Tools & Technology

The Mouse That Changed Science

A tiny animal with a big story.  

Episode 236 | November 16, 2018

The Mouse that Changed Science: A Tiny Animal With a Big Story by Distillations: Science + Culture + History

In April 1988 Harvard University was awarded a patent that was the first of its kind. U.S. Patent Number 4,736,866 was small, white, and furry, with red beady eyes. His name was OncoMouse.

The mouse, genetically engineered to have a predisposition for cancer, allowed researchers to study the disease in an intact living organism. It promised to transform cancer research, but not everyone was happy. Most critics were wary of patenting life forms at all. But academic scientists were also worried about the collision of commercial and academic science. It forced them to face difficult questions: Who should pay for science? Who does scientific knowledge belong to? And should science be for the good of the public or for profit?

Credits  |  Research Notes  |  Transcript

Credits

Hosts: Alexis Pedrick and Elisabeth Berry Drago
Senior Producer: Mariel Carr
Producer: Rigoberto Hernandez
Reporter: Jessie Wright-Mendoza
Photo illustration by Jay Muhlin
Additional audio production by Dan Drago
Additional music courtesy of the Audio Network.

Research Notes

Interviews

Elizabeth Popp Berman, Associate Professor of Sociology, SUNY Albany, and author of Creating the Market University: How Academic Science Became an Economic Engine.
David Einhorn, House Counsel, Jackson Laboratory.
Harold Varmus, Professor of Medicine, Weill Cornell Medicine.
Ken Paigen, Executive Research Fellow and Professor, Jackson Laboratory.

Sources

Adler, Jerry. “The First Patented Animal Is Still Leading the Way on Cancer Research.” Smithsonian Magazine, December 2016.

Chakrabarty, Ananda. Microorganisms having multiple compatible degradative energy-generating plasmids and preparation thereof. U.S. Patent 4259444A, filed June 7, 1981, and issued March 31, 1981.

Diamond v. Chakrabarty, 447 U.S. 303 (1980).

Fortune Names Its ’88 Products of the Year.” Associated Press, November 17, 1988.

Hanahan, Douglas, Erwin Wagner, and Richard Palmiter. “The Origins of Oncomice: A History of the First Transgenic Mice Genetically Engineered to Develop Cancer.” Genes and Development 21 (2007), 2258–2270.

Leder, Philip, and Timothy Stewart. Transgenic non-human mammals. U.S. Patent 4736866A, filed June 22, 1984, and issued April 12, 1988.

Leonelli, Sabina, and Rachel Ankeny. “Re-Thinking Organisms: The Impact of Databases on Model Organism Biology.” Working paper, University of Exeter, April 5, 2011. Published in Studies in History and Philosophy of Science Part C 43:1 (2012), 29–36.

Morse, Herbert C. III, ed. Origins of Inbred Mice. New York: Academic Press, 1978. Google Books.

Murray, Fiona. “The Oncomouse That Roared: Resistance and Accommodation to Patenting in Academic Science.” Working paper, Massachusetts Institute of Technology, 2006. Published in American Journal of Sociology 116:2 (2010), 341–388.

National Association for Biomedical Research. “Mice and Rats.” Mice and Rats. Washington, DC, 2018. nabr.org.

National Museum of American History. “OncoMouse.” Washington, DC, 2018. americanhistory.si.edu.

Palmer, Brian. “Jonas Salk: Good at Virology, Bad at Economics.Slate, April 13, 2014.

Rader, Karen. “The Mouse People: Murine Genetics Work at the Bussey Institution, 1909–1936.” Journal of the History of Biology 31:3 (Autumn 1998), 327–354.

Russell, Elizabeth. “Origins and History of Mouse Inbred Strains: Contributions of Clarence Cook Little.” Jackson Laboratory, Bar Harbor, Maine. informatics.jax.org.

Schneider, Keith. “New Animal Forms Will Be Patented.” New York Times, April 17, 1987.

Specter, Michael. “Can We Patent Life?New Yorker, April 1, 2013.

Archival Sources

Achbar, Mark, and Jennifer Abbott, dir. The Corporation. Canada: Big Picture Media Corporation, 2003.

Albert and Mary Lasker Foundation. “Lasker Archives: Passion and Optimism in Scientific Research.” April 9, 2017, laskerfoundation.org. On the 1987 Albert Lasker Basic Medical Research Award.

