Regenerative medicine has come a long way, baby
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.”
Thousands of Vaccine Volunteers Got a Dummy Shot. Should They Get the Real Deal Now?
The highly anticipated rollout of a COVID-19 vaccine poses ethical considerations: When will trial volunteers who got a placebo be vaccinated? And how will this affect the data in those trials?
It's an issue that vaccine manufacturers and study investigators are wrestling with as the Food and Drug Administration is expected to grant emergency use authorization this weekend to a vaccine developed by Pfizer and the German company BioNTech. Another vaccine, produced by Moderna, is nearing approval in the United States.
The most vulnerable—health care workers and nursing home residents—are deemed eligible to receive the initial limited supply in accordance with priority recommendations from the Centers for Disease Control and Prevention (CDC).
With health care workers constituting an estimated 20 percent of trial participants, this question also comes to the fore: "Is it now ethically imperative that we offer them the vaccine, those who have had placebo?" says William Schaffner, an infectious diseases physician at Vanderbilt University and an adviser to the CDC's immunization practices committee.
When a "gold-standard" measure becomes available, participants in the placebo group "would ordinarily be notified" of the strong public health recommendation to opt for immunization, says Johan Bester, interim assistant dean for biomedical science education and director of bioethics at the University of Nevada, Las Vegas School of Medicine.
"If a treatment or prevention exists that we know works, it is unethical to withhold it from people who would benefit from it just to answer a research question." This moral principle poses a quandary for ethicists and physicians alike, as they ponder possible paths to proceed with vaccination amid ongoing trials. Rigorous trials are double-blinded—neither the participants nor the investigators know who received the actual vaccine and who got a dummy injection.
"The intent of these trials is to follow these folks for up to two years," says Marci Drees, infection prevention officer and hospital epidemiologist for ChristianaCare in Wilmington, Delaware. At a minimum, she adds, researchers would prefer to monitor participants for six months.
"You can still follow safety over a long-term period of time without actually continuing to have a placebo group for comparison."
But in the midst of a pandemic, that may not be feasible. Prolonged exposure to the highly contagious and lethal virus could have dire consequences.
To avoid compromising the integrity of the blinded data, "there are some potentially creative solutions," Drees says. For instance, trial participants could receive the opposite of what they initially got, whether it was the vaccine or the placebo.
One factor in this decision-making process depends on when a particular trial is slated to conclude. If that time is approaching, the risk of waiting would be lower than if the trial is only halfway in progress, says Eric Lofgren, an epidemiologist at Washington State University who has studied the impact of COVID-19 in jails and at in-person sporting events.
Sometimes a study concludes earlier than the projected completion date. "All clinical trials have a data and safety monitoring board that reviews the interim results," Lofgren says. The board may halt a trial after finding evidence of harm, or when a treatment or vaccine has proven to be "sufficiently good," rendering it unethical to deprive the placebo group of its benefits.
The initial months of a trial are most crucial for assessing a vaccine's safety. Differences between the trial groups would be illuminating if fewer individuals who got the active vaccine contracted the virus and developed symptoms when compared to the placebo recipients. After that point, in vaccine-administered participants, "you can still follow safety over a long-term period of time without actually continuing to have a placebo group for comparison," says Dial Hewlett Jr., medical director for disease control at the Westchester County Department of Health in New York.
Even outside of a trial, safety is paramount and any severe side effects that occur will be closely monitored and investigated through national reporting networks. For example, regulators in the U.K. are investigating several rare but serious allergic reactions to the Pfizer vaccine given on Tuesday. The FDA has asked Pfizer to track allergic reactions in its safety monitoring plan, and some experts are proposing that Pfizer conduct a separate study of the vaccine on people with a history of severe allergies.
As the FDA eventually grants authorization to multiple vaccines, more participants are likely to leave trials and opt to be vaccinated. It is important that enough participants choose to stay in ongoing trials, says Nicole Hassoun, professor of philosophy at the State University of New York at Binghamton, where she directs the Global Health Impact program to extend medical access to the poor.
She's hopeful that younger participants and individuals without underlying medical conditions will make that determination. But the departure of too many participants at high risk for the virus would make it more difficult to evaluate the vaccine's safety and efficacy in those populations, Hassoun says, while acknowledging, "We can't have the best of both worlds."
