The culinary herb rosemary is commonly used in our kitchens to season an array of dishes, and is also considered a good source for vitamins and minerals.
Rosemary is also valued for its medicinal properties, and has traditionally been used to help alleviate muscle pain, boost the immune and circulatory system, as well as many other health benefits.
Now, scientists at Scripps Research have found evidence that a compound contained in rosemary could be a two-pronged weapon against the SARS-CoV-2 coronavirus that causes COVID-19.
The research was partly funded by the California Institute for Regenerative Medicine (CIRM).
Published in the journal Antioxidants, the study found that the compound, carnosic acid, can block the interaction between the SARS-CoV-2 outer “spike” protein and the receptor protein, ACE2, which the virus uses to gain entry to cells.
“We think that carnosic acid, or some optimized derivative, is worth investigating as a potentially cheap, safe, and effective treatment for COVID-19 and some other inflammation-related disorders,” says study senior author Dr. Stuart Lipton of Scripps Research.
The team also reviewed prior studies and presented new evidence that carnosic acid could inhibit a powerful inflammatory pathway that is active in severe COVID-19, as well as in other diseases including Alzheimer’s.
They also proposed that this effect could be beneficial in treating the post-COVID syndrome known as “long COVID” whose reported symptoms include cognitive difficulties often described as “brain fog.”
While the research is preliminary, the researchers propose that carnosic acid has this antiviral effect because it is converted to its active form by the inflammation and oxidation found at sites of infection. In that active form, they suggest, the compound modifies the ACE2 receptor for SARS-CoV-2—making the receptor impregnable to the virus and thereby blocking infection.
Lipton and his colleagues are now working with Scripps Research chemists to synthesize and test more potent derivatives of carnosic acid with improved drug characteristics for potential use in inflammation-related disorders.
The full study was co-authored by Takumi Satoh of the Tokyo University of Technology; and by Dorit Trudler, Chang-ki Oh and Stuart Lipton of Scripps Research. Read the source news release here.
Disclaimer: This research is still in its early phase and there is no suggestion that sprinkling rosemary on everything you eat could help prevent or fight COVID-19. For the latest guidance on COVID-19, see the official CDC website.
As far as Aldo Pourchet is concerned you are never too young to learn about stem cells. Aldo should know. He’s a molecular and cellular biologist and the co-founder and CEO of Omios Bio, which develops immunotherapies for cancer, infectious and inflammatory diseases.
And now Aldo is the author of a children’s book about stem cells. The book is “Nano’s Journey! A Little Stem Cell Visits the Heart and Lungs.” It’s the story of Nano, a stem cell who doesn’t know what kind of cell she wants to be when she grows up, so she goes on a journey through the body, exploring all the different kinds of cell she could be.
It’s a really sweet book, beautifully illustrated, and written in a charming way to engage children between the ages of 5 and 8. I asked Aldo what made him want to write a book like this.
“I was interested in providing very general knowledge such as the principleof life, the basic logics of nature and at the same time to entertain. It wasvery important for it not to be a textbook.
“Why Stem cells? Because it is the most fascinating biology and they are at the origin of an organism and throughout its life play an essential role. They evolve and transform, so they have a story that unfolds. An analogy with children maybe. It’s easy to imagine children are like stem cells, trying to decide who they are, while adults are like differentiated cells because they have already decided.
“For the kids to appropriate the story, I thought that humanizing cells was important. I wanted children to identify themselves with the cells andespecially Nano, the little girl main character. It’s a book written for the children, in the first place. We tell the story at their level. Not try to bring them up to the level of life science.
Aldo says right from the start he had a clear idea of who he wanted the lead character to be.
“I think the world needs more female leaders, more female voices andinfluence in general and in every domain. So quite early it became naturalfor me that Nano would be a girl and also would have a strong character,curious and adventurous.
“Blasto came later because I was looking for a companion to share the adventure with Nano. Blasto is a fibroblast so he is not supposed to leave the Bone Marrow but fibroblasts are everywhere in our organism so I thought it was an acceptable stretch.
