Michaela Kane: You’re listening to a new episode of Rate of Change, a podcast from Duke University’s Pratt School of engineering, that takes a fresh look at some of the ingenious ways engineers are tackling some of society’s toughest problems. I’m your host, Michaela Kane. Most people begin to learn about reproductive health during sex education classes in high school where the topic is typically framed around puberty and pregnancy. In reality, the field of reproductive health is incredibly varied, spanning subjects like infertility, contraception, cancer screening and prevention, and today’s topic, which is STDs, more specifically, human immunodeficiency virus or HIV.
Dr. Katz: I have broad interests in reproductive biology. I guess one could say that I’m interested in a spectrum of ways in which we, biomedical engineers, can contribute.
Dr. Katz: These span a lot of different processes and phenomena, reproductive health, having to do with fertility, contraception in fertility, and toxicology of the reproductive system… They have to do with cervical cancer and how we diagnose and treat it.
Michaela Kane: Although he spent decades working in the fields of biomedical engineering and reproductive health, it wasn’t always his intention to go into BME. Instead, his sights were set a bit further from home, more than 200,000 miles away, to be exact. During his time as a mechanical engineering student at Berkeley, Katz worked in aerospace related problems for NASA, specifically topics that had to do with the lunar surface.
Dr. Katz: After a couple of years of intense study in applied physics, and applied math, and engineering, I grew restless and really wanted to do something that I felt was more meaningful to humans. It wasn’t that I had anything against the space program. I just wanted a more human element in what I was doing. The lunar surface was rather barren.
Michaela Kane: As a student at Berkeley in the ’70s, Katz crossed paths with researchers who were working in the then young field of biomedical engineering, including one researcher who was studying how to apply fluid mechanics to the reproductive system.
Dr. Katz: He had done a sabbatical in England and was studying the reproductive system, which has objects that swim in it called sperm. He was interested in this from a fluid mechanical point of view in terms of how that works, swimming in general. I thought, “Well, my skillset seems to match the need here.” Others had worked on it primarily in the UK, but there were some real needs to expand it to make it more realistic biologically. That’s what attracted me, and in particular, not just the biological relevance of this, but the biomedical relevance of this. Could we use this information to do a better job of diagnosing and treating disease in human health? I gave up my fellowship from NASA and started taking courses in the life sciences.
Michaela Kane: Katz ended up creating a thesis that showed a mathematical model about how sperm swim to an egg, giving researchers a theoretical perspective about reproduction that hadn’t really existed at the time.
Dr. Katz: It was good science, but it was all theoretical. I really wanted to learn more about reproductive biology and medicine. Some of that work involved targeting sperm with molecules to kill them or disable them. Spermicides… There’s spermicide-like molecules.
Michaela Kane: While he was investigating these new avenues in reproductive health, a new disease was beginning to make headlines in L.A., New York, and San Francisco.
Dr. Katz: The HIV virus was starting to take its toll in the United States in creating this nasty disease, AIDS. I was aware of this because I was in the Bay Area. I was very much informed about this awful disease and the fact that it was created by a virus. At the time, there wasn’t interest in the U.S. government in this. It took a long time for the government to acknowledge and wake up to the fact that there was… This disease was going to be epidemic and have a devastating effect.
Michaela Kane: In July of 1981, Lawrence K. Altman wrote an article for the New York Times titled, Rare Cancer Seen in 41 Homosexuals, that described how gay men were dying of an unusual disease called Kaposi sarcoma, a cancer that caused purple spots and bruises to appear on their skin. By 1982, it was discovered that people with hemophilia were also showing symptoms of the disease. That same year, the CDC began using the term AIDS, or acquired immunodeficiency syndrome, to describe the disease. By 1984, researchers announced that they discovered that a retrovirus was causing AIDS, calling it HTLV-3, later changing the name to HIV. Although this discovery made it easier to create a more accurate diagnostic test for the disease, it didn’t lead to a vaccine or immediate treatment as some researchers had hoped.
