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.”
The Only Hydroxychloroquine Story You Need to Read
Hydroxychloroquine has been shown not to provide benefit for COVID-19 patients in multiple randomized controlled trials, despite continuous misinformation asserting its alleged effectiveness.
In the early days of a pandemic caused by a virus with no existing treatments, many different compounds are often considered and tried in an attempt to help patients.
It all relates back to a profound question: How do we know what we know?
Many of these treatments fall by the wayside as evidence accumulates regarding actual efficacy. At that point, other treatments become standard of care once their benefit is proven in rigorously designed trials.
However, about seven months into the pandemic, we're still seeing political resurrection of a treatment that has been systematically studied and demonstrated in well-designed randomized controlled trials to not have benefit.
The hydroxychloroquine (and by extension chloroquine) story is a complicated one that was difficult to follow even before it became infused with politics. It is a simple fact that these drugs, long approved by the Food and Drug Administration (FDA), work in Petri dishes against various viruses including coronaviruses. This set of facts provided biological plausibility to support formally studying their use in the clinical treatment and prevention of COVID-19. As evidence from these studies accumulates, it is a cognitive requirement to integrate that knowledge and not to evade it. This also means evaluating the rigor of the studies.
In recent days we have seen groups yet again promoting the use of hydroxychloroquine in, what is to me, a baffling disregard of the multiple recent studies that have shown no benefit. Indeed, though FDA-approved for other indications like autoimmune conditions and preventing malaria, the emergency use authorization for COVID-19 has been rescinded (which means the government cannot stockpile it). Still, however, many patients continue to ask for the drug, compelled by political commentary, viral videos, and anecdotal data. Yet most doctors (like myself) are refusing to write the prescriptions outside of a clinical trial – a position endorsed by professional medical organizations such as the American College of Physicians and the Infectious Diseases Society of America. Why this disconnect?
It all relates back to a profound question: How do we know what we know? In science, we use the scientific method – the process of observing reality, coming up with a hypothesis about what might be true, and testing that hypothesis as thoroughly as possible until we discover the objective truth.
The confusion we're seeing now stems from an inability to distinguish between anecdotes reported by physicians (observational data) and an actual evidence base. This is understandable among the general public but when done by a healthcare professional, it reveals a disdain for reason, logic, and the scientific method.
The Difference Between Observational Data and Randomized Controlled Trials
The power of informal observation is crucial. It is part of the scientific method but primarily as a basis for generating hypotheses that we can test. How do we conduct medical tests? The gold standard is the double-blind, randomized, placebo-controlled trial. This means that neither the researchers nor the volunteers know who is getting a drug and who is getting a sugar pill. Then both groups of the trial, called arms, can be compared to determine whether the people who got the drug fared better. This study design prevents biases and the placebo effect from confounding the data and undermining the veracity of the results.
For example, a seemingly beneficial effect might be seen in an observational study with no blinding and no control group. In such a case, all patients are openly given the drug and their doctors observe how they do. A prime example is the 36-patient single-arm study from France that generated a tremendous amount of interest after President Trump tweeted about it. But this kind of a study by its nature cannot answer the critical question: Was the positive effect because of hydroxychloroquine or just the natural course of the illness? In other words, would someone have recovered in a similar fashion regardless of the drug? What is the role of the placebo effect?
These are reasons why it is crucial to give a placebo to a control group that is as similar in every respect as possible to those receiving the intervention. Then we attempt to find out by comparing the two groups: What is the side effect profile of the drug? Are the groups large enough to detect a relatively rare safety concern? How long were the patients followed for? Was something else responsible for making the patients get better, such as the use of steroids (as likely was the case in the Henry Ford study)?
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur.
All of these considerations amount to just a fraction of the questions that can be answered more definitively in a well-designed large randomized controlled trial than in observational studies. Indeed, an observational study from New York failed to show any benefit in hospitalized patients, showing how unclear and disparate the results can be with these types of studies. A New York retrospective study (which examined patient outcomes after they were already treated) had similar results and included the use of azithromycin.
When evaluating a study, it is also important to note whether conflicts of interest exist, as well as the quality of the peer review and the data itself. In the case of the French study, for example, the paper was published in a journal in which one of the authors was editor-in-chief, and it was accepted for publication after 24 hours. Patients who fared poorly on hydroxychloroquine were also left out of the study altogether, skewing the results.
