Recently, The New York Times released a powerful article that tells the stories of four different families navigating the challenges of having a family member with a rare disease. One of these stories focused on Matt Wilsey, a tech entrepreneur and investor in California’s Silicon Valley, and his daughter Grace, who was born with an extremely rare genetic disorder named NGLY1 deficiency. This genetic disorder causes developmental delay, intellectual disability, seizures, and other movement issues.
Matt decided to put his entrepreneurial and networking skills to good use in order to form Grace Science Foundation, an organization whose focus is to pioneer approaches to scientific discovery in order to develop a cure for NGLY1 deficiency. One researcher that Matt brought on board was Carolyn Bertozzi, Ph.D., a chemist from Stanford University. A graduate student in her laboratory, Ian Blong, Ph.D., decided to study NGLY1 and was able to complete his dissertation while working on this topic at Stanford University.
In exploring the various options afforded to him by the CIRM, Ian found Dr. Bertozzi’s lab at UC Berkeley, where he focused on early stage discovery research. His master’s thesis project focused on how to generate rare neuronal and and neural crest cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Both of these stem cell types can generate virtually any kind of cell, but iPSCs are unique in that they can be generated from the adult cells (such as skin) of a patient.
Ian decided to continue his studies in Dr. Bertozzi’s lab by continuing his research in a Ph.D. program at UC Berkeley. He credits the SFSU CIRM Bridges Program with giving him the opportunity to work under a prestigious PI and in her lab at UC Berkeley, which allowed him to continue his studies there.
“The CIRM Bridges Program gave me the confidence and resources to pursue my dreams. Being able to have the capability of going to Berkeley and do research with top tier scientists along with the support from CIRM. Without CIRM, I wouldn’t have had the courage to go to those universities to get my foot in the door.”
Eventually, Dr. Bertozzi move her operations to Stanford University and Ian continued his Ph.D. studies there. Stanford provided him the opportunity to focus more on the translational stage, which is an area of research aimed at developing a therapeutic candidate. Going into his Ph.D. work, Ian was able to build upon his previous “discovery stage” knowledge of generating neuronal and neural crest cells from iPSCS and hESCs.
An area of his work at Stanford focused on generating neural crest cells from iPSCs of those with NGLY1 deficiency. The goal was to identify a phenotype, which is an observable characteristic such as physical form. Identifying this would help better understand potential differentiation pathways that underlie NGLY1 deficiency, which could lead to the development a potential treatment for the condition.
Flash forward to present day and Ian is still using the knowledge he learned from his time in the SFSU CIRM Bridges to Stem Cell Research Program. He is currently a scientist at the healthcare company Roche, where his focus is on manufacturing future diagnostics and therapeutics on a much larger scale, a complex and extremely critical process necessary in widely distributing potential stem cell-based treatments.
Ian’s experience and opportunities provided to him is just one of the many examples of how the various CIRM Bridges Programs across California have given students the resources needed to become the next generation of scientists.
It’s been a long time coming. Eighteen months to be precise. Which is a peculiarly long time for an Annual Report. The world is certainly a very different place today than when we started, and yet our core mission hasn’t changed at all, except to spring into action to make our own contribution to fighting the coronavirus.
This latest CIRM Annual Reportcovers 2019 through June 30, 2020. Why? Well, as you probably know we are running out of money and could be funding our last new awards by the end of this year. So, we wanted to produce as complete a picture of our achievements as we could – keeping in mind that we might not be around to produce a report next year.
It’s a pretty jam-packed report. It covers everything from the 14 new clinical trials we have funded this year, including three specifically focused on COVID-19. It looks at the extraordinary researchers that we fund and the progress they have made, and the billions of additional dollars our funding has helped leverage for California. But at the heart of it, and at the heart of everything we do, are the patients. They’re the reason we are here. They are the reason we do what we do.
There are stories of people like Byron Jenkins who almost died from multiple myeloma but is now back leading a full, active life with his family thanks to a CIRM-funded therapy with Poseida. There is Jordan Janz, a young man who once depended on taking 56 pills a day to keep his rare disease, cystinosis, under control but is now hoping a stem cell therapy developed by Dr. Stephanie Cherqui and her team at UC San Diego will make that something of the past.
