Doctor with a syringe on the background of DNA.
Steve, a 60-year-old resident of the DC area who works in manufacturing, was always physically fit. In college, he played lacrosse in Division I, the highest level of intercollegiate athletics in the United States. Later, he stayed active by swimming, biking, and running--up until something strange happened around two years ago.
"It was hard for me to even get upstairs. I wasted away."
Steve, who requested that his last name be withheld to protect his privacy, started to notice weakness first in his toes, then his knees. On a trip to the zoo, he had trouble keeping up. Then some months later, the same thing happened on a family hike. What was supposed to be a four-mile trek up to see a waterfall ended for him at the quarter-mile mark. He turned around and struggled back to the start just as everyone else was returning from the excursion.
Alarmed, he sought out one doctor after the next, but none could diagnose him. The disabling weakness continued to creep up his legs, and by the time he got in to see a top neurologist at Johns Hopkins University last January, he was desperate for help.
"It was hard for me to even get upstairs," he recalls. "I wasted away and had lost about forty-five pounds."
The neurologist, Dr. Michael Polydefkis, finally made the correct diagnosis based on Steve's rapid progression of symptoms, a skin and nerve biopsy, and a genetic test. It turned out that Steve had a rare inherited disease called hereditary transthyretin amyloidosis. Transthyretin is a common blood protein whose normal function is to transport vitamins and hormones in the body. When patients possess certain genetic mutations in the transthyretin gene, the resulting protein can misfold, clump and produce amyloid, an aggregate of proteins, which then interferes with normal function. Many organs are affected in this disease, but most affected are the nervous system, the GI tract, and the heart.
Dr. Michael Polydefkis, Steve's neurologist at Johns Hopkins Bayview Medical Center in Baltimore, MD.
(Courtesy of Dr. Polydefkis)
For the 50,000 patients like Steve around the world, the only treatment historically has been a liver transplant—a major, risky operation. The liver makes most of the transthyretin in a person's body. So if a person who carries a genetic mutation for a disease-causing form of transthyretin has their liver transplanted, the new liver will stop making the mutant protein. A few drugs can slow, but do not stop the disease.
Since it is a genetic condition, a regular "drug" can't tackle the problem.
"For almost all of medicine from the 18th century to today, drugs have been small molecules, typically natural, some invented by humans, that bind to proteins and block their functions," explains Dr. Phillip Zamore, chair of the department of Biomedical Sciences at the University of Massachusetts Medical School. "But with most proteins (including this one), you can't imagine how that would ever happen. Because even if it stuck, there's no reason to think it would change anything. So people threw up their hands and said, 'Unless we can find a protein that is "druggable" in disease X, we can't treat it.'"
To draw a car analogy, treating a disease like Steve's with a small molecule would be like trying to shut down the entire car industry when all you can do is cut the power cord to one machine in one local factory. With few options, patients like Steve have been at a loss, facing continual deterioration and disability.
"It's more obvious how to be specific because we use the genetic code itself to design the drug."
A Radical New Approach
Luckily, Dr. Polydefkis knew of an experimental drug made by a biotech company that Dr. Zamore co-founded called Alnylam Pharmaceuticals. They were doing something completely different: silencing the chemical blueprint for protein, called RNA, rather than targeting the protein itself. In other words, shutting down all the bad factories across the whole car industry at once – without touching the good ones.
"It's more obvious how to be specific," says Dr. Zamore, "because we use the genetic code itself to design the drug."
For Steve's doctor, the new drug, called patisiran, is a game changer.
"It's the dawn of molecular medicine," says Dr. Polydefkis. "It's really a miraculous development. The ability to selectively knock down or reduce the amount of a specific protein is remarkable. I tell patients this is science fiction that is now becoming reality."
A (Very) Short History
The strategy of silencing RNA as a method of guiding drug development began in 1998. Basic research took six years before clinical testing in humans began in 2004. Just a few months ago, in November, the results of the first double-blind, placebo-controlled phase III trials were announced, testing patisiran in patients--and they surpassed expectations.
"The results were remarkably positive," says Dr. Polydefkis. "Every primary and secondary outcome measure target was met. It's the most positive trial I have ever been associated with and that I can remember in recent memory."
FDA approval is expected to come by summer, which will mark the first official sanction of a drug based on RNA inhibition (RNAi). Experts are confident that similar drugs will eventually follow for other diseases, like familial hypercholesterol, lipid disorders, and breathing disorders. Right now, these drugs must get into the liver to work, but otherwise the future treatment possibilities are wide open, according to Dr. Zamore.
"It doesn't have to be a genetic disease," he says. "In theory, it doesn't have to be just one gene, although I don't think anyone knows how many you could target at once. There is no precedent for targeting two."
Dr. Phillip Zamore, chair of the RNA Therapeutics Institute at the University of Massachusetts Medical School.
(Courtesy of Dr. Zamore)
Alnylam, the leading company in RNAi therapeutics, plans to strategically design other new drugs based on what they have learned from this first trial – "so with each successive experience, with designing and testing, you get better at making more drugs. In a way, that's never happened before...This is a lot more efficient of a way to make drugs in the future."
And unlike gene therapy, in which a patient's own genetic code is permanently altered, this approach does not cause permanent genetic changes. Patients can stop taking it like any other drug, and its effects will vanish.
How Is Steve?
Last February, Steve started on the drug. He was granted early access since it is not yet FDA-approved and is still considered experimental. Every 21 days, he has received an IV infusion that causes some minor side effects, like headaches and facial flushing.
"The good news is, since I started on the drug, I don't see any more deterioration other than my speech."
So far, it seems to be effective. He's gained back 20 pounds, and though his enunciation is still a bit slurred, he says that his neuropathy has stopped. He plans to continue the treatment for the rest of his life.
"The good news is, since I started on the drug, I don't see any more deterioration other than my speech," he says. "I think the drug is working, but would I have continued to deteriorate without the drug? I'm not really sure."
Dr. Polydefkis jumps in with a more confident response: "If you ask me, I would say 100 percent he would have kept progressing at a fairly rapid pace without the drug. When Steve says the neuropathy has stopped, that's music to my ears."
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."