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A mostly unregulated stem cell industry is thriving in Arizona

Arizona Republic logo Arizona Republic 6/13/2021 Amanda Morris, Arizona Republic

Embryonic stem cells once seemed like a miracle cure: cells from the human body that could transform into any other cell a patient needed and treat almost any condition.

Ethical concerns and federal regulations tempered that promise of endless possibility, but the hype lingered and the market responded. 

Today, someone seeking treatment for any one of dozens of conditions can drive to a strip mall, go to a chiropractor's office and fork over a few thousand dollars for what are sold as stem cell injections.

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An Arizona Republic investigation found that such treatments are offered at hundreds of locations across the state, but few of those businesses offer the narrow range of treatments the Food and Drug Administration has approved for use of stem cells.  

Instead, many businesses offer treatments that are mostly unregulated. The investigation also found that health care workers administering the treatment may have taken no more than a weekend-long training course in stem cell treatments or may be practicing outside of their area of medical expertise.

An analysis of 169 stem cell businesses by Arizona State University researchers found that most of the treatments offered weren't made from embryonic stem cells and instead relied on other types of stem cells without the same potential.

One Arizona researcher found that some treatments contained no stem cells at all.

Nobody knows the exact size of the stem cell treatment market in the United States. There is no national registry of stem cell clinics or doctors. Multiple estimates value the global market at billions of dollars.

A University of Arizona stem cell researcher grows stem cells inside petri dishes. © Amanda Morris A University of Arizona stem cell researcher grows stem cells inside petri dishes.

Because of the hype around stem cell treatments, that market is steadily growing. One 2018 study estimated that the number of stem cell clinics in the United States doubled each year between 2009 and 2014.

Arizona has emerged as an active part of that growth. A 2019 study by ASU researchers estimated that about one-third of all U.S. stem cell clinics are based in six western and southwestern states, mostly in Arizona and California.

Currently, stem cells are only approved by the FDA as treatments for certain blood and immune disorders. There are no other approved uses for stem cells outside of investigational clinical studies.

But in practice, stem cell treatments occurred for years with little federal oversight. In an effort to bring the stem cell industry under control in 2017, the FDA announced it would step up enforcement of regulations and oversight of stem cell clinics, ruling that many stem cells products would be regulated as drugs. One exception was for "minimally manipulated" tissue that comes from the patient being treated.

Researchers are trying to create safe, effective stem cell treatments. But many unregulated clinics offer unproven and perhaps dangerous treatments. © Illustration by Rick Konopka/The Republic Researchers are trying to create safe, effective stem cell treatments. But many unregulated clinics offer unproven and perhaps dangerous treatments.

The drug classification means that to lawfully market such products, companies or clinics need an approved biologics license application or an approved investigational new drug application to perform clinical trials.

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The agency gave stem cell businesses until May 2021 to comply. 

In the meantime, the FDA also announced in 2017 that it would pursue greater enforcement of the rules and crack down on "bad actors" within the industry who "make deceptive, and sometimes corrupt, assurances to patients based on unproven and, in some cases, dangerously dubious products."

The FDA issued a warning about these unapproved treatments, calling some of them illegal and potentially dangerous. 

How stem cells work

All stem cells have two main functions, according to ASU researcher David Brafman, who works with stem cells to research neurodegenerative diseases. Stem cells can either create copies of themselves to make more stem cells, or they can turn into other types of cells.

Simply put, a stem cell is like a seed. The seed can turn into other types of cells, such as bone cells or cartilage cells, depending on what types of signals it receives.

But stem cells don't magically turn into other types of cells, said Kent Kwoh, director of the University of Arizona Arthritis Center and chief of the university's division of rheumatology. In his view, growing stem cells is like raising a baby.

"Babies need to be nurtured," he said. "If you just took a baby and left it alone and didn't do anything to the baby, would it just naturally grow into an adult?" 

One stem cell might perform differently than another, depending on its origin and makeup and may not be suited for every situation. Researchers say some may be better at turning into cartilage while others are better for creating different tissues.  

Researchers are still learning the limitations of stem cells and figuring out how to control them to create the types of cells they want. Uncontrolled stem cells could turn into something unwanted, unneeded, or even dangerous.

Sources of stem cells

Stem cells are grouped into different categories based on their ability to turn into other cells.