The drawings in the book are delightful, colorful and fun. Aldo says he had some ideas, rounded shapes for the cells for example and a simple design that reflected the fact that there are no lines in nature. Illustrator Jen Yoon took it from there:
“Based on Aldo’s direction and imagination, I envisioned the style like drawings on a chalkboard. Soft curves with rough textures. After that everything went smoothly. Following Nano’s journey with my iPad pencil, it felt like a boat ride at an amusement park.”
The books are written to be read aloud by parents, adults and teachers to kids. But, spoiler alert, we don’t find out what cell Nano decides to be in this book. She’s going to have more adventures in other books before she makes up her mind.
Bipolar disorder (BPD) is a mental disorder that causes unusual shifts in mood, energy, activity levels, concentration, and the ability to carry out day-to-day tasks. In the United States, recent research has shown that 1.6% of the population has BPD, which is roughly over 4 million people. Those with BPD are more likely to have conditions associated with chronic inflammation such as hypertension and diabetes. It is because of this that scientists have been studying the connection between inflammation and BPD for quite some time.
In a new study, researchers at the Salk Institute for Biological Studies, UC San Diego, and the Institute of Psychiatry and Neuroscience of Paris have found evidence that astrocytes, a certain type of brain cell, can trigger inflammation more easily in those that have BPD. What’s more, these astrocytes can be linked to decreased brain activity that could be harmful to mental health.
Astrocytes are star shaped (as the word “astro” might suggest) and help support neurons, the cells that relay information around the brain. One of these supporting roles includes helping trigger inflammation in the brain and the surrounding nervous system to help with injury or infection. The researchers believe that this process can go wrong in people with BPD and that astrocytes can play a role in this dysfunctional inflammation.
For this study, the team used induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any type of cell, that they created from patients with BPD and patients without BPD. They converted these iPSCs into astrocytes and compared those that came from BPD patients to those that did not. What they found is that the astrocytes from patients with BPD were noticeably different. The BPD astrocytes had a higher expression of a protein that triggers an inflammatory response when compared to the non-BPD astrocytes. When they exposed neurons to the BPD astrocytes, the team saw decreased levels of neural activity compared to the non-BPD astrocytes. Lastly, when the researchers blocked the inflammatory protein, the neurons were less affected by the BPD astrocytes.
“Our study suggests that normal function of astrocytes is affected in bipolar disorder patients’ brains, contributing to neuroinflammation,” said Dr. Renata Santos, a researcher at the Salk Institute as well as the Institute of Psychiatry and Neuroscience of Paris, in a news release.
The team hopes that their findings can not only provide insight into BPD, but to other mental illnesses linked to inflammation such as schizophrenia. The ultimate goal is to help advance research into astrocytes and inflammation in order to develop treatments that might reverse the harmful bodily changes seen in those with BPD and other mental disorders.
The full study was published in Stem Cell Reports.
Almost every day I get an email or phone call from someone asking if we have a stem cell therapy for bad knees. The inquiries are from people who’ve been told they need surgery to replace joints damaged by age and arthritis. They’re not alone. Every year around 600,000 Americans get a knee replacement. That number is expected to rise to three million by 2030.
Up till now my answer to those calls and emails has been ‘I’m sorry, we don’t have anything’. But a new CIRM-funded study from USC stem cell scientist Denis Evseenko says that may not always be the case.
The ability to regenerate joint cartilage cells instead of surgically replacing joints would be a big boon for future patients. (Photo/Nancy Liu, Denis Evseenko Lab, USC Stem Cell)
Evseenko and his team have discovered a molecule they have called Regulator of Cartilage Growth and Differentiation or RCGD 423. This cunning molecule works in two different ways. One is to reduce the inflammation that many people with arthritis have in their joints. The second is to help stimulate the regeneration of the cartilage destroyed by arthritis.
