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.”
The Troubling Reason I Obsessively Researched My Pregnancy
At the end of my second trimester of pregnancy, I answered a call from an unknown number.
To be pregnant is to exist on a never-ending receiving line of advice, whether we want it or not.
"I know your due date is approaching," said a stranger at the other end of the line, completely freaking me out. She identified herself as being from Natera, a company that my doctor had used for genetic testing I had consented to months ago.
"Excuse me?" I said.
"Have you considered cord-blood banking?" she said.
"No, I'm not doing that," I said. I had read enough about cord-blood banking, the process of saving stem cell-containing blood from your baby's umbilical cord, to understand that my family was in the vast majority of those that would with extremely high likelihood derive no medical benefit from it. Of course, in the societally sanctioned spending spree that accompanies new parenthood, plenty of companies are happy to charge anyone hundreds if not thousands of dollars plus annual storage fees to collect and manage your cord blood.
"Why not? Have you considered all the bene—"
"I'm not doing it and I don't want to explain my decision," I said before hanging up. I would later learn I neglected to check a miniscule box on my testing consent forms at the doctor to opt out of solicitations. Still, I was angry that I was being telemarketed unnecessary and costly medical services by someone who had been trained to immediately call my judgment into question. I was annoyed that my doctor's office would allow such intrusions at all. When I asked my OB about it at my next visit, she told me there's no way Natera would have gotten my information from them. Apparently even she didn't realize what was on those forms.
The incident with Natera did nothing to heighten my trust of the medical establishment during my pregnancy. I was hardly alone. Almost every mom I knew had expressed a similar sentiment.
"I don't trust doctors," read the text of a loved one when I told her I would probably get an epidural after my doctor recommended getting one because, she said, it can help relax the pelvic muscles during labor. But this friend, a highly educated woman who had had done her research and had two unmedicated births, believed firmly otherwise. "Look it up," she said. Thus commenced more of the furious Googling I found myself doing multiple times a day since deciding I wanted to become pregnant.
To be pregnant is to exist on a never-ending receiving line of advice, whether we want it or not. Information presents to us from Google's never-out-of-reach search bar, friends and family eager to use our pregnancies as an excuse to recall their own, and the doctor's office, where the wisdom of medical professionals neatly comingles with brochures and free samples from myriad companies that would really, really like our business as new moms. Separating the "good" advice from the rest is a Herculean task that many pregnant women manage only with vigorous fact-finding missions of their own.
The medical community in America is poorly equipped to help women navigate the enormous pressures that come with birth and transitioning to motherhood.
Doing my research during pregnancy felt like a defense against the scary unknowns, overabundance of opinions, and disturbing marketing schemes that come with entering parenthood. The medical community in America is poorly equipped to help women navigate the enormous emotional and societal pressures that come with birth and transitioning to motherhood. Too much of what pregnant women experience at the doctor has to do with dated ideas about our care, mandated by tradition or a fear of being sued rather than medical necessity. These practices, like weigh-ins at every appointment or medically unnecessary C-sections (which are estimated to account, horrifically, for almost 50 percent of all C-sections performed in the U.S.), only heighten anxiety.
Meanwhile, things that might alleviate stress – like having thorough discussions about the kinds of interventions we might be asked to accept at the hospital during labor and delivery – are left to outside educators and doulas that insurance plans typically don't cover. The net effect isn't better health outcomes for mom and baby, but rather a normalized sense of distrust many American women feel toward their OBGYNs, and the burden of going to every appointment and the delivery room on the defensive. Instead of being wed to dated medical practices and tangled in America's new motherhood industrial complex, shouldn't our doctors, of all people, be our biggest advocates?
As soon as I found out I was pregnant, I devoured Expecting Better, by Emily Oster, an economist who embarked on her own fact-finding mission during her first pregnancy, predicated on the belief that the advice OBGYNs have been giving pregnant women for decades is out of date and unnecessarily restrictive. The book includes controversial stances, like that having small amounts of alcohol while pregnant is OK. (More recent research has called this view into question.) Oster writes that for the vast majority of pregnant women, it's perfectly fine to lie on your back, do sit-ups, and eat Brie — all things I was relieved to learn I wouldn't have to give up for nine months, despite the traditional advice, which my doctor also gave to me.
