Researchers from the University of Cambridge have laid the foundations for growing synthetic embryos that could develop a beating heart, gut and brain.
Story by Big Think
For over a century, scientists have dreamed of growing human organs sans humans. This technology could put an end to the scarcity of organs for transplants. But that’s just the tip of the iceberg. The capability to grow fully functional organs would revolutionize research. For example, scientists could observe mysterious biological processes, such as how human cells and organs develop a disease and respond (or fail to respond) to medication without involving human subjects.
Recently, a team of researchers from the University of Cambridge has laid the foundations not just for growing functional organs but functional synthetic embryos capable of developing a beating heart, gut, and brain. Their report was published in Nature.
The organoid revolution
In 1981, scientists discovered how to keep stem cells alive. This was a significant breakthrough, as stem cells have notoriously rigorous demands. Nevertheless, stem cells remained a relatively niche research area, mainly because scientists didn’t know how to convince the cells to turn into other cells.
Then, in 1987, scientists embedded isolated stem cells in a gelatinous protein mixture called Matrigel, which simulated the three-dimensional environment of animal tissue. The cells thrived, but they also did something remarkable: they created breast tissue capable of producing milk proteins. This was the first organoid — a clump of cells that behave and function like a real organ. The organoid revolution had begun, and it all started with a boob in Jello.
For the next 20 years, it was rare to find a scientist who identified as an “organoid researcher,” but there were many “stem cell researchers” who wanted to figure out how to turn stem cells into other cells. Eventually, they discovered the signals (called growth factors) that stem cells require to differentiate into other types of cells.
For a human embryo (and its organs) to develop successfully, there needs to be a “dialogue” between these three types of stem cells.
By the end of the 2000s, researchers began combining stem cells, Matrigel, and the newly characterized growth factors to create dozens of organoids, from liver organoids capable of producing the bile salts necessary for digesting fat to brain organoids with components that resemble eyes, the spinal cord, and arguably, the beginnings of sentience.
Synthetic embryos
Organoids possess an intrinsic flaw: they are organ-like. They share some characteristics with real organs, making them powerful tools for research. However, no one has found a way to create an organoid with all the characteristics and functions of a real organ. But Magdalena Żernicka-Goetz, a developmental biologist, might have set the foundation for that discovery.
Żernicka-Goetz hypothesized that organoids fail to develop into fully functional organs because organs develop as a collective. Organoid research often uses embryonic stem cells, which are the cells from which the developing organism is created. However, there are two other types of stem cells in an early embryo: stem cells that become the placenta and those that become the yolk sac (where the embryo grows and gets its nutrients in early development). For a human embryo (and its organs) to develop successfully, there needs to be a “dialogue” between these three types of stem cells. In other words, Żernicka-Goetz suspected the best way to grow a functional organoid was to produce a synthetic embryoid.
As described in the aforementioned Nature paper, Żernicka-Goetz and her team mimicked the embryonic environment by mixing these three types of stem cells from mice. Amazingly, the stem cells self-organized into structures and progressed through the successive developmental stages until they had beating hearts and the foundations of the brain.
“Our mouse embryo model not only develops a brain, but also a beating heart [and] all the components that go on to make up the body,” said Żernicka-Goetz. “It’s just unbelievable that we’ve got this far. This has been the dream of our community for years and major focus of our work for a decade and finally we’ve done it.”
If the methods developed by Żernicka-Goetz’s team are successful with human stem cells, scientists someday could use them to guide the development of synthetic organs for patients awaiting transplants. It also opens the door to studying how embryos develop during pregnancy.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.
Phages, which are harmless viruses that destroy specific bacteria, are becoming useful tools to protect our food supply.
Food producers and packagers fight bacteria by potent chemicals, with chlorine being the go-to disinfectant. Cattle carcasses, for example, are typically washed by chlorine solutions as the animals' intestines are removed. Leafy greens are bathed in water with added chlorine solutions. However, because the same "bath" can be used for multiple veggie batches and chlorine evaporates over time, the later rounds may not kill all of the bacteria, sparing some. The natural and organic producers avoid chlorine, substituting it with lactic acid, a more holistic sanitizer, but even with all these efforts, some pathogens survive, sickening consumers and causing food recalls. As we farm more animals and grow more produce, while also striving to use fewer chemicals and more organic growing methods, it will be harder to control bacteria's spread.
