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Can Blood Thinners Keep Moderately Ill COVID-19 Patients Out of the ICU?

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Blood Clot
Credit: iStock

One of many troubling complications of infection with SARS-CoV-2, the coronavirus that causes COVID-19, is its ability to trigger the formation of multiple blood clots, most often in older people but sometimes in younger ones, too. It raises the question of whether and when more aggressive blood thinning treatments might improve outcomes for people hospitalized for COVID-19.

The answer to this question is desperately needed to help guide clinical practice. So, I’m happy to report interim results of three large clinical trials spanning four continents and more than 300 hospitals that are beginning to provide critical evidence on this very question [1]. While it will take time to reach a solid consensus, the findings based on more than 1,000 moderately ill patients suggest that full doses of blood thinners are safe and can help to keep folks hospitalized with COVID-19 from becoming more severely ill and requiring some form of organ support.

The results that are in so far suggest that individuals hospitalized, but not severely ill, with COVID-19 who received a full intravenous dose of the common blood thinner heparin were less likely to need vital organ support, including mechanical ventilation, compared to those who received the lower “prophylactic” subcutaneous dose. It’s important to note that these findings are in contrast to results announced last month indicating that routine use of a full dose of blood thinner for patients already critically ill and in the ICU wasn’t beneficial and may even have been harmful in some cases [2]. This is a compelling example of how critical it is to stratify patients with different severity in clinical trials—what might help one subgroup might be of no benefit, or even harmful, in another.

More study is clearly needed to sort out all the details about when more aggressive blood thinning treatment is warranted. Trial investigators are now working to make the full results available to help inform a doctor’s decisions about how to best to treat their patients hospitalized with COVID-19. It’s worth noting that these trials are overseen by independent review boards, which routinely evaluate the data and are composed of experts in ethics, biostatistics, clinical trials, and blood clotting disorders.

These clinical trials were made possible in part by the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership and its ACTIV-4 Antithrombotics trials—along with similar initiatives in Canada, Australia, and the European Union. The ACTIV-4 trials are overseen by the NIH’s National Heart, Lung, and Blood institute and funded by Operation Warp Speed.

This ACTIV-4 trial is one of three Phase 3 clinical trials evaluating the safety and effectiveness of blood thinners for patients with COVID-19 [3]. Another ongoing trial is investigating whether blood thinners are beneficial for newly diagnosed COVID-19 patients who do not require hospitalization. There are also plans to explore the use of blood thinners for patients after they’ve been discharged from the hospital following a diagnosis of moderate to severe COVID-19 and to establish more precise methods for identifying which patients with COVID-19 are most at risk for developing life-threatening blood clots.

Meanwhile, research teams are exploring other potentially promising ways to repurpose existing therapeutics and improve COVID-19 outcomes. In fact, the very day that these latest findings on blood thinners were announced, another group at The Montreal Heart Institute, Canada, announced preliminary results of the international COLCORONA trial, testing the use of colchicine—an anti-inflammatory drug widely used to treat gout and other conditions—for patients diagnosed with COVID-19 [4].

Their early findings in treating patients just after a confirmed diagnosis of COVID-19 suggest that colchicine might reduce the risk of death or hospitalization compared to patients given a placebo. In the more than 4,100 individuals with a proven diagnosis of COVID-19, colchicine significantly reduced hospitalizations by 25 percent, the need for mechanical ventilation by 50 percent, and deaths by 44 percent. Still, the actual numbers of individuals represented by these percentages was small.

Time will tell whether and for which patients colchicine and blood thinners prove most useful in treating COVID-19. For those answers, we’ll have to await the analysis of more data. But the early findings on both treatment strategies come as a welcome reminder that we continue to make progress each day on such critical questions about which existing treatments can be put to work to improve outcomes for people with COVID-19. Together with our efforts to slow the spread of SARS-CoV-2, finding better ways to treat those who do get sick and prevent some of the worst outcomes will help us finally put this terrible pandemic behind us.

References:

[1] Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. National Heart, Lung, and Blood Institute. January 22, 2021.