Murrow, Edward. See It Now (Jonas Salk). CBS, April 12, 1955. paleycenter.org

Potter, Deborah, and Dan Rather. “Animal Patents.” CBS Evening News, April 12, 1988.

Ronald Reagan Presidential Library. “Candidacy for Presidency: Ronald Reagan’s Announcement for President of U.S.” November 13, 1979. youtube.com.

Transcript

The Mouse that Changed Science

Today the job of building this nation geographically is completed. There are no new frontiers within our borders. So to what new horizons can we look now? Where are tomorrow’s opportunities? What’s ahead for you? For your children? The frontiers of the future are not on any map. They are in the test tubes and laboratories of the great industries.

Alexis: Hello, and welcome to Distillations, a podcast powered by the Science History Institute. I’m Alexis Pedrick.

Lisa: And I’m Lisa Berry Drago.

Alexis: Each episode of Distillations takes a deep dive into a moment of science-related history in order to shed some light on the present. Today we’re talking about a small animal that became a big story.

And a big controversy in the 1980s.

<1988 CBS news clip>

Something really new today from the U.S. Patent Office for the first time a patent for an animal.

Alexis: Chapter One. Patenting Life.

Lisa: In April 1988, Harvard University was awarded a patent that was the first of its kind. Patent Number 4,736,866 (Four million, seven hundred thirty-six thousand, eight hundred and sixty-six) was small, white, and furry. With little red beady eyes. His name was OncoMouse [ONKO-mouse].

< 1988 CBS news clip>

CBS Host: The inventors didn't build a better mouse. They changed one genetically in the lab. Deborah Potter reports on the latest Future Shock Over money medicine and ethics and whose life is it anyway.

CBS Reporter: Scientists at Harvard University genetically altered the mouse by adding cancer genes to make it more sensitive to cancer causing substances. It will be used along with its offspring to test new drugs.

Alexis: Mice and rats are ubiquitous in biomedical research labs throughout the world. They account for 95% of the animals used in scientific research. They’re really important tools for science, but they’re not necessarily that exciting. But this mouse, this mouse was different. This mouse was special. In 1988 it was on Fortune Magazine’s “product of the year” list -- alongside E.T. on videotape, Rogaine, and the personal fax machine.

Lisa: OncoMouse was transgenic. This genetic engineering made it predisposed to getting cancer. And it also ensured that it would pass those cancer genes on to its offspring. Cancer researchers really needed this mouse. They needed to study cancer in an intact living organism—rather than just cell lines in petri dishes.

Alexis: The mouse was developed by molecular geneticist Phil Leder with help from Harvard researcher Timothy Stewart. And also funding from DuPont, the company that brought us Teflon and Kevlar. Phil Leder had already made significant contributions to understanding the genetic basis of cancer and he developed OncoMouse specifically to model the behavior of breast cancer in humans. He was optimistic about how the mouse would advance cancer research.

<Back to news clip>

Phil Leder: For the first time there is hope for mankind that some of the age- old scourges can be treated.

CBS Reporter: But critics say that patenting lab animals is just a first step toward allowing scientists to play God.

Critics: The whole range of the animal kingdom is now open to anybody who can afford a patent application for genetic altering of animals for whatever purpose.

CBS Reporter: The patent office says it’s up to Congress to resolve the dispute over where to draw the line. As the law stands now, the only animal that can’t be patented is a human being.

Lisa: OncoMouse was the first mammal to be patented. But it wasn’t the first life-form to be patented. That happened seven years earlier, in 1981.

Justice Burger: We will hear arguments next in Diamond, Commissioner of Patents v. Chakrabarty.

Wallace: Mr. Chief Justice, and may it please the Court. The question before the court in this case is whether a living organism is patentable subject matter under Section 101 of the patent law.

Alexis: Diamond versus Chakrabarty was a Supreme Court case that opened the door to patenting lifeforms. It all started with bacteria.

Lisa: Oil-eating bacteria, to be exact. Microbiologist Ananda Chakrabarty [CHA-krah-BAR-tee] was working for General Electric when he developed a bacteria that could break down crude oil—making oil spill clean-ups a lot easier. He applied for a patent for it, but he was turned down by the U.S. patent office, on the grounds that this bacteria was a product of nature. But the case went all the way to the Supreme Court. And the Supreme Court saw things very differently. Here’s a clip from the 2003 documentary, The Corporation.