"It took us a long time to convince the FDA phages were safe and efficient alternatives. But we had worked with them to gather all the data they needed, and the FDA was very supportive in the end."
Luckily, bacteria have their own killers. Called bacteriophages, or phages for short, they are viruses that prey on bacteria only. Under the electron microscope, they look like fantasy spaceships, with oblong bodies, spider-like legs and long tails. Much smaller than a bacterium, phages pierce the microbes' cells with their tails, sneak in and begin multiplying inside, eventually bursting the microbes open—and then proceed to infect more of them.
The best part is that these phages are harmless to humans. Moreover, recent research finds that millions of phages dwell on us and in us—in our nose, throat, skin and gut, protecting us from bacterial infections as part of our healthy microbiome. A recent study suggested that we absorb about 30 billion phages into our bodies on a daily basis. Now, ingeniously, they are starting to be deployed as anti-microbial agents in the food industry.
A Maryland-based phage research company called Intralytix is doing just that. Founded by Alexander Sulakvelidze, a microbiologist and epidemiologist who came to the United States from Tbilisi, the capital of Georgia, Intralytix makes and sells five different FDA-approved phage cocktails that work against some of the most notorious food pathogens: ListShield for Listeria, SalmoFresh for Salmonella, ShigaShield for Shigella, another foodborne bug, and EcoShield for E.coli, including the infamous strain that caused the Jack in the Box outbreak in 1993 that killed four children and sickened 732 people across four states. Last year, the FDA granted its approval to yet another Intralytix phage for managing Campylobacter contamination, named CampyShield. "We call it safety by nature," Sulakvelidze says.
Intralytix grows phages inside massive 1500-liter fermenters, feeding them bacterial "fodder."
Photo credit: Living Radiant Photography
Phage preparations are relatively straightforward to make. In nature, phages thrive in any body of water where bacteria live too, including rivers, lakes and bays. "I can dip a bucket into the Chesapeake Bay, and it will be full of all kinds of phages," Sulakvelidze says. "Sewage is another great place to look for specific phages of interest, because it's teeming with all sorts of bacteria—and therefore the viruses that prey on them."
In lab settings, Intralytix grows phages inside massive 1500-liter fermenters, feeding them bacterial "fodder." Once phages multiply enough, they are harvested, dispensed into containers and shipped to food producers who have adopted this disinfecting practice into their preparation process. Typically, it's done by computer-controlled sprayer systems that disperse mist-like phage preparations onto the food.
Unlike chemicals like chlorine or antibiotics, which kill a wide spectrum of bacteria, phages are more specialized, each feeding on specific microbial species. A phage that targets salmonella will not prey on listeria and vice versa. So food producers may sometimes use a combo of different phage preparations. Intralytix is continuously researching and testing new phages. With a contract from the National Institutes of Health, Intralytix is expanding its automated high-throughput robot that tests which phages work best against which bacteria, speeding up the development of the new phage cocktails.
Phages have other "talents." In her recent study, Jaroni found that phages have the ability to destroy bacterial biofilms—colonies of microorganisms that tend to grow on surfaces of the food processing equipment, surrounding themselves with protective coating that even very harsh chemicals can't crack.
"Phages are very clever," Jaroni says. "They produce enzymes that target the biofilms, and once they break through, they can reach the bacteria."
Convincing the FDA that phages were safe to use on food products was no easy feat, Sulakvelidze says. In his home country of Georgia, phages have been used as antimicrobial remedies for over a century, but the FDA was leery of using viruses as food safety agents. "It took us a long time to convince the FDA phages were safe and efficient alternatives," Sulakvelidze says. "But we had worked with them to gather all the data they needed, and the FDA was very supportive in the end."
The agency had granted Intralytix its first approval in 2006, and over the past 10 years, the company's sales increased by over 15-fold. "We currently sell to about 40 companies and are in discussions with several other large food producers," Sulakvelidze says. One indicator that the industry now understands and appreciates the science of phages was that his company was ranked as Top Food Safety Provider in 2021 by Food and Beverage Technology Review, he adds. Notably, phage sprays are kosher, halal and organic-certified.
