Discovering the HIV/AIDS Drug "Cocktail" in an Equation

Question: How did your education prepare you for your eventual development of an HIV drug "cocktail?" 

David Ho: In terms of the most important scientific discovery to come out of my group there was an acute moment, an eureka moment so to speak, and this was in 1994. By that time my colleagues and I had been immersed in AIDS research already and we realized that for any given patient with HIV infection his or her viral load or the amount of virus in the blood tends to remain rather constant over time. We had been thinking about that, why does it remain constant? And gradually we realized that it was a what we call a dynamic equilibrium, that is the amount of the virus being made is approximately equal to the amount of virus being cleared, so it was a steady state. And then the eureka moment came when we had the opportunity to administer new drugs to HIV-infected people. And within weeks of doing so we collected the data and it showed that viral load actually dropped precipitously. And of course that is a great outcome for the patient and for the doctor, but the question that we posed was "Why does it drop and why does it drop in that acute manner?"

This is where my quantitative background in physics applied; we realized that we could actually write that out mathematically in a straightforward differential equation that an AP high school student would be able to do. From there, fitting the data and doing the calculation we were able to come up with the idea. We were using the drugs to block virus infection and production and therefore the precipitous decline reflected the fact that the virus was constantly being cleared at a very rapid rate. So using that quantitative background we were able to calculate what the turnover of virus was all the time in a given infected person and that number turned out to be enormously large, so the virus was just replicating away at a rapid clip. 

And from there we also knew that HIV changes every time it replicates, so high replication rate meant high error rate and therefore HIV was able to mutate very quickly. We could then do the additional calculation to show that if you treat this virus with one or two drugs at a time the virus is predictably going to mutate and escape from the action of the drugs. But at the same time we could also calculate what it would take to corner the virus so it’s not able to escape. Those calculations suggested to us that three or more drugs would do the trick. So we knew that by 1995 and launched a series of experiments in patients using what is now called a cocktail therapy of three drugs or more. And immediately within weeks we saw the good result. But we wanted to wait to see if the results could be sustained and it was only by middle of 1996 we realized that we were able to keep the virus below detection level for a good year and that opened up the door for what is called combination therapy today. 

Question: When did you first know that you wanted to be a scientist? 

David Ho: I’m not sure there was one moment that sparked my interest in math and sciences. I think as far as I could recall I have always had some interest in these areas. I certainly remember being a very curious child and perhaps that is a precursor to pursuing science, but I think there is also quite a bit of family influence that affected me gradually and that has to do with having a number of important family members who pursue science or engineering, including my father and a very important uncle. Their interest in technology and in sciences I think had a great deal of influence on my decision ultimately to pursue science. 

Question: How intense was your early education in science and math? 

David Ho: In terms of the math education in Taiwan, it was quite intense. So the math that I had learned by sixth grade served me pretty well until about eighth or ninth grade here in the U.S. In terms of science education we didn’t have that much formal science in Taiwan and I began to be exposed to that in the later years in middle school and of course in high school and so I think I was first grounded in math and then gradually shifted into the sciences. That is what I remember. 

Question: How did your early education influence your career? 

David Ho: My career did not go as planned. Initially as I said my interest was in physics, but through my college education I saw the coming of new biology and the promises of biomedical research, so I shifted my interest from physics to life sciences and ultimately went to medical school with the idea that I would somehow pursue medical research. And my real focus in medicine did not come until sometime later when I was doing my clinical training when I first encountered patients with what we now call AIDS and that sparked a real interest in me and I have pursued that kind of research ever since 1982. 

Question: Why did you get interested in infectious diseases? 

David Ho: I was initially interested in cardiology, but gradually I realized infections affect many, many people throughout the world and many of the infections are actually manageable or treatable and we can make an impact. In particular, I was interested in new infections that plague the world and when I was doing my medical training there were a number of new infections that emerged, including what we call Legionnaires’ disease and Lyme disease today. But as I was finishing medical training I encountered some of the earliest cases of HIV/AIDS and I realized that was a fascinating scientific challenge in terms of trying to understand what was the underlying cause, but I did not realize that it would become a major public health problem until sometime later. 

Question: What were your initial thoughts when you saw some of the first cases of AIDS? 