What Randomized Controlled Trials Have Shown
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur. The most important of these studies to announce results was part of the Recovery trial, which was designed to test multiple interventions in the treatment of COVID-19. This trial, which has yet to be formally published, was a randomized controlled trial that involved over 1500 hospitalized patients being administered hydroxychloroquine compared to over 3000 who did not receive the medication. Clinical testing requires large numbers of patients to have the power to demonstrate statistical significance -- the threshold at which any apparent benefit is more than you would expect by random chance alone.
In this study, hydroxychloroquine provided no mortality benefit or even a benefit in hospital length of stay. In fact, the opposite occurred. Hydroxychloroquine patients were more likely to stay in the hospital longer and were more likely to require mechanical ventilation. Additionally, smaller randomized trials conducted in China have not shown benefit either.
Another major study involved the use of hydroxychloroquine to prevent illness in people who were exposed to COVID-19. These results, published in The New England Journal of Medicine, included over 800 patients who were studied in a randomized double-blind controlled trial and also failed to show any benefit.
But what about adding the antibiotic azithromycin in conjunction with hydroxychloroquine? A three-arm randomized controlled study involving over 500 patients hospitalized with mild to moderate COVID-19 was conducted. Its results, also published in The New England Journal of Medicine, failed to show any benefit – with or without azithromycin – and demonstrated evidence of harm. Those who received these treatments had elevations of their liver function tests and heart rhythm abnormalities. These findings hold despite the retraction of an observational study showing similar results.
Additionally, when used in combination with remdesivir – an experimental antiviral – hydroxychloroquine has been shown to be associated with worse outcomes and more side effects.
But what about in mildly ill patients not requiring hospitalization? There was no benefit found in a randomized double-blind placebo-controlled trial of 400 patients, the majority of whom were given the drug within one day of symptoms.
Some randomized controlled studies have yet to report their findings on hydroxychloroquine in non-hospitalized patients, with the use of zinc (which has some evidence in the treatment of the common cold, another ailment that can be caused by coronaviruses). And studies have yet to come out regarding whether hydroxychloroquine can prevent people from getting sick before they are even exposed. But the preponderance of the evidence from studies designed specifically to find benefit for treating COVID-19 does not support its use outside of a research setting.
Today – even with some studies (including those with zinc) still ongoing – if a patient asked me to prescribe them hydroxychloroquine for any severity or stage of illness, with or without zinc, with or without azithromycin, I would refrain. I would explain that, based on the evidence from clinical trials that has been amassed, there is no reason to believe that it will alter the course of illness for the better.
Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
What has been occurring is a continual shifting of goalposts with each negative hydroxychloroquine study. Those in favor of the drug protest that a trial did not include azithromycin or zinc or wasn't given at the right time to the right patients. While there may be biological plausibility to treating illness early or combining treatments with zinc, it can only be definitively shown in a randomized, controlled prospective study.
The bottom line: A study that only looks at past outcomes in one group of patients – even when well conducted – is at most hypothesis generating and cannot be used as the sole basis for a new treatment paradigm.
Some may argue that there is no time to wait for definitive studies, but no treatment is benign. The risk/benefit ratio is not the same for every possible use of the drug. For example, hydroxychloroquine has a long record of use in rheumatoid arthritis and systemic lupus (whose patients are facing shortages because of COVID-19 related demand). But the risk of side effects for many of these patients is worth taking because of the substantial benefit the drug provides in treating those conditions.
In COVID-19, however, the disease apparently causes cardiac abnormalities in a great deal of many mild cases, a situation that should prompt caution when using any drugs that have known effects on the cardiac system -- drugs like hydroxychloroquine and azithromycin.
My Own Experience
It is not the case that every physician was biased against this drug from the start. Indeed, most of us wanted it to be shown to be beneficial, as it was a generic drug that was widely available and very familiar. In fact, early in the pandemic I prescribed it to hospitalized patients on two occasions per a hospital protocol. However, it is impossible for me as a sole clinician to know whether it worked, was neutral, or was harmful. In recent days, however, I have found the hydroxychloroquine talk to have polluted the atmosphere. One recent patient was initially refusing remdesivir, a drug proven in large randomized trials to have effectiveness, because he had confused it with hydroxychloroquine.
