The Ongoing Transformation

A Cutting-Edge Bureaucracy

The word "bureaucracy" conjures up images of red tape and long lines at the DMV, not cutting-edge innovation. But some of the most significant scientific and health innovations of the past century have actually come from scientist-bureaucrats at government research institutes.

On this episode, host Jason Lloyd is joined by Natalie Aviles, an assistant professor at the University of Virginia and author of An Ungovernable Foe: Science and Policy Innovation in the US National Cancer Institute. Aviles explains what the National Cancer Institute does and how the mission and culture of the agency have enabled its scientist-bureaucrats to conduct pioneering cancer research, such as the invention of the human papillomavirus, or HPV, vaccine.

Resources: Check out Natalie Aviles’s book, An Ungovernable Foe: Science and Policy Innovation in the U.S. National Cancer Institute, to learn more about the NCI.

Read “How Federal Science Agencies Innovate in the Public Interest” at Issues.org to learn more about the development of the HPV vaccine and the importance of agency discretion.

Duration:: 37m
Broadcast on:: 03 Dec 2024
Audio Format:: other

One of the most interesting histories within the National Cancer Institute that's been told is this really interesting history of what seems to be failure and turns out to sort of plant the seeds for future success. "We don't have to turn around, but all those people keep saying about what we've always done in that way. So young people are going to have to do it." Welcome to the ongoing transformation, a podcast from issues in science and technology. Issues is a quarterly journal published by the National Academy of Sciences and Arizona State University. What do you think when you hear the word bureaucracy? For many, it's the image of annoying red tape and stodgy paper pushers. Because I have a four-year-old son, I picture the DMV run by sloths in the Disney movie Zootopia. But some of the most significant scientific and health innovations of the past century have actually come from scientists bureaucrats at government research institutes. I'm Jason Lloyd, managing editor of Issues. I'm joined by Natalie Aviles, an assistant professor at the University of Virginia, and author of the recent book An Ungovernable Faux, Science and Policy Innovation in the U.S. National Cancer Institute. She adapted a chapter of the book for issues in an article about the NCI and its role in developing the vaccine for human papilloma virus, or HPV. Natalie talks to us about what the National Cancer Institute does and how the mission and culture of the NCI have enabled its scientists bureaucrats to perform cutting-edge cancer research. Natalie, welcome. I'm delighted to talk to you about your research and the little-known history of the National Cancer Institute. Yes, thank you for having me. I thought a good place to start would be if you could talk about what the National Cancer Institute is and how you became interested in studying it. So the National Cancer Institute is the largest agency within the National Institutes of Health, and it is an agency whose mission is specifically to both do research related to cancer and to try to work to improve the health of the American population related to cancer. The way that I became interested in studying the National Cancer Institute is that I initially was interested in studying viruses. I've always been really interested in viruses, and I chose as an undergraduate to become a sociologist, but I retained this interest in biomedicine and biology and how we can think very humanistically about our relationship to things like viruses. And so I became interested in cancers that were caused by viruses, and I was interested in telling a much more straightforward history of viral cancers, but this one agency kept popping up over and over and over again as I was doing this research on the oncologists and on the basic researchers who were doing the most work on viral cancers, and that was the National Cancer Institute. And so being a sociologist, I am also very interested in how we organize science, and so what I ended up doing was taking a little bit of a deeper dive into, well, what is the National Cancer Institute? Why are people so focused on viral cancers? And what's the history of this organization that in fact does a lot of things in biomedicine in general? It helps distribute grants to the tune of billions of dollars in taxpayer money. It also has this intramural or in-house research program where people who are employees of the federal government conduct their research and government labs. And yet there's very little that's actually been directly written about this organization. And so this ended up becoming the question. And I maintain this focus on on viruses and viral cancers and vaccine development, because I am personally still very interested in that. I think it's a fascinating topic, but I really am writing about this organization and what this organization is doing as an organization that has this very important position within the entire research ecosystem of the United States. You mentioned in your book that the NCI's mission has shaped some of the most significant innovations in both cancer research policy and public health oriented breakthroughs of the past 70 years. And so I don't want you to summarize your entire book, but could you just talk about some of those breakthroughs and innovations and how they came about at NCI? One of the most interesting histories within the National Cancer Institute that's been told is this really interesting history of what seems to be failure and turns out to sort of plant the seeds for future success. And so in the 1960s, there was this very big push within the Institute to demonstrate that cancers are caused by viruses. This was a hypothesis that a lot of researchers who worked at the National Cancer Institute