Embryonic stem cells

diagram, schematic: Embryonic stem cells are the first cells to form after a sperm fertilizes an egg. © REPUBLIC REPORTING; ILLUSTRATION BY NICOLE SCHAUB Embryonic stem cells are the first cells to form after a sperm fertilizes an egg.

Embryonic stem cells are the first cells to form after a sperm fertilizes an egg, and are the ultimate seed with the most potential to turn into other cells. UA researcher John Szivek said that's because a human body can turn them into any type of cell and they can can theoretically divide endlessly.

"Their job is to turn into bone cells, heart blood cells, nerve cells, or muscle cells or fat cells, and they do that through a process that's called differentiation," Szivek said.

Ethical issues about destroying embryos to obtain the cells keep many researchers from using them. 

Adult stem cells

Some researchers and stem cell clinics use adult stem cells, which can come from a variety of sources inside a person's body, such as within bone marrow, skin, organs, fat, or even teeth. One type of adult stem cell is called a mesenchymal stem cell.

"Within our body, there's adult stem cells in pretty much every tissue and organ that contribute to maintaining the health ... of the tissue," Brafman said.

For example, if someone gets a cut on their skin, there's a high number of stem cells in the skin that help repair it, he said.

diagram: Adult stem cells can be found throughout the body. © REPUBLIC REPORTING; ILLUSTRATION BY NICOLE SCHAUB Adult stem cells can be found throughout the body.

Because adult stem cells are more specialized, they could be limited in what types of cells they can become, scientists say. Often they are thought to turn into cells specific to the tissue or organ environment they live in.

Two of the most common sources for stem cells in research and treatments are bone marrow or fat tissue. These can apparently differentiate into a variety of cells, but the process of making them differentiate into specific types of tissue isn't fully understood. 

"They can become bone, cartilage, tendon, muscle, fat. ... They can become all these things," Kwoh said. "The challenge is having them become the right thing."

Some studies have shown that adult stem cells from fat or bone marrow can be turned into cells that have similar characteristics to other cells, such as heart cells. Those studies occurred in lab settings outside the human body and are not conclusive, according to Brafman, and tests that may succeed in a lab often don't succeed in a human body. 

Instead, Brafman believes that stem cells coming from fat tissue may not truly be stem cells because they cannot turn into anything. 

"Outside of musculoskeletal lineages, these cells have little ability to differentiate," Brafman said.

There are different pathways a stem cell can take to determine what it becomes. One pathway may lead it to become a bone cell, another to becoming a blood cell.

To direct a stem cell down a specific pathway, researchers use special molecules called proteins that send signals to the cell about what it should become. 

But it's not always that simple. Stem cells can also get stuck on a pathway at an earlier stage of development and turn into a different type of cell.

That's why most osteoarthritis treatments done in stem cell clinics wouldn't work to regrow cartilage, according to Kwoh, who has reviewed numerous studies on stem cell treatments for osteoarthritis.

"Most of the time, what people do is take these fat-derived stem cells or umbilical cord (stem cells) and squirt them into the knee," Kwoh said. "Well, that generally is not how it's really going to work, because there's a lot of things in the steps between a stem cell and ultimately growing cartilage."

Birth tissue stem cells

Researchers can also get stem cells from birth tissue, such as umbilical cord blood or amniotic fluid. Since they do not come from adults, there are theories that these younger stem cells might have different properties.

diagram: Stem cells can also be found in birth tissue. © REPUBLIC REPORTING; ILLUSTRATION BY NICOLE SCHAUB Stem cells can also be found in birth tissue.

UA stem cell scientist David Harris believes umbilical cord blood stem cells might have more potential to turn into different types of cells.

"We think that it maintains a lot of the fetal characteristics to be able to do many things," he said. "The best thing about it is that it's the cleanest source of stem cell. It's not stem cells after you spent 20 years smoking or drinking or other stuff, so it doesn't have any of the mutations and things you might see in adult stem cells."

Harris said these types of cells are thought to cause less of an immune system response if they are transplanted into a person. That means there is less risk of graft-versus-host disease or a rejection of the stem cells.

Umbilical cord blood stem cells have already been well established and approved as treatments for certain blood disorders, cancers and diseases because they easily turn into blood cells. There are no other approved or proven uses for these stem cells outside of investigational clinical studies.

Induced-pluripotent stem cells

The newest discovered source of stem cells is sometimes described as one in between embryonic stem cells and adult stem cells. They are called induced-pluripotent stem cells and are created in labs.

diagram: Researchers can reprogram cells to make induced-pluripotent stem cells. © REPUBLIC REPORTING; ILLUSTRATION BY NICOLE SCHAUB Researchers can reprogram cells to make induced-pluripotent stem cells.