[2] NIH ACTIV trial of blood thinners pauses enrollment of critically ill COVID-19 patients. National Heart, Lung, and Blood Institute. December 22, 2020.

[3] NIH ACTIV initiative launches adaptive clinical trials of blood-clotting treatments for COVID-19. National Heart, Lung, and Blood Institute. September 10, 2020.

[4] Colchicine reduces the risk of COVID-19-related complications. The Montreal Heart Institute. January 22, 2021.

Links:

COVID-19 Research (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

NIH Support: National Heart, Lung, and Blood Institute


Discussing the Long Arc of Discovery with NIH’s Newest Nobelist

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Discussion with Dr. Harvey Alter

It’s been a tough year for our whole world because of everything that’s happening as a result of the coronavirus disease 2019 (COVID-19) pandemic. Yet there are bright spots that still shine through, and this week brought some fantastic news about NIH-supported researchers being named 2020 Nobel Prize Laureates for their pioneering work in two important fields: Chemistry and Physiology or Medicine.

In the wee hours of Wednesday morning, NIH grantee Jennifer A. Doudna, a biochemist at the University of California, Berkeley, got word that she and Emmanuelle Charpentier, a microbiologist at the Max Planck Institute for Infection Biology, Berlin, Germany, had won the 2020 Nobel Prize in Chemistry for developing the CRISPR/cas approach to genome editing. Doudna has received continuous NIH funding since 1997, mainly from the National Institute of General Medical Sciences and National Human Genome Research Institute.

The CRISPR/cas system, which consists of a short segment of RNA attached to the cas enzyme, provides the ability to make very precise changes in the sequence, or spelling, of the genetic instruction books of humans and other species. If used to make non-heritable edits in relevant tissues, such technology holds enormous potential to treat or even cure a wide range of devastating diseases, including thousands of genetic disorders where the DNA misspelling is precisely known.

Just two days before Doudna learned of her big award, a scientist who’s spent almost his entire career at the NIH campus in Bethesda, MD, received news that he too was getting a Nobel—the 2020 Nobel Prize in Physiology or Medicine. Harvey Alter, a senior scholar in the NIH Clinical Center’s Transfusion Medicine Department, was recognized for his contributions in identifying the potentially deadly hepatitis C virus. He shares this year’s prize with Michael Houghton, now with University of Alberta, Edmonton, and Charles M. Rice, The Rockefeller University, New York, who’s received continuous NIH funding since 1987, mainly from the National Institute of Allergy and Infectious Diseases.

In a long arc of discovery rooted in basic, translational, and clinical research that spanned several decades, Alter and his colleagues doggedly pursued biological clues that at first led to tests, then life-saving treatments, and, today, the very real hope of eradicating the global health threat posed by hepatitis C infections.

We at NIH are particularly proud of the fact that Alter is the sixth Nobel Prize winner—and the first in 26 years—to have done the entirety of his award-winning research in our Intramural Research Program. So, I jumped at the opportunity to talk with Harvey on NIH’s Facebook Live and Twitter chats just hours after he got the good news on Monday. Here’s a condensed version of our conversation, which took place on the NIH campus, but at a safe physical distance to minimize the risk of COVID-19 spread.

Collins: Harvey, let me start off by asking, how did you find out you’d won the Nobel Prize?

Alter: At 4:15 this morning. I was asleep and heard the telephone ringing. I ignored it. Five minutes later, I got another call. Now, I’m getting kind of perturbed. But I ignored it, thinking the call must be some kind of solicitation. Then, the phone rang a third time. I answered it, prepared to tell the person on the other end not to call me anymore. I heard a man’s voice say, “I’m the Secretary General of the Nobel Prize, calling you from Stockholm.” At that point, I just froze.

Collins: Did you think it might be a hoax?

Alter: No, I didn’t think it was a hoax. But I wasn’t expecting to win the prize. I knew about three years ago that I’d been on a Nobel list. But it didn’t happen, and I just forgot about it. Truthfully, I didn’t know that today was the day that the announcement was being made. The news came as a complete shock.