The Corporation: And they said this microbe looks more like a detergent or reagent than a horse or a honeybee. I laugh because they didn’t understand basic biology. It looked like a chemical to them. Had it had an antenna or eyes or wings or legs, it would have never crossed their table and been patented. Chief Justice Warren Burger said, sure some of these are big issues but we think this is a small decision. Seven years later the

U.S. patent office issued a one sentence decree. You can patent anything in the world that’s alive, except a full-birth human being.

Alexis: Scientists in the field had quickly recognized that their discoveries could also be commercial products—but only if they had patents.

Lisa: By 1987 the U.S. Patent office decided that they’d start patenting higher level organisms. And they wanted their first pick to be symbolic. So they chose OncoMouse. Because of the ways this little creature could help humanity.

Alexis: Most people who were concerned about OncoMouse were worried about the ethics of patenting life at all. But the academic science community found it alarming for entirely different reasons. Here’s Phil Leder in an interview from 1987.

Leder: What really received a lot of publicity wasn’t the fundamental science that was generated by creating these animal models, but the fact that they were patented and that was grist for a lot of cartoonists mills...It’s both amusing of course and also ominous when you when you think about it…

Interviewer: Well let’s talk about that issue because Leder: Sure

Interviewer: because it’s a controversial issue wherever you come down on it. The fact is the private sector has an enormous amount of control now.

Leder: That’s our system. You know you may like it you may not like it. But that is our system.

Interviewer: But does private sector bring sources bring resources to the table that otherwise would not be?...

Leder: That’s absolutely. Private resources in this case supported the research. They

made the original investment…somebody has to feel that they can get a return on this.

Alexis: The story we’re going to tell you today is about this tension. Between commercial and academic science.

Lisa: Patenting OncoMouse set in action a chain of events that fundamentally changed academic science. It changed how academic scientists did science. And it forced them to face difficult questions, like who should pay for science? And who does scientific knowledge belong to? And should it be for the good of the public, or for profit?

Alexis: Jessie Wright-Mendoza has been reporting on this story for Distillations, and she’s going to take it from here.

Lisa: Chapter Two. Who Patents?

Jessie: In the world of commercial science patenting was—and still is—the norm. So patenting OncoMouse was a no-brainer for DuPont. But in academic science patenting was not the norm. Which isn’t to say that academic science didn’t have its own kind of reward system. It did. It was publishing. Which put your work in the spotlight and gave it—and you—validation. Again, here’s Phil Leder:

Leder: What you work for in this business is perhaps as the most valuable reward is the grudging appreciation of a few colleagues who really understand what you're doing.

Jessie: Beth Berman is an associate professor of sociology at SUNY Albany. She wrote a book called,

Creating the Market University: How Academic Science Became an Economic Engine.

Beth Berman: Historically things had not necessarily been patented. So like the polio vaccine for example was notoriously not patented.

< 1952 archive audio>

Edward R. Murrow: Who owns the patent on this vaccine?

Jonas Salk: Well, the people I would say. There is no patent. This is...could you patent the sun? [Laughs]

Beth Berman: And Jonas Salk said how could you patent the sun? That it would just be completely inappropriate to patent something that was a scientific discovery that was meant to share and so that idea of openness was really in conflict with the idea that you would patent something and then use it to make money off of.

Jessie: The polio vaccine wasn’t alone. Penicillin was also intentionally not patented for ethical reasons. So that it could be accessed by as many people as possible.

Jessie: When OncoMouse was patented it really threw one particular group of academic scientists who were especially invested in lab mice.

Alexis: Chapter Three: The Mouse Club.

Pinky and the Brain: “They’re Pinky and the Brain! They’re Pinky and the Brain! One is a genius, the other’s insane. They’re laboratory mice! Their genes have been spliced!”

Alexis: This story is about how OncoMouse disrupted science. But within it there’s a small story and a big story. Now the small story is about how it affected a little group of scientists called mouse geneticists. Scientists who develop mouse models and use them to study illness. These scientists were a subset of the larger genetics community and they stuck together. They even had a club—The Mouse Club of America. Now that’s right. The Mouse Club. And they had a newsletter: “The Mouse Club

Newsletter” that shared information on mouse strains and mouse happenings. You get the point.