Once a safe and effective vaccine is approved in the United States, "it would not be ethically appropriate to do placebo trials to test new vaccines."
One solution would entail allowing health care workers to exit a trial after a vaccine is approved, even though this would result in "a conundrum when the next group of people are brought forward to get the vaccine—whether they're people age 65 and older or they're essential workers, or whoever they are," says Vanderbilt physician Schaffner, who is a former board member of the Infectious Diseases Society of America. "All of a sudden, you'll have an erosion of the volunteers who are in the trial."
For now, one way or another, experts agree that current and subsequent trials should proceed. There is a compelling reason to identify additional vaccines with potentially greater effectiveness but with fewer side effects or less complex delivery methods that don't require storage at extremely low temperatures.
"Continuing with existing vaccine trials and starting others remains important," says Nir Eyal, professor and director of Rutgers University's Center for Population-Level Bioethics in New Brunswick, New Jersey. "We still need to tell how much proven vaccines block infections and how long their duration lasts. And populations around the world need vaccines that are easier to store and deliver, or simply cheaper."
But once a safe and effective vaccine is approved in the United States, "it would not be ethically appropriate to do placebo trials to test new vaccines," says bioethicist Bester at the University of Nevada, Las Vegas School of Medicine. "One possibility if a new vaccine emerges, is to test it against existing vaccines."
In a letter sent to trial volunteers in November, Pfizer and BioNTech committed to establishing "a process that would allow interested participants in the placebo group who meet the eligibility criteria for early access in their country to 'cross-over' to the vaccine group." The trial plans to continue monitoring all subjects regardless of whether people in the placebo group cross over, Pfizer said in a presentation to the FDA today. After Pfizer has collected six months of safety data, in April 2021, it plans to ask the FDA for full approval of the vaccine.
In the meantime, the company pledged to update volunteers as they obtain more input from regulatory authorities. "Thank you again for making a difference by being a part of this study," they wrote. "It is only through the efforts of volunteers like you that reaching this important milestone and developing a potential vaccine against COVID-19 is possible."
CORRECTION: An earlier version of this article mistakenly stated that the FDA would be granting emergency "approval" to the Pfizer/BioNTech vaccine, rather than "emergency use authorization." We regret the error.
Since March, 35 patients in the care of Dr. Gregory Jicha, a neurologist at the University of Kentucky, have died of Alzheimer's disease or related dementia.
Meanwhile, with 233 active clinical trials underway to find treatments, Jicha wonders why mainstream media outlets don't do more to highlight potential solutions to the physical, emotional and economic devastation of these diseases. "Unfortunately, it's not until we're right at the cusp of a major discovery that anybody pays attention to these very promising agents," he says.
Heightened awareness would bring more resources for faster progress, according to Jicha. Otherwise, he's concerned that current research pipelines will take over a decade.
In recent years, newspapers with national readerships have devoted more technology reporting to key developments in social media, artificial intelligence, wired gadgets and telecom. Less prominent has been news about biotech—innovations based on biology research—and new medicines emerging from this technology. That's the impression of Jicha as well as Craig Lipset, former head of clinical innovation at Pfizer. "Scientists and clinicians are entirely invested [in biotech], yet no one talks about their discoveries," he says.
With the popular press rightly focusing on progress with a vaccine for COVID-19 this year, notable developments in biomarkers, Alzheimer's and cancer research, gene therapies for cystic fibrosis, and therapeutics related to biological age may be going unreported. Jennifer Goldsack, Executive Director of the nonprofit Digital Medicine Society, is confused over the media's soft touch with biotech. "I'm genuinely interested in understanding what editors of technology sections think the public wants to be reading."
The Numbers on Media Coverage
A newspaper's health section is a sensible fit for biotech reporting. In 2020, these departments have concentrated largely on COVID-19—as they should—while sections on technology and science don't necessarily pick up on other biotech news. Emily Mullin, staff writer for the tech magazine OneZero, has observed a gap in newspaper coverage. "You have a lot of [niche outlets] reporting biotech on the business side for industry experts, and you have a lot of reporting heavily from the science side focused on [readers who are] scientists. But there aren't a lot of outlets doing more humanizing coverage of biotech."
