The Universe of Universal Stem Cells: Rewards vs Risks

Many incurable health problems are characterized by the death of cells that cannot regenerate or repair themselves upon damage or injury. For example, cardiac muscle cells die in heart attack, nerve cells perish in the brain during a stroke, and insulin-producing cells vanish in diabetes. Unfortunately, these cells are incapable of regeneration, leading to irreversible damage. Laboratory scientists are developing potential solutions to replace these cells. 

Stem cell scientists are studying the use of stem cells to produce functional cells that could be transplanted into patients to treat and potentially reverse the damage. Remarkably, scientists can take skin or blood cells and turn them into cells that can become any cell in the body, known as an induced pluripotent stem cells (iPSCs). These characteristics make iPSCs an accessible and versatile source for generating cells to replace those lost due to disease or damage. iPSCs can be made from anyone, and consequently could theoretically be used to make individual batches of replacement cells for every patient. However, such a process is inefficient and expensive. Scientists are working to make universal donor stem cells that could ideally be transplanted into anyone without immune rejection.

A key requirement for cell transplantation is an immune match between the donor and recipient to avoid immune rejection, just like organ transplants. The key factors governing this tissue compatibility are called the human leukocyte antigens (HLAs). They are expressed on the cell’s surface and enable the immune system to distinguish self from non-self, acting as a personal cell “ID card.” If HLAs between the donor cells are mismatched to the recipient, the immune system will identify the transplanted cells as foreign and attack and kill them. Such immune rejection can be life-threatening to the recipient. The probability of a perfect HLA match is about 1 in 100,000 between two unrelated individuals, representing a fundamental challenge for any transplantations, including cell-based therapies. 

A Universal Stem Cell Bank

To solve this problem, scientists have proposed several different strategies. In one proposed strategy, scientists are attempting to isolate and “bank,” or store, iPSCs that would be immunologically compatible with many different people. In another, researchers are using genetic approaches to engineer stem cells that would be accepted by any recipient.  

The Global Alliance for iPSC Therapies (GAiT) was established to create an international registry of clinical grade iPSCs. “This is similar to how the international bone marrow donor registry has worked, where the stem cells of a donor are available to recipients living in different countries,” says Associate Professor Ngaire Elwood, Director of the BMDI Cord Blood Bank in Melbourne, Australia, and a collaborator of Global Alliance for iPSC Therapies. Accordingly, banks like GAiT enable.” iPSC-based therapies by providing a resource to find compatible transplantable materials.

Researchers in some countries are undertaking efforts to establish iPSC lines that would be compatible with the majority of the population. In general, there is less genetic diversity in the Japanese population than in other countries and theoretically only a small number of iPSC lines would be needed to be HLA-compatible with a large proportion of the population. Nobel Laureate Shinya Yamanaka has led an effort at the Kyoto University Center for iPSC Research and Application to bank these compatible stem cell lines. So far, they have created 27 iPSC lines, which in principle, would be compatible with 40 percent of the Japanese population. Similarly, Cambridge University, UK scientists predict that as few as 150 selected donors would cover at least 90 percent of the UK population.

Genetic differences, however, may still cause immune rejection. In these cases, recipients would need to take immunosuppressant drugs long-term, which impairs their ability to fight off infections. An alternative transplant strategy is to create genetically modified stem cells that can completely hide from the immune system of anyone, so-called “universal” stem cells.

Creating Universal Stem Cells
Given that HLA mismatching is the chief barrier for cell transplantation, scientists have used gene-editing tools to inactivate key HLA genes of iPSCs. These bioengineered iPSCs, designated “universal” stem cells, are able to evade immune rejection and represent a unique approach to developing transplantable cells for genetically diverse populations. Inactivating the HLA genes in universal stem cells, however, does have a potential risk. HLA genes are required for the elimination of cancer cells and there is concern that should these universal cells become cancerous, that they could grow unchecked by the recipient’s immune system.

A potential solution to mitigate the risk is to include a mechanism that would kill the universal cells if needed. Andras Nagy’s team in Toronto, Canada is a leading the way in developing a “cell suicide system” to make universal stem cells safer. In this system, stem cells are engineered to contain a suicide switch that could be activated when the cells start showing any abnormalities, such as uncontrolled growth. As a result, problematic cells would be killed before they form tumors. 

“Universal cells require significant genetic manipulation, including a suicide switch, this approach will have a more difficult time being approved by the regulators for routine clinical use,” says Ngaire, who has 13 years of experience running a cell manufacturing facility licensed by the Therapeutic Goods Administrations in Australia.  

Either by banking iPS cells from a variety of donors or by genetically manipulating them, these approaches to using stem cells are laying the foundation to develop new transplantation treatments for incurable diseases. Like all currently available treatments, the balance of the benefits versus risks is the key consideration towards successful clinical translation. 

Blog by guest contributor S.C. Jacky Sun, PhD candidate in the labs of Ed Stanley and Andrew Elefanty at the Murdoch Children’s Research Institute, Melbourne.