These individuals are remarkable on so many levels, not the least because they were willing to be among the first people ever to try these therapies. They are pioneers in every sense of the word.
There is a lot of information in the report, charting the work we have done over the last 18 months. But it’s also a celebration of everyone who made it possible, and our way of saying thank you to the people of California who gave us this incredible honor and opportunity to do this work.
On December 12th we hosted our latest ‘Facebook Live: Ask the Stem Cell Team’ event. This time around we really did mean team. We had a host of our Science Officers answering questions from friends and supporters of CIRM. We got a lot of questions and didn’t have enough time to address them all. So here’s answers to all the questions.
What are the obstacles to using partial cellular reprogramming to return people’s entire bodies to a youthful state.Paul Hartman. San Leandro, California
Dr. Kelly Shepard: Certainly, scientists have observed that various manipulations of cells, including reprogramming, partial reprogramming, de-differentiation and trans-differentiation, can restore or change properties of cells, and in some cases, these changes can reflect a more “youthful” state, such as having longer telomeres, better proliferative capacity, etc. However, some of these same rejuvenating properties, outside of their normal context, could be harmful or deadly, for example if a cell began to grow and divide when or where it shouldn’t, similar to cancer. For this reason, I believe the biggest obstacles to making this approach a reality are twofold: 1) our current, limited understanding of the nature of partially reprogrammed cells; and 2) our inability to control the fate of those cells that have been partially reprogrammed, especially if they are inside a living organism. Despite the challenges, I think there will be step wise advances where these types of approaches will be applied, starting with specific tissues. For example, CIRM has recently funded an approach that uses reprogramming to make “rejuvenated” versions of T cells for fighting lung cancer. There is also a lot of interest in using such approaches to restore the reparative capacity of aged muscle. Perhaps some successes in these more limited areas will be the basis for expanding to a broader use.
What’s going on with Stanford’s stem cell trials for stroke? I remember the first trial went really well In 2016 have not heard anything about since? Elvis Arnold
Dr. Lila Collins: Hi Elvis, this is an evolving story. I believe you are referring to SanBio’s phase 1/2a stroke trial, for which Stanford was a site. This trial looked at the safety and feasibility of SanBio’s donor or allogeneic stem cell product in chronic stroke patients who still had motor deficits from their strokes, even after completing physical therapy when natural recovery has stabilized. As you note, some of the treated subjects had promising motor recoveries.
SanBio has since completed a larger, randomized phase 2b trial in stroke, and they have released the high-level results in a press release. While the trial did not meet its primary endpoint of improving motor deficits in chronic stroke, SanBio conducted a very similar randomized trial in patients with stable motor deficits from chronic traumatic brain injury (TBI). In this trial, SanBio saw positive results on motor recovery with their product. In fact, this product is planned to move towards a conditional approval in Japan and has achieved expedited regulatory status in the US, termed RMAT, in TBI which means it could be available more quickly to patients if all goes well. SanBio plans to continue to investigate their product in stroke, so I would stay tuned as the work unfolds.
Also, since you mentioned Stanford, I should note that Dr Gary Steinberg, who was a clinical investigator in the SanBio trial you mentioned, will soon be conducting a trial with a different product that he is developing, neural progenitor cells, in chronic stroke. The therapy looks promising in preclinical models and we are hopeful it will perform well for patients in the clinic.
I am a stroke survivor will stem cell treatment able to restore my motor skills?Ruperto
Dr. Lila Collins:
Hi Ruperto. Restoring motor loss after stroke is a very active area of research. I’ll touch upon a few ongoing stem cell trials. I’d just like to please advise that you watch my colleague’s comments on stem cell clinics (these can be found towards the end of the blog) to be sure that any clinical research in which you participate is as safe as possible and regulated by FDA.
Back to stroke, I mentioned SanBio’s ongoing work to address motor skill loss in chronic stroke earlier. UK based Reneuron is also conducting a phase 2 trial, using a neural progenitor cell as a candidate therapy to help recover persistent motor disability after stroke (chronic). Dr Gary Steinberg at Stanford is also planning to conduct a clinical trial of a human embryonic stem cell-derived neuronal progenitor cell in stroke.