Indeed, the volume of coverage by top-tier media outlets in the U.S. for non-COVID biotech has dropped 32 percent since the pandemic spiked in March, according to an analysis run for this article by Commetric, a company that looks at media reputation for clients in many sectors including biotech and artificial intelligence. Meanwhile, the volume of coverage for AI has held steady, up one percent.
Commetric's CEO, Magnus Hakansson, thinks important biotech stories were omitted from mainstream coverage even before the world fell into the grips of the virus. "Apart from COVID, it's been extremely difficult for biotech companies to push out their discoveries," he says. "People in biotech have to be quite creative when they want to communicate [progress in] different therapeutic areas, and that is a problem."
In mid-February, just before the pandemic dominated the news cycle, researchers used machine learning to find a powerful new antibiotic capable of killing strains of disease-causing bacteria that had previously resisted all known antibiotics. Science-focused outlets hailed the work as a breakthrough, but some nationally-read newspapers didn't mention it. "There is this very silent crisis around antibiotic resistance that no one is aware of," says Goldsack. "We could be 50 years away from not being able to give elective surgeries because we are at such a high risk of being unable to control infection."
Could mainstream media strike a better balance between cynicism toward biotech and hyping animal studies that probably won't ever benefit the humans reading about them?
What's to Gain from More Mainstream Biotech
A brighter public spotlight on biotech could result in greater support and faster progress with research, says Lipset. "One of the biggest delays in drug development is patient recruitment. Patients don't know about the opportunities," he said, because, "clinical research pipelines aren't talked about in the mainstream news." Only about eight percent of oncology patients participate.
The current focus on COVID-19, while warranted, could also be excluding lines of research that seem separate from the virus, but are actually relevant. In September, Nir Barzilai, director of the Institute of Aging Research at Albert Einstein College of Medicine, told me about eight different observational studies finding decreased COVID-19 severity among people taking a drug called metformin, which is believed to slow down the major hallmarks of biological aging, such as inflammation. Once a vaccine is approved and distributed, biologically older people could supplement it with metformin.
"Shining the spotlight on this research now could really be critical because COVID has shown what happens in older adults and how they're more at risk," says Jenna Bartley, a researcher of aging and immunology at the University of Connecticut, but she believes mainstream media sometimes miss stories on anti-aging therapies or portray them inaccurately.
The question remains why.
The Theranos Effect and Other Image Problems
Before the pandemic, Mullin, the biotech writer at OneZero, looked into a story for her editor about a company with a new test for infectious diseases. The company said its test, based on technology for editing genes, was fast, easy to use, and could be tailored to any pathogen. Mullin told her editor the evidence for the test's validity was impressive.
He wondered if readers would agree. "This is starting to sound like Theranos," he said.
The brainchild of entrepreneur Elizabeth Holmes, Theranos was valued at $9 billion in 2014. Time Magazine named Holmes one of its most influential people, and the blood-testing company was heavily covered by the media as a game changer for health outcomes—until Holmes was exposed by the Wall Street Journal as a fraud and criminally charged.
In the OneZero article, Mullin and her editor were careful to explain the gene-editing tech was legit, explicitly distinguishing it from Theranos. "I was like, yes—but this actually works! And they can show it works."
While the Holmes scandal explains some of the mistrust, it's part of a bigger pattern. The public's hopes for biotech have been frustrated repeatedly in recent decades, fostering a media mantra of fool me twice, shame on me. A recent report by Commetric noted that after the bursting of the biotech market bubble in the early 2000s, commentators grew deeply skeptical of the field. An additional source of caution may be the number of researchers in biotech with conflicts of interest such as patents or their own startups. "It's a landmine," Mullin said. "We're conditioned to think that scientists are out for the common good, but they have their own biases."
Yet another source of uncertainty: the long regulatory road and cost for new therapies to be approved by the FDA. The process can take 15 years and over a billion dollars; the percentage of drugs actually crossing the final strand of red tape is notoriously low.
"The only time stories have reached the news is when there's a sensational headline about the cure for cancer," said Lipset, "when, in fact it's about mice, and then things drop off." Meanwhile, consumer protection hurdles for some technologies, such as computer chips, are less onerous than the FDA gauntlet for new medicines. The media may view research breakthroughs in digital tech as more impactful because they're likelier to find their way into commercially available products.