Stem Cells May Offer Key to Treating Venomous Snake Bites

Each year people around the world fall victim to about 1.8 – 2.7 million venomous snake bites. Many of these injuries go untreated due to lack of access to available treatments or health insurance, resulting in more than 100,000 deaths and approximately three times as many permanent disabilities. New therapies are needed to treat snakebite envenoming, a neglected public health issue. A new therapeutic tool to treat venomous snake bites may have come from an unlikely source &ndash; stem cell research.</p>
<p>There are about 250 types of venomous snake species with the highest prevalence of snakebite envenoming in Africa, Asia, and Latin America. Snake venom is composed of multiple natural toxins, enzymes, proteins, and peptides, which act together to cause rapid tissue damage or death. The exact venom composition is incredibly diverse and species-dependent, making treatment highly specific for each snake species. Snake bites can be lethal or lead to life-long, chronic health problems, such as neurotoxicity and nerve-related paralysis, irreversible kidney damage after excessive renal bleeding, or limb amputation.</p>
<p><img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2020/11/snake-venom-figure-1.tmb-300×400-1.jpg” data-displaymode=”Thumbnail” alt=”Snake Venom Blog Figure 1″ title=”Snake Venom Blog Figure 1″ style=”float: left; margin-right: 10px;” />Most current treatments aim to neutralize the venom, such as antivenom. In general, antivenom is made by harvesting snake venom through manually milking the snake (see Figure 1 on left) and injecting small doses of the venom into donor animals, such as horses, to elicit an immune response and antibody production. These anti-venom antibodies are then injected into the snake bite victim where they selectively recognize and bind to structural components of the snake venom, neutralizing the toxins.</p>
<p>Making anti-venom in this way is time consuming, hard to scale up, and must be done individually for each species of venomous snake. According to the World Health Organization, many antivenom-manufacturers have ceased production in the last 20 years, causing reduced supply and drastically increased prices. Unfortunately, effective alternative therapeutic approaches are scarce.</p>
<p><strong><br />
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Using Stem Cells to Fight Snake Bites</strong></p>
<p>Recently, scientists turned to stem cells to solve this problem. Researchers can use stem cells to grow three dimensional mini organs, called organoids, which maintain essential characteristics of the specific organ or tissue. For the first time, scientists tried to derive organoids from snake stem cells to see if they could grow <a href=”https://edition.cnn.com/2020/01/29/health/snake-venom-lab-organoids-stem-cell-scn/index.html”>venom-producing mini organs in the lab</a>. Researchers dissected venom glands of nine species of snake and successfully grew organoids from stem cells found in snake salivary glands (see Figure 2 on right).<img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2020/11/snake-venom-figure-2.tmb-300×400-1.jpg” data-displaymode=”Thumbnail” alt=”Snake Venom Blog Figure 2″ title=”Snake Venom Blog Figure 2″ style=”float: right; margin-top: 10px; margin-bottom: 10px; margin-left: 10px;” /> </p>
<p><em>Figure 2: Snake venom gland organoids from the&nbsp;Aspidelaps&nbsp;lubricus&nbsp;snake. Credit: Ravian&nbsp;van&nbsp;Ineveld, Princess&nbsp;M&aacute;xima Center for Pediatric Oncology, the Netherlands</em>.<br />
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Strikingly, these organoids contained cells that could secrete functionally active venom that exerted species-specific effects on neurons and muscle cells in the lab. Further, organoid-derived venom has similar composition to venom directly milked from snakes. Scientists are now hoping to establish a biobank, or repository, of snake gland organoids for all venomous snakes of medical relevance, in order to create an unlimited supply of venom.</p>
<p>Since publishing the initial research paper, Jens Puschhof says the group has already expanded the organoid repertoire to include a broader selection of venomous snakes. He added that &nbsp;using venom from organoids rather than milking snakes could help produce a safer, more reliable product, as there is variation in venom components of individual snakes. Next steps include using venom organoids to purify the toxic components and make antibodies in the lab, rather than in horses, to more efficiently manufacture antidotes and enhance global access.&nbsp; </p>
<p><strong>Can Snake Venom Treat Tumors?</strong></p>
<p>A biobank of snake venom organoids could potentially provide treatments for other diseases. The U.S. Food and Drug Administration (FDA) has previously approved drugs that are derived from snake venom for treating acute cerebral infarction, acute coronary syndrome, and as prophylaxis for hemorrhage during surgery. </p>
<p>Strikingly, early research indicates that peptides from snake venom may have antitumor effects. Components of snake venom called disintegrins, such as Contortrostatin from the snake <em>Agkistrodon contortrix contortrix</em>, can inhibit blood vessel formation and cancer cell adhesion in lab models of human metastatic skin cancer. Additional research indicates that a potent peptide found in venom could interfere with blood vessel formation, reducing delivery of nutrients to tumors in a mouse model of breast cancer. The availability of venom-biobanks would allow scientists to further study snake venom components to see if there are opportunities for biomedical innovation.</p>
<p><strong>The Bite</strong></p>
<p>Fifty people are bitten by a snake every five minutes, and one will die in this silent healthcare crisis. Novel stem cell research has allowed scientists to successfully grow mini venom-producing organoids&nbsp; in a petri dish, which may be used to develop accessible and affordable antivenom therapies. This scientific innovation of developing snake venom gland organoids has the potential to save people around the world from deadly snake bites and other diseases.</p>
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<p><em>Blog by guest contributor Felix Buchner, Masters student </em><em>at the CRTD/TU Dresden in Germany.</em></p>
<p><em>Thank you to </em><em>the three graduate students in Hans Clevers&rsquo; lab at the Hubrecht Institute in the Netherlands, Jens Puschhof, Yoep Beumer, and Yorick Post who contributed to work shown in Figure 2.</em></p>