When they tested RCGD 423 in rats with damaged cartilage, the rats cartilage improved. The study is published in the Annals of Rheumatic Diseases.
In an article in USC News, Evseenko, says there is a lot of work to do but that this approach could ultimately help people with osteoarthritis or juvenile arthritis.
“The goal is to make an injectable therapy for an early to moderate level of arthritis. It’s not going to cure arthritis, but it will delay the progression of arthritis to the damaging stages when patients need joint replacements, which account for a million surgeries a year in the U.S.”
CIRM-funded spinal cord injury trial keeping a steady pace
Taking an idea for a stem cell treatment and developing it into a Food and Drug Administration-approved cell therapy is like running the Boston Marathon because it requires incremental progress rather than a quick sprint. Asterias Biotherapeutics continues to keep a steady pace and to hit the proper milestones in its race to develop a stem cell-based treatment for acute spinal cord injury.
Just this week in fact, the company announced an important safety milestone for its CIRM-funded SciStar clinical trial. This trial is testing the safety and effectiveness of AST-OPC1, a human embryonic stem cell-derived cell therapy that aims to regenerate some of the lost movement and feeling resulting from spinal cord injuries to the neck.
Periodically, an independent safety review board called the Data Monitoring Committee (DMC) reviews the clinical trial data to make sure the treatment is safe in patients. That’s exactly what the DMC concluded as its latest review. They recommended that treatments with 10 and 20 million cell doses should continue as planned with newly enrolled clinical trial participants.
About a month ago, Asterias reported that six of the six participants who had received a 10 million cell dose – which is transplanted directly into the spinal cord at the site of injury – have shown improvement in arm, hand and finger function nine months after the treatment. These outcomes are better than what would be expected by spontaneous recovery often observed in patients without stem cell treatment. So, we’re hopeful for further good news later this year when Asterias expects to provide more safety and efficacy data on participants given the 10 million cell dose as well as the 20 million cell dose.
It’s a two-fer: SMART cells that make cartilage and release anti-inflammation drug “It’s a floor wax!”….“No, it’s a dessert topping!”
“Hey, hey calm down you two. New Shimmer is a floor wax and a dessert topping!”
Those are a few lines from the classic Saturday Night Live skit that I was reminded of when reading about research published yesterday in Stem Cell Reports. The clever study generated stem cells that not only specialize into cartilage tissue that could help repair arthritic joints but the cells also act as a drug dispenser that triggers the release of a protein that dampens inflammation.
Using CRISPR technology, a team of researchers led by Farshid Guilak, PhD, at Washington University School of Medicine in St. Louis, rewired stem cells’ genetic circuits to produce an anti-inflammatory arthritis drug when the cells encounter inflammation. The technique eventually could act as a vaccine for arthritis and other chronic conditions. Image: ELLA MARUSHCHENKO
The cells were devised by a research team at Washington University School of Medicine in St. Louis. They started out with skin cells collected from the tails of mice. Using the induced pluripotent stem cell technique, the skin cells were reprogrammed into an embryonic stem cell-like state. Then came the ingenious steps. The team used the CRISPR gene-editing method to create a negative feedback loop in the cells’ inflammation response. They removed a gene that is activated by the potent inflammatory protein, TNF-alpha and replaced it with a gene that blocks TNF-alpha. Analogous experiments were carried out with another protein called IL-1.
Rheumatoid arthritis often affects the small joints causing painful swelling and disfigurement. Image: Wikipedia
Now, TNF-alpha plays a key role in triggering inflammation in arthritic joints. But this engineered cell, in the presence of TNF-alpha, activates the production of a protein that inhibits the actions of TNF-alpha. Then the team converted these stem cells into cartilage tissue and they went on to show that the cartilage was indeed resistant to inflammation. Pretty smart, huh? In fact, the researchers called them SMART cells for “Stem cells Modified for Autonomous Regenerative Therapy.” First author Dr. Jonathan Brunger summed up the approach succinctly in a press release:
“We hijacked an inflammatory pathway to create cells that produced a protective drug.”