Oster recommends hiring a doula, based both on research and personal experience. It's a worthwhile investment for those who can afford it: according to one study, 20.4 percent of laboring women with doulas had C-sections compared with 34.2 percent of women without them. A doula can do many things for a pregnant client, including helping her write a birth plan, massaging her back in labor, and cheering her on, which is especially useful for women who plan to labor without pain medication. Use of doulas is on the rise; according to DONA International, the world's largest and oldest doula association, the number of doulas who have been certified to date is over 12,000, up from 2,000 in 2002.
But the most significant role a doula plays is that of patient advocate in the hospital. This is a profound commentary on the way the medical establishment handles childbirth, a medical event that 86 percent of women aged 40 to 44 had gone through as of 2016. Recognizing the maternal mortality crisis in the U.S., where women are far more likely to die as a result of childbirth than anywhere else in the developed world and black women are three times more likely to die in childbirth than white women, a few states now allow Medicaid to cover doulas. Can you imagine feeling the need to hire an independent non-medical care provider to help you run interference with your doctors and nurses for something like an appendectomy?
I wouldn't have been aware of all the imminent interventions during my labor if my doula hadn't told me about them. Things happen fast in the hospital and doctors and nurses may rush patients to consent before proceeding with things like breaking their water or hooking them up to an IV of Pitocin. Only because my husband and I had spent six hours in birth class — a suggestion by my doula — did I realize that I was empowered to say "no" to such procedures.
Expecting more trustworthy advice to come from my doctor than books or Google or even a doula hardly seems unreasonable.
Of course, we all feel immense pressure to become good parents, and questioning conventional medical wisdom is a natural response to that pressure. "Looking around at the world and saying, who am I as a parent? What is important to me? Who are the wise people? What do I think wisdom is? What is a good decision? If you're a certain type of introspective person, if you're really asking those questions, that's going to include like taking a second look at things that doctors, for example, say," says Koyuki Smith, a doula and birth educator.
Expecting more trustworthy advice to come from my doctor than books or Google or even a doula hardly seems unreasonable. Yet my doctor's office seemed more concerned with checking off a list of boxes rather than providing me with personalized care that might have relieved my understandable anxiety about my first birth. When I still hadn't gone into labor around the time of my due date, my doctor encouraged me to be induced because my baby appeared to be large. I declined but scheduled an induction to "hold my spot" around the 42-week mark.
When I asked what medication would be used for an induction if I had one and she said Cytotec, I told her I had read that drug could cause serious complications, but she dismissed my concerns after I told her they stemmed from a book I read on natural childbirth. The FDA's page on Cytotec isn't exactly reassuring.
The nurse who took me in triage after I went into labor a week past my due date practically scolded me for waiting to go into labor naturally instead of opting for induction sooner. My doula told her while I was struggling to speak through labor pains to get off my case about it. I hadn't even become a mom and I was already doing so many things "wrong." Because I had done my own reading, I felt confident that my choices weren't harming my baby or me.
Becoming a mom would be less daunting if the medical community found a way to help women navigate the pressures of motherhood instead of adding to them. "Our culture at large doesn't support women enough in the complicated emotions that are a part of this process," said Alexandra Saks, a reproductive psychologist and author of What No One Tells You: A Guide to Your Emotions From Pregnancy to Motherhood. "I hope that every practitioner that works with women around reproductive health prioritizes her emotions around her experience."
For many of us, that will mean doctors who help us understand the pros and cons of conventional advice, don't use their offices as marketing channels, and don't pressure women into medically unnecessary inductions. Moms should also receive more attention after delivery both in the hospital and after they get home; a single, quick postpartum visit at six weeks is not an adequate way to care for women recovering from the trauma of childbirth, nor is it an adequate way to ensure women are emotionally supported during the transition. While several people interrogated me about my mental health at the hospital and my doctor's office just before and after birth, if I had been concerned about postpartum depression, I can't imagine feeling comfortable enough in those moments to tell strangers filling out obligatory worksheets.