Closing in on Pluripotent Stem Cell Therapies for Liver Diseases

The liver, our largest internal organ, plays vital roles in food metabolism, energy storage, and elimination of toxins. Liver disorders kill more than two million people per year, representing a significant global health challenge. In addition, liver failure is the end stage of many life-threatening diseases, such as alcoholic hepatitis, Hepatitis B infection, and liver cancer. In such conditions, liver failure results from the widespread death of the major cell type of the liver, the hepatocyte.
<p style=”text-align: left;”>Organ transplantation is the only available therapeutic option for people with end-stage liver disease. However, because of difficulties in finding immune-matched donors, only around 10 percent of patients requiring a transplant receive a new functional liver, and many patients die before a suitable donor can be found. Researchers are looking to the potential of stem cell research to provide novel treatments to patients who do not have access to a liver transplant.</p>
<p style=”text-align: left;”><a href=”https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/”>Pluripotent stem cells</a> can become any cell type in the body. These stem cells can be grown in the lab in large numbers and can be transformed into functional cells with the goal that they will be able to integrate into a human organ and successfully carry out physiological activities or even potentially replace the need for donated organs for transplantation.</p>
<p style=”text-align: left;”>Scientists have been working towards the production of functional liver cells for more than 20 years. After great effort, scientists determined how to mimic the various stages of embryonic liver development in the laboratory to produce stem cell-derived hepatocytes that are comparable to normal liver cells, in terms of food metabolism, energy storage, and elimination of toxins. Scientists are studying whether these stem cell-derived liver cells can safely be transplanted into a patient or used to create an artificial liver that would function outside of the body.&nbsp;&nbsp;</p>
<p style=”text-align: left;”>Recently, a group led by Mureo Kasahara at the National Center for Child Health and Development in Japan <a href=”https://medicalxpress.com/news/2020-05-japan-newborn-liver-stem-cells.html”>treated a six-day-old baby</a> with pluripotent stem cell-derived hepatocytes for the first time. This newborn suffered a rare genetic urea cycle disorder where the liver cannot eliminate ammonia, resulting in the accumulation of this toxic compound in the baby&rsquo;s blood. This disease normally requires a liver transplantation, but this complex surgery is too dangerous until about three to six months.</p>
<p style=”text-align: left;”>To &ldquo;bridge&rdquo; the patient until the time when the baby could safely receive a liver transplant, doctors decided to try a novel stem cell treatment. Doctors injected stem cell-derived hepatocytes into the baby&rsquo;s liver with the hope of providing temporary support until a transplant was feasible. Strikingly, after the stem cell treatment, the level of ammonia in the blood stabilized, allowing the baby to survive until five months of age. The baby then received a successful liver transplant from the father and is now healthy and home from the hospital. While further studies are required to test the safety and efficacy of this procedure, it is a promising finding that the transplanted stem cell-derived hepatocytes appeared to bridge the baby&rsquo;s liver function until transplantation was possible.</p>
<p style=”text-align: left;”>Researchers also are exploring ways that stem cell-derived liver cells might help patients through external devices. As an alternative to transplantation, stem cell-derived hepatocytes can be used to create a dialysis-like device that treats liver disease by clearing blood toxins. Such a machine, also known as a bioartificial liver, may ease the symptoms of liver failure and prolong the time until a liver transplant is needed.</p>
<p style=”text-align: left;”>&ldquo;We are currently using these stem cell-derived hepatocytes to devise a bioartificial liver system to treat liver failure patients,&rdquo; said Dr Xiaolei Shi, chief hepatobiliary surgeon at the Drum Tower Hospital of Nanjing University, China.</p>
<p style=”text-align: left;”>Shi and colleagues used stem cell-derived hepatocytes to make &ldquo;mini liver tissues,&rdquo; called hepatic spheroids. In pre-clinical studies, these spheroids were used to create a bioartificial liver that was able to rescue pigs from severe liver failure. This is a significant result because pigs are comparable in size and weight to humans and therefore offer insight into how these machines may function in human patients. This research is important pre-clinical support for going forward with clinical trials in humans, which will thoroughly test whether the bioartificial liver is safe and effective for treating liver disease.</p>
<p style=”text-align: left;”>While there has been significant progress, challenges remain. There are ongoing concerns whether stem cell therapy might form tumors following transplantation. External devices, however, physically separate stem cell derivatives from the patient, which could circumvent certain safety issues as the cells can easily be removed if issues arise.</p>
<p style=”text-align: left;”>Recent advances shed light on the ways that stem cell-derived liver cells might be used to help patients with various types of liver diseases. Ongoing research will continue to explore how pluripotent cell therapies can safely be used to help treat millions suffering worldwide. </p>
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<p style=”text-align: left;”>Blog by guest contributor S.C. Jacky Sun, PhD candidate in the labs of Ed Stanley and Andrew Elefanty at the Murdoch Children&rsquo;s Research Institute, Melbourne.</p>