Moving On to Other COVID Treatments: What a Treatment Should Do
The story of hydroxychloroquine illustrates a fruitless search for what we are actually looking for in a COVID-19 treatment. In short, we are looking for a medication that can decrease symptoms, decrease complications, hasten recovery, decrease hospitalizations, decrease contagiousness, decrease deaths, and prevent infection. While it is unlikely to find a single antiviral that can accomplish all of these, fulfilling even just one is important.
For example, remdesivir hastens recovery and dexamethasone decreases mortality. Definitive results of the use of convalescent plasma and immunomodulating drugs such as siltuxamab, baricitinib, and anakinra (for use in the cytokine storms characteristic of severe disease) are still pending, as are the trials with monoclonal antibodies.
While it was crucial that the medical and scientific community definitively answer the questions surrounding the use of chloroquine and hydroxychloroquine in the treatment of COVID-19, it is time to face the facts and accept that its use for the treatment of this disease is not likely to be beneficial. Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
Drugs That Trick Older People’s Bodies to Behave Younger Might Boost the Effectiveness of a COVID-19 Vaccine
Because vaccination may be less effective in older people, it is imperative to test now whether immune boosters could help the efficacy of a COVID-19 vaccine in the elderly.
In our April 23rd editorial for this magazine, we argued that addressing the COVID-19 pandemic requires that we both fight the SARS-CoV-2 virus and fortify the human hosts who are most vulnerable to it.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults.
Because people over 70 account for more than 80 percent of reported COVID-19 deaths globally, this means we must do everything possible to protect our elders.
A range of recent studies have suggested that systemic knobs might metaphorically be turned to slow the cellular aging process, making us better able to fight off the many diseases correlated with aging. These types of systemic changes might be used to stem the specific decline in immunity caused by aging and to increases the biological capacity of elderly people to effectively fight viral infection.
But while helping make older people more resilient in the face of a viral infection is critical, that's not the only way geroscience can help in our fight against this deadly pandemic.
As we move toward hopefully developing one or more COVID-19 vaccines, researchers must more fully appreciate the ways in which traditional vaccines can be less effective in older people than in younger ones.
Repeated studies have shown that the flu vaccine, for example, has lower efficacy in older people than in younger ones. Older people tend to develop fewer antibodies after being vaccinated because a subset of their white blood cells, called T cells, have become less responsive over time. Some inflammatory peptides that increase with aging are also preventing the action of those T cells.
This is why there's a distinct possibility that a future COVD-19 vaccine, particularly one utilizing the traditional attenuated virus approach, could be less effective in older people than in younger ones.
Given the extreme urgency of developing vaccines that work well for everyone, we need to make sure that researchers are exploring all of the ways our elders can be best protected. While generating a vaccine that works equally well for people of all ages would be ideal, we can't count on that.
One way to bridge this gap might be to trick the bodies of older people into behaving as if they are younger just at the moment what a vaccine is delivered by giving them pre-immunization boosters.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults. Use of the drug for a short time period before flu shot immunization increased the antibody production for the flu and resulted in a 52 percent decrease in the occurrence of severe diseases needing medical help or hospitalization. This short-term pre-immunization intervention can also decrease the severity of serious respiratory tract infections, the deadliest manifestations of COVID-19, by similar magnitude. These patients also had almost half the incidence of the non-COVID-19 coronaviruses associated with the common cold.
The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
An inexpensive generic drug called metformin similarly targets the decline in immunity and inflammation (and extends health span and lifespan) in animals and has been used for decades to protect against the flu. A recent paper from a hospital in Wuhan, China showed that mortality of elderly COVID-19 diabetic patients on metformin was 25 percent less than that of patients with diabetes but not on metformin.
Another study from the U.S. showed that COVID-19 patients on metformin had a 20 percent decrease in mortality and lower inflammation. The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
We don't yet know whether rapalogues or metformin could be used as COVID-19 immunization boosters, not least because we don't have those vaccines. But we can and should make sure that all vaccine trials including older subjects also consider offering a subset of those subjects appropriate doses of rapalogues or metformin to explore whether doing so can boost the efficacy of a given vaccine.
If we weren't in the middle of the worst pandemic in a century, we would have more time to test our vaccines slowly and sequentially. In the context of the current crisis, however, testing whether immunization boosters might increase the efficacy of potential COVID-19 vaccines for older adults is at the very least a hypothesis worth exploring.