Collins: Please say a few words about viral hepatitis. What is it?

Alter: Sure. Viral hepatitis is an infection of the liver that causes inflammation and can lead to scarring, or cirrhosis. Early in my career, two viruses were known to cause the disease. One was the hepatitis A virus. You got it from consuming contaminated water or food. The second was the hepatitis B virus, which has a blood-borne transmission, typically from blood transfusions. In the 1970s, we realized that some other agent was causing most of the hepatitis from blood transfusions. Since it wasn’t A and it wasn’t B, we cleverly decided to call it: non-A, non-B. We did that because we hadn’t yet proven that the causative agent was a virus.

Collins: So, even though you screened donor units for the hepatitis B virus to eliminate tainted blood, people were still getting hepatitis from blood transfusions. How did you go about trying to solve this mystery?

Alter: The main thing was to follow patients prospectively, meaning forward in time. We drew a blood sample before they were transfused, and then serially afterwards. We saved those samples and also the donor samples to compare them. Using a liver function test, we found that 30 percent of patients who had open heart surgery at NIH prior to 1970 developed liver abnormalities indicative of hepatitis. That’s 1 in 3 people.

We then looked for the reasons. We found the main one was our source of blood. We were buying blood, which was then in short supply, from commercial laboratories. It turned out that their paid donors were engaging in high-risk behaviors [Note: like IV drug users sharing hypodermic needles]. We immediately stopped using these laboratories, and, through various other measures, we got the rate down to around 4 percent in 1987.

That’s when Michael Houghton, then at Chiron Corp. and a co-recipient of this year’s prize, cloned the virus. Think about it, he and his colleagues looked at 6 million clones and found just one that reacted with the convalescent serum of a patient with non-A, non-B. In other words, having contracted the virus, the patient already made antibodies against it that were present in the serum. If that one clone came from the virus, the antibodies in the serum would recognize it. They did, and Chiron then developed an assay to detect antibodies to the virus.

Collins: And that’s when they contacted you.

Alter: Yes, they wanted to use our panel of patient blood samples that had fooled a lot of people who claimed to have developed a non-A, non-B assay. Nobody else had “broken” this panel, but the Chiron Corp. did. We found that every case of non-A, non-B was really hepatitis C, the agent that they had cloned. Hepatitis C was the missing piece. As far as we could tell, there were no other agents beside hepatitis B and C that would result in transfusion transmission of the disease.

Collins: This story is clearly one of persistence. So, say something about persistence as an important characteristic of a scientist. You’re a great example of someone who was always looking out for opportunities that might not have seemed so promising at first.

Alter: I first learned persistence from Dr. Baruch Blumberg, my first NIH mentor who discovered the hepatitis B virus in 1967. [Note: Other NIH researchers identified the hepatitis A virus in 1977] The discovery started when we found this “Australian antigen,” a molecular structure that the immune system recognizes as foreign and attacks. It was a serendipitous finding that could have been easily just dropped. But he just kept at it, kept at it, kept at it. He had this famous wall where he diagrammed his hypotheses with all the contingencies if one worked or failed. Then, all of a sudden, the antigen was associated with hepatitis B. It became the basis of the hepatitis B vaccine, which is highly effective and used throughout the world. Dr. Blumberg won the Nobel Prize for his work on the hepatitis B virus in 1976.

Collins: Sometimes people look at NIH and ask why we don’t focus all of our efforts on curing a particular disease. I keep answering, ‘Wait a moment, we don’t know enough to know how to do that.’ What’s the balance that we ought to be seeking between basic research and clinical applications?

Alter: There is this tendency now to pursue highly directed research to solve a problem. That’s certainly how biopharma works. They want a payoff. The NIH is different. It’s a place where you can pursue your scientific interests, wherever they lead. The NIH leadership understands that the details of a problem often aren’t obvious at first. Researchers need to be allowed to observe things and then to pursue their leads as far as possible, with the understanding that not everything will work out. I think it’s very important to keep this basic research component in parallel with the more clinical applications. In the case of hepatitis C, it started as a clinical problem that led to a basic research investigation, which led back to a clinical problem. It was bedside-to-bench-to-bedside.