were very invested in. And early on, they sort of identified retroviruses as potential candidates for pretty much universal viral causes of human cancers. And a lot of money was put into this. It was seen as being sort of a NASA-like moonshot style project for trying to develop these universal vaccines to prevent cancer. And it turned out that they were not correct about their basic hypothesis that retroviruses caused cancer, but they were actually kind of close. They were just looking at the wrong thing. It turned out the laboratory of Harold Varmus and J. Michael Bishop, and they ended up demonstrating that it was different genes inside of human cells that are responsible for causing cancer. But most of their research was actually funded by the National Cancer Institute. And it was actually in an effort to try to prove this hypothesis about retroviruses causing cancer that they proved the opposite. They noticed these aberrations, and then they tested it and they realized that these National Cancer Institute scientists kind of had it backwards, but they were on the right track. So that was a big failure at the time. In the 1970s and the immediate aftermath of the discovery of these cellular oncogenes, as they were called, the discovery of these genes inside of cells that are actually responsible for causing human cancer. A lot of people saw this as a very embarrassing hit against the National Cancer Institute. Fast forward, though, just a few years and another group of scientists working in the National Cancer Institute led by Robert Gallo discovered the first retrovirus that actually does cause human cancer. And it was Robert Gallo's laboratory that had this very focused expertise on retroviruses that ended up being incredibly central to proving that HIV is the viral cause of AIDS. So it was Gallo's work along with the work of a few other people like Luke Montignet in France that contributed to our understanding of HIV is the viral cause of AIDS. So this is a very long running investment that the National Cancer Institute has made. They ended up doing a lot of the work to develop some of the first antivirals, antiretrovirals that were effective against HIV. And those efforts were led by a lab pied by Samuel Broder, who was in the clinical oncology program in the National Cancer Institute. He subsequently became the director of the National Cancer Institute. And at the time that he was director, a group of National Cancer Institute scientists led by Douglas Lowey and John Schiller discovered the enabling technology for a vaccine against another cancer-causing virus, this time a DNA virus called human papilloma virus. And this is a virus that's responsible for the overwhelming majority of cervical cancers, as well as it turns out a lot of other anagenetal cancers and increasingly many head and neck cancers. So this is a fairly ubiquitous virus in the human population globally. And it's one where we have developed a lot of very effective vaccines for preventing these viral cancer-related deaths in no small part due to the efforts of these National Cancer Institute scientists. So these are primarily the intramural scientists that you're talking about? Yes. So the book is really an exploration of the intramural laboratories in the National Cancer Institute. This is a small part of the NCI's budget at different parts of history. It's been between 10 and 18% of the Institute's entire budget. So it's not what most people think about when they think about the National Cancer Institute. When most people think about the National Cancer Institute or the NIH that it's part of, they tend to think about extramural grants. So these are grants that get awarded to academic scientists and scientists working in research institutes. And so the intramural program has largely been neglected when we talk about policy. And one of the things that I'm able to demonstrate in the book is that actually it plays a really special role in shaping policy. And one that we ought to look at because it really helps us understand how knowledgeable experts who are employed as civil servants in the US federal government play a really crucial role in helping to ensure that the policies that we develop are not just scientifically sound, but also accountable to the public. Could you describe kind of that environment of the intramural scientists a little bit? Are they all on a campus together? Are they all in Bethesda? I actually don't even know where they're located. Yes. So the main campus of the entire NIH is located in Bethesda. And there's something that's a little bit special about the intramural program in the National Institutes of Health generally, which is that this is a place where a lot of expert scientists with really great reputations are sort of concentrated together in a way that we actually don't often even see in universities. And one of the things that intramural scientists sort of talk about that they think makes the National Institutes of Health and the National Cancer Institute special is that they really are at these agencies in order to do science and sometimes to be involved in this policy-making process and sort of like the basic bureaucratic administrative tasks of making sure that science policy works. But they're not teaching. Unlike university scientists, they don't have to teach. Unlike scientists in working for commercial firms or in private industry, they aren't accountable to the same kind of market-focused managerial impulses. And so they really feel like they are able to do science and they're able to do really high-risk, high-impact science because the mission of these agencies is also very big. The mission is really make a big impact on the health of the populace. And so one of the things that many people who are part of the intramural program throughout the National Institutes of Health will say is that this is a really special environment for them to work in. It