A blood test for analysis of HIV.
Last week, top experts on HIV/AIDS convened in Amsterdam for the 22nd International AIDS conference, and the mood was not great. Even though remarkable advances in treating HIV have led to effective management for many people living with the disease, and its overall incidence has declined, there are signs that the virus could make a troubling comeback.
"In a perfect world, we'd get a vaccine like the HPV vaccine that was 100% effective and I think that's ultimately what we're going to strive for."
Growing resistance to current HIV drugs, a population boom in Sub-Saharan Africa, and insufficient public health resources are all poised to contribute to a second AIDS pandemic, according to published reports.
Already, the virus is nowhere near under control. Though the infection rate has declined 47 percent since its peak in 1996, last year 1.8 million people became newly infected with HIV around the world, and 37 million people are currently living with it. About 1 million people die of AIDS every year, making it the fourth biggest killer in low-income countries.
Leapsmag Editor-in-Chief Kira Peikoff reached out to Dr. Carl Dieffenbach, Director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, to find out what the U.S. government is doing to develop an HIV vaccine and cure. This interview has been edited and condensed for clarity.
What is the general trajectory of research in HIV/AIDS today?
We can break it down to two specific domains: focus on treatment and cure, and prevention.
Let's start with people living with HIV. This is the area where we've had the most success over the past 30 plus years, because we've taken a disease that was essentially a death sentence and converted it through the development of medications to a treatable chronic disease.
The second half of this equation is, can we cure or create a functional cure for people living with HIV? And the definition of functional cure would be the absence of circulating virus in the body in the absence of therapy. Essentially the human body would control the HIV infection within the individual. That is a much more, very early research stage of discovery. There are some interesting signals but it's still in need of innovation.
I'd like to make a contrast between what we are able to do with a virus called Hepatitis C and what we can do with the virus HIV. Hep C, with 12 weeks of highly active antiviral therapy, we can cure 95 to 100% of infections. With HIV, we cannot do that. The difference is the behavior of the virus. HIV integrates into the host's genome. Hep C is an RNA virus that stays in the cytoplasm of the cell and never gets into the DNA.
On the prevention side, we have two strategies: The first is pre-exposure prophylaxis. Then of course, we have the need for a safe, effective and durable HIV vaccine, which is a very active area of discovery. We've had some spectacular success with RV144, and we're following up on that success, and other vaccines are in the pipeline. Whether they are sufficient to provide the level of durability and activity is not yet clear, but progress has been made and there's still the need for innovation.
The most important breakthrough in the past 5 to 10 years has been the discovery of broad neutralizing monoclonal antibodies. They are proteins that the body makes, and not everybody who's HIV infected makes these antibodies, but we've been able to clone out these antibodies from certain individuals that are highly potent, and when used either singly or in combination, can truly neutralize the vast majority of HIV strains. Can those be used by themselves as treatment or as prevention? That is the question.
Can you explain more about RV144 and why you consider it a success?
Prior to RV144, we had run a number of vaccine studies and nothing had ever statistically shown to be protective. RV144 showed a level of efficacy of about 31 percent, which was statistically significant. Not enough to take forward into other studies, but it allowed us to generate some ideas about why this worked, go back to the drawing board, and redesign the immunogens to optimize and test the next generation for this vaccine. We just recently opened that new study, the follow-up to RV144, called HVTN702. That's up and enrolling and moving along quite nicely.
Carl Dieffenbach, Director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases
(Courtesy)
Where is that enrolling?
Primarily in Sub-Saharan Africa and South Africa.
When will you expect to see signals from that?
Between 2020 and 2021. It's complicated because the signal also takes into account the durability. After a certain time of vaccination, we're going to count up endpoints.
How would you explain the main scientific obstacle in the way of creating a very efficacious HIV vaccine?
Simply put, it's the black box of the human immune system. HIV employs a shield technology, and the virus is constantly changing its shield to protect itself, but there are some key parts of the virus that it cannot shield, so that's the trick – to be able to target that.
So, you're trying to find the Achilles' Heel of the virus?
