Snake venom can be deadly without proper treatment. Interestingly enough, it may also hold the key for treatments against pain, high blood pressure, and cancer according to one analysis. Despite this, scientists still do not understand much about the biology behind the wide range of different snake venoms, which can make it challenging to develop effective treatments in the event of snake bites.
Fortunately, a new study by Dr. Hans Clevers and his team at the Hubrecht Institute in the Netherlands could significantly aid the understanding of snake venom. Dr. Clevers and his team were able to grow miniature snake venom glands using snake stem cells. What’s more remarkable is that these “mini-organs” produced real venom!
In an article posted in Science Magazine, Dr. Clevers talks about how his study was navigating uncharted waters.
“Nobody knew anything about stem cells in snakes. We didn’t know if it was possible at all.”
To produce these “mini-organs”, the researchers removed the stem cells from the venom glands of nine different types of snake and placed them in a mixture of growth factors that contained different hormones and proteins. It turns out that the snake stem cells responded to the same factors used on human and mouse stem cells.
Eventually, the stem cells grew into little clumps of tissue and when the researchers removed the growth factors, they started to change into the same kind of cells that produce venom in the glands of snakes. Additionally, they were able to find that these “mini-organs” expressed similar genes as those observed in real venom glands.
The scientists were even able to test the nature of the “mini-organ” venom as well. A chemical and genetic analysis of the venom revealed that it matched the one made by real snakes. After testing this venom on mouse muscle cells and rat neurons, they also found that it damaged these cells similar to real venom.
The type of toxins and concentration levels can vary drastically in snake venom, even within the same species. This can make developing treatments challenging since they can only be used to combat one type of venom.
Dr. Clevers and his team now plan to study the complexities of venom and venom glands by compiling a “biobank” of frozen organoids from venomous reptiles around the world that could help researchers find broader treatments. With the aid of their newly developed “mini-organs”, all of this can be done without the handling of live, dangerous snakes, some of which are rare and difficult to keep in captivity.
Anytime you read a news headline that claims a new discovery “may treat all cancer” it’s time to put your skeptic’s hat on. After all, there have been so many over-hyped “discoveries” over the years that later flopped, that it would be natural to question the headline writer. And yet, this time, maybe, this one has some substance behind it.
Researchers at the University of Cardiff in Wales have discovered a new kind of immune cell, a so-called “killer T-cell”, that appears to be able to target and kill many human cancer cells, such as those found in breast, prostate and lung cancer. At least in the lab.
The immune system is our body’s defense against all sorts of threats, from colds and flu to cancer. But many cancers are able to trick the immune system and evade detection as they spread throughout the body. The researchers found one T-cell receptor (TCR) that appears to be able to identify cancer cells and target them, but leave healthy tissues alone.
In an interview with the BBC, Prof. Andrew Sewell, the lead researcher on the study said: “There’s a chance here to treat every patient. Previously nobody believed this could be possible. It raises the prospect of a ‘one-size-fits-all’ cancer treatment, a single type of T-cell that could be capable of destroying many different types of cancers across the population.”
The study, published in the journal Nature Immunology, suggests the TCR works by using a molecule called MR1 to identify cancerous cells. MR1 is found on every cell in our body but in cancerous cells it appears to give off a different signal, which enables the TCR to identify it as a threat.
When the researchers injected this TCR into mice that had cancer it was able to clear away many of the cells. The researchers admit there is still a long way to go before they know if this approach will work in people, but Sewell says they are encouraged by their early results.
“There are plenty of hurdles to overcome. However, if this testing is successful, then I would hope this new treatment could be in use in patients in a few years’ time.”
CIRM is funding a number of clinical trials that use a similar approach to targeting cancers, taking the patient’s own immune T-cells and, in the lab, “re-educating” to be able to recognize the cancerous cells. Those cells are then returned to the patient where it’s hoped they’ll identify and destroy the cancer. You can read about those here , here, here, here, and here.
Zika virus is caused by a virus transmitted by Aedes mosquitoes. People usually develop mild symptoms that include fever, rash, and muscle and joint pain. However, Zika virus infection during pregnancy can lead to much more serious problems. The virus causes infants to be born with microcephaly, a condition in which the brain does not develop properly, resulting in an abnormally small head. In 2015-2016, the rapid spread of the virus was observed in Latin America and the Caribbean, increasing the urgency of understanding how the virus affected brain development.
