An Elegant Defense

by Matt Richtel

  17

  Flash Gordon

  In a 1960s Flash Gordon comic, doctors on a spaceship used a wonder drug called interferon to cure a patient on the verge of death. Flash Gordon was fictional. The drug was not. The concept had emerged several years earlier when two scientists, one Swiss and one British, made a curious observation while experimenting with viruses and baby chickens.

  The scientists took a virus from chicken eggs and killed the virus in an acid bath. Then they added this “deadened” virus to another chicken egg and then added live virus. The live virus didn’t grow. The deadened virus had interfered with the development of the live virus.

  Hence the name: interferon (IFN).

  The scientists’ theory was that the healthy cells had picked up a signal from the inactivated virus that deterred growth. Did this mean that some message had been sent blaring: This is an inhospitable environment, so don’t waste resources here? It wasn’t clear how interferon worked, or even exactly what it was.

  Immunology became increasingly enamored with the idea that it might isolate and corral the messaging system. What made this notion so significant is that it entailed using a natural substance to fight disease. The alternative, building medicines around foreign substances, almost invariably provokes side effects because it stimulates interest from the immune system and causes inflammation. Or consider the horror of chemotherapy, in which terrible toxins attack tumors but at the cost of scorching self.

  Imagine if, instead, a harmless dead virus—a wholly natural and innocuous compound—could be harnessed to stop deadly live viruses. The promise inherent in that possibility grew as microbiological technology improved and scientists could see that one of the key properties of interferon was that it prompted the activation of genes that produce chemicals that attack viruses. Also, in the 1970s, it became clear that interferon, identified by now as a protein, had several subtypes. Maybe then it could have broad applicability.

  Indeed!

  There was a period (speeding briefly ahead) during which drugs built around interferon had a market value worth tens of billions of dollars, though it is typically no longer a front-line treatment. Diseases like hepatitis were treated with drugs that entail an injection of interferon in combination with ribavirin. The interferon bolsters the body’s own defenses by sending a message to the immune system to attack the virus.

  But to get to this point (speeding back in time now) required scientists to purify interferon, a key step not unlike the challenge of purifying interleukin. Enter what until this point had been a kind of foreign organism in the world of immunology: a woman.

  Her name is Kathryn Zoon, part of a generation of women shattering gender barriers in science and expanding the definition of “self” in a field long dominated by men. In 1966, at the Rensselaer Polytechnic Institute, Zoon held the distinction of being the only female chemistry major in her class. She was one of only a few women at the prestigious technical school—“a rare bird,” she said. Fellow students seemed largely unfazed, including her future husband. Not always the flummoxed male teachers. “Some of them just wouldn’t even look you in the eye,” she recalled.

  Her merit prevailed. At her graduation, she won the prize for being the top chemistry student.

  By the mid-1970s, the world of science was at last changing. Zoon went on to obtain her PhD in biochemistry at Johns Hopkins in 1976 and then was accepted onto the ninth floor of Building 10 at the National Institutes of Health, where Zoon joined the lab of Christian Anfinsen. It was Anfinsen who had counseled Dr. Dinarello on chemistry techniques to isolate interleukin.

  Dr. Dinarello on the eleventh floor worked with rabbits. For Zoon on nine, the guinea pigs were sheep. Sheep, you don’t keep in the lab. They were housed on a farm in Poolesville, Maryland, about a forty-five-minute drive from Building 10 in Bethesda. It was a veritable zoo, with mice, sheep, monkeys, and, yes, rabbits too. A courier would drive from Building 10 every few days to the farm with a deadened human virus.

  At the farm, vets injected the partially purified interferon into the sheep. Then the vets would withdraw plasma, including white blood cells, from the sheep. The idea was that the sheep plasma included antibodies that had reacted to the interferon, and these antibodies were used in the purification of the interferon. Then once the IFN was pure, Zoon and her colleagues, including collaborators at Caltech, sequenced the interferon.