There is also promising work being sponsored by Athersys in acute stroke. Athersys published results from their randomized, double blinded placebo controlled Ph2 trial of their Multistem product in patients who had suffered a stroke within 24-48 hours. After intravenous delivery, the cells improved a composite measure of stroke recovery, including motor recovery. Rather than acting directly on the brain, Multistem seems to work by traveling to the spleen and reducing the inflammatory response to a stroke that can make the injury worse.
Athersys is currently recruiting a phase 3 trial of its Multistem product in acute stroke (within 1.5 days of the stroke). The trial has an accelerated FDA designation, called RMAT and a special protocol assessment. This means that if the trial is conducted as planned and it reaches the results agreed to with the FDA, the therapy could be cleared for marketing. Results from this trial should be available in about two years.
Questions from several hemorrhagic stroke survivors who say most clinical trials are for people with ischemic strokes. Could stem cells help hemorrhagic stroke patients as well?
Dr. Lila Collins:
Regarding hemorrhagic stroke, you are correct the bulk of cell therapies for stroke target ischemic stroke, perhaps because this accounts for the vast bulk of strokes, about 85%.
That said, hemorrhagic strokes are not rare and tend to be more deadly. These strokes are caused by bleeding into or around the brain which damages neurons. They can even increase pressure in the skull causing further damage. Because of this the immediate steps treating these strokes are aimed at addressing the initial bleeding insult and the blood in the brain.
While most therapies in development target ischemic stroke, successful therapies developed to repair neuronal damage or even some day replace lost neurons, could be beneficial after hemorrhagic stroke as well.
I had an Ischemic stroke in 2014, and my vision was also affected. Can stem cells possibly help with my vision issues. James Russell
Dr. Lila Collins:
Hi James. Vision loss from stroke is complex and the type of loss depends upon where the stroke occurred (in the actual eye, the optic nerve or to the other parts of the brain controlling they eye or interpreting vision). The results could be:
Visual loss from damage to the retina
You could have a normal eye with damage to the area of the brain that controls the eye’s movement
You could have damage to the part of the brain that interprets vision.
You can see that to address these various issues, we’d need different cell replacement approaches to repair the retina or the parts of the brain that were damaged.
Replacing lost neurons is an active effort that at the moment is still in the research stages. As you can imagine, this is complex because the neurons have to make just the right connections to be useful.
Is there any stem cell therapy for optical nerve damage? Deanna Rice
Dr. Ingrid Caras: There is currently no proven stem cell therapy to treat optical nerve damage, even though there are shady stem cell clinics offering treatments. However, there are some encouraging early gene therapy studies in mice using a virus called AAV to deliver growth factors that trigger regeneration of the damaged nerve. These studies suggest that it may be possible to restore at least some visual function in people blinded by optic nerve damage from glaucoma
I read an article about ReNeuron’s retinitis pigmentosa clinical trial update. In the article, it states: “The company’s treatment is a subretinal injection of human retinal progenitors — cells which have almost fully developed into photoreceptors, the light-sensing retinal cells that make vision possible.” My question is: If they can inject hRPC, why not fully developed photoreceptors?Leonard
Dr. Kelly Shepard: There is evidence from other studies, including from other tissue types such as blood, pancreas, heart and liver, that fully developed (mature) cell types tend not to engraft as well upon transplantation, that is the cells do not establish themselves and survive long term in their new environment. In contrast, it has been observed that cells in a slightly less “mature” state, such as those in the progenitor stage, are much more likely to establish themselves in a tissue, and then differentiate into more mature cell types over time. This question gets at the crux of a key issue for many new therapies, i.e. what is the best cell type to use, and the best timing to use it.
My question for the “Ask the Stem Cell Team” event is: When will jCyte publish their Phase IIb clinical trial results. Chris Allen
Dr. Ingrid Caras: The results will be available sometime in 2020.