Lisa: Mouse club was an established group with an established culture. And it all started at the beginning of the 20th century when the field of genetics was brand-new. Most research was done on plants, flies, and mice. If you wanted to study with mice, there was really one place you could do it – the Bussey Institute at Harvard, where zoologist W.E. Castle trained most of the first generation of mouse

geneticists. Castle’s program was always short on time, money, and mice, so the early mouse men

learned to share resources, including mice. When Castle’s students went off to start their own programs at other institutions, they carried this ethos of openness and sharing with them. It became part of the culture. Something else that was part of the Mouse Club culture was that they didn’t patent their mice. But OncoMouse changed everything.

Ken Paigen: The culture of the research community in the mouse genetics world was that if you had a mouse that had been genetically constructed once you had published the first description you were obligated by custom to distribute that mouse to anybody else who asked for it and people did that very freely. So there was a completely open exchange of mice among laboratories. And that worked.

Jessie: Ken Paigen is a research scientist at Jackson Laboratory in Bar Harbor Maine. Jackson Labs, or JAX, as it’s known, is an institution in the world of mouse genetics. For nearly a century, the lab has developed and distributed specialized mice for biomedical research. Today, mice from JAX go out to over 60 countries, to virtually every major research institution in the world.

David Einhorn: I’m David Einhorn. I was the House counsel for the Jackson Laboratory for about 23 years, I’m now retired. If I may add, if I may add on Ken, he’s still a very active researcher at the lab despite the fact that he’s passed 90 years old.

Jessie: Ken Paigen became the director of Jackson labs in 1989. About a year after Harvard was granted the OncoMouse patent. He didn’t know it then, but the lab was about to get swept right into the middle of the controversy over OncoMouse.

Jessie: Before I go any further I want to talk a bit more about the history of model mice and why they’re so crucial to science.

Ken: Well the primary mammalian model that we have as a surrogate for human research has been the laboratory mouse. All mammals have very similar structures to their genomes. Their basic compliment of DNA. And since it’s so difficult to do so many experiments if not morally impossible to do them in human beings we need some animal surrogate that can serve as a substitute.

Jessie: A mouse model is a representation of a human disease or illness. Just like an architectural model is a representation of a building. It’s really the only way for researchers to observe how diseases act in a living being. You can do similar studies on the cellular level, but cells don’t really have a lifecycle like a human do. But a mouse is born and goes through stages of development. It reproduces and has babies. It ages just like we do. So a researcher can see how cancer cells, for example, how they behave, what activates them. And where, how, and why they spread to other parts of the body.

Jessie: The first mouse models for research were created by selectively inbreeding mice to create a colony that all shared the same trait. Jackson Lab was founded in 1929 by CC Little. He had studied under W.E. Castle at the Bussey Institute. At that time mouse models were made through selective inbreeding, or they were spontaneous mutants. These were mice born with some kind of abnormality. Tumors for example. They would be separated from the colony and bred to create a new colony of mice to share that mutation. The whole process was pretty hit or miss. Researchers usually had to bread multiple generations before that mouse family would reliably display that desired characteristics. Most

scientists aren’t particularly interesting in moonlighting as mouse breeders, but sometimes it’s necessary. Phill Leder created OncoMouse because he wanted to study a particular type of cancer. The mouse he needed didn’t exist, so he made it. But maintaining mouse colonies is extremely time consuming and expensive. That’s where JAX comes in. CC Little realized he could make a business out of making, caring for and distributing mice to other scientists. And that business could underwrite the research of Jackson Lab scientist.

Ken: It’s really a problem to maintain a colony…if you have a mouse which is popular and is needed in large numbers around the world… it’s difficult to do it from an individual research lab. And so over time the custom had become for people to deposit their mutants, their mice here at Jackson Lab and then we would serve as the central distribution facility for the rest of the world. That relieved the individual researcher of the problem of maintaining shipping conditions, health status and all the rest of it.

Jessie: Scientists doing biomedical research need laboratory mice, and the mouse genetics community was built on the sharing of mouse models. They can get them from the repository at JAXS or get a breeding pair from another researcher. In 1947 JAXS was devastated when a fire swept through the town of Bar Harbor. Tens of thousands of mice were lost in the blaze. Within days scientists from around the country started sending breeding pairs that had come from Jackson’s own stock. That’s just how the community worked. So the patenting—and subsequent restricting of OncoMouse—a very hard pill to swallow. Harold Varmus is a Nobel Prize-winning cancer researcher who also worked with model mice.

Harold Varmus: It would never have occurred to me that that I should provide any kind of protection of that property. I didn’t think it was property. I thought of it as the creation of mouse strains that others might use to try to understand how these genes work and how breast cancer arises. It was a research tool.