Michaela Kane: Why is HIV so hard to, not necessarily even treat, but it just is a difficult virus to work with?
Dr. Katz: The infection by HIV is very challenging for a number of reasons. The virus is such that you can literally get infected by HIV by a single virion. That’s what a single HIV virus is called, a virion. It only takes one. We know this from a variety of studies, some of which were informed by work at Duke, having to do with essentially the genetics of HIV. To prevent infection, you’re dealing with a virus that… They’re not a lot of virions that are introduced into the body. Because it only takes one, the way you deal with prevention is a little different than if you’re just… In a lot of infections in the body, we know that if we reduce the size of the inoculum of the pathogen, a certain amount, the likelihood of infection is going to go down.
Dr. Katz: In the case of HIV, the math is a little different. That’s particularly challenging in terms of how forgiving various methods of prevention can be to just differences in people’s bodies and their susceptibility to infection, how many virions are introduced. Secondly, another factor is that the HIV virus is… We read about this a lot. It’s sneaky. It will infect you and then it’ll sort of disappear for a while, difficult to detect.
Dr. Katz: You may be infected but you may not have… When you’re first infected by HIV, the numbers of virions, the viral load as it’s called, that are in your body fluids, go up. Then soon thereafter, they go down. They can remain dormant for a long time. For people who have been infected but didn’t get tested early on, they may not know they’re infected. This can go on for months, even years. That’s another reason why this is such a perplexing virus. We think about HIV almost like trench warfare in the First World War. It goes in. It hunkers down. You try to disable it but you can’t get to it. You can’t find it. It’s in these hidden reservoirs.
Michaela Kane: “This hunkering down,” as Dr. Katz says, “Is called the latent HIV infection,” which occurs when a group of immune cells in the body are infected with HIV but are not actively producing new virions. This allows the virus to hide themselves for years, which makes it hard to clear out of the system. It wasn’t until 1987 when the first medication for AIDS, called AZT, was approved for use. AZT didn’t remove the virus from the body but instead, slow its progression by prolonging this latent stage.
Dr. Katz: When HIV was discovered… It was a retrovirus. People started thinking, “Well I can create a drug or I can find a drug that works against this retrovirus by attaching to the cells that the virus infects.” They found an early… It’s called antiretroviral drug. They gave it to people who had been infected. Guess what? They started getting better. Their viral loads went down. This was great. There was this feeling of euphoria for a couple of months. Then they got sick again or their viral loads went up. The reason was that the virus was mutating.
Dr. Katz: This drug alone was not sufficient. Then they said, “Well, let’s put a different kind of drug in at the same time and see how that works.” They did that. Guess what? The people stayed… The viral loads went down for a longer period of time, but then they came back. Finally, when they put a third drug in, they discovered that they could start to treat the disease through the combined effects of these three different drugs.
Michaela Kane: The spread of and subsequent health response to the AIDS epidemic caused Katz, then a faculty member at UC Davis, to explore how his research could be used to potentially help prevent the transmission of HIV and other sexually transmitted diseases.
Dr. Katz: The connection was that sexually transmitted HIV causes infection in the same environment where sperm move. I knew a great deal about that environment by then, its physiology, its anatomy, its endocrinology. I also knew quite a bit about sticking molecules in there to make things better or worse. That is to say, for contraception, or to treat infertility, a lot of maneuvers. It was quite natural to begin to imagine how I could contribute to understanding various modalities for preventing infection by sexually transmitted HIV.
Dr. Katz: That marked my transition to becoming interested in HIV. I moved to Duke from Davis in… at Christmas time in 1993. When I came here, Duke was already becoming interested in the immunology of HIV. I started changing the emphasis of what I was doing more towards sexually transmitted infections like HIV.
Michaela Kane: It’s been nearly 40 years since AIDS and HIV first broke into the public consciousness. While the disease is no longer a death sentence, there is still no true cure. In fact, as of this recording, only two men have ever been functionally cured of HIV after receiving a bone marrow transplant as a treatment for leukemia. While bone marrow transplants are not likely to be a cure for the disease, people who are at risk of contracting HIV can take Pre-exposure prophylaxis, also known as PrEP, to reduce the likelihood of contracting HIV. These are notable successes in the fight against HIV, but the virus’s biology hasn’t been the only roadblock in the pursuit of a cure.