This type of targeted treatment of arthritis would have a huge advantage over current anti-TNF-alpha therapies. Arthritis drugs like Enbrel, Humira and Remicade are very effective but they block the immune response throughout the body which carries an increased risk for serious infections and even cancer.
The team is now testing the cells in animal models of rheumatoid arthritis as well as other inflammation disorders. Those results will be important to determine whether or not this approach can work in a living animal. But senior Dr. Farshid Guilak also has an eye on future applications of SMART cells:
“We believe this strategy also may work for other systems that depend on a feedback loop. In diabetes, for example, it’s possible we could make stem cells that would sense glucose and turn on insulin in response. We are using pluripotent stem cells, so we can make them into any cell type, and with CRISPR, we can remove or insert genes that have the potential to treat many types of disorders.”
Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.
Inflammation is the immune system’s natural protective response to infection and injury. It involves the activation and mobilization of immune cells that can kill off foreign invaders and help repair damaged tissue. At the heart of the inflammatory response are hematopoietic stem cells (HSCs). These are blood stem cells found in the bone marrow that give rise to all blood cell types.
Under normal conditions, HSCs lie in a dormant state. But in response to inflammation they are triggered to rapidly divide and to differentiate into the immune cells needed. This initial response is beneficial in fighting off infection, however if left on for too long, HSCs lose their ability to self-renew (or make more of themselves) and regenerate a healthy blood system.
IL-1:Good Cop or Bad Cop?
A key player in the immune response to inflammation is a cytokine protein called Interleukin-1 or IL-1. It plays a beneficial role during an initial or acute inflammatory response: IL-1 along with other pro-inflammatory cytokines signals to HSCs that inflammation or infection is occurring and recruits certain immune cells from the blood into the tissue where they are needed.
However, IL-1 can also have negative effects on the immune system and high levels of this cytokine are found in patients with chronic inflammatory diseases such as obesity, diabetes and atherosclerosis. When HSCs are exposed IL-1 for long periods of time, they lose their regenerative abilities and overproduce specific types of aggressive immune cells called myeloid cells that are needed to fight infection and repair injury but can also cause chronic inflammation and tissue damage. This can create an imbalance of blood cell types that impairs the function of the immune system.
So is IL-1 the good cop or the bad cop when it comes to inflammation and disease? A new CIRM-funded study from the University of California San Francisco (UCSF), published yesterday in Nature Cell Biology, might have the answer.
A double-edged sword
The study was led by first author Dr. Eric Pietras, who is now an Assistant Professor of Hematology at the University of Colorado Anschutz Medical Campus. He along with senior author and UCSF Professor Dr. Emmanuelle Passegue, were interested in understanding whether IL-1 was a bystander or an active player in causing this transformation in HSCs that leads to chronic inflammatory disease.
To answer this question, Pietras and Passegue exposed mouse HSCs to IL-1, both in a cell culture dish and in mice. They found that IL-1 drove HSCs to rapidly differentiate into myeloid cells by activating a molecular circuit directed by the PU.1 gene, which is important for regulating HSC blood production. However, when mice were exposed to IL-1 for an extended period of 70 days – to mimic chronic inflammation – their HSCs were no longer able to do their normal job of regenerating all the cells of the blood and immune system.
I reached out to Dr. Pietras and asked him to explain what new insights his study has produced about the role of IL-1 during inflammation.
“IL-1 really is a double-edged sword; it’s great for turning on HSCs when you need them to make new first-responder myeloid cells quickly due to an injury or infection, and on the other hand, failure to turn the signal back off severely disrupts the ability of HSCs to make a balanced, healthy blood system, particularly in a regenerative context. I think this provides us with a clearer picture of why the blood system often functions poorly in chronic inflammatory disease patients.”
