A fierce champion fighter in action, representing the incredible power of the human immune system.
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.
***
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.
A company called Second Sight made an implant that partially restored vision to people who'd been blind for decades. But when Second Sight pivoted, it stopped servicing its product, leaving many in the dark.
The Argus II uses the implant and a video camera embedded in a special pair of glasses to provide limited vision to those with retinitis pigmentosa, a genetic disease that causes cells in the retina to deteriorate. The camera feeds information to the implant, which sends electrical impulses into the retina to recapitulate what the camera sees. The impulses appear in the Argus II as a 60-pixel grid of blacks, grays and whites in the user’s eye that can render rough outlines of objects and their motion.
Smartphone and computer manufacturers typically stop issuing software upgrades to their devices after two or three years, eventually rendering them bricks. But is the smartphone approach acceptable for a device that helps restore the most crucial sense a human being possesses?
Ross Doerr, a retired disability rights attorney in Maine who received an Argus II in 2019, describes the field of vision as the equivalent of an index card held at arm’s length. Perk often brings objects close to his face to decipher them. Moreover, users must swivel their heads to take in visual data; moving their eyeballs does not work.
Despite its limitations, the Argus II beats the alternative. Perk no longer relies on his guide dog. Doerr was uplifted when he was able to see the outlines of Christmas trees at a holiday show.
“The fairy godmother department sort of reaches out and taps you on the shoulder once in a while,” Doerr says of his implant, which came about purely by chance. A surgeon treating his cataracts was partnered with the son of another surgeon who was implanting the devices, and he was referred.
Doerr had no reason to believe the shower of fairy dust wouldn’t continue. Second Sight held out promises that the Argus II recipients’ vision would gradually improve through upgrades to much higher pixel densities. The ability to recognize individual faces was even touted as a possibility. In the winter of 2020, Doerr was preparing to travel across the U.S. to Second Sight’s headquarters to receive an upgrade. But then COVID-19 descended, and the trip was canceled.
The pandemic also hit Second Sight’s bottom line. Doerr found out about its tribulations only from one of the company’s vision therapists, who told him the entire department was being laid off. Second Sight cut nearly 80% of its workforce in March 2020 and announced it would wind down operations.
Ross Doerr has mostly stopped using his Argus II, the result of combination of fear of losing its assistance from wear and tear and disdain for the company that brought it to market.
Jan Doerr
Second Sight’s implosion left some 350 Argus recipients in the metaphorical dark about what to do if their implants failed. Skeleton staff seem to have rarely responded to queries from their customers, at least based on the experiences of Perk and Doerr. And some recipients have unfortunately returned to the actual dark as well, as reports have surfaced of Argus II failures due to aging or worn-down parts.
Product support for complex products is remarkably uneven. Although the iconic Ford Mustang ceased production in the late 1960s, its parts market is so robust that it’s theoretically possible to assemble a new vehicle from recently crafted components. Conversely, smartphone and computer manufacturers typically stop issuing software upgrades to their devices after two or three years, eventually rendering them bricks. Consumers have accepted both extremes.
But is the smartphone approach acceptable for a device that helps restore the most crucial sense a human being possesses?
Margaret McLean, a senior fellow at the Markkula Center for Applied Ethics at Santa Clara University in California, notes companies like Second Sight have a greater obligation for product support than other consumer product ventures.
“In this particular case, you have a great deal of risk that is involved in using this device, the implant, and the after care of this device,” she says. “You cannot, like with your car, decide that ‘I don’t like my Mustang anymore,’ and go out and buy a Corvette.”
And, whether the Argus II implant works or not, its physical presence can impact critical medical decisions. Doerr’s doctor wanted him to undergo an MRI to assist in diagnosing attacks of vertigo. But the physician was concerned his implant might interfere. With the latest available manufacturer advisories on his implant nearly a decade old, the procedure was held up. Doerr spent months importuning Second Sight through phone calls, emails and Facebook postings to learn if his implant was contraindicated with MRIs, which he never received. Although the cause of his vertigo was found without an MRI, Doerr was hardly assured.
“Put that into context for a minute. I get into a serious car accident. I end up in the emergency room, and I have a tag saying I have an implanted medical device,” he says. “You can’t do an MRI until you get the proper information from the company. Who’s going to answer the phone?”
Second Sight’s management did answer the call to revamp its business. It netted nearly $78 million through a private stock placement and an initial public offering last year. At the end of 2021, Second Sight had nearly $70 million in cash on hand, according to a recent filing with the Securities and Exchange Commission.
And while the Argus II is still touted at length on Second Sight’s home page, it appears little of its corporate coffers are earmarked toward its support. These days, the company is focused on obtaining federal approvals for Orion, a new implant that would go directly into the recipient’s brain and could be used to remedy blindness from a variety of causes. It obtained a $6.4 million grant from the National Institutes of Health in May 2021 to help develop Orion.
Presented with a list of written questions by email, Second Sight’s spokesperson, Dave Gentry of the investor relations firm Red Chip Companies, copied a subordinate with an abrupt message to “please handle.” That was the only response from a company representative. A call to Second Sight acting chief executive officer Scott Dunbar went unreturned.
Whether or not the Orion succeeds remains to be seen. The company’s SEC filings suggest a viable and FDA-approved device is years away, and that operational losses are expected for the “foreseeable future.” Second Sight reported zero revenue in 2020 or 2021.
Moreover, the experiences of the Argus II recipients could color the reception of future Second Sight products. Doerr notes that his insurer paid nearly $500,000 to implant his device and for training on how to use it.
“What’s the insurance industry going to say the next time this crops up?” Doerr asks, noting that the company’s reputation is “completely shot” with the recipients of its implants.
Perk, who made speeches to praise the Argus II and is still featured in a video on the Second Sight website, says he also no longer supports the company.
Jeroen Perk, an investigator for the Dutch customs service, cried for joy after partially regaining his sight, but he no longer trusts Second Sight, the company that provided his implant.
Nanda Perk
Nevertheless, Perk remains highly reliant on the technology. When he dropped an external component of his device in late 2020 and it broke, Perk briefly debated whether to remain blind or find a way to get his Argus II working again. Three months later, he was able to revive it by crowdsourcing parts, primarily from surgeons with spare components or other Argus II recipients who no longer use their devices. Perk now has several spare parts in reserve in case of future breakdowns.
Despite the frantic efforts to retain what little sight he has, Perk has no regrets about having the device implanted. And while he no longer trusts Second Sight, he is looking forward to possibly obtaining more advanced implants from companies in the Netherlands and Australia working on their own products.
Doerr suggests that biotech firms whose implants are distributed globally be bound to some sort of international treaty requiring them to service their products in perpetuity. Such treaties are still applied to the salvage rights for ships that sunk centuries ago, he notes.
“I think that in a global tech economy, that would be a good thing,” says McLean, the fellow at Santa Clara, “but I am not optimistic about it in the near term. Business incentives push toward return on share to stockholders, not to patients and other stakeholders. We likely need to rely on some combination of corporately responsibility…and [international] government regulation. It’s tough—the Paris Climate Accord implementation at a slow walk comes to mind.”
Unlike Perk, Doerr has mostly stopped using his Argus II, the result of combination of fear of losing its assistance from wear and tear and disdain for the company that brought it to market. At 70, Doerr says he does not have the time or energy to hold the company more accountable. And with Second Sight having gone through a considerable corporate reorganization, Doerr believes a lawsuit to compel it to better serve its Argus recipients would be nothing but an extremely costly longshot.
“It’s corporate America at its best,” he observes.