It also means figuring out how to talk to patients who are prone to Googling their pregnancies with gusto every single day. It would be impossible for many women to shun independent research during pregnancy altogether. But it would also be nice if our doctors didn't add to our impulse to do it.
“Coming Back from the Dead” Is No Longer Science Fiction
Last year, there were widespread reports of a 53-year-old Frenchman who had suffered a cardiac arrest and "died," but was then resuscitated back to life 18 hours after his heart had stopped.
The once black-and-white line between life and death is now blurrier than ever.
This was thought to have been possible in part because his body had progressively cooled down naturally after his heart had stopped, through exposure to the outside cold. The medical team who revived him were reported as being "stupefied" that they had been able to bring him back to life, in particular since he had not even suffered brain damage.
Interestingly, this man represents one of a growing number of extraordinary cases in which people who would otherwise be declared dead have now been revived. It is a testament to the incredible impact of resuscitation science -- a science that is providing opportunities to literally reverse death, and in doing so, shedding light on the age-old question of what happens when we die.
Death: Past and Present
Throughout history, the boundary between life and death was marked by the moment a person's heart stopped, breathing ceased, and brain function shut down. A person became motionless, lifeless, and was deemed irreversibly dead. This is because once the heart stops beating, blood flow stops and oxygen is cut off from all the body's organs, including the brain. Consequently, within seconds, breathing stops and brain activity comes to a halt. Since the cessation of the heart literally occurs in a "moment," the philosophical notion of a specific point in time of "irreversible" death still pervades society today. The law, for example, relies on "time of death," which corresponds to when the heart stops beating.
The advent of cardiopulmonary resuscitation (CPR) in the 1960s was revolutionary, demonstrating that the heart could potentially be restarted after it had stopped, and what had been a clear black-and-white line was shown to be potentially reversible in some people. What was once called death—the ultimate end point— was now widely called cardiac arrest, and became a starting point.
From then on, it was only if somebody had requested not to be resuscitated or when CPR was deemed to have failed that people would be declared dead by "cardiopulmonary criteria." Biologically, cardiac arrest and death by cardiopulmonary criteria are the same process, albeit marked at different points in time depending on when a declaration of death is made.
The apparent irreversibility of death as we know it may not necessarily reflect true irretrievable cellular damage inside the body.
Clearly, contrary to many people's perceptions, cardiac arrest is not a heart attack; it is the final step in death irrespective of cause, whether it be a stroke, a heart attack, a car accident, an overwhelming infection or cancer. This is how roughly 95 percent of the population are declared dead.
The only exception is the small proportion of people who may have suffered catastrophic brain injuries, but whose hearts can be artificially kept beating for a period of time on life-support machines. These people can be legally declared dead based on brain death criteria before their hearts have stopped. This is because the brain can die either from oxygen starvation after cardiac arrest or from massive trauma and internal bleeding. Either way, the brain dies hours or possibly longer after these injuries have taken place and not just minutes.
A Profound Realization
What has become increasingly clear is that the apparent irreversibility of death as we know it may not necessarily reflect true irretrievable cellular damage inside the body. This is consistent with a mounting understanding: it is only after a person actually dies that the cells in the body start to undergo their own process of death. Intriguingly, this process is something that can now be manipulated through medical intervention. Being cold is one of the factors that slows down the rate of cellular decay. The 53-year-old Frenchman's case and the other recent cases of resuscitation after prolonged periods of time illustrate this new understanding.
Last week's earth-shattering announcement by neuroscientist Dr. Nenad Sestan and his team out of Yale, published in the prestigious scientific journal Nature, provides further evidence that a time gap exists between actual death and cellular death in cadavers. In this seminal study, these researchers were able to restore partial function in pig brains four hours after their heads were severed from their bodies. These results follow from the pioneering work in 2001 of geneticist Fred Gage and colleagues from the Salk Institute, also published in Nature, which demonstrated the possibility of growing human brain cells in the laboratory by taking brain biopsies from cadavers in the mortuary up to 21 hours post-mortem.