  It took four years, but in 1980 they released a paper describing the pure form of interferon, allowing the substance to be manipulated, tested, and turned to medicine. Eventually researchers would identify three types of interferon: alpha (A), beta (B), and gamma (G), and then much later, lambda (L).

  The role of these took a long time to fully understand. But it’s worth skipping ahead to fill in the significance and role of the mighty, tiny secretion that is interferon A, a family of twelve related proteins.

  “It’s the first step that our bodies have to deal with a foreign agent, a virus, or a tumor. It’s the first line of defense,” Zoon told me.

  I can sense readers’ puzzled looks, an eyebrow raised over your book or gadget. Haven’t you already read in this book that some other cell or substance is the first line of defense?

  Yes, you are correct to raise an eyebrow. You are not missing something. The thing is, the immune system has multiple overlapping, sometimes redundant first lines of defense, and second lines too. This festival—our take-all-comers cocktail party—is nothing if not chaotic and multifaceted. There also is method to the madness. Multiple actors roam the party, using different tactics, often overlapping.

  Not just that. “A lot of different cell types can make interferon,” Zoon explained.

  Say, for instance, a virus seeps into your nose or slips down your throat. The invader interacts with a healthy cell. That cell detects molecules consistent with a foreign agent. Within that tiny cell, a kind of supercomputer-like process starts that leads to changes in proteins and, in turn, the secretion of alpha, beta, and lambda interferons. Or maybe the cell dies from the invasion, but before it succumbs, it manages to go through the protein changes to create interferon. Other surrounding cells pick up the presence of interferon.

  “This starts a chain reaction,” Zoon explained.

  It can cover an isolated region—say, an organ—or spread through your entire body within just a few hours. Cell after cell begins to pick up the signal and create interferon and other proteins that protect the cell. Once it does so, the interferon, true to its namesake, induces the manufacture of proteins that interfere with the ability of the virus to reproduce itself.

  It comes with a side effect.

  “When interferon is secreted, you feel sick. It causes aches and pains; you feel terrible,” Zoon explained. Your behavior is being modified—not by the virus directly, but by the response. In very practical terms, a virus invades. The early warning system then sets off a cascade that leads to inflammation, and that also makes you feel rotten. Tired, sore, hot, as I described earlier. You are slowed down, and this can have the very beneficial impact of diverting your body’s resources to fighting the virus and not, say, focusing on your job or going for a jog. Your defense system needs your limited energy.

  Your immune system takes care of you partly by making you take care of yourself. And it would be tempting to say without reservation that your feeling rotten is a sign to withdraw and let your body heal. But it turns out the practical side of this is much more complicated. This is where the forthcoming stories of autoimmune sufferers Linda and Merredith become instructive. Sometimes the immune system overreacts, while other times, it is beneficial to push through feelings of sickness to reduce the inflammation. For more on this, stay tuned.

  Their stories become more accessible, more meaningful, with additional core science. Interferon belongs to a broader set of chemicals that prompts immune system action. This set of chemicals informs virtually all of disease, including how we respond to it.

  Meet the cytokine
s.

  A cytokine is a secretion from a cell that prompts action by other immune cells. It is a messenger. It can be sent by an interferon or any of a number of other immune system actors. In the Festival of Life, when a foreign agent bursts into the party, immune cells might send lots of cytokines to one another—pulses of communication.

  This puts a fine point on a major concept in the understanding of the immune system: It has a telecommunications network. Full stop. Our defense network is sending signals across the body. In the case of fever, signals wind up in the brain, at the hypothalamus, a neurological region central to temperature regulation. Then the signal travels through the body, calling on other cells to stimulate a fever. Interferon works in a similar fashion.

  The immune system’s communications network rivals in power, speed, and reach any communications network the world has ever invented. (Take note, Silicon Valley!) The monocytes call out across the body’s galaxy. And do so without wires and across vast distances millions of times greater than the actual cell itself.