Collins: Are people still getting infected with hepatitis C?

Alter: Yes, hepatitis C remains a global problem. Seventy million people have contracted the virus, though the majority are generally asymptomatic, meaning they don’t get sick from it. Instead, they carry around the virus for decades without knowing it. That’s because the hepatitis C virus likes to persist, and our immune system doesn’t seem to be able to get rid of it easily.

However, some of those infected will have bad outcomes, such as cirrhosis or cancer of the liver. But there’s no way of knowing who will and who won’t get sick over time. The trick now is to identify people when they’re asymptomatic and without obvious disease.

That involves testing. We’re in a unique position with hepatitis C, where we have great tests that are highly sensitive and very specific to the virus. We also have great treatments. We can cure everybody who is tested and found to be positive.

Collins: People may be surprised to hear that. Here is a chronic viral illness, for which we actually have a cure. That’s come along fairly recently. Say a bit more about that—it’s such a great story of success.

Alter: For many years, the only treatment for hepatitis C was interferon, a very difficult treatment that initially had only about a 6 percent cure rate. With further progress, it got up to around 50 percent. But the big breakthrough came in the late 1990s when Gilead Corp., having the sequenced genome of the hepatitis C virus, deduced what it needs to replicate. If we know what it needs and we interfere with that, we can stop the replication. Gilead came out with a blockbuster drug that, now in combination with another drug, aims at two different sites on the virus and cures at least 98 percent of people. It’s an oral therapy taken for only 12 weeks, sometimes as little as 8 weeks, and with virtually no side-effects. It’s like a miracle drug.

Collins: What would you say to somebody who is thinking about becoming a scientist? How do you pick an area of research that will be right for you?

Alter: It’s a tough question. Medical research is very difficult, but there’s nothing more rewarding than doing something for patients and to see a good outcome like we had with hepatitis C.

The best path forward is to work for somebody who’s already an established investigator and a good teacher. Work in his or her lab for a few years and get involved in a project. I’ve learned not get into a lot of projects. Get into something where you can become the expert and pursue it.
The other thing is to collaborate. There’s no way that one person can do everything these days. You need too much technology and lots of different areas of expertise.

Collins: You took on a high-risk project in which you didn’t know that you’d find the answer. What’s the right balance between a project that you know will be productive, and something that might be risky, but, boy, if it works, could be transformative? How did you decide which of those paths to go?

Alter: I don’t think I decided. I just went! But there were interim rewards. Finding that the paid donors were bad was a reward and it had a big impact. And the different donor testing, decreasing the amount of blood [transfused], there were all kinds of steps along the way that gave you a reward. Now, did I think that there would be a treatment, an eradication of post-transfusion hepatitis at the end of my line? No, I didn’t.

And it wouldn’t have happened if it was only me. I just got the ball rolling. But it needed Houghton’s group. It needed the technology of Charlie Rice, a co-recipient of this year’s Nobel Prize. It needed joint company involvement. So, it required massive cooperation, and I have to say that here at NIH, Bob Purcell did most of the really basic work in his lab. Patrizia Farci, my closest collaborator, does things that I can’t do. You just need people who have a different expertise.

Collins: Harvey, it’s been maybe six hours since you found out that you won the Nobel Prize. How are you going to spend the rest of your day?

Alter: Well, I have to tell you a story that just happened. We had a press conference earlier today at NIH. Afterwards, I wanted to return to my NIH office and the easiest route was through the parking garage across the street from where we held the press conference. When I entered the garage, a security guard said, “You can’t come in, you haven’t been screened for COVID.” I assured him that I had been screened when I drove onto the NIH campus. He repeated that I had to go around to the front of the building to get screened.

Finally, I said to him, “Would it make any difference if I told you that I won the Nobel Prize today?” He replied, ‘That’s nice, but you must go around to the front of the building.’” So, winning the Nobel doesn’t give you immediate rewards!

Collins: Let me find that security guard and give him a bonus for doing a good job. Well, Harvey, will there be that trip to Stockholm coming up in December?