Dr. Katz: There are massive behavioral, social, societal factors, stigmas, prejudices, and so on that underlie addressing the AIDS pandemic. These have been a big constraint because it originally developed in men who have sex with men. It’s much, much, much more ubiquitous than that. The stigma associated with that that was prevalent in this country in the ’80s and in the minds of our government have remained a constraint in our treatment of the disease. This is a social, a behavioral, as well as a biological challenge to us as a disease.
Dr. Katz: Most diseases aren’t like that. You get polio. No one is going to dispute the fact. “Oh, we need to treat polio because all our kids are getting it,” which they were in the ’50s until Jonas Salk made his vaccine. Remember, HIV infection is not AIDS. AIDS develops from HIV infection over time. This is really beset with all these challenges, all these stigmas, all these prejudices, which play out very differently across this planet. It’s different in Sub-Saharan Africa than it is in India, than it is in the Middle East, than it is in China, than it is in South America, than it is in the United States, it is in Scandinavia. Societal mores, and practices, and behaviors are… They vary. The common theme and across these, however, is sexism. That’s the theme that is common to all of the above. Really, what I do is very deliberately intended to empower women with control of their bodies in terms of susceptibility to infection and contraception, for that matter.
Michaela Kane: While condoms can be a reliable tool to help prevent HIV and other sexually transmitted diseases, they are only useful if a man agrees to wear one. Instead, researchers like Dr. Katz are investigating how to create tools that women, who make up more than 20% of new HIV cases, can control on their own.
Dr. Katz: One characteristic that’s been central to my work for a while now is the integration of… I’ll call them biological and pharmacological processes involved in creating something that will work if somebody uses it. For example, one of the things that I’ve been working on recently are intravaginal rings. We have an intravaginal ring that delivers contraceptive hormones. NuvaRing… They’re new contraceptive rings in development.
Dr. Katz: We have evidence that these have a epidemiologic niche in the menu of options that women need for… whether it’s for contraception or for prevention of sexually transmitted infections. I’m interested in, and this is collaborative work, in delivering different drugs and intravaginal rings to prevent infection by HIV. Concomitantly, I, of necessity, have to understand, are we designing rings and products in general that women will use?
Dr. Katz: I worked with behavioral scientists on this for a number of years now. Over 10 years now, I’ve worked with a psychologist at Brown University named Kate Guthrie. Her earlier name was Kate Morrow. She’s a behavioral scientist. She works on people’s sensory perceptions, and experiences, and preferences for things that they put on or in their bodies. We’ve done a lot of work together in the HIV field, having to do with delivering products that apply molecules that we call microbicides to the body. All kinds of products… rings, gels, films, suppositories. What we’ve done is to try to understand how the properties of these products and the dosage requirements for them, how frequently you have to apply them, or keep them in, or et cetera, are perceived and accepted by users.
Michaela Kane: An example of this work involves the first microbicide that went to efficacy testing. This gel contained a drug called Tenofovir, which is used to treat HIV. In the first study with this gel, researchers found that it could reduce the chances of contracting HIV during sex if used correctly.
Dr. Katz: They did two follow-up studies. It didn’t work. They discovered that the reason why it didn’t work was that women weren’t using it as directed because it was messy. To me, this was just evidence that you’ve got to design something that people will use. You’ve also got to understand how to design a gel that people will use. That’s where my engineering came in. A very simple example was this Tenofovir gel was too runny. The volume was too high. It was very messy. In the light of what we learned from the Tenofovir gel trials and their successes and their failures, we clearly needed to emphasize user acceptability in designing products, and that led us to a renewed emphasis on intravaginal rings as devices for delivering anti-HIV drugs. And the good news is that there is a ring that delivers a different drug from Tenofovir that’s called Dapiverine that has been successful in several clinical trials for reducing infection by sexually transmitted HIV, and this is well along in the path to approval and distribution and commercial distribution worldwide. That success has really been a stimulus to many of us who work in this field.