Scientists Use Stem Cells to Uncover COVID-19 Effects on the Heart

Scientists and medical professionals worldwide are collaborating to discover how to address the coronavirus pandemic and to better understand its effects on the body. It is well known that COVID-19 can devastate the lungs, causing symptoms including cough, shortness of breath, pneumonia, and acute respiratory distress syndrome<a href=”https://isscresearch-my.sharepoint.com/personal/jperlin_isscr_org/Documents/A%20closer%20look/Blog%202020/September%20-%20COVID%20and%20stem%20cells/ACL%20Sept%202020%20Blog%20Arun%20Sharma%20final.docx#_ENREF_2″ title=”Madjid, 2020 #5″></a>. However, there is mounting evidence that the coronavirus may directly or indirectly infect other cell types as well. Of particular interest is how the coronavirus affects the heart. About 20-30% of patients hospitalized with COVID-19 have cardiac injury, such as arrythmia, inflammation of the heart, or heart attack, which is associated with higher risk of death. Those that recover from COVID-19 can exhibit cardiac dysfunction for months afterwards, even if they exhibited only mild COVID-19 symptoms. Researchers are using stem cell models to study coronavirus infection in the lab to determine how different cell types in the body are affected. </p>
<p>An important question to address is whether cells are indirectly or directly infected by the coronavirus. In the cardiovascular system, heart cells may be injured indirectly by a lack of oxygen supply to the heart due to COVID-19&rsquo;s impact on the lungs, or the virus may directly infect heart muscle and associated blood vessels. Direct damage to the heart muscle cells could lead to heart rhythm problems or heart failure, while direct damage to blood vessel cells could impair circulation. Insight into the infection process and the resulting impact can improve our understanding of the disease and lead to the development of safe and effective treatment options. </p>
<p>Initial clinical studies indicate that coronavirus infection can directly cause injury to the heart, resulting in a dangerous condition known as myocarditis, a condition where immune cells are hyperactivated in the heart muscle. Otherwise healthy individuals who are infected with coronavirus can exhibit this inflammation of the heart, which in severe cases can lead to cardiac arrest. Even high-level college athletes have been observed to develop myocarditis after coronavirus infection. <a href=”https://www.nytimes.com/2020/08/23/sports/ncaafootball/college-football-myocarditis-coronavirus.html?auth=login-email&amp;login=email”>Initial reports</a> indicate that about 15% of these athletes that recovered from COVID-19 showed signs of myocarditis, whether or not they ever showed COVID-19 symptoms. </p>
<p>To address whether coronavirus indirectly or directly infects different cells in the body scientists can use human <a href=”https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/#induced-pluripotent”>induced pluripotent stem cells</a> (hiPSCs), which are made from a small sample of skin or blood. These are powerful stem cells that can be transformed into various cell types and then infected with the coronavirus in order to study the infection process and the resulting effects on the body. Using this method, researchers have shown that both stem cell-derived heart muscle cells and blood vessels are directly susceptible to coronavirus infection. This is not true of cells in all tissues. &nbsp;Some types of brain tissue, for example, cannot be directly infected by the coronavirus. These laboratory studies parallel clinical reports that some tissues are more susceptible to coronavirus infection than others.</p>
<p>Scientists found that after stem cell-derived heart muscle cells were infected with coronavirus, some cells stopped beating and died within three days. Infection also led to an immune response and an attempt to alleviate the viral infection. Researchers can now use these infected heart cells to screen for drugs that can improve their function and survival. These cells could also be used to identify new antiviral drugs that could directly and specifically reduce coronavirus replication in the heart, potentially reducing cardiac injury and limiting the spread of the virus. Scientists are also using the cells to study COVID-induced myocarditis by adding immune cells to their experiments.</p>
<p>The extent and conditions in which the coronavirus impacts the heart and blood vessels is becoming more clear as scientists learn more about the virus using these human iPSC models. However, better clinical data is needed to understand the different ways that infection directly and indirectly affects the cardiovascular system in patients. Human iPSC models could help identify potential new treatments that could alleviate both of these types of cardiovascular complications, leading to better outcomes for COVID-19 patients<em>. </em>Stem cell models are a valuable ally to the global stem cell research community, which is working collaboratively on many fronts to fight coronavirus and COVID-19. </p>
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<p>Blog by guest contributor Arun Sharma, PhD, postdoctoral fellow in the lab of Clive Svendsen, PhD at Cedars Sinai, CA, USA.&nbsp;&nbsp;</p>

Basic Research: The Wind Beneath Innovation’s Wings

<p>Biomedical research &ndash; the science of investigating the mechanisms and causes of disease &ndash; has been the driving force for many of the greatest medical advances in history: from drugs like penicillin to fight bacterial infections to medications like insulin to control diabetes. Its importance feels even more pertinent nowadays amidst the COVID-19 pandemic. While the wait for treatments might feel long, vaccine development is moving forward at an exceptional pace. Such rapid progress can be achieved because scientists are armed with the knowledge from earlier discoveries that laid the groundwork for today&rsquo;s progress.</p>
<p>Research falls under two broad categories: applied and basic. Applied research solves practical questions, for instance, &ldquo;What is the cure for COVID-19?&rdquo;. Basic research answers curiosity-driven questions about fundamental principles, like &ldquo;How is sugar processed in the body?&rdquo;. The gravity of drug discovery makes tinkering with sugar sound childish, but it is only because of the latter that we now have <a href="https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html">Remdesivir</a>, the first drug to receive the United States Food and Drug Administration&rsquo;s emergency authorization for use on COVID-19. </p>
<p>Remdesivir was adapted from a nucleotide (the building block of DNA) through subtle changes in its structure. This drug is similar enough to a nucleotide to fake its way into a virus&rsquo;s own genetic code. Yet it is different enough such that once inside, it disables the virus from making more copies of itself. Thus, the answer to &ldquo;How is sugar processed in the body?&rdquo; enabled scientists to transform a simple sugar into a potential Trojan horse against COVID-19.</p>
<p>Solving basic scientific questions allows us to comprehend the elementary processes of the world around us, without which, the innovation of new tools, technologies, or cures would not be possible. Stem cell biology research is no exception; its contributions to regenerative medicine took flight riding the wind of basic research. For example, decades of basic research have recently led to a cure for the fatal skin disease known as <a href="https://www.closerlookatstemcells.org/2018/02/13/novel-stem-cell-therapy-grows-new-skin/">junctional epidermolysis bullosa</a> (JEB) through the development of stem cell therapy.</p>
<p>With JEB, a condition caused by a known genetic mutation, the skin&rsquo;s attachment to the body is severely weakened. Blisters and wounds appear from the slightest amount of friction: from wearing a shirt, laying on bed, or receiving what should be a warming hug. This disease is so devastating that patients rarely survive beyond childhood. They are dubbed &ldquo;butterfly children,&rdquo; with skin as fragile as butterfly wings. </p>
<p>In June 2015, this cruel genetic disease endangered a 7-year old boy named Hassan by leaving only 20% of his skin intact. Hassan was hospitalized at the brink of death, weighing a mere 17 kilograms (37 pounds) and suffering from multiple life-threatening bacterial infections. With no cure available, doctors turned to scientists, who came up with an idea: cultivate the boy&rsquo;s skin stem cells in the laboratory, repair the mutation that causes the disease, grow skin with the corrected gene, and transplant this healthy skin onto his body. </p>
<p>This experimental treatment was not conceived by chance; rather, it was a completed puzzle, pieced together from knowledge obtained by asking<strong><em> </em></strong>questions about how biological systems operate.</p>
<p><strong><em>Can stem cells survive outside the body?</em></strong><em> </em>After numerous failed attempts and rigorous optimization, scientists in 1975 succeeded in growing the <a href="https://www.sciencedirect.com/science/article/pii/S0092867475800018?via%3Dihub">first human stem cells</a> in a dish from skin tissue. Decades later, Hassan&rsquo;s skin stem cells were grown from a small skin biopsy using the same technology. &nbsp;</p>
<p><strong><em>What anchors the skin to our bodies?</em></strong><em> </em>To appreciate why our skin remains attached to our bodies, molecular biologists in the early 1990s examined the proteins that sit under the skin&rsquo;s bottommost layer. They identified a protein called laminin-332, which plays a critical role in adhesion. Scientists later determined that JEB patients have a <a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0625.1992.tb00080.x?sid=nlm%3Apubmed">mutation</a> in the laminin-332 gene, identifying the error in Hassan&rsquo;s stem cells that needed to be corrected.</p>
<p><strong><em>How can a virus cause cancer in chickens?</em></strong><em> </em>Basic research from a different field provided another critical step. Virologists from the 1960s hoped to understand cancer better by investigating what exactly a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC300279/">tumor-causing virus</a> does inside chicken cells. While they did not unlock the secrets of cancer (we&rsquo;re still trying to figure that out!), they instead observed that the virus can permanently write genetic information onto the chicken cells&rsquo; DNA. This unexpected discovery led geneticists to meticulously refashion those viruses to deliver nearly any gene without any inherent detrimental effects on humans. In Hassan&rsquo;s case, a virus modified to contain a functional version of<em> </em>laminin-332 gene was sufficient to repair his stem cells.</p>
<p>Thanks to the intellectual curiosity of past minds to answer these basic biological questions, Hassan&rsquo;s stem cells were isolated and corrected in just four months. His now-healthy stem cells were then expanded to become large sheets of skin that were grafted back to his body. By November 2015, almost all of Hassan&rsquo;s open lesions had been covered by the lab-grown skin, and today, he is living not as a butterfly child but as a normal 12-year-old boy, attending school and playing soccer.</p>
<p>This transgenic stem cell therapy is now a reality thanks to basic researchers and their sense of wonder about how the world and our bodies work. So be curious. No question is meaningless under the expanse of science&rsquo;s sky. Because later in the scientific voyage, many lives &ndash; including yours &ndash; might be saved simply because the right question was already answered. </p>
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<p>Blog by guest contributor Kevin Gonzales, PhD, postdoctoral fellow in the lab of Elaine Fuchs at The Rockefeller University, NY, USA.</p>