  “These telecommunications are essentially wireless. One cell doesn’t have to touch another,” said Dr. Fauci. The system “is plastic, flexible, and enormously complicated.

  “It’s like a supercomputer.”

  It’s worth pausing to think about how far immunology had come since the late 1950s when Dr. Miller discovered that the thymus wasn’t just a waste of space, or God’s throwaway line. The thymus makes T cells. The bone marrow is the origin of B Cells. They flow in the tunnels and vessels that make up the lymphatic system and congregate in lymph nodes and lymphatic tissue. These are like command centers, surveillance hubs where the firefighters are awaiting a call. The T cells, when alerted by dendritic cells, behave as soldiers and generals, spitting out cytokines; the B cells use antibodies to connect to antigens as if they are keys in search of a lock. Macrophages, neutrophils, and natural killer cells roam the body, tasting and exploring, killing. These networks get connected by signals, chemical transmissions, or processes; are spurred on by interferon and interleukin; and can induce powerful side effects, like fever.

  Conceptually, this is the kind of cascade that keeps you healthy. The system goes after parasites and viruses, bacteria and malignancies. It works nonstop, picking up minor threats that we never experience on a conscious level, and midlevel threats that send us to bed, and myriad major threats that might well kill us absent the presence of this system. In an historical sense, I’ve described a complex system—at least compared to what science understood in Dr. Miller’s day.

  The stage was set, through science and the technology that supported it, to discover lots of different molecules and cytokines. Once there were only T cells and B cells, and then suddenly, there was a laundry list of molecules monitoring and policing the Festival of Life. Their individual discoveries came with a revelation about their overall purpose. Some, of course, are involved in identifying and attacking outsiders, but many others monitor our own immune system to make sure that it doesn’t overreact. Together they are the interleukins, known as IL for short. They roam the Festival of Life, checking for outsiders, inspecting each other.

  For example:

  IL-1 induces fever.

  IL-2 causes T cells to grow.

  There’s IL-6. That causes B cells to grow.

  IL-2 and IL-6 are powerful ones, with a twist. The problem with these interleukins is that they can become too abundant, their signals too aggressive. That leads the body to attack with too much ferocity. This is called autoimmunity. Even if you’ve never experienced the dramatic, chronic challenges faced by people like Merredith and Linda, you’ve surely in your own life felt the impact of your immune system firing too aggressively, causing you, for instance, to feel fatigued when you’d be better off getting off the couch and walking, or to experience pain that has no apparent external cause or a hint of fever.

  If left unchecked, the threat from autoimmunity is no less than deadly. That’s why our immune system has evolved to have its own system of checks and balances. In fact, many interleukins are designed to be anti-inflammatory. They are immune system brakes, not accelerants.

  In fact, some of the sets of monocyte cells that help fuel inflammation also have subsets that dampen inflammation. For example, we now know that the IL-1 family has dozens of members, of which many are anti-inflammatory. At least a third of the variations of this key principal immune system protein are designed to stop the immune system from inflaming.

  “Before antibiotics, these inflammatory cytokines helped kill off infection,” Dr. Dinarello says, and the cytokines still play that role. How do the cytokines know to turn off? What happens if they don’t turn off? “If you fail to make anti-inflammatory cytokines, you die of mild inflammation.”

  That’s how powerful this system is. Mild inflammation, wholly unchecked, can kill. Dinarello likes the analogy that the immune system has turned the body into a police state. “You need inflammation to protect against invaders. You need policemen. But if police get too rambunctious, they cause damage and kill innocent people.”

  The discovery of all these proteins provides evidence of what Dr. Fauci told me so eloquently about the immune system. It’s a supercomputer.

  Dr. Fauci was poised to redefine its purpose.

