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.”
Dr. Barry Marshall (along with a collaborator) discovered that the bacteria H. Pylori, pictured, caused stomach ulcers.
[Editor's Note: Welcome to Leaps of the Past, a new monthly column that spotlights the fascinating backstory behind a medical or scientific breakthrough from history.]
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Until about 40 years ago, ulcers were a mysterious – and sometimes deadly – ailment. Found in a person's stomach lining or intestine, ulcers are small sores that cause a variety of painful symptoms, such as vomiting, a burning or aching sensation, internal bleeding and stomach obstruction. Patients with ulcers suffered for years without a cure and sometimes even needed their stomachs completely removed to rid them from pain.
"To gastroenterologists, the concept of a germ causing ulcers was like saying the Earth is flat."
In the early 1980s, the majority of scientists thought that ulcers were caused by stress or poor diet. But a handful of scientists had a different theory: They believed that ulcers were caused by a corkscrew-shaped bacterium called Helicobacter pylori, or H. pylori for short. Robin Warren, a pathologist, and Barry Marshall, an internist, were the two pioneers of this theory, and the two teamed up to study H. pylori at the Royal Perth Hospital in 1981.
The pair started off by trying to culture the bacteria in the stomachs of patients with gastritis, an inflammation of the stomach lining and a precursor to developing an ulcer. Initially, the microbiologists involved in their clinical trial found no trace of the bacteria from patient samples – but after a few weeks, the microbiologists discovered that their lab techs had been throwing away the cultures before H. pylori could grow. "After that, we let the cultures grow longer and found 13 patients with duodenal ulcer," said Marshall in a later interview. "All of them had the bacteria."
Marshall and Warren also cultured H. pylori in the stomachs of patients with stomach cancer. They observed that "everybody with stomach cancer developed it on a background of gastritis. Whenever we found a person without Helicobacter, we couldn't find gastritis either." Marshall and Warren were convinced that H. pylori not only caused gastritis and peptic ulcers, but stomach cancer as well.
But when the team presented their findings at an annual meeting of the Royal Australasian College of Physicians in Perth, they were mostly met with skepticism. "To gastroenterologists, the concept of a germ causing ulcers was like saying the Earth is flat," Marshall said. "The idea was too weird."
Warren started treating his gastritis patients with antibiotics with great success – but other internists remained doubtful, continuing to treat their patients with antacids instead. Making matters more complicated, neither Warren nor Marshall could readily test their theory, since the pair only had lab mice at their disposal and H. pylori infects only humans and non-human primates, such as rhesus monkeys.
So Marshall took an unconventional approach. First, he underwent two tests to get a baseline reading of his stomach, which showed no presence of H. pylori. Then, Marshall took some H. pylori bacteria from a petri dish, mixed it with beef extract to create a broth, and gulped it down. If his theory was correct, a second gastric biopsy would show that his stomach was overrun with H. pylori bacteria, and a second endoscopy would show a painfully inflamed stomach – gastritis.
Less than a week later, Marshall started feeling sick. "I expected to develop an asymptomatic infection," he later said in an interview published in the Canadian Journal of Gastroenterology. "… [but] after five days, I started to have bloating and fullness after the evening meal, and my appetite decreased. My breath was bad and I vomited clear watery liquid, without acid, each morning."
At his wife's urging, Marshall started on a regimen of antibiotics to kill off the burgeoning bacteria, so a follow-up biopsy showed no signs of H. pylori. A follow-up endoscopy, however, showed "severe active gastritis" along with epithelial damage. This was the smoking gun other clinicians needed to believe that H. pylori caused gastritis and stomach cancer. When they began to treat their gastritis patients with antibiotics, the rate of peptic ulcers in the Australian population diminished by 70 percent.
Today, antibiotics are the standard of care for anyone afflicted with gastritis.
In 2005, Marshall and Warren were awarded the Nobel Prize in Physiology or Medicine for their discovery of H. Pylori and its role in developing gastritis and peptic ulcers. "Thanks to the pioneering discovery by Marshall and Warren, peptic ulcer disease is no longer a chronic, frequently disabling condition, but a disease that can be cured by a short regimen of antibiotics and acid secretion inhibitors," the Nobel Prize Committee said.