Alter: Not this year. I’ve heard that they will invite us to Stockholm next year to receive the award. But there’s going to be something in the US. I don’t know what it will be. I’ll invite you.

Collins: I will be glad to take part in the celebration. Well, Harvey, I really want to thank you for taking some time on this special day to reflect on your career and how the Nobel Committee came calling at 4:30 this morning. We’re really proud of you!

Alter: Thank you.

Links:

Hepatitis C (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

The Nobel Assembly at Karolinska Institutet has today decided to award the 2020 Nobel Prize in Physiology or Medicine jointly to Harvey J. Alter, Michael Houghton and Charles M. Rice for the discovery of Hepatitis C virus,” Nobel Prize announcement, October 5,2020.

Harvey Alter (Clinical Center/NIH)

The Road Not Taken, or How I Learned to Love the Liver: A Personal Perspective on Hepatitis History” Alter HJ, Hepatology. 2014 Jan;59(1):4-12.

Reflections on the History of HCV: A Posthumous Examination.” Alter HJ, Farci P, Bukh J, Purcell RH. Clinical Liver Disease, 15:1, Feb 2020.

Is Elimination of Hepatitis B and C a Pipe Dream or Reality?” Alter HJ, Chisari FV. Gastroenterology. 2019 Jan;156(2):294-296.

Michael Houghton (University of Alberta, Edmonton)

Charles Rice (The Rockefeller University, New York)

What is genome editing? (National Human Genome Research Institute/NIH)

Jennifer Doudna (University of California, Berkeley)

Emmanuelle Charpentier (Max Planck Institute for Infection Biology, Berlin, Germany)


Genome Data Help Track Community Spread of COVID-19

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RNA Virus
Credit: iStock/vchal

Contact tracing, a term that’s been in the news lately, is a crucial tool for controlling the spread of SARS-CoV-2, the novel coronavirus that causes COVID-19. It depends on quick, efficient identification of an infected individual, followed by identification of all who’ve recently been in close contact with that person so the contacts can self-quarantine to break the chain of transmission.

Properly carried out, contact tracing can be extremely effective. It can also be extremely challenging when battling a stealth virus like SARS-CoV-2, especially when the virus is spreading rapidly.

But there are some innovative ways to enhance contact tracing. In a new study, published in the journal Nature Medicine, researchers in Australia demonstrate one of them: assembling genomic data about the virus to assist contact tracing efforts. This so-called genomic surveillance builds on the idea that when the virus is passed from person to person over a few months, it can acquire random variations in the sequence of its genetic material. These unique variations serve as distinctive genomic “fingerprints.”

When COVID-19 starts circulating in a community, researchers can fingerprint the genomes of SARS-CoV-2 obtained from newly infected people. This timely information helps to tell whether that particular virus has been spreading locally for a while or has just arrived from another part of the world. It can also show where the viral subtype has been spreading through a community or, best of all, when it has stopped circulating.

The recent study was led by Vitali Sintchenko at the University of Sydney. His team worked in parallel with contact tracers at the Ministry of Health in New South Wales (NSW), Australia’s most populous state, to contain the initial SARS-CoV-2 outbreak from late January through March 2020.

The team performed genomic surveillance, using sequencing data obtained within about five days, to understand local transmission patterns. They also wanted to compare what they learned from genomic surveillance to predictions made by a sophisticated computer model of how the virus might spread amongst Australia’s approximately 24 million citizens.

Of the 1,617 known cases in Sydney over the three-month study period, researchers sequenced viral genomes from 209 (13 percent) of them. By comparing those sequences to others circulating overseas, they found a lot of sequence diversity, indicating that the novel coronavirus had been introduced to Sydney many times from many places all over the world.

They then used the sequencing data to better understand how the virus was spreading through the local community. Their analysis found that the 209 cases under study included 27 distinct genomic fingerprints. Based on the close similarity of their genomic fingerprints, a significant share of the COVID-19 cases appeared to have stemmed from the direct spread of the virus among people in specific places or facilities.