Jessie: The OncoMouse patent made it difficult to obtain what was a crucial research tool for mouse geneticists and other scientists. For one thing, the mice were expensive—$50 a piece as opposed to $5 from JAXS or free from a colleague. Many researchers felt like the carpet had been swept from under them.

Alexis: Maybe it seems like this shouldn’t have been such a big deal. I mean it’s just the Mouse Club, right? Why are we even talking about this?

Lisa: It seems like that. But for them it was a huge paradigm shift. It completely changed how they had to work. Also, they have kind of a silly name, but the Mouse Club equals Cancer Research. And I think we can all agree that that’s important. And patenting OncoMouse slowed that down.

Ken: And the truth was it was all said to be enormously inhibitory of research in the field of cancer.

Alexis: And from there scientists were left wondering, “Whoa? What’s next? What are you going to patent next?”

Lisa: Which brings us to the big part of the story. The effects of patenting OncoMouse radiated out of the mouse club and into academic science as a whole. And forever changed that culture too.

Chapter Four: Commercial Science. Academic Science.

Jessie: Outside of the mouse club many other academic scientists were concerned. They saw patenting as incompatible with the idea of open science. One unencumbered by money. One that was for the good of humanity. Not just for making a profit. Here’s sociologist Beth Berman again.

Beth: So universities tended not to be very oriented towards this kind of commercial activity. So they, it was it was kind of unfamiliar and there was a lot of resistance to it. But at the same time there are also a lot of financial opportunities that were very appealing for universities.

Jessie: Part of what made OncoMouse possible was an unusual relationship between academic and commercial science. At least it was unusual at that time.

Everything is preventative through chemistry. That’s the promise of DuPont.

David: Phil Leder had been funded by DuPont in his research and Harvard in return for that funding had given DuPont exclusive rights to commercialize any invention made from that funding.

Jessie: That was David Einhorn. He was Jackson Lab’s legal counsel at the time.

David: So they had the entire rights to commercialize once the patent was granted. I think a decision that Harvard regretted later on when it became very controversial and when other academic researchers weren’t able to obtain the mice. Because Harvard had given up all the rights.

Jessie: If OncoMouse had been created a decade earlier Phil Leder and Harvard would have gained the typical prestige from making such an innovative research tool. But they wouldn’t have gotten a patent for it. Two things had to happen in 1980 for that patent to be possible in 1988. The first was Diamond v. Chakrabarty, the Supreme Court case that opened the door to patenting life. The second was a new law that redefined ownership of scientific innovations.

Beth: The Bayh-Dole Act was legislation that was passed in 1980 in order to make it easier for universities to patent the results of their research. There were certain kinds of inventions that were hard to actually get into use without a patent. So if you had some kind of discovery, for example, something like an early stage drug but you couldn’t patent it, it would take a lot of additional investment in order to get it to the point where it could reach the market. And so, there were at least some things that were not reaching the market because there was no incentive for anybody to invest in actually producing them. So the Bayh-Dole act gave them the right by default to patent anything that was funded by the federal government. And then to license it and to keep the revenue from that.

Jessie: Computers, semiconductors, GPS, and Google were all products developed by research that was funded by federal dollars…taxpayer dollars.

Jessie: Harvard received substantial amounts of federal funding from places like the National Institutes of Science, the National Cancer Institute, and the National Science Foundation. And before the Bayh-

Dole Act any product or innovation that came from government-supported research de facto belong to the federal government. But many people, including Phil Leder, found that problematic.

Leder: It used to be the policy at the National Institutes of Health—to pursue patents… to obtain patents on their discoveries and then to dedicate the patent to the public domain. Now that sounds terrific. What could be better than that? The government has achieved a patent and it has then dedicated to the public domain that anybody can use. The problem with that is as I’ve encountered it was that nobody was interested in unprotected patents. Nobody was ready to make the investment in the utilization of that technology. You know I wish the world were different, but that’s what it seems to be like.

Jessie: A little bit of background here: the government really started to pour money into funding university science during World War II. After the war, agencies like the National Science Foundation and the National Institute of Health were created to oversee the distribution of funds to academic researchers. The 1950s and 1960s were the golden age of American science. But the economic malaise of the 1970s did not spare the science community. There was a feeling in the air that the pot of government funding seemed to be getting smaller.

