A retrovirus illustration.
(© fotoliaxrender/Fotolia)
Even with groundbreaking advances in cancer treatment and research over the past two centuries, the problem remains that some cancer does not respond to treatment. A subset of patients experience recurrence or metastasis, even when the original tumor is detected at an early stage.
"Why do some tumors evolve into metastatic disease that is then capable of spreading, while other tumors do not?"
Moreover, doctors are not able to tell in advance which patients will respond to treatment and which will not. This means that many patients endure conventional cancer therapies, like countless rounds of chemo and radiation, that do not ultimately increase their likelihood of survival.
Researchers are beginning to understand why some tumors respond to treatment and others do not. The answer appears to lie in the strange connection between human life at its earliest stages — and retroviruses. A retrovirus is different than a regular virus in that its RNA is reverse-transcribed into DNA, which makes it possible for its genetic material to be integrated into a host's genome, and passed on to subsequent generations.
Researchers have shown that reactivation of retroviral sequences is associated with the survival of developing embryos. Certain retroviral sequences must be expressed around the 8-cell stage for successful embryonic development. Active expression of retroviral sequences is required for proper functioning of human embryonic stem cells. These sequences must then shut down at the later state, or the embryo will fail to develop. And here's where things get really interesting: If specific stem cell-associated retroviral sequences become activated again later in life, they seem to play a role in some cancers becoming lethal.
"Eight to 10 million years ago, at the time when we became primates, the population was infected with a virus."
While some retroviral sequences in our genome contribute to the restriction of viral infection and appear to have contributed to the development of the placenta, they can also, if expressed at the wrong time, drive the development of cancer stem cells. Described as the "beating hearts" of treatment-resistant tumors, cancer stem cells are robust and long-living, and they can maintain the ability to proliferate indefinitely.
This apparent connection has inspired Gennadi V. Glinsky, a research scientist at the Institute of Engineering in Medicine at UC San Diego, to find better ways to diagnose and treat metastatic cancer. Glinsky specializes in the development of new technologies, methods, and system integration approaches for personalized genomics-guided prevention and precision therapy of cancer and other common human disorders. We spoke with him about his work and the exciting possibilities it may open up for cancer patients. This interview has been edited and condensed for clarity.
What key questions have driven your research in this area?
I was thinking for years that the major mysteries are: Why do some tumors evolve into metastatic disease that is then capable of spreading, while other tumors do not? What explains some cancer cells' ability to get into the blood or lymph nodes and be able to survive in this very foreign, hostile environment of circulatory channels, and then be able to escape and take root elsewhere in the body?
"If you detect conventional cancer early, and treat it early, it will be cured. But with cancer involving stem cells, even if you diagnose it early, it will come back."
When we were able to do genomic analysis on enough early stage cancers, we arrived at an alternative concept of cancer that starts in the stem cells. Stem cells exist throughout our bodies, so in the case of cancer starting in stem cells you will have metastatic properties … because that's what stem cells do. They can travel throughout the body, they can make any other type of cell or resemble them.
So there are basically two types of cancer: conventional non-stem cell cancer and stem cell-like cancer. If you detect conventional cancer early, and treat it early, it will be cured. But with cancer involving stem cells, even if you diagnose it early, it will come back.
What causes some cancer to originate in stem cells?
Cancer stem cells possess stemness [or the ability to self-renew, differentiate, and survive chemical and physical insults]. Stemness is driven by the reactivation of retroviral sequences that have been integrated into the human genome.
Tell me about these retroviral sequences.
Eight to 10 million years ago, at the time when we became primates, the population was infected with a virus. Part of the population survived and the virus was integrated into our primate ancestors' genome. These are known as human endogenous retroviruses, or HERVs. The DNA of the host cells became carriers of these retroviral sequences, and whenever the host cells multiply, they carry the sequences in them and pass them on to future generations.
This pattern of infection and integration of retroviral sequences has happened thousands of times during our evolutionary history. As a result, eight percent of the human genome is derived from these different retroviral sequences.
We've found that some HERVs are expressed in some cancers. For example, 10-15 percent of prostate cancer is stem cell-like. But at first it was not understood what this HERV expression meant.
Gennadi V. Glinsky, a research scientist at the Institute of Engineering in Medicine at UC San Diego.
(Courtesy)
How have you endeavored to solve this in your lab?
We were trying to track down metastatic prostate cancer. We found a molecular signature of prostate cancer that made the prostate tumors look like stem cells. And those were the ones likely to fail cancer therapy. Then we applied this signature to other types of cancers and we found that uniformly, tumors that exhibit stemness fail therapy.
Then in 2014, several breakthrough papers came out that linked the activation of the retroviral sequences in human embryonic stem cells and in human embryo development. When I read these papers, it occurred to me that if these retroviral sequences are required for pluripotency in human embryonic stem cells, they must be involved in stem cell-resembling human cancer that's likely to fail therapy.
What was one of the biggest aha moments in your cancer research?
Several major labs around the U.S. took advantage of The Cancer Genome Anatomy Project, which made it possible to have access to about 12,000 individual human tumors across a spectrum of 30 or so cancer types. This is the largest set of tumors that's ever been made available in a comprehensive and state of the art way. So we now know all there is to know about the genetics of these tumors, including the long-term clinical outcome.
"When we cross-referenced these 10,713 human cancer survival genes to see how many are part of the retroviral network in human cells, we found that the answer was 97 percent!"
These labs identified 10,713 human genes that were associated with the likelihood of patients surviving or dying after [cancer] treatment. I call them the human cancer survival genes, and there are two classes of them: one whose high expression in tumors correlates with an increased likelihood of survival and one whose high expression in tumors correlates with a decreased likelihood of survival.
When we cross-referenced these 10,713 human cancer survival genes to see how many are part of the retroviral network in human cells, we found that the answer was 97 percent!
How will all of this new knowledge change how cancer is treated?
To make cancer stem cells vulnerable to treatment, you need to interfere with stemness and the stemness network. And to do this, you would need to identify the retroviral component of the network, and interfere with this component therapeutically.
The real breakthrough will come when we start to treat these early stage stem cell-like cancers with stem cell-targeting therapy that we are trying to develop. And with our ability to detect the retroviral genome activation, we will be able to detect stem cell-like cancer very early on.
How far away are we from being able to apply this information clinically?
We have two molecule [treatment] candidates. We know that they efficiently interfere with the stemness program in the cells. The road to clinical trials is typically a long one, but since we're clear about our targets, it's a shorter road. We would like to say it's two to three years until we can start a human trial.
Katalin Karikó, pictured, and Drew Weissman won the Nobel Prize for advances in mRNA research that led to the first Covid vaccines.
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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.
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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."