Regenerative medicine has come a long way, baby
After a cloned baby sheep, what started as one of the most controversial areas in medicine is now promising to transform it.
The field of regenerative medicine had a shaky start. In 2002, when news spread about the first cloned animal, Dolly the sheep, a raucous debate ensued. Scary headlines and organized opposition groups put pressure on government leaders, who responded by tightening restrictions on this type of research.
Fast forward to today, and regenerative medicine, which focuses on making unhealthy tissues and organs healthy again, is rewriting the code to healing many disorders, though it’s still young enough to be considered nascent. What started as one of the most controversial areas in medicine is now promising to transform it.
Progress in the lab has addressed previous concerns. Back in the early 2000s, some of the most fervent controversy centered around somatic cell nuclear transfer (SCNT), the process used by scientists to produce Dolly. There was fear that this technique could be used in humans, with possibly adverse effects, considering the many medical problems of the animals who had been cloned.
But today, scientists have discovered better approaches with fewer risks. Pioneers in the field are embracing new possibilities for cellular reprogramming, 3D organ printing, AI collaboration, and even growing organs in space. It could bring a new era of personalized medicine for longer, healthier lives - while potentially sparking new controversies.
Engineering tissues from amniotic fluids
Work in regenerative medicine seeks to reverse damage to organs and tissues by culling, modifying and replacing cells in the human body. Scientists in this field reach deep into the mechanisms of diseases and the breakdowns of cells, the little workhorses that perform all life-giving processes. If cells can’t do their jobs, they take whole organs and systems down with them. Regenerative medicine seeks to harness the power of healthy cells derived from stem cells to do the work that can literally restore patients to a state of health—by giving them healthy, functioning tissues and organs.
Modern-day regenerative medicine takes its origin from the 1998 isolation of human embryonic stem cells, first achieved by John Gearhart at Johns Hopkins University. Gearhart isolated the pluripotent cells that can differentiate into virtually every kind of cell in the human body. There was a raging controversy about the use of these cells in research because at that time they came exclusively from early-stage embryos or fetal tissue.
Back then, the highly controversial SCNT cells were the only way to produce genetically matched stem cells to treat patients. Since then, the picture has changed radically because other sources of highly versatile stem cells have been developed. Today, scientists can derive stem cells from amniotic fluid or reprogram patients’ skin cells back to an immature state, so they can differentiate into whatever types of cells the patient needs.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
The ethical debate has been dialed back and, in the last few decades, the field has produced important innovations, spurring the development of whole new FDA processes and categories, says Anthony Atala, a bioengineer and director of the Wake Forest Institute for Regenerative Medicine. Atala and a large team of researchers have pioneered many of the first applications of 3D printed tissues and organs using cells developed from patients or those obtained from amniotic fluid or placentas.
His lab, considered to be the largest devoted to translational regenerative medicine, is currently working with 40 different engineered human tissues. Sixteen of them have been transplanted into patients. That includes skin, bladders, urethras, muscles, kidneys and vaginal organs, to name just a few.
These achievements are made possible by converging disciplines and technologies, such as cell therapies, bioengineering, gene editing, nanotechnology and 3D printing, to create living tissues and organs for human transplants. Atala is currently overseeing clinical trials to test the safety of tissues and organs engineered in the Wake Forest lab, a significant step toward FDA approval.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
“It’s never fast enough,” Atala says. “We want to get new treatments into the clinic faster, but the reality is that you have to dot all your i’s and cross all your t’s—and rightly so, for the sake of patient safety. People want predictions, but you can never predict how much work it will take to go from conceptualization to utilization.”
As a surgeon, he also treats patients and is able to follow transplant recipients. “At the end of the day, the goal is to get these technologies into patients, and working with the patients is a very rewarding experience,” he says. Will the 3D printed organs ever outrun the shortage of donated organs? “That’s the hope,” Atala says, “but this technology won’t eliminate the need for them in our lifetime.”
New methods are out of this world
Jeanne Loring, another pioneer in the field and director of the Center for Regenerative Medicine at Scripps Research Institute in San Diego, says that investment in regenerative medicine is not only paying off, but is leading to truly personalized medicine, one of the holy grails of modern science.
This is because a patient’s own skin cells can be reprogrammed to become replacements for various malfunctioning cells causing incurable diseases, such as diabetes, heart disease, macular degeneration and Parkinson’s. If the cells are obtained from a source other than the patient, they can be rejected by the immune system. This means that patients need lifelong immunosuppression, which isn’t ideal. “With Covid,” says Loring, “I became acutely aware of the dangers of immunosuppression.” Using the patient’s own cells eliminates that problem.
Microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, Loring's own cells have been sent to the ISS for study.