Exactly. To make a flu vaccine or a Zika vaccine or even an Ebola vaccine, the virus is a little bit more forthcoming with the target. In HIV, the virus does everything in its power to hide the target, so we're dealing with a well-adapted [adversary] that actively avoids neutralization. That's the scientific challenge we face.
What's next?
On the vaccine side, we are currently performing, in collaboration with partners, two vaccine trials – HVTN702, which we talked about, and another one called 705. If either of those are highly successful, they would both require an additional phase 3 clinical trial before they could be licensed. This is an important but not final step. Then we would move into scale up to global vaccination. Those conversations have begun but they are not very far along and need additional attention.
What percent of people in the current trials would need to be protected to move on to phase 3?
Between 50 and 60 percent. That comes with this question of durability: how long does the vaccine last?
It also includes, can we simplify the vaccine regimen? The vaccines we're testing right now are multiple shots over a period of time. Can we get more like the polio or smallpox vaccine, a shot with a booster down the road?
We're dealing with sovereign nations. We're doing this in partnership, not as helicopter-type researchers.
If these current trials pan out, do you think kids in the developed world will end up getting an HIV vaccine one day? Or just people in-at risk areas?
That's a good question. I don't have an answer to that. In a perfect world, we'd get a vaccine like the HPV vaccine that was 100% effective and I think that's ultimately what we're going to strive for. That's where that second or third generation of vaccines that trigger broad neutralizing antibodies come in.
With any luck at all, globally, the combination of antiretroviral treatment, pre-exposure prophylaxis and other prevention and treatment strategies will lower the incidence rate where the HIV pandemic continues to wane, and we will then be able to either target the vaccine or roll it out in a way that is both cost effective and destigmatizing.
And also, what does the country want? We're dealing with sovereign nations. We're doing this in partnership, not as helicopter-type researchers.
How close do you think we are globally to eradicating HIV infections?
Eradication's a big word. It means no new infections. We are nowhere close to eradicating HIV. Whether or not we can continue to bend the curve on the epidemic and have less infections so that the total number of people continues to decline over time, I think we can achieve that if we had the political will. And that's not just the U.S. political will. That's the will of the world. We have the tools, albeit they're not perfect. But that's where a vaccine that is efficacious and simple to deliver could be the gamechanger.
Katalin Karikó, pictured, and Drew Weissman won the Nobel Prize for advances in mRNA research that led to the first Covid vaccines.
The work for which they garnered the illustrious award and its accompanying $1,000,000 cash windfall was completed about two decades ago, wrought through long hours in the lab over many arduous years. But humanity collectively benefited from its life-saving outcome three years ago, when both Moderna and Pfizer/BioNTech’s mRNA vaccines against COVID were found to be safe and highly effective at preventing severe disease. Billions of doses have since been given out to protect humans from the upstart viral scourge.
“I thought of going somewhere else, or doing something else,” said Katalin Karikó. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
Unlocking the power of mRNA
Weissman and Karikó unlocked mRNA vaccines for the world back in the early 2000s when they made a key breakthrough. Messenger RNA molecules are essentially instructions for cells’ ribosomes to make specific proteins, so in the 1980s and 1990s, researchers started wondering if sneaking mRNA into the body could trigger cells to manufacture antibodies, enzymes, or growth agents for protecting against infection, treating disease, or repairing tissues. But there was a big problem: injecting this synthetic mRNA triggered a dangerous, inflammatory immune response resulting in the mRNA’s destruction.
While most other researchers chose not to tackle this perplexing problem to instead pursue more lucrative and publishable exploits, Karikó stuck with it. The choice sent her academic career into depressing doldrums. Nobody would fund her work, publications dried up, and after six years as an assistant professor at the University of Pennsylvania, Karikó got demoted. She was going backward.
“I thought of going somewhere else, or doing something else,” Karikó told Stat in 2020. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
A tale of tenacity
Collaborating with Drew Weissman, a new professor at the University of Pennsylvania, in the late 1990s helped provide Karikó with the tenacity to continue. Weissman nurtured a goal of developing a vaccine against HIV-1, and saw mRNA as a potential way to do it.
