a vast array of genetic coding sharpened into this particular, even unique, strand of genetic material.
This is complex stuff. But a pep talk: This section is as deep and important as any in describing the wonder of the human body. Dear reader, please soldier on!
Researchers, who, eventually, sought a handy way to define the nature of the genetic change to the material of genes, labeled the key genetic material in an antibody with three initials: V, D, and J.
The letter V stands for variable. The variable part of the genetic material is drawn from hundreds of genes.
D stands for diversity, which is drawn from a pool of dozens of different genes.
And J is drawn from another half dozen genes.
In an immature B cell, the strands of V, D, and J material are in separate groupings, and they are separated by a relatively massive distance. But as the cell matures, a single, random copy of V remains, along with a single each of D and J, and all the other intervening material drops out. As I began to grasp this, it helped me to picture a line of genetic material stretching many miles. Suddenly, three random pieces step forward, and the rest drops away.
The combination of these genetic slices, grouped and condensed into a single cell, creates, by the power of math, trillions of different and virtually unique genetic codes.
In anticipation of threats from the unfathomable, our defenses evolved as infinity machines.
Or if you prefer a different metaphor, the body has randomly made hundreds of millions of different keys, or antibodies. Each fits a lock that is located on a pathogen. Many of these antibodies are combined such that they are alien genetic material—at least to us—and their locks will never surface in the human body. Some may not exist in the entire universe. Our bodies have come stocked with keys to the rarest and even unimaginable locks, forms of evil the world has not yet seen, but someday might. In anticipation of threats from the unfathomable, our defenses evolved as infinity machines.
"The discoveries of Tonegawa explain the genetic background allowing the enormous richness of variation among antibodies," the Nobel Prize committee wrote in its award to him years later, in 1987. "Beyond deeper knowledge of the basic structure of the immune system these discoveries will have importance in improving immunological therapy of different kinds, such as, for instance, the enforcement of vaccinations and inhibition of reactions during transplantation. Another area of importance is those diseases where the immune defense of the individual now attacks the body's own tissues, the so-called autoimmune diseases."
Indeed, these revelations are part of a period of time it would be fair to call the era of immunology, stretching from the middle of the 20th century to the present. During that period, we've come from sheer ignorance of the most basic aspects of the immune system to now being able to tinker under the hood with monoclonal antibodies and other therapies. And we are, in many ways, just at the beginning.
On the morning of April 12, 1955, newsrooms across the United States inked headlines onto newsprint: the Salk Polio vaccine was "safe, effective, and potent." This was long-awaited news. Americans had limped through decades of fear, unaware of what caused polio or how to cure it, faced with the disease's terrifying, visible power to paralyze and kill, particularly children.
The announcement of the polio vaccine was celebrated with noisy jubilation: church bells rang, factory whistles sounded, people wept in the streets. Within weeks, mass inoculation began as the nation put its faith in a vaccine that would end polio.
Today, most of us are blissfully ignorant of child polio deaths, making it easier to believe that we have not personally benefited from the development of vaccines. According to Dr. Steven Pinker, cognitive psychologist and author of the bestselling book Enlightenment Now, we've become blasé to the gifts of science. "The default expectation is not that disease is part of life and science is a godsend, but that health is the default, and any disease is some outrage," he says.
The Rise and Fall of Public Trust<p>When the polio vaccine was released in 1955, "we were nearing an all-time high point in public trust," says Matt Baum, Harvard Kennedy School professor and lead author of <a href="http://www.kateto.net/covid19/COVID19%20CONSORTIUM%20REPORT%2013%20TRUST%20SEP%202020.pdf" target="_blank" rel="noopener noreferrer"><u>several</u></a> <a href="https://shorensteincenter.org/wp-content/uploads/2020/09/COVID19-CONSORTIUM-REPORT-14-MISINFO-SEP-2020.pdf" target="_blank" rel="noopener noreferrer"><u>reports</u></a> measuring public trust and vaccine confidence. Baum explains that the U.S. was experiencing a post-war boom following the Allied triumph in WWII, a popular Roosevelt presidency, and the rapid innovation that elevated the country to an international superpower.</p><p> The 1950s witnessed the emergence of nuclear technology, a space program, and unprecedented medical breakthroughs, adds Emily Brunson, Texas State University anthropologist and co-chair of the Working Group on Readying Populations for COVID-19 Vaccine. "Antibiotics were a game changer," she states. While before, people got sick with pneumonia for a month, suddenly they had access to pills that accelerated recovery. </p><p>During this period, science seemed to hold all the answers; people embraced the idea that we could "come to know the world with an absolute truth," Brunson explains. Doctors were portrayed as unquestioned gods, so Americans were primed to trust experts who told them the polio vaccine was safe. </p>