Today, antibiotics are the standard of care for anyone afflicted with gastritis – and stomach cancer has been significantly reduced in the Western world.
Would a Broad-Spectrum Antiviral Drug Stop the Pandemic?
An illustration of the novel coronavirus infecting human tissue.
The refocusing of medical research to COVID-19 is unprecedented in human history. Seven months ago, we barely were aware that the virus existed, and now a torrent of new information greets us each day online.
There are many unanswered questions about COVID-19, but perhaps the most fascinating is whether we even need to directly go after the virus itself.
Clinicaltrials.gov, the most commonly used registry for worldwide medical research, listed 1358 clinical trials on the disease, including using scores of different potential drugs and multiple combinations, when I first wrote this sentence. The following day that number of trials had increased to 1409. Laboratory work to prepare for trials presents an even broader and untabulated scope of activity.
Most trials will fail or not be as good as what has been discovered in the interim, but the hope is that a handful of them will yield vaccines for prevention and treatments to attenuate and ultimately cure the deadly infection.
The first impulse is to grab whatever drugs are on the shelf and see if any work against the new foe. We know their safety profiles and they have passed some regulatory hurdles. Remdesivir is the first to register some success against SARS-CoV-2, the virus behind the disease. The FDA has granted it expedited-use status, pending presentation of data that may lead to full approval of the drug.
Most observers see it as a treatment that might help, but not one that by itself is likely to break the back of the pandemic. Part of that is because it is delivered though IV infusion, which requires hospitalization, and as with most antiviral drugs, appears to be most beneficial when started early in disease. "The most effective products are going to be that ones that are developed by actually understanding more about this coronavirus," says Margaret "Peggy" Hamburg, who once led the New York City public health department and later the U.S. Food and Drug Administration.
Combination therapy that uses different drugs to hit a virus at different places in its life cycle have proven to work best in treating HIV and hepatitis C, and likely will be needed with this virus as well. Most viruses are simply too facile at evolving resistance to a single drug, and so require multiple hits to keep them down.
Laboratory work suggests that other drugs, both off-the-shelf and in development, particularly those to treat HIV and hepatitis, might also be of some benefit against SARS-CoV-2. But the number of possible drug combinations is mind-bogglingly large and the capacity to test them all right now is limited.
Broad-Spectrum Antivirals
Viruses are simple quasi-life forms. Effective treatments are more likely to be specific to a given virus, or at best its close relatives. That is unlike bacteria, where broad-spectrum antibiotics often can be used against common elements like the bacterial cell wall, or can disrupt quorum sensing signals that bacteria use to function as biofilms.
More than a decade ago, virologist Benhur Lee's lab at UCLA (now at Mt. Sinai in New York City) stumbled upon a broad-spectrum antiviral approach that seemed to work against all enveloped viruses they tested. The list ranged from the common flu to HIV to Ebola.
Other researchers grabbed this lead to develop a compound that worked quite well in cell cultures, but when they tried it in animals, a frustrating snag emerged; the compound needed to be activated by light. As the greatest medical need is to counter viruses deep inside the body, the research was put on the shelf. So Lee was surprised to learn recently that a company has inquired about rights to develop the compound not as a treatment but as a possible disinfectant. The tale illustrates both the unanticipated difficulties of drug development and that one never knows how knowledge ultimately might be put to use.
Remdesivir is a failed drug for Ebola that has found new life with SARS-CoV-2. It targets polymerase, an enzyme that the virus produces to use host cell machinery to replicate itself, and since the genetic sequence of polymerase is very similar among all of the different coronaviruses, scientists hope that the drug might be useful against known members of the family and others that might emerge in the future.
But nature isn't always that simple. Viral RNA is not a two-dimensional assemblage of genes in a flat line on a table; rather it is a three-dimensional matrix of twists and turns where a single atom change within the polymerase gene or another gene close by might change the orientation of the RNA or a molecular arm within it and block a drug from accessing the targeted binding site on the virus. One drug might need to bind to a large flat surface, while another might be able to slip a dagger-like molecular arm through a space in the matrix to reach its binding target.
That is why a broad-spectrum antiviral is so hard to develop, and why researchers continue to work on a wide variety of compounds that target polymerase as a binding site.
