Revisionist History - The Obscure Virus Club

Episode Date: August 22, 2019

Throughout the 1960s, a biologist named Howard Temin became convinced that something wasn’t right in science’s understanding of viruses. His colleagues dismissed him as a heretic. He turned out to be right — and you're alive today as a result.  Season Four ends with a bedtime story about how we should be freed by our doubts, not imprisoned by them. Learn more about your ad-choices at https://www.iheartpodcastnetwork.comSee omnystudio.com/listener for privacy information.

In the second half of the 20th century, a group of scientists became obsessed with an obscure family of viruses. There weren't many people in the Obscure Virus Club. They all knew each other. The rest of the world rolled its eyes at them. Read the letter. Okay. Dear Bob, I regret that your paper on the T-cell retrovirus

is not acceptable for publication in the Journal of Virology. Exhibit A in the archives of the Obscure Virus Club, a rejection letter. I completely agree with reviewer number one. There's little point in perpetuating this controversy about the presumed viral nature of this material. Not, thank you very much, this is fascinating, but you're not quite there yet. Just, no. I hope you understand we can only accept definitive data to resolve this question. Therefore, I have no alternative

but to reject this paper outright and advise you we cannot consider the present manuscript in any form. In any form. If you were in the Obscure Virus Club, you got this a lot. It didn't stop them. Thank God. My name is Malcolm Gladwell. You're listening to Revisionist History, my podcast about things overlooked and misunderstood. This is the final episode of Season 4, a season of Jesuits and lawyers and gangsters and disputatious musicians, iconoclasts and skeptics. And I want to finish with the story of the Obscure Virus Club, maybe the biggest band of iconoclasts of all.

This is a bedtime story for this season of Revisionist History. And as with any story, you have to wait till the very end to understand what it's all about. The Obscure Virus Club had adjunct members, honorary members, hangers-on, but I want to focus on the three people at its core. Ludwig Gross, Howard Temin, Robert Gallo. Bob Gallo is the only one still alive, 82 years old, still at the office every day. He has pictures of his old compatriots on his walls. I think he sent this to me.

Oh, there he is. His wife, yeah. Oh, yeah, yeah, yeah. This is just, you know, an unforgettable character. But that captures him, you know? Yeah. First, Ludwig Gross, head of cancer research for the Veterans Administration in the Bronx.

Gallo remembers asking him whether he wanted to get rich. Gross told him, no, he had everything he needed, and he counted it off. First, he had his car. He'd escaped Poland in his car after the Nazis invaded. He drove everywhere. When he came to see me at NIH, he drove from New York. His first experiments were in the backseat trunk of his car. So he said, number two, I have my television, I can see Perry Mason. He was a Perry Mason addict. Number three, I have my work.

And number four, I have my wife. That's Ludwig Gross. At scientific meetings in the 1950s, people wouldn't sit next to Ludwig Gross. Everyone thought he was crazy. Next came the ringleader of the obscure virus club, Howard Temin. The remarkable Howard Temin.

Wait, can you do the invitation? I can do it right now. Get self-conscious. Vernon, where are the controls? You don't have any damn controls and you're making too many claims. With the hair like you, the same hairdo. Howard Temin, Ludwig Gross, Robert Gallo. And what did they have in common? I mean, what's in common is we got pissed on. We all had our time of horror, I would say. Three scientists shunned by their peers. That was the price of admission

to the Obscure Virus Club. In 1911, a young physician named Francis Payton Rouse set up a cancer research laboratory in New York at what is now Rockefeller University. A woman came to see Rouse. She had a poultry farm just outside the city, and she brought with her a hen with a large lump on its chest. The lump was cancer,

a sarcoma, that is, a tumor of the connective tissue. We don't know why a cancer doctor would be curious about a dying chicken, but he was. Rouse removed the tumor, ground it up, mixed it with saline solution, and injected the solution into healthy chickens. And what happened? The healthy chickens developed the same tumors. Rouse was perplexed. Cancer is not supposed to be a communicable disease. It's caused by a malfunction of the genetic machinery inside a cell.