David Ho: I was doing my chief medical year as chief resident in internal medicine in the west side of Los Angeles when the very first case was a young homosexual man who presented to the hospital with a multitude of problems all of which suggest that his immune system was not functioning very well and that was curious to me because he was not getting any chemotherapy or radiation or any drugs that would suppress the immune system. It was immediately clear that we were looking at something new because such a case was never described in the textbooks. Then he was treated for his acute problems, but only to die a few weeks later. And then another case that was quite similar came in, and another and another. In rapid succession we had five such cases and it was too much of a coincidence to observe this. We realized that something was going on with a common theme and from their medical history it was pretty clear that it was a transmissible disease and the search was on to hunt down that microbe that was the underlying cause.

Recorded on April 20, 2010

The pioneering HIV/AIDS researcher used high school math in creating a drug "cocktail" to combat the worldwide epidemic.

Photos: Courtesy of Let Grow
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We don't have to tell you what it feels like when you don't get enough sleep. A night or two of that can be miserable; long-term sleeplessness is out-and-out debilitating. Though we know from personal experience that we need sleep — our cognitive, metabolic, cardiovascular, and immune functioning depend on it — a lack of it does more than just make you feel like you want to die. It can actually kill you, according to study of rats published in 1989. But why?

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The study, from researchers at Harvard Medical School (HMS), is published in the journal Cell.

An unexpected culprit

The new research examines the mechanisms at play in sleep-deprived fruit flies and in mice — long-term sleep-deprivation experiments with humans are considered ethically iffy.

What the scientists found is that death from sleep deprivation is always preceded by a buildup of Reactive Oxygen Species (ROS) in the gut. These are not, as their name implies, living organisms. ROS are reactive molecules that are part of the immune system's response to invading microbes, and recent research suggests they're paradoxically key players in normal cell signal transduction and cell cycling as well. However, having an excess of ROS leads to oxidative stress, which is linked to "macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging." To prevent this, cellular defenses typically maintain a balance between ROS production and removal.

"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation," says senior study author Dragana Rogulja, admitting, "We were surprised to find it was the gut that plays a key role in causing death." The accumulation occurred in both sleep-deprived fruit flies and mice.

"Even more surprising," Rogulja recalls, "we found that premature death could be prevented. Each morning, we would all gather around to look at the flies, with disbelief to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies." Fruit flies given any of 11 antioxidant compounds — including melatonin, lipoic acid and NAD — that neutralize ROS buildups remained active and lived a normal length of time in spite of sleep deprivation. (The researchers note that these antioxidants did not extend the lifespans of non-sleep deprived control subjects.)

fly with thought bubble that says "What? I'm awake!"

Image source: Tomasz Klejdysz/Shutterstock/Big Think

The experiments

The study's tests were managed by co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows at HMS.

You may wonder how you compel a fruit fly to sleep, or for that matter, how you keep one awake. The researchers ascertained that fruit flies doze off in response to being shaken, and thus were the control subjects induced to snooze in their individual, warmed tubes. Each subject occupied its own 29 °C (84F) tube.

For their sleepless cohort, fruit flies were genetically manipulated to express a heat-sensitive protein in specific neurons. These neurons are known to suppress sleep, and did so — the fruit flies' activity levels, or lack thereof, were tracked using infrared beams.

Starting at Day 10 of sleep deprivation, fruit flies began dying, with all of them dead by Day 20. Control flies lived up to 40 days.

The scientists sought out markers that would indicate cell damage in their sleepless subjects. They saw no difference in brain tissue and elsewhere between the well-rested and sleep-deprived fruit flies, with the exception of one fruit fly.

However, in the guts of sleep-deprived fruit flies was a massive accumulation of ROS, which peaked around Day 10. Says Vaccaro, "We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut." She adds, "I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research."

The experiments were repeated with mice who were gently kept awake for five days. Again, ROS built up over time in their small and large intestines but nowhere else.

As noted above, the administering of antioxidants alleviated the effect of the ROS buildup. In addition, flies that were modified to overproduce gut antioxidant enzymes were found to be immune to the damaging effects of sleep deprivation.

The research leaves some important questions unanswered. Says Kaplan Dor, "We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal." He hypothesizes, "Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these."

The HMS researchers are now investigating the chemical pathways by which sleep-deprivation triggers the ROS buildup, and the means by which the ROS wreak cell havoc.

"We need to understand the biology of how sleep deprivation damages the body so that we can find ways to prevent this harm," says Rogulja.

Referring to the value of this study to humans, she notes,"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it. We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."

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