Your Body Has This Astonishing Magical Power
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.
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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.
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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.
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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!
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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.
Few things are more painful than a urinary tract infection (UTI). Common in men and women, these infections account for more than 8 million trips to the doctor each year and can cause an array of uncomfortable symptoms, from a burning feeling during urination to fever, vomiting, and chills. For an unlucky few, UTIs can be chronic—meaning that, despite treatment, they just keep coming back.
But new research, presented at the European Association of Urology (EAU) Congress in Paris this week, brings some hope to people who suffer from UTIs.
Clinicians from the Royal Berkshire Hospital presented the results of a long-term, nine-year clinical trial where 89 men and women who suffered from recurrent UTIs were given an oral vaccine called MV140, designed to prevent the infections. Every day for three months, the participants were given two sprays of the vaccine (flavored to taste like pineapple) and then followed over the course of nine years. Clinicians analyzed medical records and asked the study participants about symptoms to check whether any experienced UTIs or had any adverse reactions from taking the vaccine.
The results showed that across nine years, 48 of the participants (about 54%) remained completely infection-free. On average, the study participants remained infection free for 54.7 months—four and a half years.
“While we need to be pragmatic, this vaccine is a potential breakthrough in preventing UTIs and could offer a safe and effective alternative to conventional treatments,” said Gernot Bonita, Professor of Urology at the Alta Bro Medical Centre for Urology in Switzerland, who is also the EAU Chairman of Guidelines on Urological Infections.
The news comes as a relief not only for people who suffer chronic UTIs, but also to doctors who have seen an uptick in antibiotic-resistant UTIs in the past several years. Because UTIs usually require antibiotics, patients run the risk of developing a resistance to the antibiotics, making infections more difficult to treat. A preventative vaccine could mean less infections, less antibiotics, and less drug resistance overall.
“Many of our participants told us that having the vaccine restored their quality of life,” said Dr. Bob Yang, Consultant Urologist at the Royal Berkshire NHS Foundation Trust, who helped lead the research. “While we’re yet to look at the effect of this vaccine in different patient groups, this follow-up data suggests it could be a game-changer for UTI prevention if it’s offered widely, reducing the need for antibiotic treatments.”
MILESTONE: Doctors have transplanted a pig organ into a human for the first time in history
Surgeons at Massachusetts General Hospital made history last week when they successfully transplanted a pig kidney into a human patient for the first time ever.
The recipient was a 62-year-old man named Richard Slayman who had been living with end-stage kidney disease caused by diabetes. While Slayman had received a kidney transplant in 2018 from a human donor, his diabetes ultimately caused the kidney to fail less than five years after the transplant. Slayman had undergone dialysis ever since—a procedure that uses an artificial kidney to remove waste products from a person’s blood when the kidneys are unable to—but the dialysis frequently caused blood clots and other complications that landed him in the hospital multiple times.
As a last resort, Slayman’s kidney specialist suggested a transplant using a pig kidney provided by eGenesis, a pharmaceutical company based in Cambridge, Mass. The highly experimental surgery was made possible with the Food and Drug Administration’s “compassionate use” initiative, which allows patients with life-threatening medical conditions access to experimental treatments.
The new frontier of organ donation
Like Slayman, more than 100,000 people are currently on the national organ transplant waiting list, and roughly 17 people die every day waiting for an available organ. To make up for the shortage of human organs, scientists have been experimenting for the past several decades with using organs from animals such as pigs—a new field of medicine known as xenotransplantation. But putting an animal organ into a human body is much more complicated than it might appear, experts say.
“The human immune system reacts incredibly violently to a pig organ, much more so than a human organ,” said Dr. Joren Madsen, director of the Mass General Transplant Center. Even with immunosuppressant drugs that suppress the body’s ability to reject the transplant organ, Madsen said, a human body would reject an animal organ “within minutes.”
So scientists have had to use gene-editing technology to change the animal organs so that they would work inside a human body. The pig kidney in Slayman’s surgery, for instance, had been genetically altered using CRISPR-Cas9 technology to remove harmful pig genes and add human ones. The kidney was also edited to remove pig viruses that could potentially infect a human after transplant.
With CRISPR technology, scientists have been able to prove that interspecies organ transplants are not only possible, but may be able to successfully work long term, too. In the past several years, scientists were able to transplant a pig kidney into a monkey and have the monkey survive for more than two years. More recently, doctors have transplanted pig hearts into human beings—though each recipient of a pig heart only managed to live a couple of months after the transplant. In one of the patients, researchers noted evidence of a pig virus in the man’s heart that had not been identified before the surgery and could be a possible explanation for his heart failure.
So far, so good
Slayman and his medical team ultimately decided to pursue the surgery—and the risk paid off. When the pig organ started producing urine at the end of the four-hour surgery, the entire operating room erupted in applause.
Slayman is currently receiving an infusion of immunosuppressant drugs to prevent the kidney from being rejected, while his doctors monitor the kidney’s function with frequent ultrasounds. Slayman is reported to be “recovering well” at Massachusetts General Hospital and is expected to be discharged within the next several days.