allows them to take these risks that end up paying off in very big ways sometimes. So let's talk about one of those risks. One of the most interesting aspects of the story that you tell in your issues piece is the development of the HPV vaccine. And I was hoping you could sort of tell us what lessons the folks at NCI, specifically Samuel Broder, and then you talk about John Schiller and Douglas Lowey. What they learned from their experience with the development of HIV/AIDS drugs that they then applied to the development of the HPV vaccine. This is a really fascinating story and one that I think very powerfully demonstrates how the scientific missions and the bureaucratic missions of the National Cancer Institute can work together to create a very distinct kind of science. And the story is that Samuel Broder was part of this, what he considered very crack team of interdisciplinary scientists at the National Cancer Institute. It was assembled among people who worked in the intramural program in the National Cancer Institute because very soon after cases of AIDS were first being reported roughly in 1982, people started to realize that this had the potential to be a very serious epidemic. And they also realized that the National Cancer Institute had spent so much time and invested so much money and developed so much expertise in viruses and in immunology that they were uniquely positioned to really address this public health crisis. And so it was working with this laboratory scientist, Robert Gallo, that Samuel Broder sort of developed this idea that if you can get people in the lab together with people in the clinic, you can sort of orient yourself towards this mission to make sure that these "basic science developments" are actually going to deliver something very useful in a short time span when it comes to either clinical outcomes or public health crises of the nature that people were dealing with when it came to the HIV/AIDS crisis. And so it was these lessons of working with these laboratory scientists who were trying to figure out and identify what's the agent that's actually causing AIDS and then immediately trying to take that knowledge of, you know, here is the virus and here are the pathways and look for anti-retroviral agents that would have some immediate clinical effect so that they could just start getting this crisis under control. It was that experience of, you know, going bench to bedside that Samuel Broder really was motivated by when he became director of the National Cancer Institute. And there's this very intuitive metaphor of translational research, basically taking what's going on at the laboratory bench and translating it, you know, making it make sense for clinical practice. And this really became a policy paradigm starting in the 1990s and the National Cancer Institute had a huge role to play in that. And Samuel Broder committed very strongly to this idea of translational research. And it was the work that he did working with laboratory scientists, trying to find agents that would help to combat this disease very rapidly that inspired him and his vision of what translational research can look like. And so when he came in to the directorship of the National Cancer Institute, one of the things that he decided from his position as NCI director is that the institute had focused a lot of its investments in extramural research on cultivating basic research, which is very valuable, but that there was this whole other dimension of making sure that that basic research could actually, you know, be incorporated into medical practice. And so what he did is say, we need to develop some funding instruments to make sure that we are actually putting some money into strategically trying to get some of these new and exciting developments at the laboratory bench to have some impact as quickly as possible. And so he developed all of these novel funding instruments. And sometimes it was taking an existing funding instrument like the PO1, which is a project grant, and saying we're going to make sure that these are really interdisciplinary, that they have a clinical focus and that they're translational, that they're doing what we say needs to be done here to make sure that our investments in basic research are actually having that impact that the agency is supposed to be accountable for when it comes to human health. And then he spearheaded the development of this other more centers-based program, which is called SPOR, the specialized programs of research excellence, which tended to focus on specific kinds of cancer or specific organ sites and actually, you know, get these interdisciplinary teams together so that they could take these cutting-edge findings and then actually, you know, try to figure out what use they're going to have clinically. And so this was the first way that he really took his experiences doing that interdisciplinary AIDS research and applied it to our funding, our funding policies, and our funding practices at the national level, to try to ensure that the research that we're supporting with taxpayer funds is actually, you know, making an investment in the most promising basic research, but then also having some application to human health and population health. He set up these novel funding mechanisms and kind of had that translational goal in mind because he saw sort of some shortcomings in the pharmaceutical market space that he was looking to like kind of make up for, or what was kind of the motivation that he saw to doing this? Yes. Broder had a very distinct experience as someone who was trying to develop a clinical armament to try to combat the AIDS epidemic. Broder, because of his very close ties with laboratory scientists, had already identified this class of antiretrovirals called nucleoside analogs as the most likely class of drugs that was going to be effective in combating HIV. And so he went to a series of private companies and asked