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MedShadow Regenerative Medicine Series: Part 1 | Part 2 | Part 3 | Part 4
What is a stem cell therapy? There are at least six octopus trinkets on the desk separating me from Duncan Ross, PhD, CEO of Kimera Labs, a company that produces exosomes, stem cell derivatives that contain molecular information believed to help cells heal.
Ross may just think the eight-limbed mollusk is a smart, interesting animal. If I had to guess, though, I would say, he has the knickknacks because an octopus can regrow a damaged or lost tentacle. Giving humans the ability to regenerate damaged organs or tissues is the holy grail of regenerative medicine. And the reason I’m here, in April 2021, still wearing my face mask, counting the octopuses on Ross’s desk is because a doctor who researches and provides stem cell treatments 1,000 miles away told me that exosomes, which Ross’ company produces, are the future of regenerative medicine.
Of course, another doctor I spoke with referred to exosomes as “the newest snake oil.”
It’s a controversial topic.
Most experts agree that regenerative medicine, which aims to repair cells and tissues damaged by disease often using stem cells or related products, has the potential to transform healthcare. However, many of those same experts also believe that after decades of little to no regulatory oversight, the field is saturated with providers making bold and unsubstantiated claims about expensive treatments that may do nothing at all. Even worse, in some cases, providers sell treatments that may harm patients.
Regenerative medicine comes in many forms. Stem cells can be extracted from a person and injected back into that same person in a single office visit. In other cases, cells are harvested from outside sources — donors or a baby’s umbilical cords, for example — then grown or processed in labs before being infused or injected into a patient’s body. Ross’ products, exosomes, don’t contain stem cells at all. Instead, exosomes are vesicles — packages of molecular signals produced by stem cells to communicate with other cells. “They’re very tiny packets of information. They basically act like general contractors. They come in and they say, ‘You guys, here’s the plan: we need synovial stem cells over here to become chondrocytes. We need bone marrow to become bone. We need you to become fat,’” explains Daniel Grande, PhD, director of the Center for Regenerative Orthopedic Medicine at the Feinstein Institutes for Medical Research.
Because cells and tissues are harvested rather than being manufactured in labs like the pills in your bathroom cabinet, the Food and Drug Administration (FDA) hasn’t regulated regenerative therapies the same way it has other drugs. Rarely have they been subjected to all three phases of clinical trials and regulatory review before being offered directly to patients. The result is that the existing data can be difficult to evaluate and interpret.
In 2017, the FDA released a set of guidelines outlining which types of treatments need different levels of approval or regulatory oversight. The agency announced that companies providing these treatments would have about three years to get their operations in line. Now, that time has come. On May 31, 2021, the FDA says it will take punitive action against those companies that don’t comply by getting the necessary approvals.
What Are Stem Cells?
Stem cells maintain the ability to grow into a variety of different types of cells to perform unique functions throughout the body. After conception, a single cell in the womb called a zygote, starts dividing. As the cells divide, molecular signals tell them whether to become bone cells, skin cells, heart cells or any other type of cell to form a fetus. Once they turn into the specific cells they’ve been instructed to become, they lose the potential to be other types of cells. You can imagine why. It would be problematic if your heart cells, responsible for the rhythmic contractions that feed blood throughout your body, were to suddenly turn into skin cells.
The initial theory behind using stem cells to treat disease is that they could be coaxed into becoming whatever type of cells you would need to replace tissue damaged by injury or illness. Lungs ravaged by chronic obstructive pulmonary disease? Maybe some stem cells could rebuild a portion of that damaged tissue and help you breathe clearly again.
Stem cells have been controversial since Day One. Initially, federal laws limited the use of these cells in research, because they came from fetuses. But over time, those restrictions became less restrictive, especially as scientists found that stem cells could be derived from other sources, like umbilical cord blood rather than directly from the fetus, or even from reservoirs in adults’ bone-marrow and fat tissue.
Eventually, researchers realized that it may not even be the stem cells themselves responsible for the regeneration they’ve seen, rather the molecular signals they harbor that trigger existing cells to reduce inflammation or otherwise heal themselves. “Most of the things we’re trying to treat today, we’re treating inflammation, and inflammation can be treated without having to use the [stem] cell,” explains Ross. “The cell is a pretty good factory of anti-inflammatory factors. Those are secreted in these little balls called exosomes. . . and using those exosomes alone, just the anti-inflammatory factors, could suppress the same inflammation that a cell can, without the dangers of a cell.”