I understand the hRPC cells are primarily neurotropic (rescue/halt cell death); however, the literature also says hRPC can become new photoreceptors. My questions are:Approximately what percentage develop into functioning photoreceptors? And what percentage of the injected hRPC are currently surviving?Leonard Furber, an RP Patient
Dr. Kelly Shepard: While we can address these questions in the lab and in animal models, until there is a clinical trial, it is not possible to truly recreate the environment and stresses that the cells will undergo once they are transplanted into a human, into the site where they are expected to survive and function. Thus, the true answer to this question may not be known until after clinical trials are performed and the results can be evaluated. Even then, it is not always possible to monitor the fate of cells after transplantation without removing tissues to analyze (which may not be feasible), or without being able to transplant labeled cells that can be readily traced.
Dr. Ingrid Caras – Although the cells have been shown to be capable of developing into photoreceptors, we don’t know if this actually happens when the cells are injected into a patient’s eye. The data so far suggest that the cells work predominantly by secreting growth factors that rescue damaged retinal cells or even reverse the damage. So one possible outcome is that the cells slow or prevent further deterioration of vision. But an additional possibility is that damaged retinal cells that are still alive but are not functioning properly may become healthy and functional again which could result in an improvement in vision.
What advances have been made using stem cells for the treatment of Type 2 Diabetes?Mary Rizzo
Dr. Ross Okamura: Type 2 Diabetes (T2D) is a disease where the body is unable to maintain normal glucose levels due to either resistance to insulin-regulated control of blood sugar or insufficient insulin production from pancreatic beta cells. The onset of disease has been associated with lifestyle influenced factors including body mass, stress, sleep apnea and physical activity, but it also appears to have a genetic component based upon its higher prevalence in certain populations.
Type 1 Diabetes (T1D) differs from T2D in that in T1D patients the pancreatic beta cells have been destroyed by the body’s immune system and the requirement for insulin therapy is absolute upon disease onset rather than gradually developing over time as in many T2D cases. Currently the only curative approach to alleviate the heavy burden of disease management in T1D has been donor pancreas or islet transplantation. However, the supply of donor tissue is small relative to the number of diabetic patients. Donor islet and pancreas transplants also require immune suppressive drugs to prevent allogenic immune rejection and the use of these drugs carry additional health concerns. However, for some patients with T1D, especially those who may develop potentially fatal hypoglycemia, immune suppression is worth the risk.
To address the issue of supply, there has been significant activity in stem cell research to produce insulin secreting beta cells from pluripotent stem cells and recent clinical data from Viacyte’s CIRM funded trial indicates that implanted allogeneic human stem cell derived cells in T1D patients can produce circulating c-peptide, a biomarker for insulin. While the trial is not designed specifically to cure insulin-dependent T2D patients, the ability to produce and successfully engraft stem cell-derived beta cells would be able to help all insulin-dependent diabetic patients.
It’s also worth noting that there is a sound scientific reason to clinically test a patient-derived pluripotent stem cell-based insulin-producing cells in insulin-dependent T2D diabetic patients; the cells in this case could be evaluated for their ability to cure diabetes in the absence of needing to prevent both allogeneic and autoimmune responses.
SPINAL CORD INJURY
Is there any news on clinical trials for spinal cord injury? Le Ly
Kevin McCormack: The clinical trial CIRM was funding, with Asterias (now part of a bigger company called Lineage Cell Therapeutics, is now completed and the results were quite encouraging. In a news release from November of 2019 Brian Culley, CEO of Lineage Cell Therapeutics, described the results this way.
“We remain extremely excited about the potential for OPC1 (the name of the therapy used) to provide enhanced motor recovery to patients with spinal cord injuries. We are not aware of any other investigative therapy for SCI (spinal cord injury) which has reported as encouraging clinical outcomes as OPC1, particularly with continued improvement beyond 1 year. Overall gains in motor function for the population assessed to date have continued, with Year 2 assessments measuring the same or higher than at Year 1. For example, 5 out of 6 Cohort 2 patients have recovered two or more motor levels on at least one side as of their Year 2 visit whereas 4 of 6 patients in this group had recovered two motor levels as of their Year 1 visit. To put these improvements into perspective, a one motor level gain means the ability to move one’s arm, which contributes to the ability to feed and clothe oneself or lift and transfer oneself from a wheelchair. These are tremendously meaningful improvements to quality of life and independence. Just as importantly, the overall safety of OPC1 has remained excellent and has been maintained 2 years following administration, as measured by MRI’s in patients who have had their Year 2 follow-up visits to date. We look forward to providing further updates on clinical data from SCiStar as patients continue to come in for their scheduled follow up visits.”