them if they would be willing to partner by sending their basically pharmaceutical catalog to them so that they could rapidly test all of the nucleoside analogs that had been developed so far. And so one of these companies was Burrough's Welcome, and they sent a series of compounds for Broder and some of his collaborators at Duke II test. Broder very quickly identified AZT as a promising compound to combat HIV/AIDS and rapidly was able to move into clinical trials. His vision though at the National Cancer Institute was that private companies were going to be true partners. They were going to sort of help run the clinical trials and help with the testing. And Burrough's Welcome actually didn't do that. It backed out of the clinical testing very early. And so what ended up happening is that the National Cancer Institute was responsible for most of the early screening testing in both animals and humans that demonstrated the efficacy of AZT as an anti-AIDS drug. But unbeknownst to Broder and his team at the National Cancer Institute, Burrough's Welcome had actually applied for a patent for AZT in the United Kingdom. And so they were able to essentially claim full credit for the development of AZT as an anti-AIDS drug, even though it was this team of National Cancer Institute scientists who had done most of the work. And this really upset Broder, but it upset him most of all because when AZT hit the market as a branded medication, it was astronomically expensive. It was $10,000 a year. And given the concern for trying to stem the tide of this very significant public health crisis related to HIV/AIDS, Broder was very upset by the price tag. And a lot of activists and other scientists were very upset. They felt they needed to build in greater safeguards to ensure that any kinds of drugs that were developed by the federal government using taxpayer money would actually be more accessible to taxpayers who are suffering from these diseases. And so when Broder became director, he was very instrumental in making some changes at the level of the entire National Institutes of Health to try to competitively license any new drugs or technologies that were developed by intramural scientists using taxpayer funding. And so the approach to competitive licensing that he used is to ensure that any drug or any new technology developed by employees of the National Institutes of Health has to be licensed to at least two different private companies so that they would compete with one another when a branded medicine based on this patent hit the market. And the idea was that this would drive the cost of medications down. And so we would realize taxpayer savings this way. And so he actually was able to change the patenting and licensing practices in the National Institutes of Health to reflect this. So could you tell me then how these new practices were applied to the development of the HPV vaccine? Am I right in thinking that partnering with pharmaceutical companies is still necessary because the NCI can't manufacture drugs at scale? Or I guess how did the NCI maintain some control over drug development while still partnering with industry? Yes. So this is a really important thing just sort of to keep in mind for understanding how innovation works in the US. The way the innovation ecosystem has been developed is that private industry has always really had the native productive capacity for turning any new developments in basic science into commercially scaled drugs or technologies. And so even people who are employed within the federal government, if they want to see their innovations or their inventions become products that are useful to people, they really depend on private industry to develop these new interventions to scale and distribute them through the market, which is how we tend to distribute healthcare in the United States. And so whenever any of these inventions actually happen within the federal government, there still is this relationship of dependency to private industry. They need someone to actually develop these new technologies to scale. And in the case of National Cancer Institute scientists, they are specifically motivated by the idea that they can eliminate cancer by preventing it very quickly and very easily through these safe and effective vaccines. And so their interest is to get as many vaccines as possible into as many bodies as possible around the world so that they can eliminate cancer. And they kind of recognize that this objective is intention with the objectives of private industry, which are to make profitable drugs. And so a lot of these policy decisions are playing in this very interesting space where they have to balance the concerns of government scientists, which are oriented towards doing the maximum to realize the public good that it's possible for them to do. And then the concerns of companies that want to be able to profit. So one of the interesting things about the National Cancer Institute, just to bring this back to sort of like the high risk research, when I talk to Douglas Lowey and John Schiller, who I interviewed for this book, they pointed out that neither of them really had that much experience in things like vaccinology or vaccine development. This was pretty new for them. And so this is one of these amazing stories where they actually weren't necessarily heading out to create a vaccine against the human papilloma virus, but they saw a scientific opportunity. They were driven by curiosity. And then once they realized, oh, we have a vaccine, they then were able to realize like, oh, this could be a huge intervention. It could be one of the most significant things we can do to actually improve women's health around the globe, because vaccines are very effective and a vaccine against cancer is a very big deal. They developed this vaccine in the climate of a National Cancer Institute that had just changed its patenting and licensing practices to