It can't be passed from one person to another like the flu. But this is exactly what seemed to be happening. The chicken's tumor, Rouse concluded, had to be caused by a virus. People didn't believe him. They said, well, maybe that tumor isn't really cancer. Or, so what? This is just some weird thing that happens with chickens. Rouse got discouraged.

He stopped working on viruses entirely. Years later, this same problem, whether cancer could spread like a virus, came to obsess Ludwig Gross. He worked with mice. Sometimes mice came down with leukemia, murine leukemia, which is a lot like human leukemia. Gross bred mice to show how the disease was communicated from one generation to the next. He became convinced that the leukemia was caused by a virus passed from mother to offspring. But the same thing happened.

Other scientists didn't believe him. Here was this strange émigré in the Bronx imagining cancer-causing viruses in mice. Why couldn't that just be a set of faulty genes being passed down? He proved it was an oral disease. Everybody said, oh, you know, that his cages are filthy and there's no technology whatsoever. He doesn't know, you know, really what he's doing.

You know, it was all bad, bad mouth completely, essentially virtually destroyed. Gross finally won the Lasker Award, one of the most prestigious prizes in medicine, in 1974, when he was 70. In the obscure virus club, you often had to wait your entire career for validation. After Gross comes Howard Temin, the remarkable Howard Temin. Temin was the second of three sons of a lawyer and an activist from Philadelphia. The biologist David Baltimore met Temin

when they were both part of the student summer program at the Jackson Laboratory in Maine. If you had a question or there was a lecture and you didn't understand something, you could go to Howard, and Howard knew everything. He was an amazing intellect. And so I spent the summer, in a sense, as his student. He was famous at Swarthmore, actually, because they said he had read every book in the

library and they had to buy more for him. I mean, I wasn't the only one to notice that there was something very special about him. This is the kind of person he was. Temin donated his bar mitzvah money to a refugee camp. Years later, when he visited the Soviet Union, he smuggled in Hebrew prayer books. I met Temin once, when I was a cub reporter for the Washington Post. I happened to be in Madison, Wisconsin, at the University of Wisconsin, where he taught his whole career. I went to see him. I don't remember the specifics of what he talked about, and I've lost my notes. What I remember with absolute clarity is the feeling I had after leaving his office, which is that I had never met someone so completely in command of his own thinking.

I've only ever gotten that sense of command, of mastery, from watching great athletes. Never biologists with squeaky voices. Temin's wife, Rayla, says that when Temin first got to Wisconsin, he would sit in on seminars in other departments. And as soon as he got here, he drew attention of people because he would sit up in the front and then he would ask the most pointed, brilliant, important questions of the speaker. So everyone said, well, who is he? Who is he? But once you met Howard Temin, you remembered Howard Temin. One of his former graduate students, Sandy Weller, says she could barely keep up with him.

He rode his bike to work every day. He never took the elevator. If he had to go to the ninth floor, he walked nine floors. And several times he made me do that, or he just assumed I would do that with him if we were going up to the seminar on the ninth floor. Temin could have done anything, walked into any field in science and left his mark. But he became obsessed by the chicken tumor that Peyton Rouse had discovered 50 years earlier, now known as Rouse sarcoma virus. And so what I was interested in doing was understanding how that virus causes cancer.

That's Temin in an oral history taken a few years before his death. In the 1950s, you could not have picked a more obscure topic to study than a cancer virus. People were still avoiding Ludwig Gross at conferences. The University of Wisconsin had a virology position open at their cancer institute. No one wanted it. You said when you came to Wisconsin that the virology position had been offered to several people and they hadn't been interested. How come these people had turned down the position?

Viruses at that time were not considered very important in cancer research. They had always been a sideshow for cancer research. His first office at Wisconsin was in the basement next to the sump pump. And my office was in what had been a transfer room, a little isolated room about the size of just where you're sitting, a couple of square feet. But none of that mattered. Temin was hooked. Rouse's sarcoma was a weird, enthralling puzzle. He began to notice all kinds of anomalies. For example, sometimes the virus would mutate, it would take on a strange new shape, and then afterwards, the cell it infected would take on the same strange shape.