“For the 20 years that we’ve worked together before anybody knew what RNA is, or cared, it was the two of us literally side by side at a bench working together,” Weissman said in an interview with Adam Smith of the Nobel Foundation.
In 2005, the duo made their 2023 Nobel Prize-winning breakthrough, detailing it in a relatively small journal, Immunity. (Their paper was rejected by larger journals, including Science and Nature.) They figured out that chemically modifying the nucleoside bases that make up mRNA allowed the molecule to slip past the body’s immune defenses. Karikó and Weissman followed up that finding by creating mRNA that’s more efficiently translated within cells, greatly boosting protein production. In 2020, scientists at Moderna and BioNTech (where Karikó worked from 2013 to 2022) rushed to craft vaccines against COVID, putting their methods to life-saving use.
The future of vaccines
Buoyed by the resounding success of mRNA vaccines, scientists are now hurriedly researching ways to use mRNA medicine against other infectious diseases, cancer, and genetic disorders. The now ubiquitous efforts stand in stark contrast to Karikó and Weissman’s previously unheralded struggles years ago as they doggedly worked to realize a shared dream that so many others shied away from. Katalin Karikó and Drew Weissman were brave enough to walk a scientific path that very well could have ended in a dead end, and for that, they absolutely deserve their 2023 Nobel Prize.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.
With conventional fuel cells as their model, researchers learned to use similar chemical reactions to make a fuel from microbes in pee.
Plus, urine contains water, phosphorus, potassium and nitrogen, the key ingredients plants need to grow and survive. Human urine could replace about 25 percent of current nitrogen and phosphorous fertilizers worldwide and could save water for gardens and crops. The average U.S. resident flushes a toilet bowl containing only pee and paper about six to seven times a day, which adds up to about 3,500 gallons of water down per year. Plus cows in the U.S. produce 231 gallons of the stuff each year.
Pee power
A conventional fuel cell uses chemical reactions to produce energy, as electrons move from one electrode to another to power a lightbulb or phone. Ioannis Ieropoulos, a professor and chair of Environmental Engineering at the University of Southampton in England, realized the same type of reaction could be used to make a fuel from microbes in pee.
Bacterial species like Shewanella oneidensis and Pseudomonas aeruginosa can consume carbon and other nutrients in urine and pop out electrons as a result of their digestion. In a microbial fuel cell, one electrode is covered in microbes, immersed in urine and kept away from oxygen. Another electrode is in contact with oxygen. When the microbes feed on nutrients, they produce the electrons that flow through the circuit from one electrod to another to combine with oxygen on the other side. As long as the microbes have fresh pee to chomp on, electrons keep flowing. And after the microbes are done with the pee, it can be used as fertilizer.
These microbes are easily found in wastewater treatment plants, ponds, lakes, rivers or soil. Keeping them alive is the easy part, says Ieropoulos. Once the cells start producing stable power, his group sequences the microbes and keeps using them.
Like many promising technologies, scaling these devices for mass consumption won’t be easy, says Kevin Orner, a civil engineering professor at West Virginia University. But it’s moving in the right direction. Ieropoulos’s device has shrunk from the size of about three packs of cards to a large glue stick. It looks and works much like a AAA battery and produce about the same power. By itself, the device can barely power a light bulb, but when stacked together, they can do much more—just like photovoltaic cells in solar panels. His lab has produced 1760 fuel cells stacked together, and with manufacturing support, there’s no theoretical ceiling, he says.
Although pure urine produces the most power, Ieropoulos’s devices also work with the mixed liquids of the wastewater treatment plants, so they can be retrofit into urban wastewater utilities.
This image shows how the pee-powered system works. Pee feeds bacteria in the stack of fuel cells (1), which give off electrons (2) stored in parallel cylindrical cells (3). These cells are connected to a voltage regulator (4), which smooths out the electrical signal to ensure consistent power to the LED strips lighting the toilet.