Negative effects of IL-1 are reversible
There’s good news though. Pietras and his team were able to reverse the negative effects of chronic IL-1 exposure on HSCs by simply removing IL-1. They proved this by transplanting HSCs from mice that were chronically treated with IL-1 and then taken off the treatment for a few weeks into irradiated mice that had no bone marrow and therefore no immune system. The transplanted HSCs were able to repopulate the entire immune system of the irradiated mice and did not show any regenerative dysfunction due to previous IL-1 treatment.
Dr. Pietras commented on the importance of their study:
“An important dimension of our study is to show in principle that HSCs can recover their functionality and return to making a healthy and balanced blood system if you can give them a break from the constant presence of inflammatory signals. This tells us that the negative effects of chronic inflammation on HSCs can be largely reversed if you can provide them with a break from the constant ‘emergency’ state IL-1 makes them think they’re in. This could impact how we treat chronic inflammatory disease.
Blocking IL-1 to treat chronic inflammation
So will drugs that inhibit IL-1 be a future therapy for patients suffering from chronic inflammatory disease? Anti-IL-1 drugs have been around for a while – one example is Kineret, which is an FDA-approved treatment for rheumatoid arthritis. But there are many other diseases caused by chronic inflammation that may or may not benefit from such treatment.
Dr. Passegue, in a UCSF press release, explained that their study’s findings are important for determining how anti-IL-1 therapy could be beneficial for patients.
“Understanding this mechanism helps us understand why these drugs are such promising treatments for patients with chronic inflammation.”
She also hinted that IL-1 could be a double-edged sword in stem cell populations of other tissues and that “reducing chronic IL-1 exposure may be an important approach for improving stem cell health and tissue function in the context of both inflammatory disease and normal aging.”
I’m going to tell you a secret: I love sugar. I love it so much that as a little kid my mom used to tell me scary stories about how my teeth would fall out and that I might get diabetes one day if I ate too many sweets. Thankfully, none of these things happened. I have a full set of teeth (and they’re real), my blood sugar level is normal, and I’ve become one with the term “everything in moderation”.
I am not out of the woods, however: a newly discovered type of diabetes could strike in a few decades. A research team has found the cause of a type of diabetes that occurs because of old age, and a potential cure, at least in mice.
Diabetes comes in different flavors
People who suffer from diabetes (which is almost 30 million Americans) lack the ability to regulate the amount of sugar in their blood. The pancreas is the organ that regulates blood sugar by producing a hormone called insulin. If blood has a high sugar level, the pancreas releases insulin, which helps muscle, liver, and fat cells to absorb the excess sugar until the levels in the blood are back to normal.
There are two main forms of diabetes, type 1 and 2, both of which cause hyperglycemia or high blood sugar. Type 1 is an autoimmune disorder where the immune system attacks and kills the insulin-producing cells in the pancreas. As a result, these type 1 diabetics aren’t able to produce insulin and endure a lifetime of daily insulin shots to manage their condition. Type 2 diabetes is the more common form of the disease and occurs when the body’s cells become unresponsive, or resistant, to insulin and stop absorbing sugar from the bloodstream.
The cause of type 1 diabetes is not known although genetic factors are sure to be involved. Type 2 diabetes can be caused by a combination of factors including poor diet, obesity, genetics, stress, and old age. Both forms of the disease can be fatal if not managed properly and raise the risk of other medical complications such as heart disease, blindness, ulcers, and kidney failure.
While type 1 or 2 diabetes make up the vast majority of the cases, there are actually other forms of this disease that we are only just beginning to understand. One of them is type 3, which is linked to Alzheimer’s disease. (To learn more about the link between AD and diabetes, read this blog.)
Old age can cause diabetes
Another form of diabetes, which is in the running for the title of type 4, is caused by old age. Unlike type 2 diabetes which also occurs in adults, type 4 individuals don’t have the typical associated risk factors like weight gain. The exact mechanism behind age-related type 4 diabetes in humans isn’t known, but a CIRM-funded study published today in Nature identified the cause of diabetes in older, non-obese mice.