As if the virus weren't just occupying the cell it infected, the way, say, a flu virus does. The flu just sits inside your cells, multiplying until your immune system drives it out. The flu is a squatter. But Roussarkoma seemed like it was conquering the cells it was infecting, inserting its own genetic information into the DNA of its host. How it did that made no sense. At the time, the field of genetics had something scientists called the central dogma. The central dogma held that genetic information only moved in one direction. DNA gave instructions to RNA, whichoussarcoma was an RNA virus. According to the central dogma then,

it was impossible for it to insert its genetic information into the DNA of the cells it was infecting. RNA didn't move in that direction. We knew the basic lifestyle of most viruses, but now the cancer-inducing viruses stood out as different then and hard to understand. David Baltimore again. What was different and hard to understand about them? Well, the fundamental thing was that they had RNA as their genome, and yet they were able to establish a permanent position inside the cell and run the cell. So he turned it from a normal cell to a cancer cell. And so here it was behaving a bit like DNA, and yet it

was an RNA virus. And that didn't make sense. Howard had been driven by that question for ten years previously. David Baltimore watched his old friend Howard Temin stand up at conferences and try to convince everyone else to take this weird anomaly seriously. Why did that question assume such importance for him? Well, because he was thinking 24 hours a day about these viruses. As he obsessed over the puzzle of Rouse's sarcoma,

Temin decided it could only mean one thing. The central dogma must be wrong. One of the fundamental facts about human genetics, taught in every science textbook and every science classroom in the world, had to be in error. There must be a class of viruses like Rouse's sarcoma virus that could somehow work backwards from RNA to DNA. It was as if he said, yes, the Earth rotates around the sun in an anticlockwise manner. But the only explanation for what I'm seeing with Rouse is that, on occasion, the Earth must stop and go clockwise. And then he spent about 10 years at

University of Wisconsin trying to find an experiment that would convince anybody else of that. And he couldn't. Temin had an intuition, a hunch, but no one was going to overturn the central dogma because some guy from

Wisconsin had a hunch it wasn't right. Science is a social process. People within a field are in constant contact. They share notes. They gossip. They compete for the brightest graduate students, for grant money, for prizes. When you say something that the group doesn't believe,

you pay a price. And with every year that passes, with you saying one thing and the group saying another, the price gets higher. First of all, people thought he was crazy. I mean, he didn't prove his theory for six years after proposing it. Temin's former graduate student, Sandy Weller. And that six years was a very difficult period for all of his students.

And for him, he was a pariah. They thought his students were nuts for working with him. At one point, Howard Temin wrote Francis Crick, Sir Francis Crick, Nobel Prize winner of Watson and Crick, the co-discoverers of DNA, the authors of the central dogma itself. Temin writes Crick a letter gently suggesting that an amendment to the central dogma might be in order. Crick writes back. Very condescending, arrogant letter. Well, I'm sure you think this is true, but you must realize you're wrong.

And to talk like that to Howard, to me, that's just such a... Most people would have given up, but he doesn't, because he's Howard Temin. The word that comes to mind is righteous, which has a negative tone to it. I don't mean to be negative. This is Temin's daughter, Miriam. But he has a strong moral compass and was an incredibly, incredibly confident person, was blessed with that, and so was not shy about speaking his mind. Yeah. Where do you think the, what was the source of his confidence? That's what I asked my uncle, Michael Temin,

the source of his stick-with-it-ness was, and his answer was, well, he knew he was right. And then one day in 1970, he came home to his wife, Rayla, full of excitement. He was going to be away on our anniversary, which was May 27th. And he was explaining why he had to leave and that we would celebrate later. I said, well, that's fine, that's fine. And he said that actually he had something that was a bombshell that he was going to announce at the meeting, but he couldn't tell me what it was.

She said, let me guess, you found it. He nodded. After years of trying, Temin had located the part of the virus that enabled it to work backwards. And by an incredible stroke, his old friend David Baltimore had found it too. By then, Baltimore had fashioned his own equally brilliant career. At almost exactly the same moment, the two old friends independently discover a little enzyme

lurking in a distant corner of this strange class of RNA viruses, an interpreter, something that speaks RNA and can translate into DNA, so that the virus had a mechanism for inserting its own genetic information into the cells it infected. Temin finds the enzyme in Rouss' sarcoma virus. Baltimore went looking for it in mouse leukemia virus, the same virus that had haunted Ludwig Gross. Temin and Baltimore call it reverse transcriptase. And the class of viruses that had obsessed them all for so long now had a name, retroviruses.