Working independently, Dr. Tariq Rana and Dr. Jeremy Rich from UC San Diego identified the same molecule, αvβ5 integrin, as the Zika virus’ key to entering brain stem cells. The two studies, with the aid of CIRM funding, discovered how to take advantage of the molecule in order to block the Zika virus from infecting cells. In addition to this, they were able to turn it into something useful: a way to destroy brain cancer stem cells.
In the first study, Dr. Rana and his team used CRISPR gene editing on brain cancer stem cells to delete individual genes, which was done to see which genes are required for the Zika virus to enter the cells. They discovered that the gene responsible for αvβ5 integrin also enabled the Zika virus.
In a press release by UC San Diego, Dr. Rana elaborates on the importance of his findings.
“…we found Zika uses αvβ5, which is unique. When we further examined αvβ5 expression in brain, it made perfect sense because αvβ5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that αvβ5 is the key contributor to Zika’s ability to infect brain cells.”
In the second study, Dr. Rich and his team use an antibody to block αvβ5 integrin and found that it prevented the virus from infecting brain cancer stem cells and normal brain stem cells. The team then went on to block αvβ5 integrin in a mouse model for glioblastoma, an aggressive type of brain tumor, by using an antibody or deactivating the gene responsible for the molecule. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice.
Dr. Rich then partnered with Dr. Alysson Muotri at UC San Diego to transplant glioblastoma tumors into laboratory “mini-brains” that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the mini-brains. Additionally, blocking αvβ5 integrin reversed that anti-cancer activity, further demonstrating the molecule’s crucial role in Zika virus’ ability to destroy cells.
In the same UC San Diego press release, Dr. Rich talks about how understanding Zika virus could help in treating glioblastoma.
“While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma.”
Dr. Rana’s full study was published in Cell Reports and Dr. Rich’s full study was published in Cell Stem Cell.
The thought of microscopic robots brings the image of Hollywood blockbusters such as “Terminator” and other science-fiction movies to mind that are set years into the distant future. But a group of scientists have gotten one step closer to bringing these elements only seen on the big screen to reality.
Researchers at the University of Vermont and Tufts University were able to create what they call “xenobots” – the world’s first living, self healing robots created from frog stem cells. Named after the African clawed frog, Xenopus laevis, they are tiny blobs of moving cells made from stem cells obtained from frog embryos. They are less than a millimeter wide, making them small enough to travel inside the human body. Additionally, they have the ability to walk and swim, survive for weeks without food, and work together in groups.
Here is a brief video showing what these cells look like under the microscope:
The researchers were able take the stem cells from the embryo and increased their numbers by incubating them. After this, the cells were cut and rejoined using tiny forceps under a microscope into specific forms designed by artificial intelligence. These newly created forms are ones not found in nature and what is more remarkable is that they started working together. The skin cells bonded to form a structure while the heart cells worked together to create motion. These cells also displayed the ability to heal themselves after being cut.
In a news release from the University of Vermont, Dr. Josh Bongard, who co-led this research, described the xenobots in more detail.
“These are novel living machines. They’re neither a traditional robot nor a known species of animal. It’s a new class of artifact: a living, programmable organism.”
In the same news release, Dr. Michael Levin, who also co-led this research, talks about the possibilities these xenobots have for real world applications for a wide range of issues.
“We can imagine many useful applications of these living robots that other machines can’t do, like searching out nasty compounds or radioactive contamination, gathering microplastic in the oceans, traveling in arteries to scrape out plaque.”
The full results to this study was published in the Proceedings of the National Academy of Sciences (PNAS).
You can learn more about this work in the video below:
The briefing is a traditional kick-off event to mark JP Morgan week in the City, a time when hotel rooms go for $1,000 a night and just reserving a table in the lobby for meetings can set you back hundreds of dollars. Fortunately, the ARM briefing is free. And worth every penny.
987 companies world wide – most of those in the US
1,000 + clinical trials
$9.8 billion in revenue/investments
Saying “for many of these patients these therapies don’t just bring improvements, they bring dramatic improvements” Lambert pointed out that when those 1,000 clinical trials are fully enrolled it will mean 60,000 patients getting stem cell and gene therapies. She says it’s estimated that in the coming years around half a million patients in the US alone will get one of those therapies.
More and more of the clinical trials are at advanced stages:
100 Phase 3
591 Phase 2
381 Phase 1
The biggest sector for clinical trials is cancer, but there are also substantial numbers for central nervous system therapies, muscular skeletal and even rare diseases.
Lambert said there are two key issues facing the field in the coming year. One is improving the industry’s manufacturing capability to ensure we are able to produce the cells needed to treat large numbers of patients. As evidence she cited the fact that Pfizer and Novartis are investing hundreds of millions of dollars in in-house manufacturing facilities.