Courtesy Ioannis Ieropoulos
Key to the long-term success of any urine reclamation effort, says Orner, is avoiding what he calls “parachute engineering”—when well-meaning scientists solve a problem with novel tech and then abandon it. “The way around that is to have either the need come from the community or to have an organization in a community that is committed to seeing a project operate and maintained,” he says.
Success with urine reclamation also depends on the economy. “If energy prices are low, it may not make sense to recover energy,” says Orner. “But right now, fertilizer prices worldwide are generally pretty high, so it may make sense to recover fertilizer and nutrients.” There are obstacles, too, such as few incentives for builders to incorporate urine recycling into new construction. And any hiccups like leaks or waste seepage will cost builders money and reputation. Right now, Orner says, the risks are just too high.
Despite the challenges, Ieropoulos envisions a future in which urine is passed through microbial fuel cells at wastewater treatment plants, retrofitted septic tanks, and building basements, and is then delivered to businesses to use as agricultural fertilizers. Although pure urine produces the most power, Ieropoulos’s devices also work with the mixed liquids of the wastewater treatment plants, so they can be retrofitted into urban wastewater utilities where they can make electricity from the effluent. And unlike solar cells, which are a common target of theft in some areas, nobody wants to steal a bunch of pee.
When Ieropoulos’s team returned to wrap up their pilot project 18 months later, the school’s director begged them to leave the fuel cells in place—because they made a major difference in students’ lives. “We replaced it with a substantial photovoltaic panel,” says Ieropoulos, They couldn’t leave the units forever, he explained, because of intellectual property reasons—their funders worried about theft of both the technology and the idea. But the photovoltaic replacement could be stolen, too, leaving the girls in the dark.
The story repeated itself at another school, in Nairobi, Kenya, as well as in an informal settlement in Durban, South Africa. Each time, Ieropoulos vowed to return. Though the pandemic has delayed his promise, he is resolute about continuing his work—it is a moral and legal obligation. “We've made a commitment to ourselves and to the pupils,” he says. “That's why we need to go back.”
Urine as fertilizer
Modern day industrial systems perpetuate the broken cycle of nutrients. When plants grow, they use up nutrients the soil. We eat the plans and excrete some of the nutrients we pass them into rivers and oceans. As a result, farmers must keep fertilizing the fields while our waste keeps fertilizing the waterways, where the algae, overfertilized with nitrogen, phosphorous and other nutrients grows out of control, sucking up oxygen that other marine species need to live. Few global communities remain untouched by the related challenges this broken chain create: insufficient clean water, food, and energy, and too much human and animal waste.
The Rich Earth Institute in Vermont runs a community-wide urine nutrient recovery program, which collects urine from homes and businesses, transports it for processing, and then supplies it as fertilizer to local farms.
One solution to this broken cycle is reclaiming urine and returning it back to the land. The Rich Earth Institute in Vermont is one of several organizations around the world working to divert and save urine for agricultural use. “The urine produced by an adult in one day contains enough fertilizer to grow all the wheat in one loaf of bread,” states their website.
Notably, while urine is not entirely sterile, it tends to harbor fewer pathogens than feces. That’s largely because urine has less organic matter and therefore less food for pathogens to feed on, but also because the urinary tract and the bladder have built-in antimicrobial defenses that kill many germs. In fact, the Rich Earth Institute says it’s safe to put your own urine onto crops grown for home consumption. Nonetheless, you’ll want to dilute it first because pee usually has too much nitrogen and can cause “fertilizer burn” if applied straight without dilution. Other projects to turn urine into fertilizer are in progress in Niger, South Africa, Kenya, Ethiopia, Sweden, Switzerland, The Netherlands, Australia, and France.
Eleven years ago, the Institute started a program that collects urine from homes and businesses, transports it for processing, and then supplies it as fertilizer to local farms. By 2021, the program included 180 donors producing over 12,000 gallons of urine each year. This urine is helping to fertilize hay fields at four partnering farms. Orner, the West Virginia professor, sees it as a success story. “They've shown how you can do this right--implementing it at a community level scale."