Because by virtue of their onboard translator, they had the ability to work in reverse. How hard was it to find this particular enzyme? Is it trivial? Oh, really? Yeah. It's really the notion of it. Two days of experiments.

Two days? Yeah. So it's just the idea of knowing where to look. Yeah, and what to look for. And what to look for. Right. You have to design, very specifically design your search so that it will show up this enzyme. Right.

If you don't look in exactly the right way, you're not going to spot it. Right. Just like that, the great puzzle was resolved. When I got to the point where I knew that the enzyme was in the virus particle, the first thing I did was to call Howard and say, I want to tell you about this. How did he respond? He responded by saying, we're doing those experiments too. Oh, I see. In 1970, Baltimore and Temin jointly publish a famous series of papers in the prestigious

journal Nature. Five years later, they were awarded the Nobel Prize, along with their old teacher, Renato Dalbecco. Temin trades in his two first-class tickets to Sweden for coach seats so he can take along his two daughters. It's always seven when he got the Nobel Prize, and one of the things I remember is that his pants were too long and they were sort of all bunched around the bottom of his socks. At the ceremony? Yes.

Did you go to the ceremony? Yes. Oh, you did? Yes. I kind of remember meeting the king and I definitely remember a banquet. Very, very fancy in this enormous wide staircase where the laureates came down and their spouses all paired with somebody else. So my father had a, I believe, a Danish princess on her arm,

if I'm remembering correctly, in a long pink dress. I remember that. And my mother was escorted by some lesser prince person. And the waiters, you know, all in this procession with the most beautiful food. It was the 75th anniversary of the Nobel Prize, so all previous laureates were invited. There was a huge banquet

in the Golden Hall. By tradition, one representative from each set of new laureates was allowed to speak. Temin was chosen. He stood up with his baggy tuxedo trousers

and his squeaky voice. And he went up to the microphone in front of these 1,200 people and thanked them very, very much for the prize you have given us for cancer research. His wife, Rayla, was sitting in the audience with their daughters. And then Temin said, Here we are, being rewarded for our work in understanding cancer and you're all smoking. The king was smoking. The queen was smoking. Everybody there was smoking. So they were just aghast that he would get up and say that in front of all the royalty.

Did they put out their cigarettes? Yeah, I think many of them did because I was down in the floor on the table. I was sitting next to the Prince of Denmark, was my partner that night. And I looked, and people just looked shocked when he said it. I remember the look on the faces, and then they stubbed out the cigarettes. The story of the Obscure Virus Club could end here. Baltimore and Temin getting their medals from the King of Sweden, then Temin calling out the whole crew for their hypocrisy.

A happy ending. But there's a whole other chapter to come. When David Baltimore and Howard Temin discovered reverse transcriptase and shattered the central dogma, Bob Gallo, the third charter member of the Obscure Virus Club, was still in his early 30s. The son of Italian working-class immigrants, lean, ambitious, raw, a rising star at the National Cancer Institute. He went to a scientific conference in Paris, was stuck in a cab when he looked out the window and saw Howard Temin. He's walking on the streets in Paris like a lost soul. November of 1970, he's now a hero.

Howard the hero. I don't know, window shopping or something. By himself. That just seems different. Yeah. Oh, there you are. I say, yes, there you are. I think sometimes we overestimate the importance of ideas in science.

Yes, you read a paper in Nature, and it changes the way you think about the central dogma. But what is it that really changes the way you think about the central dogma? When you meet the person who challenged the central dogma, and because that person is so remarkable, you realize, oh, I want to be like that. Bob Gallo met Howard Temin and decided then and there to join the Obscure Virus Club. He was a hero to me. When I was a child, it was Joe DiMaggio. Okay, when I was an adult, it was Howard Temin.

So, you know, he was not that much older than me. That's about a decade or so. But no, I couldn't identify with him like that. I just appreciated him a lot. I was just fascinated by him. I was just taken in by it. And I just said, you know, I'm going to listen to every goddamn thing this guy says.