Loring has a special interest in neurons, or brain cells that can be developed by manipulating cells found in the skin. She is looking to eventually treat Parkinson’s disease using them. The manipulated cells produce dopamine, the critical hormone or neurotransmitter lacking in the brains of patients. A company she founded plans to start a Phase I clinical trial using cell therapies for Parkinson’s soon, she says.
This is the culmination of many years of basic research on her part, some of it on her own cells. In 2007, Loring had her own cells reprogrammed, so there’s a cell line that carries her DNA. “They’re just like embryonic stem cells, but personal,” she said.
Loring has another special interest—sending immature cells into space to be studied at the International Space Station. There, microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, her own cells have been sent to the ISS for study. “My colleagues and I have completed four missions at the space station,” she says. “The last cells came down last August. They were my own cells reprogrammed into pluripotent cells in 2009. No one else can say that,” she adds.
Future controversies and tipping points
Although the original SCNT debate has calmed down, more controversies may arise, Loring thinks.
One of them could concern growing synthetic embryos. The embryos are ultimately derived from embryonic stem cells, and it’s not clear to what stage these embryos can or will be grown in an artificial uterus—another recent invention. The science, so far done only in animals, is still new and has not been widely publicized but, eventually, “People will notice the production of synthetic embryos and growing them in an artificial uterus,” Loring says. It’s likely to incite many of the same reactions as the use of embryonic stem cells.
Bernard Siegel, the founder and director of the Regenerative Medicine Foundation and executive director of the newly formed Healthspan Action Coalition (HSAC), believes that stem cell science is rapidly approaching tipping point and changing all of medical science. (For disclosure, I do consulting work for HSAC). Siegel says that regenerative medicine has become a new pillar of medicine that has recently been fast-tracked by new technology.
Artificial intelligence is speeding up discoveries and the convergence of key disciplines, as demonstrated in Atala’s lab, which is creating complex new medical products that replace the body’s natural parts. Just as importantly, those parts are genetically matched and pose no risk of rejection.
These new technologies must be regulated, which can be a challenge, Siegel notes. “Cell therapies represent a challenge to the existing regulatory structure, including payment, reimbursement and infrastructure issues that 20 years ago, didn’t exist.” Now the FDA and other agencies are faced with this revolution, and they’re just beginning to adapt.
Siegel cited the 2021 FDA Modernization Act as a major step. The Act allows drug developers to use alternatives to animal testing in investigating the safety and efficacy of new compounds, loosening the agency’s requirement for extensive animal testing before a new drug can move into clinical trials. The Act is a recognition of the profound effect that cultured human cells are having on research. Being able to test drugs using actual human cells promises to be far safer and more accurate in predicting how they will act in the human body, and could accelerate drug development.
Siegel, a longtime veteran and founding father of several health advocacy organizations, believes this work helped bring cell therapies to people sooner rather than later. His new focus, through the HSAC, is to leverage regenerative medicine into extending not just the lifespan but the worldwide human healthspan, the period of life lived with health and vigor. “When you look at the HSAC as a tree,” asks Siegel, “what are the roots of that tree? Stem cell science and the huge ecosystem it has created.” The study of human aging is another root to the tree that has potential to lengthen healthspans.
The revolutionary science underlying the extension of the healthspan needs to be available to the whole world, Siegel says. “We need to take all these roots and come up with a way to improve the life of all mankind,” he says. “Everyone should be able to take advantage of this promising new world.”
While lab-grown meat is not yet ready to crisis-proof the food supply chain, it offers key benefits that could make it an important solution beyond this pandemic.
The coronavirus pandemic exposed significant weaknesses in the country's food supply chain. Grocery store meat counters were bare. Transportation interruptions influenced supply. Finding beef, poultry, and pork at the store has been, in some places, as challenging as finding toilet paper.
In traditional agriculture models, it takes at least three months to raise chicken, six to nine months for pigs, and 18 months for cattle.
It wasn't a lack of supply -- millions of animals were in the pipeline.
"There's certainly enough food out there, but it can't get anywhere because of the way our system is set up," said Amy Rowat, an associate professor of integrative biology and physiology at UCLA. "Having a more self-contained, self-sufficient way to produce meat could make the supply chain more robust."
Cultured meat could be one way of making the meat supply chain more resilient despite disruptions due to pandemics such as COVID-19. But is the country ready to embrace lab-grown food?
According to a Good Food Institute study, GenZ is almost twice as likely to embrace meat alternatives for reasons related to social and environmental awareness, even prior to the pandemic. That's because this group wants food choices that reflect their values around food justice, equity, and animal welfare.
Largely, the interest in protein alternatives has been plant-based foods. However, factors directly related to COVID-19 may accelerate consumer interest in the scaling up of cell-grown products, according to Liz Specht, the associate director of science and technology at The Good Food Institute. The latter is a nonprofit organization that supports scientists, investors, and entrepreneurs working to develop food alternatives to conventional animal products.