Scientists from the Salk Institute compared the immune systems of healthy mice to lean mice with age-associated insulin resistance or mice with obesity-associated insulin resistance (the equivalent to type 2 diabetes in humans). When they studied the fat tissue in the three animal models, they noticed a striking difference in the number of immune cells called T regulatory cells (Tregs). These cells are the “keepers of the immune system”, and they keep inflammation and excessive activity of other immune cells to a minimum.
Lean mice with age-related diabetes, had a substantially larger number of Tregs in their fat tissue compared to obesity-related diabetic and normal mice. Instead of being their usual helpful selves, the overabundance of Tregs in the age-related diabetic mice caused insulin resistance.
Diabetes in elderly, lean animals is caused by an overabundance of immune cells called Tregs (orange) in fat tissue (brown cells). In aged mice with diabetes (right), Tregs are overexpressed in fat tissue and trigger insulin resistance. When Tregs are blocked, the fat cells in mice become insulin sensitive again. (Image courtesy of Salk Institute)
Normally, Tregs help calm inflammation. Because fat tissue is constantly broken down and built back up as it stores and releases energy, it requires low levels of inflammation to constantly remodel itself. But as someone ages, the new research suggests, Tregs gradually accumulate within fat. And if the cells reach a tipping point where they completely block inflammation in fat tissue, they can cause fat deposits to build up inside unseen areas of the body, including the liver, leading to insulin resistance.
A cure for type 4 diabetes, but in mice…
After they identified the cause, the authors next searched for a solution. They blocked the build up of Tregs in the fat tissue of age-related diabetic mice using an antibody drug that inhibits the production of Tregs. The drug successfully cured the age-related diabetic mice of their insulin resistance, but didn’t do the same for the obesity-related diabetic mice. The authors concluded that the two forms of diabetes have different causes and type 4 can be cured by removing excessive Tregs from fat tissue.
This study is only the beginning for understanding age-related diabetes. The authors next want to find out why Tregs accumulate in the fat tissue of older mice, and if they also build up in other tissues and organs. They are also curious to know if the same phenomenon happens in elderly humans who become diabetic but don’t have type 2 diabetes.
Understanding the cause of age-related diabetes in humans is of upmost importance to Ronald Evans who is the director of the Gene Expression Lab at the Salk Institute, and senior author on the study.
A lot of diabetes in the elderly goes undiagnosed because they don’t have the classical risk factors for type 2 diabetes, such as obesity. We hope our discovery not only leads to therapeutics, but to an increased recognition of type 4 diabetes as a distinct disease.
For more on this exciting study, check out a video interview of Dr. Evans from the Salk Institute:
When injecting stem cells into a patient, how do the cells know where to go? How do they know to travel to a specific damage site, without getting distracted along the way?
Scientists are now discovering that, in some cases they do but in many cases, they don’t. So engineers have found a way to give stem cells a little help.
As reported in today’s Cell Reports, engineers at Brigham and Women’s Hospital (BWH) in Boston, along with scientists at the pharmaceutical company Sanofi, have identified a suite of chemical compounds that can help the stem cells find their way.
Researchers identified a small molecule that can be used to program stem cells (blue and green) to home in on sites of damage. [Credit: Oren Levy, Brigham and Women’s Hospital]
“There are all kinds of techniques and tools that can be used to manipulate cells outside the body and get them into almost anything we want, but once we transplant cells we lose complete control over them,” said Jeff Karp, the paper’s co-senior author, in a news release, highlighting just how difficult it is to make sure the stem cells reach their destination.
So, Karp and his team—in collaboration with Sanofi—began to screen thousands of chemical compounds, known as small molecules, that they could physically attach to the stem cells prior to injection and that could guide the cells to the appropriate site of damage. Not unlike a molecular ‘GPS.’