And whereas a handful of digital innovations have been democratized for widespread consumption—96 percent of Americans now own a cell phone, and 72 percent use social media—journalists at nationally-read newspapers may see biotech as less attainable for the average reader. Sure, we're all aging, but will the healthcare system grant everyone fair access to treatments for slowing the aging process? Current disparities in healthcare sow reason for doubt.
And yet. Recall Lipset's point that more press coverage would drive greater participation in clinical trials, which could accelerate them and diversify participants. Could mainstream media strike a better balance between cynicism toward biotech and hyping animal studies that probably won't ever benefit the humans reading about them?
Biotech in a Post-COVID World
Imagine it's early 2022. Hopefully, much of the population is protected from the virus through some combination of vaccines, therapeutics, and herd immunity. We're starting to bounce back from the social and economic shocks of 2020. COVID-19 headlines recede from the front pages, then disappear altogether. Gradually, certain aspects of life pick up where they left off in 2019, while a few changes forced by the pandemic prove to be more lasting, some for the better.
Among its possible legacies, the virus could usher in a new era of biotech development and press coverage, with these two trends reinforcing each other. While government has mismanaged its response to the virus, the level of innovation, collaboration and investment in pandemic-related biotech has been compared to the Manhattan Project. "There's no question that vaccine acceleration is a success story," said Kevin Schulman, a professor of medicine and economics at Stanford. "We could use this experience to build new economic models to correct market failures. It could carry over to oncology or Alzheimer's."
As Winston Churchill said, never let a good crisis go to waste.
Lipset thinks the virus has primed us to pay attention, bringing biotech into the public's consciousness like never before. He's amazed at how many neighbors and old friends from high school are coming out of the woodwork to ask him how clinical trials work. "What happens next is interesting. Does this open a window of opportunity to get more content out? People's appetites have been whetted."
High-profile wins could help to sustain interest, such as deployment of rapid tests of COVID-19 to be taken at home, a version of which the FDA authorized on November 18th. The idea bears resemblance to the Theranos concept, also designed as a portable analysis, except this test met the FDA's requirements and has a legitimate chance of changing people's lives. Meanwhile, at least two vaccines are on track to gain government approval in record time. The unprecedented speed could be a catalyst for streamlining inefficiencies in the FDA's approval process in non-emergency situations.
Tests for COVID-19 represent what some view as the future of managing diseases: early detection. This paradigm may be more feasible—and deserving of journalistic ink—than research on diseases in advanced stages, says Azra Raza, professor of medicine at Columbia University. "Journalists have to challenge this conceit of thinking we can cure end-stage cancer," says Raza, author of The First Cell. Beyond animal studies and "exercise helps" articles, she thinks writers should focus on biotech for catching the earliest footprints of cancer when it's more treatable. "Not enough people appreciate the extent of this tragedy, but journalists can help us do it. COVID-19 is a great moment of truth telling."
Another pressing truth is the need for vaccination, as half of Americans have said they'll skip them due to concerns about safety and effectiveness. It's not the kind of stumbling block faced by iPhones or social media algorithms. AI stirs plenty of its own controversy, but the public's interest in learning about AI and engaging with it seems to grow regardless. "Who are the publicists doing such a good job for AI that biotechnology is lacking?" Lipset wonders.
The job description of those publicists, whoever they are, could be expanding. Scientists are increasingly using AI to measure the effects of new medicines that target diseases—including COVID-19—and the pathways of aging. Mullin noted the challenge of reporting breakthroughs in the life sciences in ways the public understands. With many newsrooms tightening budgets, fewer writers have science backgrounds, and "biotech is daunting for journalists," she says. "It's daunting for me and I work in this area." Now factor in the additional expertise required to understand biotech and AI. "I learned the ropes for how to read a biotech paper, but I have no idea how to read an AI paper."
Nevertheless, Mullin believes reporters have a duty to scrutinize whether this convergence of AI and biotech will foster better outcomes. "Is it just the shiny new tool we're employing because we can? Will algorithms help eliminate health disparities or contribute to them even more? We need to pay attention."