Intralytix's phage cocktails to safeguard food from bacteria are approved for consumers in addition to food producers, but currently the company sells to food producers only. Selling retail requires different packaging like easy-to-use spray bottles and different marketing that would inform people about phages' antimicrobial qualities. But ultimately, giving people the ability to remove pathogens from their food with probiotic phage sprays is the goal, Sulakvelidze says.
It's not the company's only goal. Now Intralytix is going a step further, investigating phages' probiotic and therapeutic abilities. Because phages are highly specialized in the bacteria they target, they can be used to treat infections caused by specific pathogens while leaving the beneficial species of our microbiome intact. In an ongoing clinical trial with Mount Sinai, Intralytix is now investigating a potential phage treatment against a certain type of E. coli for patients with Crohn's disease, and is about to start another clinical trial for treating bacterial dysentery.
"Now that we have proved that phages are safe and effective against foodborne bacteria," Sulakvelidze says, "we are going to demonstrate their potential in therapeutic applications."
This article was first published by Leaps.org on October 27, 2021.
Some argue that transgender females should be banned from competing with women in sports, while others think such bans are unfair, as the NCAA and other organizations try to keep up with research on how testosterone affects performance.
However, in 18 states, many of which are politically conservative, laws prohibit transgender students from participating in sports consistent with their gender identity, according to the Movement Advancement Project, an independent, nonprofit think tank based in Boulder, Colo., that focuses on the rights of LGBTQ people. The first ban was passed in Idaho in 2020, although federal district judges have halted this legislation and a similar law in West Virginia from taking effect.
Proponents of the bans caution that transgender females would have an unfair biological advantage in competitive school sports with other girls or women as a result of being born as stronger males, potentially usurping the athletic accomplishments of other athletes.
“The future of women’s sports is at risk, and the equal rights of female athletes is being infringed,” said Penny Nance, CEO and president of Concerned Women for America, a legislative action committee in D.C. that seeks to impact culture to promote religious values.
“As the tidal wave of gender activism consumes sports from the Olympics on down, a backlash is being felt as parents are furious about the disregard for their daughters who have worked very hard to achieve success as athletes,” Nance added. “Former athletes, whose records are being shattered, are demanding answers.”
Meanwhile, opponents of the bans contend that they bar transgender athletes from playing sports with friends and learning the value of teamwork and other life lessons. These laws target transgender girls most often in kindergarten through high school but sometimes in college as well. Many local schools and state athletic associations already have their own guidelines “to both protect transgender people and ensure a level playing field for all athletes,” according to the Movement Advancement Project’s website. But statewide bans take precedence over these policies.
"It’s easy to sympathize on some level with arguments on both sides, and it’s likely going to be impossible to make everyone happy,” said Liz Joy, a past president of the American College of Sports Medicine.
In January, the National Collegiate Athletic Association (NCAA), based in Indianapolis, tried to sort out the controversy by implementing a new policy. It requires transgender students participating in female sports to prove that they’ve been taking treatments to suppress testosterone for at least one year before competition, as well as demonstrating that their testosterone level is sufficiently low, depending on the sport, through a blood test.
Then, in August, the NCAA clarified that these athletes also must take another blood test six months after their season has started that shows their testosterone levels aren’t too high. Additional guidelines will take effect next August.
Even with these requirements, “there is no plan that is going to be considered equitable and fair to all,” said Bradley Anawalt, an endocrinologist at the University of Washington School of Medicine. Biologically, he noted, there is still some evidence that a transgender female who initiates hormone therapy with estrogen and drops her testosterone to very low levels may have some advantage over other females, based on characteristics such as hand and foot size, height and perhaps strength.
Liz Joy, a past president of the American College of Sports Medicine, agrees that allowing transgender athletes to compete on teams of their self-identifying gender poses challenges. “It’s easy to sympathize on some level with arguments on both sides, and it’s likely going to be impossible to make everyone happy,” said Joy, a physician and senior medical director of wellness and nutrition at Intermountain Healthcare in Salt Lake City, Utah. While advocating for inclusion, she added that “sport was incredibly important in my life. I just want everyone to be able to benefit from it.”
One solution may be to allow transgender youth to play sports in a way that aligns with their gender identity until a certain age and before an elite level. “There are minimal or no potential financial stakes for most youth sports before age 13 or 14, and you do not have a lot of separation in athlete performance between most boys and girls until about age 13,” said Anwalt, who was a reviewer of the Endocrine Society’s national guidelines on transgender care.