reflect the competitive co-licensing that Samuel Broder had developed. And so when they licensed this technology, they co-licensed it to two companies. Merck was one. Another company was called Metemune, and they shortly after transferred their interest to GlaxoSmithKline. So these are two very large global pharmaceutical companies that have pretty good vaccine development portfolios. And they were able to compete with one another to try to get this human papilloma vaccine on the market. What Schiller and Lowey from their position at the National Cancer Institute realized is that, well, this could be a very effective global health technology. They were familiar with some of their colleagues in epidemiology who were conducting a study on the natural history of human papilloma virus in Costa Rica, which is a Central American country where there's a large rural population. There's not as robust healthcare infrastructure. And so it looks a lot more like developing nations where most of the cervical cancer morbidity and mortality actually happens. And so they joined this study and created a new phase two, three human trial arm. And so it was in the process of doing this that they decided that they were going to follow up on some of the women in this trial who had dropped out from one recenter or another. So the original protocol for this vaccine was to administer the vaccine in three different doses over the course of nine to 12 months. And this is an expensive vaccine because it has to be refrigerated. So it needs total cold chain storage from beginning to end. And that makes it a really difficult technology to administer in low resource environments where there's not a lot of infrastructure. And so following up with women who had only received one or two doses of this vaccine, they realized that that was enough to create a sufficient immune response to protect women against human papilloma virus. And it was because they wanted to follow up with these women, assuming that private pharmaceutical companies would not do this, because it's not really in their interest to spend more money following people who essentially have dropped out of the trials. They followed these women who dropped out of the trials to see if fewer doses would actually be just as effective. And when you think about the priorities of private companies saying, let's do fewer doses is not really in alignment with one's interest in maximizing profit. And so they were certainly driven by this desire to have the greatest possible impact on public health, whether it was profitable or not. And the really amazing outcome of this is that they were able to demonstrate that two shots and even one shot of the human papilloma virus vaccine was sufficient to prevent over 90% of cervical cancers and other HPV related cancers. And the World Health Organization now recommends one shot as an effective public health intervention. And so it was the fact that these National Cancer Institute scientists were really oriented towards trying to make the biggest possible impact on public health without regard to national borders, without regard to whether this was going to be a profitable technology or not, they were able to realize that they could have a much more effective global health campaign if they used fewer doses of this vaccine that they helped develop. So that's a really interesting story where you can see the difference that it makes for scientists to be in an agency where their mission is really to on the one hand, you know, do the best science that they can. But then on the other hand, make the biggest impact on public health possible. So being driven by that dual mission of the National Cancer Institute where they work was really instrumental in shaping this technology. There seems to be a lot of policy implications for the innovations that you're describing happening at the National Cancer Institute. And I want to talk about them in two ways. So one, what kind of, maybe it's the mission, maybe it's the structure or the organization itself, but what about the NCI is maybe applicable to other federal agencies trying to do innovative work in the public interests. I'm thinking of, I mean, maybe the National Institutes of Health more broadly, but maybe other kind of smaller agencies that maybe attempting to do similar things. But what can they learn from NCI's experience that you describe in your research? Yes. So the National Cancer Institute is a really great example of how to maximize the effectiveness of doing high impact mission driven research. And the reason the National Cancer Institute is so effective at meeting both its scientific and its policy goals has to do both with its structure and with the organization's culture. And the structure that makes policy at the National Cancer Institute so effective is the fact that this is an organization where leadership has to defend its scientific priorities in front of other scientists on advisory boards who have a great perspective on what the scientific community wants. And so they have to be accountable to other scientists and their representatives, but then they also have to be accountable to Congress. And so it's this accountability structure of having to be accountable both to the scientific community and to representatives of the broader populace that I think interacts very well with the mission of the agency. And this is what manifests, I think, in the organization's culture in ways that are really, really effective. So the National Cancer Institute has historically promoted from within. So people who do very well in the intramural program as researchers have opportunities to really be instrumental in the administration of the agency. And that means they get to be in the room when these policies are created and they have this very unique expertise because of that. They're career scientists, they're working scientists who have specific expertise and can converse