Stem Cells as Tools to Identify COVID-19 Treatments

<img src="https://www.closerlookatstemcells.org/wp-content/uploads/2020/06/nih-covid-image-full-size.tmb-medium.jpg" data-displaymode="Thumbnail" alt="NIH Covid image full size" title="NIH Covid image full size" style="float: left; margin-bottom: 10px; margin-left: 10px; margin-right: 10px;" />
<p>COVID-19 has had profound and far-reaching impacts, affecting the health and safety of millions of people worldwide. Scientists from different disciplines are coming together and pooling their unique skill sets and resources to better understand coronavirus infection and COVID-19 treatment. Stem cells previously have helped scientists better understand other viruses and infectious diseases, such as HIV, Zika, Hepatitis C, and Dengue fever. Today, many stem cell researchers are refocusing their attention towards combatting this global pandemic. </p>
<p>In a recent <a href="https://www.isscr.org/scientific-clinical-resources/isscr-covid-19-survey-results">survey of the stem cell community</a>, the International Society for Stem Cell Research (ISSCR) found that nearly a quarter of respondents have pivoted to work on COVID-19-related research. There is significant energy around coming together as a community to act quickly to try to identify COVID-19 treatments, joining laboratories across expertise and international borders. Some major questions in coronavirus infection revolve around which cell types can be infected, why infection responses vary greatly, and which drugs are effective and safe. Stem cells can help us address these questions, understand infection, and identify new treatments. </p>
<p><a href="https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/#induced-pluripotent">Pluripotent stem cells</a>, or cells that can become any cell in the body, can be directed to become different types of cells in a laboratory, such as lung, heart, kidney, or intestinal cells. Scientists can use these cells to understand how different organs are infected by coronavirus and find drugs that might prevent or treat the infection. Stem cell models also can be derived from patients with various diseases, such as cardiovascular disease or cystic fibrosis, to understand variation in coronavirus infection and test the safety and response of different treatments in people with preexisting conditions. </p>
<p>Scientists are using stem cells to address coronavirus infection and COVID-19 treatment in a variety of ways. Charles Murry, MD, PhD at the University of Washington, USA, is working with virologists to dissect how cardiac disease compounds COVID-19 effects. He is using stem cells to make cardiomyocytes, the muscle cells found in the heart. He found that cardiomyocytes can be infected and killed by coronavirus, similar to lung cells, which are an established target of the virus. &ldquo;<em>This tells us that the heart disease we&rsquo;re seeing in COVID-19 patients could include a component of direct cardiac infection. We are exploring other cell types in the heart and elsewhere to see how widespread susceptibility to this infection is. It would not have been possible to do these studies without stem cells</em>.&rdquo; Murry&rsquo;s next step is to try to identify therapies by treating these infected stem cells with panels of drugs.</p>
<p>Also looking at the effect of coronavirus infection on heart cells are Christine Mummery, PhD and Richard Davis, PhD of Leiden University Medical Centre, the Netherlands. They are using stem cell-derived cardiomyocytes to evaluate the cardiac risk of drugs that are being used in tests to treat COVID-19. &ldquo;<em>Using our stem cell-derived cardiomyocytes we can see if cells derived from patients with underlying cardiac conditions respond differently to those derived from healthy individuals. We could then forewarn clinicians if this group of individuals is more &ldquo;at risk&rdquo; for drug side effects and might require additional monitoring.&rdquo;</em></p>
<p>Lygia da Veiga Pereira, PhD, University of S&atilde;o Paulo, Brazil says &ldquo;<em>Stem cell-derived models will certainly speed up the process of drug development for COVID-19.&nbsp;Testing drugs in relevant stem cell-derived cells (lung, cardio, upper respiratory track) will allow for rapid confirmation (or rejection) of the drug, which in turn will expedite clinical trials</em>.&rdquo; In addition to efforts to identify new treatments, she is sequencing the genomes of COVID-19 patients to see if there are underlying genetic causes to the observed variation in disease response between different people. &ldquo;<em>Why do some people have full-blown disease (and die) while others are asymptomatic? There are several factors that will influence that – the state of health, age, obesity, etc., but it is reasonable to suggest that genetic variants may increase one&acute;s resistance to the disease</em>.&rdquo; This could be revealed in her sequencing studies, which may help influence future treatments.</p>
<p>In a complimentary approach, Nadia Rosenthal from The Jackson Laboratory, USA is developing a large collection of stem cell models to examine the genetic component of coronavirus infection response. Researchers can use these embryonic stem cells derived from genetically diverse mice and convert them into relevant cell types. These cells can then be infected with coronavirus to assess the role of different genetic backgrounds on viral infection in different tissues. &ldquo;<em>This approach will allow us to fast-track discoveries of genetic susceptibility, leading to new diagnostic, prognostic, and therapeutic advances in the treatment of this multi-factorial disease</em>,&rdquo; says Rosenthal. </p>
<p>This worldwide health pandemic has mobilized a global response from the stem cell and larger biomedical research communities. Melissa Little, PhD, at Murdoch Children&rsquo;s Research Institute, Australia said &ldquo;<em>This crisis will test our scientists as it will everyone, but medical research needs to be the solution</em>.&rdquo; Stem cell research has an important role to contribute to better understanding the disease and finding a treatment. But the scientific process takes time and resources, and it is important to note that there are currently <a href="https://www.isscr.org/news-publicationsss/isscr-news-articles/article-listing/2020/03/06/isscr-statement-regarding-the-marketing-of-unproven-stem-cell-treatments-for-covid-19">no approved stem cell treatments</a> for COVID-19. Continued support for scientific research is critical as the whole world races to find a cure. The ISSCR is committed to providing the public with current and credible scientific information and progress as it arises.</p>
(<em>Image:&nbsp;</em><em>T</em><em>his scanning electron microscope image shows coronavirus (round gold objects) emerging from the surface of cells cultured in the lab,</em><em>&nbsp;credit&nbsp;NIAID-RML</em>).