What was most striking was that the genomic evidence helped to provide information that contact tracers otherwise would have lacked. For instance, the genomic data allowed the researchers to identify previously unsuspected links between certain cases of COVID-19. It also helped to confirm other links that were otherwise unclear.

All told, researchers used the genomic evidence to cluster almost 40 percent of COVID-19 cases (81 of 209) for which the community-based data alone couldn’t identify a known contact source for the infection. That included 26 cases in which an individual who’d recently arrived in Australia from overseas spread the infection to others who hadn’t traveled. The genomic information also helped to identify likely sources in the community for another 15 locally acquired cases that weren’t known based on community data.

The researchers compared their genome surveillance data to SARS-CoV-2’s expected spread as modeled in a computer simulation based on travel to and from Australia over the time period in question. Because the study involved just 13 percent of all known COVID-19 cases in Sydney between late January through March, it’s not surprising that the genomic data presents an incomplete picture, detecting only a portion of the possible chains of transmission expected in the simulation model.

Nevertheless, the findings demonstrate the value of genomic data for tracking the virus and pinpointing exactly where in the community it is spreading. This can help to fill in important gaps in the community-based data that contact tracers often use. Even more exciting, by combining traditional contact tracing, genomic surveillance, and mathematical modeling with other emerging tools at our disposal, it may be possible to get a clearer picture of the movement of SARS-CoV-2 and put more targeted public health measures in place to slow and eventually stop its deadly spread.

Reference:

[1] Revealing COVID-19 transmission in Australia by SARS-CoV-2 genome sequencing and agent-based modeling. Rockett RJ, Arnott A, Lam C, et al. Nat Med. 2020 July 9. [Published online ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

Vitali Sintchenko (University of Sydney, Australia)


Happy Twentieth Anniversary, NCCIH

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Happy Twentieth, NCCIH
I was honored to give opening remarks at a day-long scientific symposium marking the 20th anniversary of NIH’s National Center for Complementary and Integrative Health (NCCIH). Lorimer Moseley, a researcher at the University of South Australia, presented the keynote lecture, “Why We Need a Pain Revolution: From Science to Practice,” as the 2019 Stephen E. Straus Distinguished Lecture in the Science of Complementary Therapies. The symposium was held on September 23, 2019. Congratulations on your 20th, NCCIH! Credit: NIH

Combating Mosquitoes with an Engineered Fungus

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Caption: Anopheles coluzzii mosquito with transgenic fungus (green) emerging from its body after death. Credit: Brian Lovett, University of Maryland, College Park

Almost everywhere humans live on this planet, mosquitoes carry microbes that cause potentially deadly diseases, from West Nile virus to malaria. While chemical insecticides offer a line of defense, mosquito populations often grow resistant to them. So, it’s intriguing to learn that we may now have another ally in this important fight: a genetically engineered fungus!

Reporting in the journal Science, an international research team supported by NIH describes how this new approach might be used to combat malaria [1]. A fungus called Metarhizium pingshaense is a natural enemy of the mosquito, but, by itself, it kills mosquitoes too slowly to control transmission of malaria. To make this fungus an even more efficient mosquito killer, researchers engineered it to carry a gene encoding a toxin, derived from a spider, that is deadly to insects. Tests of the souped-up fungus in a unique contained facility designed to simulate a West African village found it safely and rapidly killed insecticide-resistant mosquitoes, reducing their numbers by more than 99 percent within 45 days.

Mosquitoes are the deadliest animals in the world. More than 3.2 billion people—about half of all humans—are at risk for malaria, and more than 400,000 die each year from the disease. Other mosquito-borne illnesses, including Zika and dengue viruses, sicken millions more each year. By combining existing insect control strategies with the latest technical innovation, it should be possible to lower those numbers.

In the latest study, Raymond St. Leger and Brian Lovett, University of Maryland, College Park, teamed with Abdoulaye Diabate and colleagues from Institut de Recherche en Sciences de la Santé/Cente Muraz, Burkina Faso, West Africa. The researchers employed a strategy that’s been in use around the world for more than 100 years to control agricultural pests.