The Shift in How We Consume Information<p>In the 1950s, the media created an informational consensus. The fundamental ideas the public consumed about the state of the world were unified. "People argued about the best solutions, but didn't fundamentally disagree on the factual baseline," says Baum. Indeed, the messaging around the polio vaccine was centralized and consistent, led by President Roosevelt's successful <a href="https://files.eric.ed.gov/fulltext/EJ978264.pdf" target="_blank" rel="noopener noreferrer"><u>March of Dimes crusade</u></a>. People of lower socioeconomic status with limited access to this information were <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1551508/?page=3" target="_blank" rel="noopener noreferrer"><u>less likely to have confidence</u></a> in the vaccine, but most people consumed <a href="https://www.c-span.org/video/?506891-1/a-special-report-polio" target="_blank" rel="noopener noreferrer"><u>media that assured them</u></a> of the vaccine's safety and <a href="https://www.cbsnews.com/news/the-salk-polio-vaccine-greatest-public-health-experiment-in-history/" target="_blank" rel="noopener noreferrer"><u>mobilized them</u></a> to receive it. </p><p>Today, the information we consume is no longer centralized—in fact, just the opposite. "When you take that away, it's hard for people to know what to trust and what not to trust," Baum explains. We've witnessed an increase in polarization and the technology that makes it easier to give people what they want to hear, reinforcing the human tendencies to vilify the other side and reinforce our preexisting ideas. When information is engineered to further an agenda, each choice and risk calculation made while navigating the COVID-19 pandemic <a href="https://www.nytimes.com/2020/12/19/opinion/sunday/coronavirus-science.html?referringSource=articleShare" target="_blank" rel="noopener noreferrer"><u>is deeply politicized</u></a>. </p><p>This polarization maps onto a rise in socioeconomic inequality and economic uncertainty. These factors, associated with a sense of lost control, prime people to embrace misinformation, explains Baum, especially when the situation is difficult to comprehend. "The beauty of conspiratorial thinking is that it provides answers to all these questions," he says. Today's insidious fragmentation of news media accelerates the circulation of mis- and disinformation, reaching more people faster, regardless of veracity or motivation. In the case of vaccines, skepticism around their origin, safety, and motivation is intensified. </p><p>Alongside the rise in polarization, Pinker says "the emotional tone of the news has gone downward since the 1940s, and journalists consider it a professional responsibility to cover the negative." Relentless focus on everything that goes wrong further erodes public trust and paints a picture of the world getting worse. "Life saved is not a news story," says Pinker, but perhaps it should be, he continues. "If people were more aware of how much better life was generally, they might be more receptive to improvements that will continue to make life better. These improvements don't happen by themselves."</p>
The Future Depends on Vaccine Confidence<p>So far, the U.S. has been unable to mitigate the catastrophic effects of the pandemic through social distancing, testing, and contact tracing. President Trump has <a href="https://www.washingtonpost.com/politics/bob-woodward-rage-book-trump/2020/09/09/0368fe3c-efd2-11ea-b4bc-3a2098fc73d4_story.html" target="_blank" rel="noopener noreferrer"><u>downplayed the effects and threat of the virus</u></a>, <a href="https://www.washingtonpost.com/outlook/2020/07/14/cdc-directors-trump-politics/" target="_blank" rel="noopener noreferrer"><u>censored experts and scientists</u></a>, <a href="https://www.theatlantic.com/science/archive/2020/06/america-giving-up-on-pandemic/612796/" target="_blank" rel="noopener noreferrer"><u>given up on containing the spread</u></a>, and <a href="https://www.nytimes.com/2020/09/16/world/covid-coronavirus.html" target="_blank" rel="noopener noreferrer"><u>mobilized his base to protest masks</u></a>. The Trump Administration failed to devise a national plan, so our national plan has defaulted to hoping for the <a href="https://www.politico.com/news/2020/08/26/nation-of-miracles-pence-coronavirus-vaccine-rnc-402949" target="_blank" rel="noopener noreferrer"><u>"miracle" of a vaccine</u></a>. And they are "something of a miracle," Pinker says, describing vaccines as "the most benevolent invention in the history of our species." In record-breaking time, three vaccines have arrived. But their impact will be weakened unless we achieve mass vaccination. As Brunson notes, "The technology isn't the fix; it's people taking the technology."</p><p> Significant challenges remain, including facilitating widespread access and supporting on-the-ground efforts to allay concerns and build trust with <a href="https://www.newyorker.com/news/daily-comment/african-american-resistance-to-the-covid-19-vaccine-reflects-a-broader-problem" target="_blank" rel="noopener noreferrer"><u>specific populations with historic reasons for distrust</u></a>, says Brunson. Baum predicts continuing delays as well as deaths from other causes that will be linked to the vaccine. </p><p> Still, there's every reason for hope. The new administration "has its eyes wide open to these challenges. These are the kind of problems that are amenable to policy solutions if we have the will," Baum says. He forecasts widespread vaccination by late summer and a bounce back from the economic damage, a "Good News Story" that will bolster vaccine acceptance in the future. And Pinker reminds us that science, medicine, and public health have greatly extended our lives in the last few decades, a trend that can only continue if we're willing to roll up our sleeves. </p>
Imagine this scenario: you get an annoying cough and a bit of a fever. When you wake up the next morning you lose your sense of taste and smell. That sounds familiar, so you head to a doctor's office for a Covid test, which comes back positive.
Your next step? An anti-Covid nasal spray of course, a "trickster drug" that will clear the once-dangerous and deadly virus out of the body. The drug works by tricking the coronavirus with decoy receptors that appear to be just like those on the surface of our own cells. The virus latches onto the drug's molecules "thinking" it is breaking into human cells, but instead it flushes out of your system before it can cause any serious damage.
This may sounds like science fiction, but several research groups are already working on such trickster coronavirus drugs, with some candidates close to clinical trials and possibly even becoming available late this year. The teams began working on them when the pandemic arrived, and continued in lockdown.
Biochemist David Baker, pictured in his lab at the University of Washington.