Truths Around ‘Stem Cell’ Treatments

This blog space is dedicated to putting &ldquo;stem cells in focus&rdquo; for the public and potential consumers of stem cell therapies. Monthly blog posts feature authoritative, and scientifically-based information to help educate on stem cell research and its potential to impact human health. This month we want to highlight the recent commentary in Scientific American, &ldquo;<a href="https://blogs.scientificamerican.com/observations/dont-believe-everything-you-hear-about-stem-cells/">Don&rsquo;t Believe Everything You Hear about Stem Cells</a>,&rdquo; by ISSCR President, Deepak Srivastava. In this article, Srivastava outlines the public health crisis of &nbsp;unproven stem cell-based &ldquo;treatments&rdquo; and what can be done to protect patients.&nbsp;

Communicating About Unproven Stem Cell Treatments to the Public

<p>In recent years, there has been a proliferation of unregulated stem cell clinics providing unproven treatments for patients with a variety of diseases, injuries, and congenital defects. With more than 700 stem cell clinics in operation within the United States alone, and many more worldwide, patients have increasing access to risky, untested options for serious illnesses. As scientists, it is important to effectively communicate the risks of these untested treatments to the public.</p>
<p>I recently attended a lecture at Harvard Medical School on &ldquo;Human Trials: When the Science of Clinical Translation Collides with Stem Cell Tourism.&rdquo; Professors George Daley (Harvard Medical School, USA) and Insoo Hyun, (Case Western Reserve University School of Medicine and Harvard Medical School, USA) spoke to physicians, scientists, and the general public about clinical trials using stem cells, from both clinical and philosophical perspectives. The lecturers attempted to dissect the <em>when&rsquo;s, where&rsquo;s, how&rsquo;s, who&rsquo;s,</em> and <em>why&rsquo;s</em> of experimental medical practice, and the difficulties physician-scientists currently face in a time when stem cell therapies are both promising and uncertain. </p>
<p>It is important that patients understand that there are very few conditions for which stem cell-based therapies have been proven effective and are routinely implemented in medical practice. These are primarily limited to bone marrow stem cell transplantations to treat diseases of the blood and immune system. </p>
<p>Researchers are in the process of testing new stem cell therapies, but any new prospective treatments require clinical trials and a rigorous peer review process before they are accepted as safe and effective. </p>
<p>Emerging cell therapies complicate the traditional system for testing new treatments, however, because &ldquo;Cells are a different type of medicine,&rdquo; explained Dr. Daley. As a result, stem cells currently exist within a grey area of legality for medical regulatory councils within many countries. </p>
<p>This has allowed for-profit stem cell clinics to flourish around the world. These clinics, largely unregulated and unconstrained by ethical guidelines, are thriving, despite the fact that their practices have not been proven to be safe or effective, and in some cases, have caused harm. Individuals who receive unproven stem cell treatments at for-profit clinics are taking on enormous medical and financial risks. </p>
<p>Dr. Hyun explained that these risks do not appear to be strong deterrents as &ldquo;Families under spiritual distress will often seek out dangerous and unproven therapies.&rdquo; </p>
<p>I saw firsthand how the general public seemed unconvinced of the risks and limitations of stem cells, which have been sold to them as miracle cures. Questions raised during the discussion portion by patients and their family members demonstrated that many still considered stem cells to be an infallible, one-size-cures-all medical innovation. From autism to tropical infections, the public appeared to believe that stem cells have unlimited curative properties, despite the risks and complications reported by Drs. Daley and Hyun. Warnings seemed to go largely unheeded. Instead, many hands rose looking for personal referrals. </p>
<p>The communication gap between physicians, scientists, and the general public regarding stem cells and their plausible applications was illustrated to me in that auditorium. I hope future platforms, like this one, are used as an opportunity to share factual evidence with the general public, from the fundamentals of cell biology, to the steps patients and families need to take to avoid becoming victims of a predatory scam. </p>
<p>We do not yet know the full therapeutic spectrum of stem cells, nor their caveats, but it is our responsibility as members of the scientific community to uphold integrity and transparency, and not allow misinformation and anecdotal evidence to out-voice us. </p>
<p>&nbsp;</p>
<p><em>Patients are encouraged to read the </em><a href="https://www.closerlookatstemcells.org/stem-cells-medicine/nine-things-to-know-about-stem-cell-treatments/"><em>Nine Things to Know about Stem Cell Treatments</em></a><em> to learn about the potential and limitations of stem cells, and to detect commonly circulated misinformation</em><em>. </em></p>
<p><a href="https://www.isscr.org/membership/policy/2016-guidelines"><em>International guidelines</em></a><em> were spearheaded by Drs. Daley and Hyun to ensure that stem cell research and clinical trials proceed with scientific and ethical integrity. </em></p>
<p>___________________________________________________________</p>
<p>Blog by guest contributor Ashlee Conway, PhD, Postdoctoral fellow in the lab of George Daley at Harvard Medical School&rsquo;s Stem Cell Institute &amp; Department of Hematology/Oncology, Boston Children&rsquo;s Hospital, USA</p>