While lab-grown food isn't ready yet to definitively crisis-proof the food supply chain, experts say it offers promise.
Matching Supply and Demand
Companies developing cell-grown meat claim it can take as few as two months to develop a cell into an edible product, according to Anthony Chow, CFA at Agronomics Limited, an investment company focused on meat alternatives. Tissue is taken from an animal and placed in a culture that contains nutrients and proteins the cells need to grow and expand. He cites a Good Food Institute report that claims a 2.5-millimeter sample can grow three and a half tons of meat in 40 days, allowing for exponential growth when needed.
In traditional agriculture models, it takes at least three months to raise chicken, six to nine months for pigs, and 18 months for cattle. To keep enough maturing animals in the pipeline, farms must plan the number of animals to raise months -- even years -- in advance. Lab-grown meat advocates say that because cultured meat supplies can be flexible, it theoretically allows for scaling up or down in significantly less time.
"Supply and demand has drastically changed in some way around the world and cultivated meat processing would be able to adapt much quicker than conventional farming," Chow said.
Scaling Up
Lab-grown meat may provide an eventual solution, but not in the immediate future, said Paul Mozdziak, a professor of physiology at North Carolina State University who researches animal cell culture techniques, transgenic animal production, and muscle biology.
"The challenge is in culture media," he said. "It's going to take some innovation to get the cells to grow at quantities that are going to be similar to what you can get from an animal. These are questions that everybody in the space is working on."
Chow says some of the most advanced cultured meat companies, such as BlueNal, anticipate introducing products to the market midway through next year. However, he thinks COVID-19 has slowed the process. Once introduced, they will be at a premium price, most likely available at restaurants before they hit grocery store shelves.
"I think in five years' time it will be in a different place," he said. "I don't think that this will have relevance for this pandemic, but certainly beyond that."
"Plant-based meats may be perceived as 'alternatives' to meat, whereas lab-grown meat is producing the same meat, just in a much more efficient manner, without the environmental implications."
Of course, all the technological solutions in the world won't solve the problem unless people are open-minded about embracing them. At least for now, a lab-grown burger or bluefin tuna might still be too strange for many people, especially in the U.S.
For instance, a 2019 article published by "Frontiers in Sustainable Food Systems" reflects results from a study of 3,030 consumers showing that 29 percent of U.S. customers, 59 percent of Chinese consumers, and 56 percent of Indian consumers were either 'very' or 'extremely likely' to try cultivated meat.
"Lab-grown meat is genuine meat, at the cellular level, and therefore will match conventional meat with regard to its nutritional content and overall sensory experience. It could be argued that plant-based meat will never be able to achieve this," says Laura Turner, who works with Chow at Agronomics Limited. "Plant-based meats may be perceived as 'alternatives' to meat, whereas lab-grown meat is producing the same meat, just in a much more efficient manner, without the environmental implications."
A Solution Beyond This Pandemic
The coronavirus has done more than raise awareness of the fragility of food supply chains. It has also been a wakeup call for consumers and policy makers that it is time to radically rethink our meat, Specht says. Those factors have elevated the profile of lab-grown meat.
"I think the economy is getting a little bit more steam and if I was an investor, I would be getting excited about it," adds Mozdziak.
Beyond crises, Mozdziak explains that as affluence continues to increase globally, meat consumption increases exponentially. Yet farm animals can only grow so quickly and traditional farming won't be able to keep up.
"Even Tyson is saying that by 2050, there's not going to be enough capacity in the animal meat space to meet demand," he notes. "If we don't look at some innovative technologies, how are we going to overcome that?"
A COVID-19 moonshot program challenged chemists around the world to submit ideas for how best to design a drug to target the virus.
By mid-March, Alpha Lee was growing restless. A pioneer of AI-driven drug discovery, Lee leads a team of researchers at the University of Cambridge, but his lab had been closed amidst the government-initiated lockdowns spreading inexorably across Europe.
If the Moonshot proves successful, they hope it could serve as a future benchmark for finding new medicines for chronic diseases.
Having spoken to his collaborators across the globe – many of whom were seeing their own experiments and research projects postponed indefinitely due to the pandemic – he noticed a similar sense of frustration and helplessness in the face of COVID-19.
While there was talk of finding a novel treatment for the virus, Lee was well aware the process was likely to be long and laborious. Traditional methods of drug discovery risked suffering the same fate as the efforts to find a cure for SARS in the early 2000, which took years and were ultimately abandoned long before a drug ever reached the market.