Myron Genel, a professor emeritus and former chief of pediatric endocrinology at Yale School of Medicine, said it’s difficult to argue that height gives transgender females an edge because in some sports tall women already dominate over their shorter counterparts.
He added that the decision to allow transgender females to compete with other girls or women could hinge on when athletes began taking testosterone blockers. “If the process of conversion from male to female has been undertaken in the early stages of puberty, from my perspective, they have very little unique advantage,” said Genel, who advised the International Olympic Committee (IOC), based in Switzerland, on testosterone limits for transgender athletes.
Because young athletes’ bodies are still developing, “the differences in natural abilities are so massive that they would overwhelm any advantage a transgender athlete might have,” said Thomas H. Murray, president emeritus of The Hastings Center, a pioneering bioethics research institute in Garrison, New York, and author of the book “Good Sport,” which focuses on the ethics and values in the Olympics and other competitions.
“There’s no good reason to limit the participation of transgender athletes in the sports where male athletes don’t have an advantage over women,” such as sailing, archery and shooting events, Murray said. “The burden of proof rests on those who want to restrict participation by transgender athletes. They must show that in this sport, at this level of competition, transgender athletes have a conspicuous advantage.”
Last year, the IOC issued a new framework emphasizing that the Olympic rules related to transgender participation should be specific to each sport. “This is an evolving topic and there has been—as it will continue to be—new research coming out and new developments informing our approach,” and there’s currently no consensus on how testosterone affects performance across all sports, an IOC spokesperson told Leaps.org.
Many of the new laws prohibiting transgender people from competing in sports consistent with their gender identity specifically apply to transgender females. Yet, some experts say the issue also affects transgender males, nonbinary and intersex athletes.
“There has been quite a bit of attention paid to transgender females and their participation in biological female sports and almost minimal focus on transgender male competition in male sports or in any sports,” said Katherine Drabiak, associate professor of public health law and medical ethics at University of South Florida in Tampa. In fact, “transgender men, because they were born female, would be at a disadvantage of having less lean body mass, less strength and less muscular area as a general category compared to a biological male.”
While discussing transgender students’ participation in sports, it’s important to call attention to the toll that anti-transgender legislation can take on these young people’s well-being, said Jonah DeChants, a research scientist at The Trevor Project, a suicide prevention and mental health organization for LGBTQ youth. Recent polling found that 85 percent of transgender and nonbinary youth said that debates around anti-transgender laws had a negative impact on their mental health.
“The reality is simple: Most transgender girls want to play sports for the same reasons as any student—to benefit their health, to have fun, and to build connection with friends,” DeChants said. According to a new peer-reviewed qualitative study by researchers at The Trevor Project, many trans girls who participated in sports experienced harassment and stigma based on their gender identity, which can contribute to poor mental health outcomes and suicide risk.
In addition to badminton, O'Connor played other sports such as volleyball, and she plans to become an assistant coach or manager of her old high school's badminton team.
Ashley O'Connor
However, DeChants added, research also shows that young people who reported living in an accepting community, had access to LGBTQ-affirming spaces, or had social support from family and friends reported significantly lower rates of attempting suicide in the past year. “We urge coaches, educators and school administrators to seek LGBTQ-cultural competency training, implement zero tolerance policies for anti-trans bullying, and create safe, affirming environments for all transgender students on and off the field,” DeChants said.
O’Connor said her experiences on the athletic scene have been mostly positive. The politics of her community lean somewhat liberal, and she thinks it’s probably more supportive than some other areas of the country, though she noted the local library has received threats for hosting LGBTQ events. In addition to badminton, she also played baseball, lacrosse, volleyball, basketball and hockey. In the spring, she plans to become an assistant coach or manager for the girls’ badminton team at her old high school.
“When I played badminton, I never got any direct backlash from any coaches, competitors or teammates,” she said. “I had a few other teammates that identified as trans or nonbinary, [and] nearly all of the people I ever interacted with were super pleasant and treated me like any other normal person.” She added that transgender athletes “have aspirations. We have wants and needs. We have dreams. And at the end of the day, we just want to live our lives and be happy like everyone else.”