Gallo's specialty was leukemia, cancer of the blood cells. And what drew him to retroviruses was the fact that so many of them were leukemias. Ludwig Gross's mouse leukemia being the first and most famous, but soon people found others. Bovine leukemia, feline leukemia, gibbon ape leukemia, plus chicken and mouse, so five different animal systems, all infectious viruses. What no one could find was a human retrovirus. There was a growing feeling that they simply didn't exist, that maybe humans were somehow protected against this kind of infection.

But Gallo didn't buy it. There had to be one. He decided to focus on a specific subset of leukemia, leukemia that affected the blood cells known as T-cells. At the time, no one knew how to grow T-cells in the laboratory, and if you couldn't grow T-cells, you couldn't find or study anything that infected them. Gallo's lab figured out how to grow T-cells. Then he began searching, and in 1979 he found it, in the blood of a 28-year-old African-American from Mobile, Alabama. Then he began searching, and in 1979 he found it, in the blood of a 28-year-old African American from Mobile, Alabama. Gallo called what he found Human T-Lymphotropic Virus 1, HTLV-1.

It turned out the man's whole family had leukemia too. Gallo then found a man in the Merchant Marines with a history of sexual contacts in Japan and the Caribbean. Same thing. Leukemia and a weakened immune system. In his blood, Gallo could see traces of a virus with that tell-tale bit of reverse transcriptase. A human retrovirus spread by mother-to-child, sexual contact, and blood-to-blood transmission.

Previously unknown, most definitely obscure. Gallo submitted his findings to the Journal of Virology, the leading scientific journal in the field. And what happened? The same thing that happened to Howard Temin and Ludwig Gross. The world wasn't ready to accept the idea of a human retrovirus. The paper was rejected. Gallo keeps that letter on his wall. Dear Bob, I regret that your paper on the T-cell retrovirus is not acceptable for publication in the Journal of Virology, there's little point in perpetuating this controversy about the presumed viral nature of this material. Oh my goodness. Wait, give me the date.

September 15, 1980. September 15, 1980. That's the key fact. Because what's happening in the fall of 1980? It's new, it kills, and it's spreading. Young, previously healthy men were starting to die of a mysterious disease. AIDS, a disease that has medical science baffled. If you did not live through the early days of the AIDS epidemic, you have no idea what it was like.

It leveled the gay communities of major cities around the world. People were wasting away, their skin disfigured by strange lesions. Preachers stood up and denounced homosexuality from their pulpits. Doctors refused to treat gay patients. Public health officials started talking about quarantines. In those early years, I once heard a presentation at a scientific conference from a demographer trying to figure out if AIDS could cause the population explosion in Africa to go into reverse. No one knew what it was or how it spread. It was a mystery, except to the Obscure Virus Club, who thought it looked a lot like the leukemia viruses they had been studying for years. At what point in this process did you say, I think it's a retrovirus?

Wouldn't have gone in and involved in it at all if I didn't think it was a retrovirus. By definition, the day I got in it, I'm thinking it's a retrovirus. The paper by Bob Gallo rejected by the Journal of Virology in September of 1980 was about human T-lymphotropic virus 1, HTLV-1, and the possibility that this strange new retrovirus had found its way into humans. Now, a year later, Bob Gallo looked at AIDS and thought it was behaving a lot like a cousin of HTLV-1. But what led you to suspect it was a retrovirus? Our experience with HTLV-1 and the Leukemia virus. What is that experience?

Blood sex, mother to child. It infected T-cells, check. It caused immune dysfunction, check. It spread from mother to child, check. It spread through blood-to-blood contact or sexual transmission. Check. By 1983, Gallo's lab had isolated and described the AIDS virus and figured out how to grow it in the laboratory.