Michaela Kane: According to Katz, these rings occupy a unique niche, because they offer the benefits of more long-lasting protection, like those from contraceptive injections or implants, but they can also be easily removed. Now, Dr. Katz and his lab are looking into how they can continue to optimize the performance of these rings based on behaviors from their users.
Dr. Katz: We want products that have rapidly acting efficacy profiles, and that if they are removed have a long tail. That’s the term that’s used in pharmacology for activity after you remove the product. Because behaviorally we know that not all women will keep a ring in continuously throughout the month or up to three months of designated use. So we’re trying to raise the bar in new work that we’re doing on designing intravaginal rings and we’re very excited about it in the following sense.
Dr. Katz: First of all, we’re using more advanced drugs than Tenofovir that are much more potent and very long acting. Secondly, we’re building the rings and this is work that’s done at UNC with my colleague Rahina Bemabor, and we’re 3D printing these rings for the first time so we can really customize their shapes and their properties for efficient drug delivery compared to the injection molding process that’s historically been done. We’re also evaluating these rings using advanced methods of modeling that we’re doing in my group and of measurement of transport into tissue that we’re also doing in my group.
Dr. Katz: So we see intravaginal rings as becoming a mainstay and used by women for contraception, for protection against multiple sexually transmitted infections and potentially for delivery of drugs for other gynecological needs.
Michaela Kane: Katz has also been involved in a collaboration with researchers in Duke BME to help create a highly sensitive diagnostic test for HIV.
David Katz: For a number of years we’ve been interested in sticky molecules that can attach to the virus, and disable the ability of the virus to infect cells.
Michaela Kane: One of their targets involves a family of protein molecules that was originally derived from algae in the ocean. These molecules, called Lectins, are very sticky, and they can stick to the sugars on the surface of HIV. The lab has zeroed in on a particular molecule in this family called Griffithsin, which can efficiently stick to virions and disable them.
Dr. Katz: We were interested as engineers, however, in how to produce this molecule efficiently and potentially in a more potent version. And that led us to connect with another faculty member in BME, Michael Lynch in biomedical engineering, who is a true expert in making boutique molecules in bacteria. And so we approached Mike about this, and Mike was intrigued about the possibility, and this became a project in his undergraduate BME design class, where we did the original work.
Michaela Kane: Initially, the team was interested in using Griffithsin as protection against HIV, so the Katz lab completed mathematical studies about how fast acting the molecule could be, and how its activity varied as different microbicide products.
Dr. Katz: At the same time a lightbulb went off, and I’m not sure when it first went off, but it involved a very closely related use of this molecule, and that is not to disable HIV but to detect it. One of the needs that we have is to have early detection of infection by HIV. As I said earlier one of the problems is that people don’t’ know they are infected. And most methods for early detection of HIV require not the detection of the virus itself when it first appears in a body fluid, but antibodies that are created in response to it. What we saw, and this is really Mike’s idea and Tosh Chilkoti’s idea in our department was to use the stickiness of Griffithsin to create an assay that could detect very small numbers of virions in body fluid, for example in blood.
Dr. Katz: Very soon after infection, much sooner than is currently possible with antibodies. So there is a new project that is starting up now, in which we’re putting our heads together, including Tosh Chilkoti’s real expertise in developing very sophisticated assays for detection, Mike’s ability to make a molecule that has properties that we need, and our ability in my group to put the transport aspects of this together in terms of the kinetics of how quickly it would work and some of the other design features. So we have a new project that is starting up now with other investigators in BME, not looking at prevention per say, but looking at detection, which, if this works, could be a real game-changer.
Michaela Kane: If you’re interested in learning more about Dr. Katz’s work, check out his lab website on his profile on the Pratt website at pratt.duke.edu. Don’t forget to subscribe, and thanks for listening to Rate of Change, a new podcast from the Pratt School of Engineering.