Starting with more than 9,000 compounds, the Sanofi team narrowed down the candidates to just six. They then used a microfluidic device—a microscope slide with tiny glass channels designed to mimic human blood vessels. Stem cells pretreated with the compound Ro-31-8425 (one of the most promising of the six) stuck to the sides. An indication, says the team, Ro-31-8425 might help stem cells home in on their target.
But how would these pre-treated cells fare in animal models? To find out, Karp enlisted the help of Charles Lin, an expert in optical imaging at Massachusetts General Hospital. First, the team injected the pre-treated cells into mouse models each containing an inflamed ear. Then, using Lin’s optical imaging techniques, they tracked the cells’ journey. Much to their excitement, the cells went immediately to the site of inflammation—and then they began to repair the damage.
According to Oren Levy, the study’s co-first author, these results are especially encouraging because they point to how doctors may someday soon deliver much-needed stem cell therapies to patients:
“There’s a great need to develop strategies that improve the clinical impact of cell-based therapies. If you can create an engineering strategy that is safe, cost effective and simple to apply, that’s exactly what we need to achieve the promise of cell-based therapy.”
In the world of professional sports, teams invest tens of millions of dollars in players. Those players are under intense pressure to show a return on that investment for the team, and that means playing as hard as possible for as long as possible. So it’s no surprise that players facing serious injuries will often turn to any treatment that might get them back in the game.
image courtesy Scientific American
A new study published last week in 2014 World Stem Cell Report (we blogged about it here) highlighted how far some players will go to keep playing, saying at least 12 NFL players have undergone unproven stem cell treatments in the last five years. A session at the recent World Stem Cell Summit in San Antonio, Texas showed that football is not unique, that this is a trend in all professional sports.
Dr. Shane Shapiro, an orthopedic surgeon at the Mayo Clinic, says it was an article in the New York Times in 2009 about two of the NFL players named in the World Stem Cell Report that led him to becoming interested in stem cells. The article focused on two members of the Pittsburgh Steelers team who were able to overcome injuries and play in the Super Bowl after undergoing stem cell treatment, although there was no direct evidence the stem cells caused the improvement.
“The next day, the day after the article appeared, I had multiple patients in my office with copies of the New York Times asking if I could perform the same procedure on them.”
Dr. Shapiro had experienced what has since become one of the driving factors behind many people seeking stem cell therapies, even ones that are unproven; the media reports high profile athletes getting a treatment that seems to work leading many non-athletes to want the same.
“This is not just about high profile athletes it’s also about older patients, weekend warriors and all those with degenerative joint disease, which affects around 50 million Americans. Currently for a lot of these degenerative conditions we don’t have many good non- surgical options, basically physical therapy, gentle pain relievers or steroid injections. That’s it. We have to get somewhere where we have options to slow down this trend, to slow down the progression of these injuries and problems.”
Shapiro says one of the most popular stem cell-based approaches in sports medicine today is the use of plasma rich platelets or PRP. The idea behind it makes sense, at least in theory. Blood contains platelets that contain growth factors that have been shown to help tissue heal. So injecting a patient’s platelets into the injury site might speed recovery and, because it’s the patient’s own platelets, the treatment probably won’t cause any immune response or prove to be harmful.
That’s the theory. The problem is few well-designed clinical trials have been done to see if that’s actually the case. Shapiro talked about one relatively small, non-randomized study that used PRP and in a 14-month follow-up found that 83% of patients reported feeling satisfied with their pain relief. However, 84% of this group did not have any visible improved appearance on ultrasound.
He is now in the process of carrying out a clinical trial, approved by the Food and Drug Administration (FDA), using bone marrow aspirate concentrate (BMAC) cells harvested from the patient’s own bone marrow. Because those cells secrete growth factors such as cytokines and chemokines they hope they may have anti-inflammatory and regenerative properties. The cells will be injected into 25 patients, all of whom have arthritic knees. They hope to have results next year.