Beth: In the late 70s things were kind of flat. It wasn’t really decreasing but the flatness had come after this really long period of growth so it was perceived as a decrease even though it

wasn’t. So there was this sense that things were getting tighter but it was mostly about the big post war boom ending. And another big piece was by the late 70s you have the biotech revolution starting to take off and that really creates all these new opportunities for money.

WGBH documentary: Scientists and the public are trying to come to terms with a dramatic new technique. A technique that gives scientists unprecedented power to manipulate nature.

Jessie: It was called recombinant DNA. It was developed in the 1970s when scientists figured out how to identify and target specific genes or sections of DNA and introduce that genetic material into the DNA of an organism from another species. This 1977 documentary from Boston broadcaster WGBH describes the outcome of an experiment using recombinant DNA technology on bacteria.

WGBH documentary: The few bacteria that have swallowed recombinant plasmids now contain the transplanted genes from a different microbe. They can be picked out and allowed to multiply. With this experiment man this barrier that prevents different species from exchanging genes.

Jessie: For mouse geneticists this meant that instead of relying on the imprecise nature of selected inbreeding or spontaneous mutation they can now target the human gene they wanted to study. Introduce it into the genetic line of a mouse, and create a transgenic mouse that was a better more reliable model of human decease. It was a huge leap forward in understanding and treating any disease with a genetic basis, like cancer, Alzheimer’s, mental illness, or cystic fibrosis. Diamond v. Chakrabarty was the watershed moment for biotech. Entrepreneurs and venture capitalist flocked the biotech

industry and that’s where Bayh-Dole fits in.

Beth: So there’s definitely a big financial incentive in it for universities as well by the end... And then the other thing that’s going on the policy side is that policymakers are really interested by

the late 70s in trying to make American business more competitive and so they’re really interested in promoting technological innovation.

Jessie: And then it’s 1980:

Reagan montage: no problem that we face today can compare with the need to restore the health of the American economy and the strength of the American dollar;

Jessie: The Reagan years were the era of bootstraps capitalism. The free market was king. Government involvement was rarely the answer.

Reagan montage continued: The people have not created this disaster in our economy; the federal government has. It has overspent, overestimated and overregulated. It has failed …

Jessie: Bayh-Dole opened the door to money making opportunities. Scientists didn’t take much notice of it, but university administrators definitely did. The agreement between Harvard and DuPont required Phil Leder to disclose any products discovered in his research.

Leder: As an obedient employee of Harvard Medical School, Tim and I, reported this invention to our office of technology transfer licensing as an invention and a discovery which we disclosed to them and which potentially would be patentable. And they consulted with a patent attorney and the matter was patented.

Jessie: Dr. Leder is referring to Harvard’s Office of Technology Transfer. A tech transfer office is responsible for commercializing the products that come from a university’s research labs. It’s their job to pursue patents for products or technologies and license them to private companies. They started appearing on campuses of elite schools like Stanford, Harvard, and MIT in the early 1980’s after Bayh- Dole made it possible for them to patent, and now any research university worth its’ salt has one.

David: if you were a tech transfer office, you’re a tech transfer person - many of whom come from industry. Their success is to increase as much as possible the return from the inventions and the institution and their success is not a value within the basis of the sharing ethos, but in terms of how much money they’re making for the institution. That’s the problem.

Harold: And that’s where things really got hot. When Harvard sought a patent and then license it to DuPont and DuPont tried to extract licensing agreements and payments for licenses that were unprecedented and thought by most of us to be inappropriate.

Alexis: Chapter Five. DuPont vs. The Mouse Club.

Alexis: Scientific breakthroughs don’t usually happen all at once. And they’re rarely the result of just one person’s ideas. They overwhelmingly come from building off of other people’s research, using other people’s techniques and tools. And OncoMouse was no different.

Lisa: Phil Leder wasn’t the only person making a transgenic mouse for cancer research in the 1980s. In fact, two other geneticists, Ralph Brinster and Richard Palmiter had made their own “OncoMouse” two years before Leder made his. They even published an article about it a few months before Leder published. But then Leder took the next, unconventional step of patenting it.

Harold: Those were mice that got cancer as a result of genetic manipulation. These mice came originally from Brinster and Palmiter and other people, nobody was talking about providing intellectual protection against the the use of those mice by others.