The once black-and-white line between life and death is now blurrier than ever. Some people may argue this means these humans and pigs weren't truly "dead." However, that is like saying the people who were guillotined during the French Revolution were also not dead. Clearly, that is not the case. They were all dead. The problem is not death; it's our reliance on an outdated philosophical, rather than biological, notion of death.
Death can no longer be considered an absolute moment but rather a process that can be reversed even many hours after it has taken place.
But the distinction between irreversibility from a medical perspective and biological irreversibility may not matter much from a pragmatic perspective today. If medical interventions do not exist at any given time or place, then of course death cannot be reversed.
However, it is crucial to distinguish between biologically and medically: When "irreversible" loss of function arises due to inadequate treatment, then a person could be potentially brought back in the future when an alternative therapy becomes available, or even today if he or she dies in a location where novel treatments can slow down the rate of cell death. However, when true irreversible loss of function arises from a biological perspective, then no treatment will ever be able to reverse the process, whether today, tomorrow, or in a hundred years.
Probing the "Grey Zone"
Today, thanks to modern resuscitation science, death can no longer be considered an absolute moment but rather a process that can be reversed even many hours after it has taken place. How many hours? We don't really know.
One of the wider implications of our medical advances is that we can now study what happens to the human mind and consciousness after people enter the "grey zone," which marks the time after the heart stops, but before irreversible and irretrievable cell damage occurs, and people are then brought back to life. Millions have been successfully revived and many have reported experiencing a unique, universal, and transformative mental state.
Were they "dead"? Yes, according to all the criteria we have ever used. But they were able to be brought back before their "dead" bodies had reached the point of permanent, irreversible cellular damage. This reflects the period of death for all of us. So rather than a "near-death experience," I prefer a new terminology to describe these cases -- "an actual-death experience." These survivors' unique experiences are providing eyewitness testimonies of what we will all be likely to experience when we die.
Such an experience reportedly includes seeing a warm light, the presence of a compassionate perfect individual, deceased relatives, a review of their lives, a judgment of their actions and intentions as they pertain to their humanity, and in some cases a sensation of seeing doctors and nurses working to resuscitate them.
Are these experiences compatible with hallucinations or illusions? No -- in part, because these people have described real, verifiable events, which, by definition are not hallucinations, and in part, because their experiences are not compatible with confused and delirious memories that characterize oxygen deprivation.
The challenge for us scientifically is understanding how this is possible at a time when all our science tells us the brain shuts down.
For instance, it is hard to classify a structured meaningful review of one's life and one's humanity as hallucinatory or illusory. Instead, these experiences represent a new understanding of the overall human experience of death. As an intensive care unit physician for more than 10 years, I have seen numerous cases where these reports have been corroborated by my colleagues. In short, these survivors have been known to come back with reports of full consciousness, with lucid, well-structured thought processes and memory formation.
The challenge for us scientifically is understanding how this is possible at a time when all our science tells us the brain shuts down. The fact that these experiences occur is a paradox and suggests the undiscovered entity we call the "self," "consciousness," or "psyche" – the thing that makes us who we are - may not become annihilated at the point of so-called death.
At New York University, the State University of New York, and across 20 hospitals in the U.S. and Europe, we have brought together a new multi-disciplinary team of experts across many specialties, including neurology, cardiology, and intensive care. Together, we hope to improve cardiac arrest prevention and treatment, as well as to address the impact of new scientific discoveries on our understanding of what happens at death.
One of our first studies, Awareness during Resuscitation (AWARE), published in the medical journal Resuscitation in 2014, confirmed that some cardiac arrest patients report a perception of awareness without recall; others report detailed memories and experiences; and a few report full auditory and visual awareness and consciousness of their experience, from a time when brain function would be expected to have ceased.
While you probably have some opinion or belief about this based upon your own philosophical, religious, or cultural background, you may not realize that exploring what happens when we die is now a subject that science is beginning to investigate.
There is no question more intriguing to humankind. And for the first time in our history, we may finally uncover some real answers.