To make these, Brafman said researchers take cells from skin or blood and "reprogram" them. They revert back to an earlier stage and can become many different types of cells.

Functionally, induced-pluripotent stem cells have similar properties to embryonic stem cells and have the ability to become different things.

It's an attempt to "mimic in-utero development outside of the human body," Brafman said.

Though there is hope for the potential of such lab-made stem cells to be used in cellular treatments, there are still numerous factors that researchers need to account for before they can successfully replicate real tissue or prove that a treatment works.

Such lab-made stem cells don't seem to be the ones used by stem cell clinics and before any types of stem cells are advertised as a new treatment, Brafman believes more research is needed.

"These are not magic cells," Brafman said. "They aren't some kind of magic bullet to cure things."

The challenges of creating a stem cell treatment

While stem cells have potential to grow into many useful things, they can also grow into something unwanted or even harmful.

One of the biggest risks is that some, such as embryonic stem cells and induced-pluripotent stem cells, could also turn into cancer cells.

This was the case in earlier, uncontrolled studies, according to Harris.

"Years ago we thought, 'oh we'll just give embryonic stem cells,' without realizing that when you do that, they form tumors," Harris said. "They can form everything but they like to form tumors."

That's one reason controlled treatments are so important. But unlike drugs, which can be manufactured in a consistent manner, controlling live stem cells for treatment can be exceptionally difficult. 

That's partly because stem cells don't necessarily stay in the area they are intended to treat, and can travel around the body in the bloodstream.

"Just because you put it in the neck doesn't necessarily mean it's going to stay in the neck," Kwoh said. "So those are part of the challenges in terms of safety."

Another challenge is ensuring that treatments are standardized so researchers know what they are injecting into a patient.

With stem cells, each extraction is unique, so different samples might contain different amounts of stem cells, according to Szivek. Often the extracted material doesn't only contain stem cells, but can include other types of cells, such as blood cells, immune cells or fat cells.

The lack of standardization and command has made it challenging for researchers to study stem cells in a scientific, controlled way, which is often needed for FDA approval.

"The FDA is really big on standardized approaches," Szivek said. "We as scientists are  trying to find ways that we can prove that specific batches of cells are consistent in certain ways. So it's kind of difficult because your cells are different than my cells."

Szivek's team is working with samples to try to get rid of anything that isn't a stem cell so researchers can work with a "nice clean batch of material." 

To do this, his team starves cell samples of food for a period of time, because stem cells tend to be hardier and last longer than other cells. Once most of the non-stem cells have died off, his team feeds the cell samples again. Because stem cells multiply faster, he said the samples become full of mostly stem cells.

A University of Arizona stem cell researcher inspects stem cells growing inside petri dishes. © Amanda Morris A University of Arizona stem cell researcher inspects stem cells growing inside petri dishes.

After about a week, researchers analyze each sample to classify the different types of cells inside.

Ensuring that stem cell injections are clear of other types of cells can have important implications for treatment. If blood cells are accidentally injected into knee cartilage, Szivek said they could damage the cartilage, or even turn it into bone.

Even if an uncontrolled stem cell treatment succeeds in generating cartilage, that cartilage may end up being the wrong type needed for a weight-bearing joint like the knee and break down again within a year, Szivek said. 

Despite the lack of a controlled treatment method and lack of FDA approval, Kwoh said some clinics and health care providers have used the hype over stem cells to market them. A Republic investigation found that stem cells have been marketed as a treatment for conditions that have no good existing treatments, like arthritis, Alzheimer' or even autism. 

But Kwoh said there is little or sometimes no scientific evidence to support such treatments' effectiveness.

"I think there is hope," Kwoh said. "Unfortunately, there's more hype at this point," 

An FDA spokesperson told The Republic that the agency believes stem cell treatments and regenerative therapies are among the most promising new areas of medicine and that the agency is committed to helping providers develop safe treatments.

Winning FDA approval may require a level of time, money and effort on the part of the stem cell industry that many providers say they lack. A few providers offering unapproved treatments told The Republic they didn't have the resources to conduct formal research.

Independent coverage of bioscience in Arizona is supported by a grant from the Flinn Foundation.

This article originally appeared on Arizona Republic: A mostly unregulated stem cell industry is thriving in Arizona

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