To avoid such an outcome, Lee was convinced that global collaboration was required. Together with a collection of scientists in the UK, US and Israel, he launched the 'COVID Moonshot' – a project which encouraged chemists worldwide to share their ideas for potential drug designs. If the Moonshot proves successful, they hope it could serve as a future benchmark for finding new medicines for chronic diseases.
Solving a Complex Jigsaw
In February, ShanghaiTech University published the first detailed snapshots of the SARS-CoV-2 coronavirus's proteins using a technique called X-ray crystallography. In particular, they revealed a high-resolution profile of the virus's main protease – the part of its structure that enables it to replicate inside a host – and the main drug target. The images were tantalizing.
"We could see all the tiny pieces sitting in the structure like pieces of a jigsaw," said Lee. "All we needed was for someone to come up with the best idea of joining these pieces together with a drug. Then you'd be left with a strong molecule which sits in the protease, and stops it from working, killing the virus in the process."
Normally, ideas for how best to design such a drug would be kept as carefully guarded secrets within individual labs and companies due to their potential value. But as a result, the steady process of trial and error to reach an optimum design can take years to come to fruition.
However, given the scale of the global emergency, Lee felt that the scientific community would be open to collective brainstorming on a mass scale. "Big Pharma usually wouldn't necessarily do this, but time is of the essence here," he said. "It was a case of, 'Let's just rethink every drug discovery stage to see -- ok, how can we go as fast as we can?'"
On March 13, he launched the COVID moonshot, calling for chemists around the globe to come up with the most creative ideas they could think of, on their laptops at home. No design was too weird or wacky to be considered, and crucially nothing would be patented. The entire project would be done on a not-for-profit basis, meaning that any drug that makes it to market will have been created simply for the good of humanity.
It caught fire: Within just two weeks, more than 2,300 potential drug designs had been submitted. By the middle of July, over 10,000 had been received from scientists around the globe.
The Road Toward Clinical Trials
With so many designs to choose from, the team has been attempting to whittle them down to a shortlist of the most promising. Computational drug discovery experts at Diamond and the Weizmann Institute of Science in Rehovot, Israel, have enabled the Moonshot team to develop algorithms for predicting how quick and easy each design would be to make, and to predict how well each proposed drug might bind to the virus in real life.
The latter is an approach known as computational covalent docking and has previously been used in cancer research. "This was becoming more popular even before COVID-19, with several covalent drugs approved by the FDA in recent years," said Nir London, professor of organic chemistry at the Weizmann Institute, and one of the Moonshot team members. "However, all of these were for oncology. A covalent drug against SARS-CoV-2 will certainly highlight covalent drug-discovery as a viable option."
Through this approach, the team have selected 850 compounds to date, which they have manufactured and tested in various preclinical trials already. Fifty of these compounds - which appear to be especially promising when it comes to killing the virus in a test tube – are now being optimized further.
Lee is hoping that at least one of these potential drugs will be shown to be effective in curing animals of COVID-19 within the next six months, a step that would allow the Moonshot team to reach out to potential pharmaceutical partners to test their compounds in humans.
Future Implications
If the project does succeed, some believe it could open the door to scientific crowdsourcing as a future means of generating novel medicine ideas for other diseases. Frank von Delft, professor of protein science and structural biology at the University of Oxford's Nuffield Department of Medicine, described it as a new form of 'citizen science.'
"There's a vast resource of expertise and imagination that is simply dying to be tapped into," he said.
Others are slightly more skeptical, pointing out that the uniqueness of the current crisis has meant that many scientists were willing to contribute ideas without expecting any future compensation in return. This meant that it was easy to circumvent the traditional hurdles that prevent large-scale global collaborations from happening – namely how to decide who will profit from the final product and who will hold the intellectual property (IP) rights.
"I think it is too early to judge if this is a viable model for future drug discovery," says London. "I am not sure that without the existential threat we would have seen so many contributions, and so many people and institutions willing to waive compensation and future royalties. Many scientists found themselves at home, frustrated that they don't have a way to contribute to the fight against COVID-19, and this project gave them an opportunity. Plus many can get behind the fact that this project has no associated IP and no one will get rich off of this effort. This breaks down a lot of the typical barriers and red-tape for wider collaboration."
"If a drug would sprout from one of these crowdsourced ideas, it would serve as a very powerful argument to consider this mode of drug discovery further in the future."
However the Moonshot team believes that if they can succeed, it will at the very least send a strong statement to policy makers and the scientific community that greater efforts should be made to make such large-scale collaborations more feasible.
"All across the scientific world, we've seen unprecedented adoption of open-science, collaboration and collegiality during this crisis, perhaps recognizing that only a coordinated global effort could address this global challenge," says London. "If a drug would sprout from one of these crowdsourced ideas, it would serve as a very powerful argument to consider this mode of drug discovery further in the future."
[An earlier version of this article was published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]