Discovering the HIV/AIDS Drug "Cocktail" in an Equation
David Ho is the Scientific Director & CEO of the Aaron Diamond AIDS Research Center. Ho’s laboratory has focused on the pathogenesis of HIV infection. Most recently, his group has made substantial strides in the development of vaccines for HIV, as well as in the development of innovative prevention strategies. Ho also serves as head of the China AIDS Initiative, an alliance of Chinese and international organizations dedicated to helping China accelerate its response to HIV/AIDS.
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.
The pioneering HIV/AIDS researcher used high school math in creating a drug "cocktail" to combat the worldwide epidemic.
Once a week.
Subscribe to our weekly newsletter.
What makes some people more likely to shiver than others?
Some people just aren't bothered by the cold, no matter how low the temperature dips. And the reason for this may be in a person's genes.
Eating veggies is good for you. Now we can stop debating how much we should eat.
- A massive new study confirms that five servings of fruit and veggies a day can lower the risk of death.
- The maximum benefit is found at two servings of fruit and three of veggies—anything more offers no extra benefit according to the researchers.
- Not all fruits and veggies are equal. Leafy greens are better for you than starchy corn and potatoes.
An open letter predicts that a massive wall of rock is about to plunge into Barry Arm Fjord in Alaska.
- A remote area visited by tourists and cruises, and home to fishing villages, is about to be visited by a devastating tsunami.
- A wall of rock exposed by a receding glacier is about crash into the waters below.
- Glaciers hold such areas together — and when they're gone, bad stuff can be left behind.
The Barry Glacier gives its name to Alaska's Barry Arm Fjord, and a new open letter forecasts trouble ahead.
Thanks to global warming, the glacier has been retreating, so far removing two-thirds of its support for a steep mile-long slope, or scarp, containing perhaps 500 million cubic meters of material. (Think the Hoover Dam times several hundred.) The slope has been moving slowly since 1957, but scientists say it's become an avalanche waiting to happen, maybe within the next year, and likely within 20. When it does come crashing down into the fjord, it could set in motion a frightening tsunami overwhelming the fjord's normally peaceful waters .
The Barry Arm Fjord
Camping on the fjord's Black Sand Beach
Image source: Matt Zimmerman
The Barry Arm Fjord is a stretch of water between the Harriman Fjord and the Port Wills Fjord, located at the northwest corner of the well-known Prince William Sound. It's a beautiful area, home to a few hundred people supporting the local fishing industry, and it's also a popular destination for tourists — its Black Sand Beach is one of Alaska's most scenic — and cruise ships.
Not Alaska’s first watery rodeo, but likely the biggest
Image source: whrc.org
There have been at least two similar events in the state's recent history, though not on such a massive scale. On July 9, 1958, an earthquake nearby caused 40 million cubic yards of rock to suddenly slide 2,000 feet down into Lituya Bay, producing a tsunami whose peak waves reportedly reached 1,720 feet in height. By the time the wall of water reached the mouth of the bay, it was still 75 feet high. At Taan Fjord in 2015, a landslide caused a tsunami that crested at 600 feet. Both of these events thankfully occurred in sparsely populated areas, so few fatalities occurred.
The Barry Arm event will be larger than either of these by far.
"This is an enormous slope — the mass that could fail weighs over a billion tonnes," said geologist Dave Petley, speaking to Earther. "The internal structure of that rock mass, which will determine whether it collapses, is very complex. At the moment we don't know enough about it to be able to forecast its future behavior."
Outside of Alaska, on the west coast of Greenland, a landslide-produced tsunami towered 300 feet high, obliterating a fishing village in its path.
What the letter predicts for Barry Arm Fjord
Moving slowly at first...
Image source: whrc.org
"The effects would be especially severe near where the landslide enters the water at the head of Barry Arm. Additionally, areas of shallow water, or low-lying land near the shore, would be in danger even further from the source. A minor failure may not produce significant impacts beyond the inner parts of the fiord, while a complete failure could be destructive throughout Barry Arm, Harriman Fiord, and parts of Port Wells. Our initial results show complex impacts further from the landslide than Barry Arm, with over 30 foot waves in some distant bays, including Whittier."
The discovery of the impeding landslide began with an observation by the sister of geologist Hig Higman of Ground Truth, an organization in Seldovia, Alaska. Artist Valisa Higman was vacationing in the area and sent her brother some photos of worrying fractures she noticed in the slope, taken while she was on a boat cruising the fjord.
Higman confirmed his sister's hunch via available satellite imagery and, digging deeper, found that between 2009 and 2015 the slope had moved 600 feet downhill, leaving a prominent scar.
Ohio State's Chunli Dai unearthed a connection between the movement and the receding of the Barry Glacier. Comparison of the Barry Arm slope with other similar areas, combined with computer modeling of the possible resulting tsunamis, led to the publication of the group's letter.
While the full group of signatories from 14 organizations and institutions has only been working on the situation for a month, the implications were immediately clear. The signers include experts from Ohio State University, the University of Southern California, and the Anchorage and Fairbanks campuses of the University of Alaska.
Once informed of the open letter's contents, the Alaska's Department of Natural Resources immediately released a warning that "an increasingly likely landslide could generate a wave with devastating effects on fishermen and recreationalists."
How do you prepare for something like this?
Image source: whrc.org
The obvious question is what can be done to prepare for the landslide and tsunami? For one thing, there's more to understand about the upcoming event, and the researchers lay out their plan in the letter:
"To inform and refine hazard mitigation efforts, we would like to pursue several lines of investigation: Detect changes in the slope that might forewarn of a landslide, better understand what could trigger a landslide, and refine tsunami model projections. By mapping the landslide and nearby terrain, both above and below sea level, we can more accurately determine the basic physical dimensions of the landslide. This can be paired with GPS and seismic measurements made over time to see how the slope responds to changes in the glacier and to events like rainstorms and earthquakes. Field and satellite data can support near-real time hazard monitoring, while computer models of landslide and tsunami scenarios can help identify specific places that are most at risk."