Lineage Cell Therapeutics plans to meet with the FDA in 2020 to discuss possible next steps for this therapy.
In the meantime the only other clinical trial I know that is still recruiting is one run by a company called Neuralstem. Here is a link to information about that trial on the www.clinicaltrials.gov website.
Now that the Brainstorm ALS trial is finished looking for new patients do you have any idea how it’s going and when can we expect to see results? Angela Harrison Johnson
Dr. Ingrid Caras: The treated patients have to be followed for a period of time to assess how the therapy is working and then the data will need to be analyzed. So we will not expect to see the results probably for another year or two.
Are there treatments for autism or fragile x using stem cells? Magda Sedarous
Dr. Kelly Shepard: Autism and disorders on the autism spectrum represent a collection of many different disorders that share some common features, yet have different causes and manifestations, much of which we still do not understand. Knowing the origin of a disorder and how it affects cells and systems is the first step to developing new therapies. CIRM held a workshop on Autism in 2009 to brainstorm potential ways that stem cell research could have an impact. A major recommendation was to exploit stem cells and new technological advances to create cells and tissues, such as neurons, in the lab from autistic individuals that could then be studied in great detail. CIRM followed this recommendation and funded several early-stage awards to investigate the basis of autism, including Rett Syndrome, Fragile X, Timothy Syndrome, and other spectrum disorders. While these newer investigations have not yet led to therapies that can be tested in humans, this remains an active area of investigation. Outside of CIRM funding, we are aware of more mature studies exploring the effects of umbilical cord blood or other specific stem cell types in treating autism, such as an ongoing clinical trial conducted at Duke University.
What is happening with Parkinson’s research? Hanifa Gaphoor
Dr. Kent Fitzgerald: Parkinson’s disease certainly has a significant amount of ongoing work in the regenerative medicine and stem cell research.
The nature of cell loss in the brain, specifically the dopaminergic cells responsible for regulating the movement, has long been considered a good candidate for cell replacement therapy.
This is largely due to the hypothesis that restoring function to these cells would reverse Parkinson’s symptoms. This makes a lot of sense as front line therapy for the disease for many years has been dopamine replacement through L-dopa pills etc. Unfortunately, over time replacing dopamine through a pill loses its benefit, whereas replacing or fixing the cells themselves should be a more permanent fix.
Because a specific population of cells in one part of the brain are lost in the disease, multiple labs and clinicians have sought to replace or augment these cells by transplantation of “new” functional cells able to restore function to the area an theoretically restore voluntary motor control to patients with Parkinson’s disease.
Early clinical research showed some promise, however also yielded mixed results, using fetal tissue transplanted into the brains of Parkinson’s patients. As it turns out, the cell types required to restore movement and avoid side effects are somewhat nuanced. The field has moved away from fetal tissue and is currently pursuing the use of multiple stem cell types that are driven to what is believed to be the correct subtype of cell to repopulate the lost cells in the patient.
One project CIRM sponsored in this area with Jeanne Loring sought to develop a cell replacement therapy using stem cells from the patients themselves that have been reprogrammed into the kinds of cell damaged by Parkinson’s. This type of approach may ultimately avoid issues with the cells avoiding rejection by the immune system as can be seen with other types of transplants (i.e. liver, kidney, heart etc).
Still, others are using cutting edge gene therapy technology, like the clinical phase project CIRM is sponsoring with Krystof Bankiewicz to investigate the delivery of a gene (GDNF) to the brain that may help to restore the activity of neurons in the Parkinson’s brain that are no longer working as they should.
The bulk of the work in the field of PD at the present remains centered on replacing or restoring the dopamine producing population of cells in the brain that are affected in disease.