By 1985, they had developed a test for it. By 1995, there was a class of drugs available to treat HIV that meant the virus was no longer a death sentence. That is an astonishingly short amount of time to detect, understand, and treat a new disease. And why was the progress so fast? Because we had a head start. In the mountains that have been said and written about AIDS, the usual tone is one of

horror at the indifference and incompetence and resistance that greeted the epidemic. All of that is true, but you can also make the case that we got lucky. Not lucky in some ephemeral way, but massively, unequivocally, epically lucky. Lucky because Ludwig Gross insisted doggedly, year after year, that a virus could cause cancer. Because Howard Temin insisted that the central dogma was wrong. Because Temin in Baltimore found a crucial little enzyme called reverse transcriptase. Because Bob Gallo got it into his head that if there were mice retroviruses and chicken retroviruses and cat retroviruses,

there had to be human retroviruses. And then he found a human retrovirus and learned how it worked and learned to isolate it and grow it in the laboratory. And every one of those lessons turned out to be perfect preparation for the most terrifying retrovirus ever known. If HIV arrives as a force 10 years earlier,

what happens scientifically, medically? Disaster. This is David Baltimore again. The worst thing that can happen, and it was proved in the HIV epidemic, is not to know what's causing a disease. Because that gives liberty to fantasy. We could know it was infectious and know it was a virus, but not be able to...

We couldn't find it. Couldn't find it. Remember what David Baltimore said of the experiment in 1970 that led him to reverse transcriptase. It took two days. It was a trivial thing, but only because he knew what he was looking for. If you're faced with a retrovirus

and you don't know what you're looking for, you're lost. You can't find it unless you know it's this particular class of... Right. It was the search for reverse transcriptase in the virus particles that opened up the knowledge that it was a virus that was causing the disease. The world may not have been ready for HIV, but the Obscure Virus Club was. Ludwig Gross died in 1999, at the age of 95, of stomach cancer caused by infection with the bacterium Helicobacter pylori, which he himself had researched. Howard Temin died five years earlier in 1994, at the age of 59, of lung cancer, the obscure kind you can get even if you've never smoked.

Bob Gallo is still very much alive, with pictures of his old friends on the walls of his office. Oh, there he is. His wife, yeah. Oh, yeah, yeah, yeah. This is not long before he died. Oh, he's so young. It was so sad. Yeah, it he is. His wife, yeah. Oh, yeah, yeah, yeah. This is not long before he died. Oh, he's so young. It was so sad. Yeah, it's awful. At Temin's memorial service, Gallo told the story of his first encounter with his friend years before in Paris.

I found a copy of his eulogy. It's like the beginning of a love story. I was in a traffic stall taxi with a few others and we saw Howard walking alone and he was poking his nose in and out of the store windows. He was smiling. He was looking quizzical.

He was the picture of happy boyhood curiosity retained in a man. I think maybe you've been inside of it so long maybe you miss how astonishing it is. Yeah, that's true. That's true. My wife would put it in the mysteries, you know, into something more powerful than you or me or anything else or luck. What if Temin and Baltimore didn't discover reverse transcriptase? There is no field. I would start with that too. I would start here.

What if any of these people, Peyton Rouse, Ludwig Gross, Howard Temin, Robert Gallo, in their pursuit of truth, had been motivated by the expectation of reward? Where would we be? Or if they listened to what others said, as opposed to trusting in what their own experiments revealed. Or if they had only been willing to wander five years in the wilderness, instead of ten. Many of the stories in this season of Revisionist History have come down to the same issue,

how we should act in the world in novel and difficult circumstances, how we should think about what matters for a profession, or think about those who choose a crooked path, or dissent from orthodoxy, or borrow the traditions of others, or engage with someone loathsome. I could go on. But if you are looking for one example to be your guide,

start with this one. The grace and persistence of Howard Temin and the Obscure Virus Club. Thank you for listening to Season 4 of Revisionist History. Every week on Revisionist History, I say the names of the people behind the Revisionist History podcast. And for this episode, I wanted to let you hear them say their names for themselves. This is my team. Nothing would happen without them. Mia Lobel, Jacob Smith, Julia Barton, Flan Williams, Camille Baptista, Luis Guerra. Special thanks to Carly Migliore, Heather Fane, Maggie Taylor, Beth Johnson, Maya Koenig, and By the way, you can hear a longer version of my interview with David Baltimore

on The Solvable Podcast, which Pushkin produces with the Rockefeller Foundation. Revisionist History is brought to you by Pushkin Industries. I'm Malcolm Gladwell.