How Understanding Stem Cell Biology Can Improve Cancer Therapy

<p>Radiation therapy and chemotherapy have traditionally been considered the main forms of cancer treatment. While these treatments can be highly effective, they have significant negative side effects due to their unintended collateral toxicity on normal cells in the body. New treatments are needed to more safely treat cancers, which affect millions of people worldwide every year.</p>
<p>In recent years, the world of cancer therapy has rapidly expanded beyond these broad systemic approaches to include immunotherapy (using the body&rsquo;s own immune system to kill cancer cells), targeted therapy (using drugs that target specific genetic mutations), and other forms of precision medicine. However, each of these therapeutic advances comes with their own issues of toxicity and, in some cases, they can stop working if people develop resistance to them. To continue to develop new and innovative therapies for cancers, research into tumor biology is needed. One area of research that holds the potential to provide insight into tumorigenesis is stem cell biology.</p>
<p>The relationship between stem cells, development, and cancer has fascinated scientists for over one hundred years. Stem cells generate or regenerate tissues and organs by multiplying and differentiating into more specialized cell types through highly regulated cell division. This cell division is tightly controlled by specific genes both as people develop in the womb and throughout their lives. However, if the genes regulating cell division become mutated, cells can divide out of control, leading to cancer. Understanding the processes of normal cellular development can help identify effective new targets for cancer therapy.</p>
<p>One major unanswered question in the cancer biology field is regarding how a cancer starts, or what is the cell of origin? Scientists wondered, given that stem cells are mainly responsible for dividing and replenishing many adult tissues, can cancer arise from stem cells?</p>
<p>Supporting this hypothesis, scientists have found that skin and intestinal stem cells are more susceptible to becoming tumors than other cells in those organs. Damage to the network of cells that interact with the stem cells in their &ldquo;niche&rdquo; can also lead to tumor formation. More research is needed to figure out how these changes lead to cancer so that treatments can be developed to specifically stop these cells from dividing out of control.</p>
<p>Understanding stem cell biology can inform cancer treatment even if stem cells aren&rsquo;t the cell of origin. Non-stem cells can hijack the mechanisms used by stem cells to rapidly divide, forming a tumor. These tumor cells use genes that are normally involved in development and stem cell division to initiate aberrant growth.</p>
<p>This phenomenon of cancer cells inappropriately turning on developmental genes to initiate a tumor has been observed in almost every type of cancer and has been modeled in several organisms. Recently, researchers in Leonard Zon&rsquo;s laboratory at Boston Children&rsquo;s Hospital were able to observe this in a living organism, in this case, the well studied zebrafish. For the first time, researchers could watch a <a href="https://vector.childrenshospital.org/2016/01/the-cell-that-caused-melanoma-cancers-surprise-origins-caught-in-action/">single cell become a tumor in a live animal</a>. Scientists discovered that the <a href="https://vector.childrenshospital.org/2016/01/the-cell-that-caused-melanoma-cancers-surprise-origins-caught-in-action/">first event they could observe on the path to melanoma formation</a>, a type of skin cancer, was the re-activation of genes that are otherwise specific to early embryo development. This unique look into the earliest stages of cancer formation allows researchers to screen for new drugs that prevent cancer from forming.</p>
<p>Although the link between stem cells and cancer is strong, more research is needed to determine the cell of origin of different cancer types. If the cell of origin of cancer can be better understood, more specific diagnostic tools and therapies can be developed. Additionally, understanding the genes that control cell division in development and stem cells will hopefully provide new targets to diagnose, treat, and prevent cancer in the future.</p>
<p>___________________________________________________________</p>
<p>Blog by guest contributor Alicia McConnell, PhD, postdoctoral fellow in the lab of Leonard Zon at Boston Children&rsquo;s Hospital, MA, USA.</p>

Injured or Misled by Unscrupulous Stem Cell Clinics? Here’s What You Can Do About It