The approach involves the fungal species Metarhizium, which kills a variety of insects. Earlier studies had shown that spores from a specific Metarhizium strain could make a big enough dent in a mosquito population to raise the possibility of using the fungus to reduce infective bites among humans [2]. But killing off the mosquitoes required very large quantities of fungal spores and usually took a couple of weeks.

Here’s where things turned innovative. To boost the fungus’s potency, St. Leger and colleagues used genetic engineering to add a toxin derived from the Australian Blue Mountains funnel-web spider. The toxin came with a major advantage: the U.S. Environmental Protection Agency (EPA) already has approved its use as a safe-and-effective insecticidal protein.

Besides giving the engineered fungus that ability to produce a spider toxin, the researchers added another clever element. They didn’t want the fungus to produce the toxin all the time—only after it comes in contact with a mosquito’s hemolymph, the insect equivalent of blood. So, they needed to insert a control switch, and the researchers knew just where to find the needed part.

Once inside a mosquito, the fungus naturally produces a structural protein called collagen that shields it from the insect’s immune system. A genetic switch that turns “on” when it detects an insect’s hemolymph controls that collagen production. To ensure that the spider toxin was produced at just the right time, the researchers hotwired their Metarhizium to begin producing it under the control of this same genetic switch.

The next step was to test this modified organism in a more natural, but controlled, environment. The researchers spent more than a year in Burkina Faso building a specialized facility called a MosquitoSphere. It’s similar to a very large greenhouse, but with mosquito netting instead of glass.

The MosquitoSphere has six separate compartments, four of which contain West African huts, along with native plants and breeding sites for mosquitoes. The researchers hung a black cotton sheet, previously soaked in sesame oil, on the wall of a hut in each of three chambers.

In one hut, the sesame oil contained genetically engineered fungal spores. In the second hut, the oil contained natural fungal spores. In the third hut, there were no spores at all. Then, they released 1,000 adult male and 500 adult female mosquitoes into each chamber and watched what happened over the next 45 days.

In the hut without spores, the mosquitoes established a stable population of almost 1,400. In the chamber with the natural spores, 450 mosquitoes survived. But, in the chamber with the engineered fungus, the researchers counted just 13 survivors—too few to sustain a viable population.

The researchers say they suspect the fungus would be relatively easy to contain in nature. It’s sticky and not easily airborne. The spores are also extremely sensitive to sunlight, making it difficult for them to travel far. Importantly, the fungus didn’t harm other beneficial insects, including honeybees.

Caution is warranted before considering the release of a genetically engineered organism into the wild. In the meantime, the genetically engineered fungus also will serve as a platform for continued technology development.

The system can be readily adapted to target mosquitoes or other insects , perhaps using different natural toxins if insects might grow resistant to Metarhizium just as they have to traditional insecticides. Interestingly, the researchers note that the engineered fungi appear to make mosquitoes sensitive to chemical insecticides again, suggesting that the two types of insect-killers might be used successfully in combination.

References:

[1] Transgenic Metarhizium rapidly kills mosquitoes in a malaria-endemic region of Burkina Faso. Lovett B, Bilgo E, Millogo SA, Ouattarra AK, Sare I, Gnambani EJ, Dabire RK, Diabate A, St Leger RJ. Science. 2019 May 31;364(6443):894-897.

[2] An entomopathogenic fungus for control of adult African malaria mosquitoes. Scholte EJ, Ng’habi K, Kihonda J, Takken W, Paaijmans K, Abdulla S, Killeen GF, Knols BG. Science. 2005 Jun 10;308(5728):1641-2.

Links:

Transgenic Fungus Rapidly Killed Malaria Mosquitoes in West African Study (University of Maryland News Release)

Malaria (National Institute of Allergy and Infectious Diseases/NIH)

Funnel-Web Spiders (Australian Museum, Sydney)

Video: 2016 Grand Challenges Spotlight Talk: Abdoulaye Diabaté (YouTube)

Raymond St. Leger (University of Maryland, College Park)

NIH Support: National Institute of Allergy and Infectious Diseases


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