with their scientific advisors. But they also have experience as bureaucrats. They're having to make sure that policy can reasonably be interpreted as a good use of taxpayer funding. And so in the book and in this article, I talk about how there's this unique brand of scientists bureaucrats in leadership. They're sort of a hybrid role between working scientists and bureaucrats who sort of are deeply involved and invested in the policy outcomes of the agency. And I think to the extent that you can create these hybrid roles in agencies and back them up with this oversight structure where people are continually in dialogue, not just with other experts outside of the agency, but also with representatives of the broader populace. I think it's the combination of these things that really closely couples the agency's mission to the policy outcomes at that agency. That is really interesting. The second way I wanted to talk about the policy implications of NCI's work and the context in which it occurs is something that you touch on a little bit in the in the article earlier this year. The Supreme Court ruled in a case called Loperbright v. Raimundo that federal judges will now be the arbiter of what an agency is allowed to do, whether or not they are exceeding their statutory authority. Previously, a judiciary would grant deference to people working at the agencies themselves. That was something called Chevron deference that had been in place, named after a court case, I guess, 40 years ago? Was it maybe it was 1984? So I'm curious what this means for an agency like NCI. A lot of people are concerned about what it means for regulatory agencies such as environmental protection agency. But what does it mean for an agency, for an organization like the NCI? The National Institutes of Health hasn't really been a big part of the conversation because the National Institutes of Health doesn't do a lot of rulemaking. Most of our discussions of Loperbright and its implications for scientific expertise in the federal government have really focused rightfully, I think, on regulatory agencies who do do a lot of rulemaking. But I think we need to pay very careful attention to what a ruling like Loperbright can mean for the capacity for mission-oriented agencies to actually work as effectively as they can. And one of the things that is very distinctive about a lot of the relationships between Congress, which authorizes these agencies and their budgets every year, and an agency like the NIH, is that if you look at any given statute that comes from Congress to the NIH, there's usually not a lot of specification in those statutes about what the exact scientific priorities are, that the NIH should be investing in, what instruments they should use when they do this. And so this has meant a lot of autonomy for experts who work for the federal government to actually determine, based on their own scientific expertise, where should we be making our investments? And it's allowed them to be very nimble and very responsive to the state of the science. And so up until now, this has been a very convenient arrangement that I think has been very conducive to making sure that government science policy is very cutting edge when it issues from these mission-oriented agencies. But we're in a position now where there is potential for a lot of ambiguity, a lot of ambiguity for when something that comes from Congress should be interpreted as law or as a matter of sort of more routine agency-level policymaking. What the descending opinion in the Loper Bright case pointed out is that this is kind of a Pandora's box when it comes to thinking about executive agencies. And this includes the National Institutes of Health and the National Cancer Institute within it. We actually don't know what's coming next, but what we can see is that Loper Bright is part of a much larger initiative to basically try to scale back a lot of agency autonomy. And one of the major takeaways from my work is that actually agency autonomy is really conducive to good science when you have other oversight structures built in that make sure that that science can be accountable to the broader scientific community. And so I think in this environment of uncertainty, we risk losing some very effective science policymaking instruments because we have created conditions where agencies might be a little bit more timid in actually taking what are often very sparse mandates from Congress and trying to do the best that they can by looking at the state of the science. And so I think that we also need to pay very careful attention to other federal agencies like the National Institutes of Health when we're having these conversations about things like Loper Bright because a lot of the expertise that makes an organization like the National Cancer Institute so effective at both science and policy is the fact that it relies on the expertise of these federal bureaucrats, right? It's people who work for the National Cancer Institute who help set the agenda for policy around the country. To learn more about the National Cancer Institute's role in creating cancer research breakthroughs, check out Natalie of US's book An Ungovernable foe, Science and Policy Innovation in the US National Cancer Institute. Find links to it and much more in our show notes. Please subscribe to the ongoing transformation wherever you get your podcast and write to us with questions and comments at podcast@issues.org. Thanks to our audio engineer Shannon Lynch and producer Kimberly Quatch. I'm Jason Lloyd, managing editor of Issues. Thanks for listening.

Resources: Check out Natalie Aviles’s book, An Ungovernable Foe: Science and Policy Innovation in the U.S. National Cancer Institute, to learn more about the NCI.

Read “How Federal Science Agencies Innovate in the Public Interest” at Issues.org to learn more about the development of the HPV vaccine and the importance of agency discretion.