Conner Curran, now 10 years old, can walk more than two miles after gene therapy treatment for his Duchenne's muscular dystrophy.
That the medical world is on the cusp of a successful treatment for a crippling and deadly disease is the culmination of more than 35 years of work by Dr. Jude Samulski, a professor of pharmacology at the University of North Carolina School of Medicine in Chapel Hill. More recently, he's become a leading gene therapy entrepreneur.
But Samulski likens this breakthrough to the frustrations of solving a Rubik's cube. "Just because one side is now all the color yellow does not mean that it is completely aligned," he says.
Although Conner's life and future have dramatically improved, he's not cured. The gene therapy tamed but did not extinguish his disorder: Conner is now suffering from the equivalent of Becker's muscular dystrophy, a milder form of the disease with symptoms that appear later in life and progress more slowly. Moreover, the loss of muscle cells Conner suffered prior to the treatment is permanent.
"It will take more time and more innovations," Samulski says of finding an even more effective gene therapy for muscular dystrophy.
Conner's family is still overjoyed with the results. "Jude's grit and determination gave Conner a chance at a new life, one that was not in his cards before gene therapy," says his mother Jessica Curran. She adds that "Conner is more confident than before and enjoys life, even though he has limitations, if compared to his brothers or peers."
Conner Curran holding a football post gene therapy treatment.
Courtesy of the Curran family
For now, the use of gene therapy as a treatment for diseases and disorders remains relatively isolated. On paper at least, progress appears glacially slow. In 2018, there were four FDA-approved gene therapies (excluding those reliant on bone marrow/stem cell transplants or implants). Today, there are 10. One therapy is solely for the cosmetic purpose of reducing facial lines and folds.
Nevertheless, experts in the space believe gene therapy is poised to expand dramatically.
"Certainly in the next three to five years you will see dozens of gene therapies and cell therapies be approved," says Dr. Pavan Cheruvu, who is CEO of Sio Gene Therapies in New York. The company is developing treatments for Parkinson's disease and Tay-Sachs, among other diseases.
Cheruvu's conclusion is supported by NEWDIGS, a think tank at the Massachusetts Institute of Technology that keeps tabs on gene therapy developments. NEWDIGS predicts there will be at least 60 gene therapies approved for use in the U.S. by the end of the decade. That number could be closer to 100 if Chinese researchers and biotech ventures decide the American market is a good fit for the therapies they develop.
"We are watching something of a conditional evolution, like a dot-com, or cellphones that were sizes of shoeboxes that have now matured to the size of wafers. Our space will follow along very similarly."
Dr. Carsten Brunn, a chemist by training and CEO of Selecta Biosciences outside of Boston, is developing ways to reduce the immune responses in patients who receive gene therapy. He observes that there are more than 300 therapies in development and thousands of clinical trials underway. "It's definitely an exciting time in the field," he says.
That's a far cry from the environment of little more than a decade ago. Research and investment in gene therapy had been brought low for years after the death of teenager Jesse Gelsinger in 1999 while he had been enrolled in a clinical trial to treat a liver disease. Gene therapy was a completely novel concept back then, and his death created existential questions about whether it was a proper pathway to pursue. Cheruvu, a cardiologist, calls the years after Gelsinger's death an "ice age" for gene therapy.
However, those dark years eventually yielded to a thaw. And while there have been some recent stumbles, they are considered part of the trial-and-error that has often accompanied medical research as opposed to an ominous "stop" sign.
The deaths of three patients last year receiving gene therapy for myotubular myopathy – a degenerative disease that causes severe muscle weakness – promptly ended the clinical trial in which they were enrolled. However, the incident caused few ripples beyond that. Researchers linked the deaths to dosage sizes that caused liver toxicity, as opposed to the gene therapy itself being an automatic death sentence; younger patients who received lower doses due to a less advanced disease state experienced improvements.
The gene sequencing and editing that helped create vaccines for COVID-19 in record time also bolstered the argument for more investment in research and development. Cheruvu notes that the field has usually been the domain of investors with significant expertise in the field; these days, more money is flowing in from generalists.
The Challenges Ahead
What will be the next step in gene therapy's evolution? Many of Samulski's earliest innovations came in the laboratory, for example. Then that led to him forming a company called AskBio in collaboration with the Muscular Dystrophy Association. AskBio sold its gene therapy to Pfizer five years ago to assure that enough could be manufactured for stage 3 clinical trials and eventually reach the market.
Cheruvu suggests that many future gene therapy innovations will be the result of what he calls "congruent innovation." That means publicly funded laboratories and privately funded companies might develop treatments separately or in collaboration. Or, university scientists may depend on private ventures to solve one of gene therapy's most vexing issues: producing enough finished material to test and treat on a large scale. "Manufacturing is a real bottleneck right now," Brunn says.
The alternative is referred to in the sector as the "valley of death": a lab has found a promising treatment, but is not far enough along in development to submit an investigational new drug application with the FDA. The promise withers away as a result. But the new abundance of venture capital for gene therapy has made this scenario less of an issue for private firms, some of which have received hundreds of millions of dollars in funding.
There are also numerous clinical challenges. Many gene therapies use what are known as adeno-associated virus vectors (AAVs) to deliver treatments. They are hollowed-out husks of viruses that can cause a variety of mostly mild maladies ranging from colds to pink eye. They are modified to deliver the genetic material used in the therapy. Most of these vectors trigger an antibody reaction that limits treatments to a single does or a handful of smaller ones. That can limit the potential progress for patients – an issue referred to as treatment "durability."
Although vectors from animals such as horses trigger far less of an antibody reaction in patients -- and there has been significant work done on using artificial vectors -- both are likely years away from being used on a large scale. "For the foreseeable future, AAV is the delivery system of choice," Brunn says.
Also, there will likely be demand for concurrent gene therapies that can lead to a complete cure – not only halting the progress of Duchenne's in kids like Conner Curran, but regenerating their lost muscle cells, perhaps through some form of stem cell therapy or another treatment that has yet to be devised.
Nevertheless, Samulski believes demand for imperfect treatments will be high – particularly with a disease such as muscular dystrophy, where many patients are mere months from spending the remainder of their lives in wheelchairs. But Samulski believes those therapies will also inevitably evolve into something far more effective.
"We are watching something of a conditional evolution, like a dot-com, or cellphones that were sizes of shoeboxes that have now matured to the size of wafers," he says. "Our space will follow along very similarly."
Jessica Curran will remain forever grateful for what her son has received: "Jude gave us new hope. He gave us something that is priceless – a chance to watch Conner grow up and live out his own dreams."
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."