<p><strong>The Promise</strong></p>
<p>It is all too common today to come across ads declaring that stem cells can cure your [insert disease/condition here]. In fact, these marketing claims made by so-called &ldquo;stem cell" clinics are everywhere: in newspapers, on billboards on your way to and from work, on the television and radio, and littered all over the internet. &ldquo;Suffering and in pain? Have you heard of stem cells? Come by our clinic today&mdash; bring money.&rdquo;</p>
<p><strong>The Reality</strong></p>
<p>In reality, there are currently very few stem cell treatments that are both proven safe and effective and/or approved by regulatory authorities, most of which involve the transplantation blood stem cells (such as bone marrow transplants) to treat certain blood and immune system disorders and some blood cancers. However, this fact has not stopped nefarious stem cell clinics from preying upon suffering and desperate patients by falsely marketing their own stem cell &ldquo;treatment&rdquo; as a silver bullet for any and all diseases, despite the absence of any scientific rationale supporting their approach and evidence of their safety or effectiveness. The growth of unethical stem cell clinics is a <a href="https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30210-7">worldwide phenomenon</a>, including a concentration of <a href="https://www.researchgate.net/publication/325395626_The_US_Direct-to-Consumer_Marketplace_for_Autologous_Stem_Cell_Interventions">716 clinics</a> in the US alone. Importantly, the unproven &ldquo;therapies&rdquo; provided by bad-acting clinics can have exorbitant costs to both your finances and health.</p>
<p><strong>What do you have to lose?</strong></p>
<p>After having undergone unproven stem cell interventions, which can cost thousands of dollars, many patients discover they have not gained any medical benefit to accompany their bill. &nbsp;Even worse, these &ldquo;treatments&rdquo; can have very real negative health repercussions. Numerous adverse events from unproven interventions have been reported in the press, ranging from <a href="https://www.cdc.gov/hai/outbreaks/stem-cell-products.html">mild to severe infections</a>, to <a href="https://www.statnews.com/2017/03/15/stem-cell-patients-blind-macular-degeneration/">blindness</a>, and even tumors (<a href="https://www.statnews.com/2019/07/11/canada-case-long-term-risks-experimental-stem-cell-therapy/">including one on a patient&rsquo;s spine</a>). </p>
<p><strong>What you can do</strong></p>
<p>Importantly, regulatory agencies in countries around the world, including <a href="http://www.isscr.org/professional-resources/news-publicationsss/isscr-news-articles/article-detail/2019/05/21/isscr-applauds-health-canada-s-new-policy-statement-re-autologous-cell-therapy-products">Heath Canada</a><a href="http://www.isscr.org/professional-resources/news-publicationsss/isscr-news-articles/article-detail/2018/04/26/isscr-applauds-australia-s-move-to-regulate-autologous-human-cell-and-tissue-products">, Australia&rsquo;s Therapeutic Goods Administration </a>, and the <a href="http://www.isscr.org/professional-resources/news-publicationsss/isscr-news-articles/article-detail/2019/06/07/isscr-applauds-landmark-court-ruling-in-favor-of-fda-regulating-stem-cell-therapies-offered-by-florida-clinic">US Food and Drug Administration</a>, have strengthened their regulations or <a href="https://www.raps.org/news-and-articles/news-articles/2019/4/fda-to-step-up-stem-cell-enforcement-look-into-pa">stepped up their enforcement</a> of clinics selling unapproved therapies. There are also actions you can take to support these efforts. Whether you have experienced medical harm from these interventions or are simply outraged by the injustice of false marketing claims of stem cell clinics, there are proactive steps <em>you</em> can take to help fight bad acting clinics.</p>
<p><em>Reporting false marketing claims and adverse events to regulatory agencies</em></p>
<p>The ISSCR has recently published an online guide on <a href="https://www.closerlookatstemcells.org/patient-resources/how-to-report-false-marketing-claims-and-adverse-events-from-clinics-offering-unapproved-stem-cell-therapies/">How to Report False Marketing Claims and Adverse Events from Clinics Offering Unapproved Stem Cell &ldquo;Therapies&rdquo;</a> for several countries around the world. This resource includes contact information and direct links for submitting reports to medical regulatory boards, marketing and commercial trade regulators/oversight committees, and governmental health regulators. The list of countries with actionable links will continue to grow. If you have additional actionable links for countries not currently listed on that webpage, you can contact the ISSCR (<a href="mailto:cbarry@isscr.org">cbarry@isscr.org</a>). </p>
<p><em>Make sure you are part of an informed consent process before undergoing treatment</em></p>
<p>Recently, the ISSCR released a <a href="http://www.isscr.org/professional-resources/news-publicationsss/isscr-news-articles/article-detail/2019/08/12/the-isscr-releases-informed-consent-standard-for-stem-cell-based-interventions">Professional Standard for Informed Consent for Stem Cell-Based Interventions</a> meant to help ensure patients know what information should be disclosed to them prior to undergoing unproven stem cell &ldquo;therapies.&rdquo; Specifically, clinicians are required to adequately inform patients about the potential risks and benefits of the procedure before proper informed consent can be given. The new ISSCR standards can be used as a resource to gauge what constitutes proper informed consent and what information should be ethically provided preceding any stem cell-based intervention. </p>
<p><em>Educate yourself and others about red flags of stem cell &ldquo;treatment&rdquo; claims</em></p>
<p>The ISSCR has developed several important resources to help inform the public about the current clinical outlook of stem cell therapies and help spot unproven or unapproved therapies. These resources, located on the <a href="https://www.closerlookatstemcells.org/">A Closer Look at Stem Cells</a> webpage, include <a href="https://www.closerlookatstemcells.org/stem-cells-medicine/stem-cell-treatments-what-to-ask/">What to Ask</a>, <a href="https://www.closerlookatstemcells.org/stem-cells-medicine/nine-things-to-know-about-stem-cell-treatments/">Nine Things to Know About Stem Cell Treatments</a>, the <a href="https://www.closerlookatstemcells.org/patient-resources/">Patient Handbook</a>, and overviews of the current state of stem cell research relevant to <a href="https://www.closerlookatstemcells.org/stem-cells-medicine/">several diseases</a>.</p>
<p>Clinics selling unproven and unapproved stem cell &ldquo;therapies&rdquo; are an international problem and regulatory agencies have had difficulty keeping up, but the momentum is slowly shifting. There is a wave of increasing vigilance against these clinics and enforcing the laws that protect patients from them. And you can help.</p>