  18

  The Harmonious Way

  The year was 1980, and Dr. Fauci was a rising star, eventually one of the brightest lights in immunology. Since 1972, he’d been on a quest to figure out how to deal with what he calls “aberrant” immune system responses. He meant situations in which the immune system attacks the body.

  He’d done extensive pioneering work on medicines that help dampen the immune system when it attacks the body. “We had to calm down the immune system by suppressive agents without necessarily suppressing it so much they were susceptible to infection,” he said.

  During this period, Dr. Fauci hadn’t put so fine a point on it, but he was helping define a new identity for immunology. For many years, the field had viewed the immune system as something poised to “attack, seek, and destroy.”

  Dr. Fauci could see that this was just half of the equation—in fact, well less than a full definition.

  At its core, what the immune system was doing wasn’t simply seeking and destroying. Instead it was looking for a balance—between attacking and neutralizing real dangers and showing sufficient restraint such that its potency didn’t destroy the body. In 1980, Dr. Fauci helped capture this pivot in immunology by naming a new lab at the NIH. He called it the Laboratory of Immunoregulation.

  Mark the moment. The story of the immune system became the story of homeostasis—a state of harmony or stability. This is what makes our defense so elegant. It is a system precisely and delicately tailored to stay in balance, keep the peace, and do as little damage as possible to us and our surroundings.

  This balance is central to our health, as you’ll see momentarily in the lives of four individuals you’ll soon meet again—Bob, Linda, Merredith, and Jason.

  First, though, I will introduce you to three wise men and a discovery that turned the science of immunology into healing medicine. This was the point of practicality for the long-opaque world of immunology, a turning point where the decades of science became lifesaving treatment.

  19

  Three Wise Men and the Monoclonal Antibody

  “It’s a story that revolutionized science and medicine,” writes Dr. Sefik Alkan, a Turkish-born immunologist and historian. The discovery is now used in diagnosis and treatment of the pantheon of diseases “from rheumatoid arthritis to cancer.”

  Now we’re getting close. The pieces are coming together, the exploration leading to application, to real-world solutions. None, arguably, was as significant as the discovery of the monoclonal antibody. This next scientific treasure likely will touch every reader at some point, if not directly, then through a family member. So it’s useful to grasp this piece to understand what might someday be injected into your body to exten
d or save your life.

  The story starts like this: A Dane, an Argentinian Jew, and a German walk into a research lab . . .

  The first of the three wise men was Niels Jerne, a Danish immunologist who was among the elite thinkers of his era and the founder of the Basel Institute for Immunology. “In his office,” Alkan writes, “there was a long table adorned by dozens of scientific journals; all were being read regardless of language (English, Dutch, Danish, French, and German).”

  Jerne had created a way to isolate and count antibodies.

  The discovery here is referred to as the Jerne plaque assay. From the University of Windsor website, I’ll draw the first few steps in what I think of as a kind of recipe—a dip of the toe into the complexity of immunology—and then I’ll just summarize the darn thing and its meaning.

  Put 2.0 ml of Hank’s balanced salt solution (HBSS) in a small mortar and cool it in an ice bath.

  Kill the mouse with an overdose of ether by placing the mouse in a small jar with an ether-soaked cotton swab and replacing the lid.

  Remove the dead mouse from the jar, put it on a paper towel, swab the abdomen with 70% ethanol, and cut open the abdomen. Cut out the spleen and make sure that excess fat and tissue are removed. . . .

  Put the spleen in the 2.0 ml of cold HBSS and cut it into small pieces. Grind these small pieces with the pestle until an even cell suspension is formed.

  Filter the suspension through a cheesecloth that has been placed in a small funnel. This will remove any large clumps of cells. Flush the few remaining trapped cells from the cloth with 5.0 ml of cold HBSS.

  You get the idea of its complexity (which eventually involved a centrifuge; more salt baths; mouse spleen cells, having been washed, put onto slides, sealed with paraffin wax, then incubated; and finally, the viewing of the results under a microscope).