Additionally, it has taken us decades to begin to recognize the unintended consequences of broad-spectrum rather than narrowly targeted antibiotics on the gut microbiome and our overall health. Will a similar issue potentially arise in using a broad-spectrum antiviral?
"Off-target side effects are always of concern with drugs, and antivirals are no exception," says Yale University microbiologist Ben Chen. He believes that "most" bacteriophages, the viruses that infect bacteria and likely help to maintain stability in the gut microbial ecosystem, will shrug off such a drug. However, a few families of phages share polymerases that are similar to those found in coronaviruses. While the immediate need for treatment is great, we will have to keep a sharp eye out for unanticipated activity in the body's ecosystem from new drugs.
Is an Antiviral Needed?
There are many unanswered questions about COVID-19, but perhaps the most fascinating is whether we even need to directly go after the virus itself. Mounting evidence indicates that up to half the people who contract the infection don't seem to experience significant symptoms and their immune system seems to clear the virus.
The most severe cases of COVID-19 appear to result from an overactive immune response that damages surrounding tissue. Perhaps downregulating that response will be sufficient to reduce the disease burden. Several studies are underway using approved antibodies that modulate an overly active immune response.
One of the most surprising findings to date involves the monoclonal antibody leronlimab. It was originally developed to treat HIV infection and works modestly well there, but other drugs are better and its future likely will be mainly to treat patients who have developed resistance to those other drugs.
The response has been amazingly different in patients in the U.S. with COVID-19 who were given emergency access to leronlimab – two injections a week apart, though the company believes that four might be better. The immune response and inflammatory cytokines declined significantly, T cell counts were maintained, and surprisingly the amount of virus in the blood declined too. Data from the first ten patients is available in a preprint while the paper undergoes peer review for publication. Data from an additional fifty patients will be added.
"We got lucky and hit the bulls' eye from a mile away," says Jay Lalezari, the chief science officer of Cytodyn, the company behind leronlimab. Dr. Jay, as he is widely known in San Francisco, built an adoring fan base running many of the early-phase drug studies for treating HIV. While touting leronlimab, Lalezari suspects it might best be used as part of a combination therapy.
The small, under-capitalized firm is struggling for attention in the vast pool of therapies proposed to treat COVID-19. It faces the added challenge of gaining acceptance because it is based on a different approach and mechanism of action, which involves a signaling molecule important to immune cell migration, than what most researchers and the FDA anticipate as being relevant to counter SARS-CoV-2.
Common Issues
All of the therapeutics under development will face some common sets of issues. One is the pressure to have results yesterday, because people are dying. The rush to disseminate information "make me worry that certain things will become entrenched as truth, even in the scientific community, without the actual scientific documentation that ordinarily scientists would demand," says Hamburg.
"It is becoming increasingly clear that the biggest problem for drug and vaccine makers is not which therapeutics or vaccine platform to pursue."
Lack of standardization in assays and laboratory operations makes it difficult to compare results between labs studying SARS-CoV-2. In the long run, this will slow down the iterative process of research that builds upon what has gone before. And the shut down of supply chains, from chemicals to cell lines to animals to air shipment, has the potential to further hobble research.
Almost all researchers consult with the FDA in putting together their clinical trials. But the agency is overwhelmed with the surge of activity in the field, and is even less capable of handling novel approaches that fall outside of its standard guidance.
"It is becoming increasingly clear that the biggest problem for drug and vaccine makers is not which therapeutics or vaccine platform to pursue. It is that conventional clinical development paths are far too lengthy and cumbersome to address the current public health threat," John Hodgson wrote in Nature Biotechnology.
Another complicating factor with this virus is the broad range of organ and tissue types it can infect. That has implications for potential therapies, which often vary in their ability to enter different tissues. At a minimum, it complicates the drug development process.
Remdesivir has become the de facto standard of care. Ideally, clinical trials are conducted using the existing standard of care rather than a placebo as the control group. But shortages of the drug make that difficult and further inhibit learning what is the best treatment regimen for regular clinical care.
"Understandably, we all really want to respond to COVID-19 in a much, much more accelerated fashion," says Hamburg. But ultimately that depends upon "the reality of understanding the nature of the disease. And that is going to take a bit more time than we might like or wish."
[This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]