Dr. Paul Saenz is a sports medicine specialist and the team physician for the San Antonio Spurs, the current National Basketball Association champions. He says that sports teams are frequently criticized for allowing players to undergo unproven stem cell treatments but he says it’s unrealistic to expect teams to do clinical studies to see if these therapies work, that’s not their area of expertise. But he also says team physicians are very careful in what they are willing to try.
“As fervent as we are to help bring an athlete back to form, we are equally fervent in our desire not to harm a $10 million athlete. Sports physicians are very conservative and for them stem cells are never the first thing they try, they are options when other approaches have failed.”
Saenz said while there are not enough double blind, randomized controlled clinical trials he has seen many individual cases, anecdotal evidence, where the use of stem cells has made a big difference. He talked about one basketball player, a 13-year NBA veteran, who was experiencing pain and mobility problems with his knee. He put the player on a biologic regimen and performed a PRP procedure on the knee.
“What we saw over the next few years was decreased pain, and a dramatic decrease in his reliance on non-steroidal anti inflammatory drugs. We saw improved MRI findings, improved athletic performance with more time on court, more baskets and more rebounds.”
But Saenz acknowledges that for the field to advance anecdotal stories like this are not enough, well-designed clinical trials are needed. He says right now there is too much guesswork in treatments, that there is not even any agreement on best practices or standardized treatment protocols.
Dr. Shapiro says for too long the use of stem cells in sports medicine has been the realm of individual physicians or medical groups. That has to change:
“If we are ever to move forward on this it has to be opened up to the scientific community, we have to do the work, do the studies, complete the analysis, open it up to our peers, report it in a reputable journal. If we want to treat the 50 million Americans who need this kind of therapy we need to go through the FDA approval process. We can’t just continue to treat the one patient a month who can afford to pay for all this themselves. “
Our bodies generate new blood cells—both red and white blood cells—each and every day. But reproducing that feat in a petri dish has proven far more difficult.
Pictured: sections from zebrafish embryos. Blood vessels are labeled in red, the protein complex that regulates inflammation green and cell nuclei in blue. The arrowhead indicates a potential HSC. The image at bottom right combines all channels. [Credit: UC San Diego School of Medicine]
But now, scientists have identified the missing ingredient to producing hematopoietic stem cells, or HSC’s—the type of stem cell that gives rise to all blood and immune cells in the body. The results, published last week in the journal Cell, describe how a newly discovered protein plays a key role in generating HSC’s in the developing embryo—giving scientists a more complete recipe to reproduce these cells in the lab.
The research, which was led by University of California, San Diego (UCSD) professor David Traver and supported by a grant from CIRM, offers renewed hope for the possibility of generating patient-specific blood or immune cells using induced pluripotent stem cell (iPS cell) technology.
“The development of some mature cell lineages from iPS cells, such as cardiac or neural, has been reasonably straightforward, but not with HSCs. This is likely due, at least in part, to not fully understanding all the factors used by the embryo to generate HSCs.”
Indeed, the ability to generate HSCs has long challenged scientists, as outlined in a CIRM workshop from last year. But now, says Traver, they have found a crucial piece to the puzzle.
Specifically, the researchers investigated a signaling protein called tumor necrosis factor alpha—or TNFα for short— a protein known to be important for regulating inflammation and immunity. Previous research by this study’s first author, Raquel Espin-Palazon, and others also discovered it was related to the healthy function of blood vessels during embryonic development.
In this study, Traver, Espin-Palazon and the UCSD drilled down even further—and found that TNFα was required for the normal development of HSCs in the embryo. This surprised the research team, as the young embryo is generally considered to be sterile—with no need for a protein normally charged with regulating immune response to be switched on. Explained Traver:
“There was no expectation that pro-inflammatory signaling would be active at this time or in the blood-forming regions.”
While preliminary, establishing this relationship between TNFα and HSC formation will be a boon to researchers looking for new ways to generate large quantities of healthy, patient-specific red and white blood cells for those patients who so desperately need them.