The second key issue is reimbursement, so that companies can get paid for delivering those treatments to patients. “There is appetite and interest in this from people around the world, but right now most conversations about reimbursement are taking place one at a time. We haven’t yet evolved to the point where we have standard models to help get products to market and help them be commercially successful.”
The forecast for the year ahead? “Sunny with some clouds. 2019 was a year of significant growth and we enter 2020 with hopes of continued expansion, as we look to grow the impact on patients.”
Our immune system is the first line of defense our bodies use to fight off infections and disease. One crucial component of this defense mechanism are lymphocytes, which are specialized cells that give rise to various kinds of immune cells, such as a T cell, designed to attack and destroy harmful foreign bodies. Problems in how certain immune cells are formed can lead to diseases such as leukemia and other immune system related disorders.
But how exactly do immune cells form early on in the body?
Dr. Andrew Elfanty and Dr. Ed Stanley at Murdoch Children’s Research Institute in Australia have reproduced and visualized a method in the laboratory used to create human immune cells from pluripotent stem cells, a kind of stem cell that can make virtually any kind of cell in the body. Not only can this unlock a better understanding of leukemia and other immune related diseases, it could potentially lead to a patient’s own skin cells being used to produce new cells for cancer immunotherapy or to test autoimmune disease therapies.
Dr. Elefanty and Dr. Stanley used genetic engineering and a unique way of growing stem cells to make this discovery.
As observed in this video, the team was able to engineer pluripotent stem cells to glow green when they expressed a specific protein found in early immune cells. These cells can be seen migrating along blood vessels outlined in red. These cells go on to populate the thymus, which as we discussed in an earlier blog, is an organ that is crucial in developing functional T cells.
In a press release from Murdoch Children’s Research Institute, Dr. Stanley talks about the important role these early immune cells might play.
“We think these early cells might be important for the correct maturation of the thymus, the organ that acts as a nursery for T-cells”
In addition to this, the team also isolated the green, glowing pluripotent stem cells and showed that they could be used for multiple immune cell types, including those necessary for shaping the development of the immune system as a whole.
In the same press release, Dr. Elefanty discusses the future direction that their research could lead to.
“Although a clinical application is likely still years away, we can use this new knowledge to test ideas about how diseases like childhood leukemia and type 1 diabetes develop. Understanding more about the steps these cells go through, and how we can more efficiently nudge them down a desired pathway, is going to be crucial to that process.”
The full results to this study were published in Nature Cell Biology.
By Kelly Shepard, PhD., CIRM’s Associate Director, Discovery & Translation
CIRM has previously blogged about advances in treating certain forms of “bubble baby” disease”, where a person is born with a defect in their blood forming stem cells that results in a deficient immune system, rendering them vulnerable to lethal infections by all manner of bacteria, virus or germ.
If a suitable donor can be found, or if the patient’s own defective cells can be corrected through gene therapy approaches, it is now possible to treat or cure such disorders through a bone marrow transplant. In this procedure, healthy blood stem cells are infused into the patient, taking up residence in his or her bone marrow and dividing to give rise to functioning immune cells such as T cells and B cells.
Unfortunately, there is another type of “bubble baby” disease that cannot be treated by providing healthy blood stem cells, because the defective immune system is caused by a different culprit altogether- a missing or dysfunctional thymus.
T Cells Go to School
What is a thymus? Most of us give little thought to this leaf-shaped organ, which is large and important in our early childhoods, but becomes small and inconspicuous as we age. This transformation belies the critical role a thymus plays in the development of our adaptive immune systems, which takes place in our youth: to prepare our bodies to fight infections for the rest of our lives.
One might think of the thymus as a “school”, where immature T cells go to “learn” how to recognize and attack foreign antigens (surface markers), such as those found on microorganisms or tissues from other individuals. The thymus also “teaches” our immune system to distinguish “self” from “other” by eliminating any T cells that attack our own tissues. Without this critical function, our immune system could inadvertently turn against us, causing serious autoimmune disorders such as ulcerative colitis and myasthenia gravis.
Many children with a severely deficient or absent thymus, referred to as athymia, have inherited a chromosome that is missing a key stretch of genes on a region called 22q11. Doctors believe perhaps 1/2000-1/4000 babies are born with some type of deletion in this region, which leads to a variable spectrum of disorders called 22q11 syndrome that can affect just about any part of the body, and can even cause learning disabilities and mental illness.