Jessie: OncoMouse was out in the mouse genetics world in 1984, four years before the 1988 patent. And during that time—as was customary in the Mouse Club—scientists began using the animal in their work. They would get the mice from colleagues who were already using them or from central repositories like JAXS. Then in 1988 OncoMouse gets the patent. And DuPont, which was used to operating in the world of commercial science, where every product had a price, came calling to collect their fee. Scientists used to getting transgenic mice for free were suddenly informed that these mice would cost about fifty dollars each, which was ten times the price of getting it from Jackson Labs, and fifty times the price of getting it for free from a colleague. Which brings me to another stipulation that enraged the Mouse Club. The license barred anyone using OncoMouse from sharing it with colleagues.

Ken: In the research community as a whole there was outrage because this totally violated their concept of the freedom of research. And so there was a sense of violation a double violation on the part of the research community: one their own ethical standards of conduct. How one is supposed to proceed and the other one was on research on what was at that time, it still is, a major killer in the United States.

Harold: One of the things that I found particularly offensive about the way the patent was written is that it covered all mice that were genetically manipulated

Ken: I don’t know how familiar you are with patent applications but they have a kind of nested structure in which the application starts out with the broadest claim possible and then it narrows down and successive claims in the hope that the patent office will offer the broadest possible. And the original patent application was written in a way that really covered any possible genetic engineering in a mouse that could result in increased incidence of cancer. It was an incredibly broad application of the patents and they just stretched our scientific imagination.

Jessie: So scientists who had made their own oncomice, lower case “o,” were not allowed to use them. Even those who had made them before Phil Leder. The science world was on alert. DuPont was coming for your oncomice, no matter who made them or how. DuPont had trademarked the name. So it could only be used for the Harvard mouse. In 1992 the Mouse Club decided to take a stand.

Lisa: Chapter Six. The Mouse Club Fights Back.

Jessie: The tensions between DuPont and the mouse club came to a boiling point at the 1992 Mouse Molecular Genetics Conference at Cold Spring Harvard lab in New York. Coincidentally the same lab where CC Little organized the Mouse Club of America decades before.

Ken: Actually, I have a strong visual image of the conference hall. It was one of these bank audiences where people are in successive rows elevating up the auditorium. And I was down in front.

Jessie: After a regularly scheduled session a room full of angry mouse geneticists gathered, lead by Harold Varmus. They were riled up over DuPont’s licensing requirements for OncoMouse.

David: And there was not a very friendly audience of scientists but I do

remember very clearly Ken Paigin got up and said don’t worry about it. Send your mice to us and we’ll distribute them as we always have and got a big cheer.

Ken: I just got up and did it. That’s all I can tell you about it except that it was an intense thing at the moment and it turned out to be history.

David: Now we’re in the target of DuPont with respect to distribution. I mean we were the spigot we were the ones who had the mice and distributing the mice. So from DuPont’s perspective getting us to agree would solve their concerns about licensing rather than have to deal with individual academic institutions.

Jessie: It didn’t take long for the cease-and-desist to arrive.

David: DuPont said that we were infringing and they wanted a license from us. “If you’re going to distribute these mice you have to do it under our terms” and the terms that we found onerous and inconsistent...were this claim to review publications.

Jessie: There were disclosure agreements that required researchers to annually update DuPont on what they’d been working on, which scientists were reluctant to do if it hadn’t been published yet, lest their ideas be co-opted by someone else.

David: And secondly they were claiming reach-through rights.

Jessie: Basically, DuPont would be able to claim ownership or royalties on any future products that came from the research.

David: We had to make a decision about whether we were going to subject themselves to a lawsuit.

Ken: I think the thing that was very much in our minds at that point in time was

that if we acceded to DuPont claims that we’d be shutting off a considerable amount of Cancer research at basic research institutions. And there was some question about our vulnerability. And David was considerably more concerned about the legal aspects of this. My

feeling was that it would be a public relations disaster for DuPont to end up suing the small basic research laboratory in Maine. So we went ahead.

David: Well as a lawyer I didn’t have the same confidence and assurance as

Ken did. And I felt that there was a possibility that we could be sued. And so although I appreciate Ken’s thoughts and that he might be correct. I thought it was important that we not take that chance and at least try to get the help of NIH before we went any further. So that’s when we reached out to the NIH.

Jessie: By 1993 Harold Varmus had become the head of the National Institutes of Health.

Harold: I personally had taken the position that... If there were certain mice we weren’t going to get without signing a license I just would use them. And I was encouraging people to basically be lawbreakers because the patent was issued in my view was much too broad.