Any plans for Huntington’s?Nikhat Kuchiki
Dr. Lisa Kadyk: The good news is that there are now several new therapeutic approaches to Huntington’s Disease that are at various stages of preclinical and clinical development, including some that are CIRM funded. One CIRM-funded program led by Dr. Leslie Thompson at UC Irvine is developing a cell-based therapeutic that consists of neural stem cells that have been manufactured from embryonic stem cells. When these cells are injected into the brain of a mouse that has a Huntington’s Disease mutation, the cells engraft and begin to differentiate into new neurons. Improvements are seen in the behavioral and electrophysiological deficits in these mutant mice, suggesting that similar improvements might be seen in people with the disease. Currently, CIRM is funding Dr. Thompson and her team to carry out rigorous safety studies in animals using these cells, in preparation for submitting an application to the FDA to test the therapy in human patients in a clinical trial.
There are other, non-cell-based therapies also being tested in clinical trials now, using anti-sense oligonucleotides (Ionis, Takeda) to lower the expression of the Huntington protein. Another HTT-lowering approach is similar – but uses miRNAs to lower HTT levels (UniQure,Voyager)
TRAUMATIC BRAIN INJURY (TBI)
My 2.5 year old son recently suffered a hypoxic brain injury resulting in motor and speech disabilities. There are several clinical trials underway for TBI in adults. My questions are:
Will the results be scalable to pediatric use and how long do you think it would take before it is available to children?
I’m wondering why the current trials have chosen to go the route of intracranial injections as opposed to something slightly less invasive like an intrathecal injection?
Is there a time window period in which stem cells should be administered by, after which the administration is deemed not effective?
Dr. Kelly Shepard: TBI and other injuries of the nervous system are characterized by a lot of inflammation at the time of injury, which is thought to interfere with the healing process- and thus some approaches are intended to be delivered after that inflammation subsides. However, we are aware of approaches that intend to deliver a therapy to a chronic injury, or one that has occurred previously. Thus, the answer to this question may depend on how the intended therapy is supposed to work. For example, is the idea to grow new neurons, or is it to promote the survival of neurons of other cells that were spared by the injury? Is the therapy intended to address a specific symptom, such as seizures? Is the therapy intended to “fill a gap” left behind after inflammation subsides, which might not restore all function but might ameliorate certain symptoms.? There is still a lot we don’t understand about the brain and the highly sophisticated network of connections that cannot be reversed by only replacing neurons, or only reducing inflammation, etc. However, if trials are well designed, they should yield useful information even if the therapy is not as effective as hoped, and this information will pave the way to newer approaches and our technology and understanding evolves.
We have had a doctor recommending administering just the growth factors derived from MSC stem cells. Does the science work that way? Is it possible to isolate the growth factors and boost the endogenous growth factors by injecting allogenic growth factors?
Dr. Stephen Lin: Several groups have published studies on the therapeutic effects in non-human animal models of using nutrient media from MSC cultures that contain secreted factors, or extracellular vesicles from cells called exosomes that carry protein or nucleic acid factors. Scientifically it is possible to isolate the factors that are responsible for the therapeutic effect, although to date no specific factor or combination of factors have been identified to mimic the effects of the undefined mixtures in the media and exosomes. At present no regulatory approved clinical therapy has been developed using this approach.
PREDATORY STEM CELL CLINICS
What practical measures are being taken to address unethical practitioners whose bad surgeries are giving stem cell advances a bad reputation and are making forward research difficult?Kathy Jean Schultz
Dr. Geoff Lomax: Terrific question! I have been doing quite a bit research into the history of this issue of unethical practitioners and I found an 1842 reference to “quack medicines.” Clearly this is nothing new. In that day, the author appealed to make society “acquainted with the facts.”
In California, we have taken steps to (1) acquaint patients with the facts about stem cell treatments and (2) advance FDA authorized treatments for unmet medical needs.
First, CIRM work with Senator Hernandez in 2017 to write a law the requires provides to disclose to patient that a stem cell therapy has not been approved by the Food and Drug administration.
We continue to work with the State Legislature and Medical Board of California to build on policies that require accurate disclosure of the facts to patients.
