An Elegant Defense

by Matt Richtel

  Even then, though, scientists understood that there was a corollary to the immune system’s ability to learn: It is not easily taught. As often as not, efforts to create vaccines failed. The concoction seemingly had to be perfect. Little changes could render inoculations ineffective. Researchers discovered that successful vaccines were strong enough to provoke a powerful response by the immune system, but weak enough—attenuated is the scientific term—to keep it from being as nasty as the infection itself. The wrong combination entailed the risk that, instead of protecting, a vaccine could kill.

  That’s what happened with the initial mass test of the polio vaccine.

  The first polio epidemic was recorded in 1894, 132 cases in Vermont. Of the infected, 1 to 2 percent were paralyzed.

  The poliovirus gets quickly into the bloodstream, after entering through the mouth and growing in the throat and gastrointestinal tract. It winds up in the nervous system, where it attaches to nerve cells and invades them. It then takes over the nerve cell’s manufacturing process to reproduce itself—thousands of copies in an hour. Then it kills the cell and moves on to infect others. Picture a shadow creeping over our festival as cell after cell goes dark.

  The vexing effort to eradicate polio included the work in the 1930s of two competing scientists, Dr. Maurice Brodie, a Canadian working at New York University, and a Philadelphia pathologist at Temple University in Philadelphia named Dr. John Kolmer. Various histories I’ll delineate here recount their failings, even disasters.

  The two competing scientists had similar ideas. They infected monkeys with polio and tried to make a human vaccine with the nerve tissue. In Brodie’s case, he then mixed the liquefied monkey tissue with formaldehyde, called formalin, hoping to “deactivate” the virus. It would present enough, the theory went, to provoke an immune response, but would not be powerful enough to actually infect. Not so much. One history, written by a Yale doctor and historian named John Paul, is quoted as saying that Brodie’s vaccine was tested on 3,000 children, but “something went wrong, and Brodie’s vaccine was never used again.” A history published in the New York Times is more explicit: Children were left paralyzed.

  Dr. Kolmer had the same results, though he took a slightly different approach. He took the monkey nerve tissue, mixed it with chemicals, and refrigerated the mixture to attenuate it. Dr. Paul’s history calls it a “veritable witch’s brew.” More infected children. In Paul’s book, Dr. Kolmer is reported to have said at a public health conference in 1953: “This is one time I wish the floor would open up and swallow me.”

  In 1952, as Time magazine reported, the worst outbreak yet infected 58,000 Americans, killing 3,000 and paralyzing 21,000. “Parents were haunted by the stories of children stricken suddenly by the telltale cramps and fever,” Time read. “Public swimming pools were deserted for fear of contagion. And year after year polio delivered thousands of people into hospitals and wheelchairs, or into the nightmarish canisters called iron lungs.”

  The answer to the polio mystery, also well known, came from Jonas Salk, who was born in New York City of Russian Jewish immigrant parents and eventually was appointed director of the Virus Research Laboratory at the University of Pittsburgh School of Medicine (by way of New York University and Michigan). His vaccine weakened the poliovirus with formaldehyde and mineral water. It effectively “killed” the poliovirus. But it was recognizable enough for the immune system to pick it up. Ta-da! It cut the risk of infection in half.

  The country scrambled to produce and disseminate the vaccine as quickly as possible. Alas, this happy ending comes with an asterisk. The first big batch of vaccine wasn’t properly made. Cutter Laboratories in California, one of the main producers of the vaccine, inoculated more than 200,000 children in 1955, and within days there were reports of paralysis. Within a month, the program was discontinued, and investigations revealed that the Cutter vaccine had caused 40,000 cases of polio, leaving 200 children with varying degrees of paralysis and killing 10.

  These problems were ironed out and polio was all but eradicated in the United States and, eventually, worldwide. Here’s the lesson: Intervening on behalf of the immune system is no easy task, given the delicate balance. The vaccines were the first big step in that direction, even if we didn’t truly understand their dynamic. Without fully understanding the mechanisms, we had found an effective tool.

  That was true of the discovery of a second, marvelous immune system ally: antibiotics.

  Early doses of penicillin, a medicine that changed the world. (Science Museum, London/Wellcome Collection)

  Antibiotics are arguably more important than vaccines. In fact they are “probably the most successful forms of chemotherapy in the history of medicine. It is not necessary to reiterate here how many lives they have saved and how significantly they have contributed to the control of infectious diseases that were the leading causes of human morbidity and mortality for most of human existence,” according to a history published in a National Institutes of Health journal. Broadly, antibiotics work by taking advantage of differences between human cells and bacterial cells; for instance, bacterial cells have walls that human cells do not. Antibiotics can prevent bacteria from building such walls.