Individuals with one form of 22q11, called DiGeorge Syndrome, are particularly affected in the heart, thymus, and parathyroid glands. In the United States, about 20 infants are born per year with the “complete” and most severe form of DiGeorge Syndrome, who lack a thymus altogether, and have severely depressed numbers of T cells for fighting infections. Without medical intervention, this condition is usually fatal by 24 months of age.
Optimism and Setback
Although there are no therapies approved by the Food and Drug Administration (FDA) for pediatric athymia, Dr. Mary Louise Markert at Duke University and Enzyvant, Inc. have been pioneering an experimental approach to treat children with complete DiGeorge syndrome.
In this procedure, discarded thymic tissues are collected from infants undergoing cardiac surgery, where some of the thymus needs to be removed in order for the surgeon to gain access to the heart. These tissues are processed to remove potentially harmful donor T cells and then transplanted into the thigh of an athymic DiGeorge patient.
Results from early clinical trials seemed promising, with more than 70% of patients surviving, including several who are now ten years post-transplant. Based on those results, in June of 2019 Enzyvant applied to the FDA for a Biologics License Application (BLA), which is needed to be able to sell the therapy in the US. Unfortunately, only a few months later, Enzyvant announced that the FDA had declined to approve the BLA due to manufacturing concerns.
While it may be possible to address these issues in time, the need to step back to the drawing board was a devastating blow to the DiGeorge Community, who have waited decades for a promising treatment to emerge on the horizon.
Despite the setback, there is reason to hope. In early 2019, CIRM granted a “Quest” Award to team of investigators at Stanford University to develop a novel stem cell based approach for treating thymic deficiency. Co-led by Katja Weinacht, a pediatric hematologist/oncologist, and Vittorio Sebastiano, a stem cell expert and developmental biologist, the team’s strategy is to coax induced pluripotent stem cells (iPS) in the laboratory to differentiate into thymic tissue, which could then be transplanted into patients using the route pioneered by Duke and Enzyvant.
The beauty of this new approach is that pluripotent stem cells are essentially immortal in culture, providing an inexhaustible supply of fresh thymic cells for transplant, thereby allowing greater control over the quality and consistency of donor tissues. A second major advantage is the possibility of using pluripotent cells from the patient him/herself as the source, which should be perfectly immune-matched and alleviate the risk of rejection and autoimmunity that comes with use of donated tissues.
Sounds easy, so what are the challenges? As with many regenerative medicine approaches, the key is getting a pluripotent stem cell to differentiate into the right type of cells in the lab, which is a very different environment than what cells experience naturally when they develop in the context of an embryo and womb, where many cells are interacting and providing complex, instructive cues to one another. The precise factors and timing all need to be worked out and in most cases, this is done with an incomplete knowledge of human development.
A second challenge relates to using cells from DiGeorge patients to produce thymic tissue, which are missing several genes on their 22nd chromosome and will likely require sophisticated genetic engineering to restore this ability.
Fortunately, Drs. Weinacht and Sebastiano are up to the challenge, and have already made progress in differentiating human induced pluripotent stem cells (iPS) into thymic lineage intermediates that appear to be expressing the right proteins at the right time. They plan to combine these cells with engineered materials to create a three-dimensional (3D) tissue that more closely resembles an authentic organ, and which can be tested for functionality in athymic mice.
There is more work to be done, but these advances, along with continued technological improvements and renewed efforts from Enzyvant, could forge a path to the clinic and lead to a brighter future for patients suffering from congenital athymia and other forms of thymic dysfunction.
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that destroys the nerve cells in the brain and spinal cord. As a result of ALS, the motor neurons that enable bodily movement and muscle control are harmed, which can make it difficult to move, speak, eat, and breathe. This condition usually affects people from age 40 to 70, but individuals in their 20s and 30s have also been known to develop ALS. Unfortunately there is no cure for this condition.
However, a study supported by CIRM and conducted by Dr. Martin Marsala at UC San Diego is using a mouse model to look at an approach that uses a gene silencer to protect motor neurons before or shortly after ALS symptoms start to develop.
The gene silencer works by turning off a targeted gene and is delivered via injection. In the case of ALS, previous research suggests that mutations in a gene called SOD1 may cause motor neuronal cell death, resulting in ALS. For this study, Dr. Marsala and his team injected the gene silencer at two sites in the spinal cord in adult mice expressing an ALS-causing mutation of the SOD1 gene. The mice injected did not yet display symptoms of ALS or had only begun showing symptoms.