An analysis of Google Search data shows that over time, interest in stem cell therapies has grown over time. Searches dropped in the Spring of 2020, possibly due to people postponing medical procedures of all kinds during the pandemic.
What Types of Stem Cell Products Are Available?
“If you wanted stem cells now, you have two real main sources: one is from bone marrow. . . the other one is from adipose tissue, so [from] a patient’s fat,” says Grande. The key, he explains, is that the cells, no matter where they come from, are minimally manipulated. That means that after they’re removed from the body, no chemicals are added to make them grow or to separate them from the other cells. If they fall under this category, a doctor can legally treat you with them now. A clinical trial or FDA approval is not required.
But many other regenerative medicine products and procedures are also being offered on an experimental basis in clinical trials or expanded access routes, which allow patients to be treated with medicines still in clinical trials under special circumstances.
Stem Cell Sources
Embryonic Stem Cells: These cells come from a 3- to 5-day-old human embryo (fertilized egg), donated at in vitro fertilization clinics. These cells are pluripotent, meaning they retain the ability to form any type of cell in the body.
Bone Marrow or Fat: Adult bone marrow and fat contain mesenchymal stem cells, which are “multipotent,” meaning they can still become several different types of cells like cartilage, bone, muscle and connective tissue, but their futures are more limited than pluripotent cells. These cells can be harvested through liposuction or extracted from the blood or hip bone.
Birth Tissue-Derived: Extra tissue often discarded at birth, like umbilical cord blood, placenta, and amniotic fluid contain mesenchymal stem cells then can be harvested and grown in culture. You can donate umbilical cord blood for use in some FDA-approved procedures or pay to have it stored for you or your child’s own future use.
Non Stem-Cell Products:
Platelet-Rich Plasma: Platelets are blood cells that secrete molecules that stimulate the growth of damaged tissues. Scientists take blood and isolate just the platelets to inject a high concentration of these cells back into your body.
Exosomes: Cells release tiny envelopes of molecular information that tell surrounding cells what to do. These packets are called exosomes. Scientists can grow cells and harvest exosomes to be infused or injected into patients. Different exosomes may contain different signals.
Do They Work?
We know that allogeneic bone-marrow transplants, a procedure in which a leukemia patient’s bone marrow is actually replaced with bone marrow from a healthy donor, is an effective treatment. Stem cells in the healthy bone marrow give rise to healthy new blood cells in the previously leukemic patient. However, this procedure bears little resemblance to other types of regenerative medicine on the market. “That’s a whole different animal,” says Richard Bosshardt, MD, a plastic surgeon who does not use stem cells in his practice. “They’re not taking a cell and expecting it to differentiate into something that it doesn’t do normally.”
Plus, even these transplants have not been subjected to clinical trials and FDA scrutiny. “[Bone-marrow transplants] are evidence-based, but they’re not FDA-approved and they don’t have to be,” says Leigh Turner, PhD, a bioethicist at the University of Minnesota. “I think some people have this misconception that all stem cell products require FDA approval.”
Additionally, there are a small number of products derived from umbilical cord blood that the FDA has approved for use to treat specific hematologic (blood) diseases. The linked list also includes cell and gene therapies.
When it comes to evidence for most other stem cell therapies, the answer is that so far, even with thousands of studies, we just don’t know as much as we would like. There are thousands of studies on stem cell products used to treat everything from osteoarthritis to Alzheimer’s disease, but few have made it through all the phases of clinical trials used to evaluate and approve other treatments.
A 2021 meta-analysis of 18 studies conducted on the use of mesenchymal stem cells to treat spinal cord injuries suggests that the treatments were more effective than rehabilitation alone in improving patients’ motor and neurological abilities. In many of the studies, the researchers write, it wasn’t clear how patients were divided into the treatment and control (rehabilitation only) groups or whether the researchers measuring the outcomes knew who received which treatments, so there may be bias in the results. The authors note that the studies included were of varied quality, and used different numbers of injections and types of treatments. They recommend clinical head-to-head trials to compare the safety and efficacy of different types and doses of mesenchymal stem cell treatments for spinal cord injuries, since the results of the analysis were promising.
Studies also suggest that the treatments can quell inflammation, a driving factor in myriad diseases.
But when it comes to clinical trials, the studies haven’t always been designed in ways that provide definitive answers. Since most treatments aren’t FDA-approved, some providers register studies on clinicaltrials.gov and then offer the treatments to patients as participants of the trials. Be wary of stem cell trials: in some cases, they may be a sham to imply that the FDA is watching over a company’s work. A 2017 analysis of the studies registered there showed that none of the studies registered by 18 US companies were randomized or blinded, conditions usually required for a clinical study because that minimizes bias in results. And thousands of trials registered on clinicaltrials.gov are never completed and the results never published.