  That’s the mechanism behind the shot heard ’round the world in 1928, at St. Mary’s Hospital at the University of London. The world was temporarily at peace, which was fine with a Scotsman named Dr. Alexander Fleming. He’d seen plenty of the opposite in the Army Medical Corps during the Great War.

  The accident took place in a petri dish. It was filled with the strep bacteria he was studying. One day he noticed something odd. One area of the dish containing the deadly pathogen was suddenly free of bacteria. A closer looked showed it was being killed off by mold—“the mold had created a bacteria-free circle around itself,” read Fleming’s Nobel Prize biography in 1945. Why the Nobel?

  He named the medicine born of that mold penicillin.

  Whereas vaccines prompt our own response, antibiotics import a response from the outside, and that is an absolutely critical distinction for our everyday health. The reason is that when you add an outside force, you disrupt the natural order. Even if the goal is preservation of life, and even if it works, that doesn’t mean the process is without important risks. In the case of antibiotics, these terrific killers don’t just kill off bad bacteria; they target good stuff too, including bacteria crucial to your health and well-being.

  If you’ve ever taken antibiotics and gotten diarrhea, you’re in good company. The antibiotics are killing off bacteria in your gut that help you digest. They are doing real damage inside your gut, even as they get rid of the pathogens that could turn off the lights in your Festival of Life. Later, I’ll get deeper into the importance of the daily and long-term health of your gut, the microbiome, but at the time that antibiotics first emerged and became wonder drugs, the concept was more basic: survive the infection to fight another day.

  Now, because of Dr. Fleming, you wouldn’t die from getting a cut on your hand, or a small battlefield wound, ear infection, and on and on. Antibiotics have not only extended life but improved its quality by permitting myriad modern surgical procedures, like knee and hip replacements, which would be at extreme risk of infection absent these wonder drugs. Plus, antibiotics are used to keep livestock healthy, helping grow the food supply.

  But vaccines and antibiotics weren’t easy to come by, at least not effective ones. The body had to do most of the work. It had been doing most of the work—for epochs.

  Plus, the immunologists pioneering the exploration were determined to get deeper into the machine, for both intellectual reasons and practical ones—could they figure out how to extend life further and further? That meant answering the biggest question of all: how could our bodies become equipped with defenses for so many possible threats? How is it we can survive in a world in which the possible threats are practically infinite?

  12

  The Infinity Machine

  It’s vac
ation 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. 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.

  Of course, 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.

  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, like Jacques Miller, 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.

  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.

  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 threat 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.”

  These last sentences—about autoimmunity and transplantation—introduced a central challenge to understanding our body’s defense: How does something so powerful avoid attacking the healthy parts of us? And how can we treat ourselves medically through things like transplants and medication without risking that our potent antibody system will reject anything that could actually help us, even if it seems alien at first?

  What is alien, and what is self?

  13

  Transplant

  One day in the early 1970s, a family showed up at the Mayo Clinic in Rochester, Minnesota, with an infant boy suffering a mysterious condition. The baby had skin lesions that looked like measles, terrible diarrhea, and a fever. The petrified parents had further reason to be afraid. They’d previously had another child, a baby boy ailing just like this one, and he had died in mere weeks. That older boy, after his death, was discovered to have neither B cells nor T cells.

  The family brought their second infant to Mayo seeking a consultation with Dr. Max Cooper, the prominent immunologist who had helped explain the presence of T cells and B cells. Could he save their baby?

  “We were asked to make a suggestion,” Dr. Cooper recalled. He felt a dire sense of responsibility but had little science to go on. What if, he suggested, they withdrew bone marrow from the boy’s mother and then injected it into the bone marrow of the boy?

  Bone marrow is home to maturing cells, stem cells, including maturing immune system cells. Could it be that the mom’s immune system could take hold in her baby boy?

  There wasn’t much evidence to tell them what would happen. “We had only a crude road map,” Dr. Cooper recalled. The transplant needed to succeed in killing the foreign disease without causing the boy’s own hobbled defenses to react against the mom’s immune cells. Cooper theorized that the boy’s body wouldn’t reject his mother’s defenses because they had so much genetic material in common.