Jessie: The NIH and DuPont entered into negotiations which would stretch on for several years. In the meantime, many scientists openly rebelled against DuPont’s restraints, with help from Jackson Lab.

David: It was easy to ignore that with impunity as long as we continue to send the mice which we continue to do we never stop distributing the mice.

Ken: We also didn’t stop receiving mice because all during this time this was a very fertile research field and that was a period of researching cancer where genes that cause susceptibility to cancer or play an essential role in particular cancers were being identified at a rapid rate.

Harold: In 1998 after a couple of years of negotiation the NIH had reached an agreement with DuPont that allowed a more sensible approach sensible relationship between DuPont and academic investigators.

Jessie: The NIH and DuPont signed a Memorandum of Understanding that allowed researchers with federal funding free use of the mice, as long as they weren’t commercializing their work.

Harold: The patent had been issued and there’s not much you can do about that. What we’re trying to do in that situation is to find a working relationship that’s acceptable. But there clearly there were inequities that became apparent later on and resulted in further conflict…

Jessie: If the story had ended with the MOU it would be a reasonable and somewhat satisfying

conclusion. But it didn’t. Around 2002, disputes arose again between several top tier universities and DuPont. Both MIT and the University of California accused DuPont of overreaching their agreement with the NIH. Harvard tried to extend their patents in 2012, but the courts determined that they had expired in 2005. Not that it mattered. By this point new technologies had made OncoMouse obsolete anyway.

But the changes the mouse had brought to the scientific community were permanent. In the years since, universities have become much more focused on the pursuit of profits and tech transfer offices have assumed a mantle of power.

Beth: The joke that people make about Harvard sometimes is that it’s a hedge fund with a research university attached to it. Afraid that that big universities that are talking about big amounts of money are very clearly self-interested economic actors.

David: I think the legacy. I think in the beginning I mentioned how Harvard regrets today having handled DuPont the way it did. Giving them all these rights without protecting the research community. I think the lesson for the commercial companies was that Harvard became the poster boy for not how to handle a patent on a research tool. They got lots of bad publicity.

They made very little money on the patent. And I think that was a message for the commercial world not to overreach.

Jessie: And there’s another ironic conclusion to this story. And that is that after OncoMouse academic scientists started to increasingly seek out patents. At a scientific conference several years after the

OncoMouse debacle a group of researchers was complaining about patents hindering their work. But then someone asked how many of them held patents. About half of the group stood up.

Jessie: The culture had already changed. To many mouse geneticists welcomed patents as a necessary evil. If they wanted to get their products out into the world and help people they’d have to use them.

For Distillations, I’m Jessie Wright-Mendoza.

Lisa: I think on a level we can all understand the choices that mouse club made. There’s something on the surface that seems kind hypocritical. But it’s more complicated than that. Most of us have to negotiate our values with reality.

Alexis: Yeah. I mean it’s clear that OncoMouse changed the dynamic. It brought about a new set of rules and mouse club had to get with those rules or get out.

Lisa: If there is one thing the story tells us is that research paradigms can change. Maybe they will change again in the future. Maybe there will be a move away from patenting – for Jonas Salk’s humanitarian reasons or for some other reasons that we can’t yet imagine.

Alexis: And to be fair: there are also positive things about patents. They designate clear owners and boundaries, they give people credit where in publishing it can get really fuzzy. And looking at biotech specifically, for now, this is how products get out into the world.

Alexis: Distillations is more than a podcast. We’re also a multimedia magazine.

Lisa: You can find our videos, our blog, and our print stories at Distillations DOT org.

Alexis: And you can also follow the Science History Institute on Facebook, Twitter, and Instagram.

Lisa: This episode was reported by Jessie Wright-Mendoza. Alexis: And it was produced by Mariel Carr and Rigo Hernandez. Lisa: With additional audio production by Dan Drago.

Alexis: We want to give a special shout-out to MIT sociologist Fiona Murray. To produce this episode we relied heavily on her 2006 article, “The Oncomouse that Roared: Resistance and Accommodation to

Patenting in Academic Science”.

Lisa: There’s a lot of research that goes into each episode of Distillations, and we keep a list of everything we read on our website, so check it out for further reading!

Alexis: For Distillations, I’m Alexis Pedrick.

Alexis: And I’m Lisa Berry Drago.

Lisa and Alexis: Thanks for listening.