In mice not yet showing ALS symptoms, they displayed normal neurological function with no onset ALS symptoms after treatment. Additionally, near complete protection of motor neurons and other cells was observed. In mice that had just began showing ALS symptoms, the injection blocked further disease progression as well as further harm to remaining motor neurons. Both of these groups of mice lived without negative side effects for the duration of the study.
In a news release, Dr. Marsala talks about what these results mean for the study of ALS.
“At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS.”
The next steps for this research would be to conduct additional safety studies with a larger animal model in order to determine an optimal, safe dose for the treatment.
The full results of this study were published in Nature Medicine.
In addition to supporting this research for ALS, CIRM has funded two clinical trials in the field as well. One of these trials is being conducted by BrainStorm Cell Therapeutics and the other trial is being by Cedars-Sinai Medical Center.
This year the most widely read blog was actually one we wrote back in 2018. It’s the transcript of a Facebook Live: “Ask the Stem Cell Team” event about strokes and stroke recovery. Because stroke is the third leading cause of death and disability in the US it’s probably no surprise this blog has lasting power. So many people are hoping that stem cells will help them recover from a stroke.
But of the blogs that we wrote and posted this year there’s a really interesting mix of topics.
The most read 2019 blog was about a potential breakthrough in the search for a treatment for type 1 diabetes (T1D). Two researchers at UC San Francisco, Dr. Matthias Hebrok and Dr. Gopika Nair developed a new method of replacing the insulin-producing cells in the pancreas that are destroyed by type 1 diabetes.
Dr. Hebrok described it as a big advance saying: “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”
It’s not too surprising a blog about type 1 diabetes was at the top. This condition affects around 1.25 million Americans, a huge audience for any potential breakthrough. However, the blog that was the second most read is the exact opposite. It is about a rare disease called cystinosis. How rare? Well, there are only around 500 children and young adults in the US, and just 2,000 worldwide diagnosed with this condition.
It might be rare but its impact is devastating. A genetic mutation means children with this condition lack the ability to clear an amino acid – cysteine – from their body. The buildup of cysteine leads to damage to the kidneys, eyes, liver, muscles, pancreas and brain.
UC San Diego researcher Dr. Stephanie Cherqui and her team are taking the patient’s own blood stem cells and, in the lab, genetically re-engineering them to correct the mutation, then returning the cells to the patient. It’s hoped this will create a new, healthy blood system free of the disease.
Dr. Cherqui says if it works, this could help not just people with cystinosis but a wide array of other disorders: “We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders.”
The third most read blog was about another rare disease, but one that has been getting a lot of media attention this past year. Sickle cell disease affects around 100,000 Americans, mostly African Americans. In November the Food and Drug Administration (FDA) approved Oxbryta, a new therapy that reduces the likelihood of blood cells becoming sickle shaped and clumping together – causing blockages in blood vessels.
But our blog focused on a stem cell approach that aims to cure the disease altogether. In many ways the researchers in this story are using a very similar approach to the one Dr. Cherqui is using for cystinosis. Genetically correcting the mutation that causes the problem, creating a new, healthy blood system free of the sickle shaped blood cells.
Two other blogs deserve honorable mentions here as well. The first is the story of James O’Brien who lost the sight in his right eye when he was 18 years old and now, 25 years later, has had it restored thanks to stem cells.
The fifth most popular blog of the year was another one about type 1 diabetes. This piece focused on the news that the CIRM Board had awarded more than $11 million to Dr. Peter Stock at UC San Francisco for a clinical trial for T1D. His approach is transplanting donor pancreatic islets and parathyroid glands into patients, hoping this will restore the person’s ability to create their own insulin and control the disease.
2019 was certainly a busy year for CIRM. We are hoping that 2020 will prove equally busy and give us many new advances to write about. You will find them all here, on The Stem Cellar.
As we get close to the end of the year there is no shortage of lists of the “best of the year” and even this year the “best of the decade”. But when it comes to podcasts it would be hard to think of a better one than “Bad Batch”. It’s part stem cell research, part medical mystery and altogether engrossing.
It’s the work of Laura Beil, an award-winning journalist who follows the trail of a stem cell therapy that was supposed to help patients but instead left them battling life-threatening infections. It highlights how some clinics are able to find loopholes in the law that allow them to offer unproven and unapproved therapies, and how those therapies can put people’s lives at risk.
We have written about the dangers of predatory stem cell clinics several times, but in “Bad Batch” you get to hear the voices of the people affected, and ultimately the people responsible. It’s great journalism and fascinating story telling. And it’s a reminder of the work that needs to be done to stop this ever happening again.