In the letter, the authors reached out to those living in and visiting the area, asking, "What specific questions are most important to you?" and "What could be done to reduce the danger to people who want to visit or work in Barry Arm?" They also invited locals to let them know about any changes, including even small rock-falls and landslides.
The famous cognition test was reworked for cuttlefish. They did better than expected.
- Scientists recently ran the Stanford marshmallow experiment on cuttlefish and found they were pretty good at it.
- The test subjects could wait up to two minutes for a better tasting treat.
- The study suggests cuttlefish are smarter than you think but isn't the final word on how bright they are.
Proof that some people are less patient than invertebrates<iframe width="730" height="430" src="https://www.youtube.com/embed/H1yhGClUJ0U" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture" allowfullscreen></iframe><p> The common cuttlefish is a small cephalopod notable for producing sepia ink and relative intelligence for an invertebrate. Studies have shown them to be capable of remembering important details from previous foraging experiences, and to adjust their foraging strategies in response to changing circumstances. </p><p>In a new study, published in <a href="https://royalsocietypublishing.org/doi/10.1098/rspb.2020.3161" target="_blank" rel="noopener noreferrer">The Proceedings of the Royal Society B</a>, researchers demonstrated that the critters have mental capacities previously thought limited to vertebrates.</p><p>After determining that cuttlefish are willing to eat raw king prawns but prefer a live grass shrimp, the researchers trained them to associate certain symbols on see-through containers with a different level of accessibility. One symbol meant the cuttlefish could get into the box and eat the food inside right away, another meant there would be a delay before it opened, and the last indicated the container could not be opened.</p><p>The cephalopods were then trained to understand that upon entering one container, the food in the other would be removed. This training also introduced them to the idea of varying delay times for the boxes with the second <a href="https://www.sciencealert.com/cuttlefish-can-pass-a-cognitive-test-designed-for-children" target="_blank" rel="noopener noreferrer">symbol</a>. </p><p>Two of the cuttlefish recruited for the study "dropped out," at this point, but the remaining six—named Mica, Pinto, Demi, Franklin, Jebidiah, and Rogelio—all caught on to how things worked pretty quickly.</p><p>It was then that the actual experiment could begin. The cuttlefish were presented with two containers: one that could be opened immediately with a raw king prawn, and one that held a live grass shrimp that would only open after a delay. The subjects could always see both containers and had the ability to go to the immediate access option if they grew tired of waiting for the other. The poor control group was faced with a box that never opened and one they could get into right away.</p><p>In the end, the cuttlefish demonstrated that they would wait anywhere between 50 and 130 seconds for the better treat. This is the same length of time that some primates and birds have shown themselves to be able to wait for.</p><p>Further tests of the subject's cognitive abilities—they were tested to see how long it took them to associate a symbol with a prize and then on how long it took them to catch on when the symbols were switched—showed a relationship between how long a cuttlefish was willing to wait and how quickly it learned the associations. </p>
All of this is interesting, but what use could it possibly have?<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNTcxNzY2MS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY2MTM0MzYyMH0.lKFLPfutlflkzr_NM6WmnosKM1rU6UEIHWlyzWhYQNM/img.jpg?width=1245&coordinates=0%2C10%2C0%2C88&height=700" id="77c04" class="rm-shortcode" data-rm-shortcode-id="7eb9d5b2d890496756a69fb45ceac87c" data-rm-shortcode-name="rebelmouse-image" data-width="1245" data-height="700" />
A diagram showing the experimental set up. On the left is the control condition, on the right is the experimental condition.
Credit: Alexandra K. Schnell et al., 2021<p> As you can probably guess, the ability to delay gratification as part of a plan is not the most common thing in the animal kingdom. While humans, apes, some birds, and dogs can do it, less intelligent animals can't. </p><p>While it is reasonably simple to devise a hypothesis for why social humans, tool-making chimps, or hunting birds are able to delay gratification, the cuttlefish is neither social, a toolmaker, or is it hunting anything particularly <a href="https://gizmodo.com/cuttlefish-are-able-to-wait-for-a-reward-1846392756" target="_blank" rel="noopener noreferrer">intelligent</a>. Why they evolved this capacity is up for debate. </p><p>Lead author Alexandra Schnell of the University of Cambridge discussed their speculations on the evolutionary advantage cuttlefish might get out of this skill with <a href="https://www.eurekalert.org/pub_releases/2021-03/mbl-qc022621.php" target="_blank" rel="noopener noreferrer">Eurekalert:</a> </p><p style="margin-left: 20px;"> "Cuttlefish spend most of their time camouflaging, sitting and waiting, punctuated by brief periods of foraging. They break camouflage when they forage, so they are exposed to every predator in the ocean that wants to eat them. We speculate that delayed gratification may have evolved as a byproduct of this, so the cuttlefish can optimize foraging by waiting to choose better quality food."</p><p>Given the unique evolutionary tree of the cuttlefish, its cognitive abilities are an example of convergent evolution, in which two unrelated animals, in this case primates and cuttlefish, evolve the same trait to solve similar problems. These findings could help shed light on the evolution of the cuttlefish and its relatives. </p><p> It should be noted that this study isn't definitive; at the moment, we can't make a useful comparison between the overall intelligence of the cuttlefish and the other animals that can or cannot pass some variation of the marshmallow test.</p><p>Despite this, the results are quite exciting and will likely influence future research into animal intelligence. If the common cuttlefish can pass the marshmallow test, what else can?</p>