“It’s all meant to suggest a seal of approval from the federal government. And that’s what’s so dangerously misleading, because it doesn’t mean that all [of them are]. It just means someone filled out a form and pressed a button,” Turner, author of the analysis, told Wired, after the study was published.
Moreover, Wired reported that patients paid $5,000 to $15,000 per treatment, a fact that was not disclosed in the clinicaltrials.gov listings themselves. In most clinical trials, patients are responsible for little to none of the cost of treatment, though some experts say pay-to-participate trials are becoming more common.
All this means that even for the more common treatments, like injecting adipose-derived stem cells into the knees to treat osteoarthritis, which Grande says, “is probably okay,” we still don’t know whether they’re consistently effective and for whom.
For some procedures, researchers point to the fact that not only might there not be enough evidence, but the product may not even be what they think it is. “If you take bone marrow out,” says Grande, and isolate the cells with minimal manipulation, what’s left “has a relatively small percentage of stem cells. It’s not a purified stem cell preparation. You’re getting a mixture, a hodgepodge of cells, including stem cells, but the percentage is low.” Ross describes similar problems with some techniques used to isolate exosomes. He’s recently developed the Ross Unit, designed to analyze RNA [ribonucleic acid] in a sample to accurately quantify and characterize the exosomes it contains.
What Do We Know About Their Safety?
All three people I spoke with who had provided treatments to patients say that these treatments are very safe and that adverse effects are rare. Even if any did occur, they add, they would not be the result of the cells or products themselves, but complications related to anesthesia, the injection/infusion process or, in some cases, product contamination. “You can have an infection [due to contamination], clearly. That’s your biggest risk,” says Grande. “but the cells themselves, I would say, are extremely safe and, in most cases, efficacious, if done correctly.”
If the stem cells are autologous, meaning they come from your own body, your body is unlikely to reject them like they might reject a newly transplanted organ. However, rejection is a possibility if the cells come from an outside source, like a donor.
For most drugs, we would see adverse effects reported in the clinical trial data and then on an insert inside the drug’s packaging. A 2019 Pew report suggests that side effects of stem cell treatments are likely underreported, since patients may not note adverse effects outside of clinical trials. It’s important to know that you can report adverse effects, even if you were not part of a trial, through the FDA’s MedWatch.
In the case of regenerative medicine, we usually hear about adverse events in the news as isolated incidents when a particular clinic is sued, for example, after a few patients end up blind or a facility fails an FDA inspection. “There’s so little regulation in medicine for some of this stuff, that until there [are] people literally dying or getting sick or where this stuff is being reported, there’s not going to be anybody doing anything about it,” says Bosshardt.
Some examples of such events that made major headlines in the past several years include:
- In 2015, three patients who received autologous adipose-derived stem cell injections in their eyes experienced a loss of vision. Researchers are not sure whether the effects were caused by chemicals used in the cell preparation, the cells not functioning the way the doctors had predicted they would or pressure in the eyes from the injections.
- A patient in Canada developed a tumor that physicians traced back to a stem cell treatment in which practitioners harvested cells from his nasal mucus and delivered them to his spine.
- In December of 2018, 12 people were hospitalized with severe infections after being injected with blood from umbilical cords. The blood harbored bacteria.
A new Pew report, published June 1 of this year scoured FAERS, MedWatch and social media to find reports of adverse events potentially related to unapproved stem cell therapies conducted outside of clinical trials. “Public awareness of FAERS is relatively low and people whose cases may not end up in the news or may not end up in a case report published in a peer reviewed journal, they might take to social media to note that the care they received at a clinic had resulted in an adverse event,” says Liz Richardson, MS, director of the project. “So we decided to do these three lines of analysis to try to get as many adverse event reports as we could.”
The team identified 360 adverse events between 2004 and 2020. Twenty events resulted in death. Nearly a third (104) required hospitalization. Reports included infections, worsening pain, organ damage and new tumors or growths.
Most reports (242) came from a single study on insurance claims after stem cell injections in the knees, hips and shoulders in 2964 patients published this year. In that study, about 8% of patients experienced adverse effects after the stem cell treatments. The researchers compared this result to 2% of patients who experienced adverse effects after steroid injections.
Many of the reports are unverified and researchers cannot definitively determine that they were related to the treatments.