Second, our clinical trial network the — Alpha Stem Cell Clinics – have supported over 100 FDA-authorized clinical trials to advance responsible clinical research for unmet medical needs.
I’m curious if adipose stem cell being used at clinics at various places in the country is helpful or beneficial?Cheri Hicks
Adipose tissue has been widely used particularly in plastic and reconstructive surgery. Many practitioners suggest adipose cells are beneficial in this context. With regard to regenerative medicine and / or the ability to treat disease and injury, I am not aware of any large randomized clinical trials that demonstrate the safety and efficacy of adipose-derived stem cells used in accordance with FDA guidelines.
I went to a “Luncheon about Stem Cell Injections”. It sounded promising. I went thru with it and got the injections because I was desperate from my knee pain. The price of stem cell injections was $3500 per knee injection. All went well. I have had no complications, but haven’t noticed any real major improvement, and here I am a year later. My questions are:
1) I wonder on where the typical injection cells are coming from?
2) I wonder what is the actual cost of the cells?
3) What kind of results are people getting from all these “pop up” clinics or established clinics that are adding this to there list of offerings?
Dr. Geoff Lomax: You raise a number of questions and point here; they are all very good and it’s is hard to give a comprehensive response to each one, but here is my reaction:
There are many practitioners in the field of orthopedics who sincerely believe in the potential of cell-based treatments to treat injury / pain
Most of the evidence presented is case reports that individuals have benefited
The challenge we face is not know the exact type of injury and cell treatments used.
Well controlled clinical trials would really help us understand for what cells (or cell products) and for what injury would be helpful
Prices of $3000 to $5000 are not uncommon, and like other forms of private medicine there is often a considerable mark-up in relation to cost of goods.
You are correct that there have not been reports of serious injury for knee injections
However the effectiveness is not clear while simultaneously millions of people have been aided by knee replacements.
Do stem cells have benefits for patients going through chemotherapy and radiation therapy?Ruperto
Dr. Kelly Shepard: The idea that a stem cell therapy could help address effects of chemotherapy or radiation is being and has been pursued by several investigators over the years, including some with CIRM support. Towards the earlier stages, people are looking at the ability of different stem cell-derived neural cell preparations to replace or restore function of certain brain cells that are damaged by the effects of chemotherapy or radiation. In a completely different type of approach, a group at City of Hope is exploring whether a bone marrow transplant with specially modified stem cells can provide a protective effect against the chemotherapy that is used to treat a form of brain cancer, glioblastoma. This study is in the final stage of development that, if all goes well, culminates with application to the FDA to allow initiation of a clinical trial to test in people.
Dr. Ingrid Caras: That’s an interesting and valid question. There is a Phase 1 trial ongoing that is evaluating a novel type of stem/progenitor cell from the umbilical cord of healthy deliveries. In animal studies, these cells have been shown to reduce the toxic effects of chemotherapy and radiation and to speed up recovery. These cells are now being tested in a First-in-human clinical trial in patients who are undergoing high-dose chemotherapy to treat their disease.
There is a researcher at Stanford, Michelle Monje, who is investigating that the role of damage to stem cells in the cognitive problems that sometimes arise after chemo- and radiation therapy (“chemobrain”). It appears that damage to stem cells in the brain, especially those responsible for producing oligodendrocytes, contributes to chemobrain. In CIRM-funded work, Dr. Monje has identified small molecules that may help prevent or ameliorate the symptoms of chemobrain.
Is it possible to use a technique developed to fight one disease to also fight another? For instance, the bubble baby disease, which has cured (I think) more than 50 children, may also help fight sickle cell anemia? Don Reed.
Dr. Lisa Kadyk: Hi Don. Yes, the same general technique can often be applied to more than one disease, although it needs to be “customized” for each disease. In the example you cite, the technique is an “autologous gene-modified bone marrow transplant” – meaning the cells come from the patient themselves. This technique is relevant for single gene mutations that cause diseases of the blood (hematopoietic) system. For example, in the case of “bubble baby” diseases, a single mutation can cause failure of immune cell development, leaving the child unable to fight infections, hence the need to have them live in a sterile “bubble”. To cure that disease, blood stem cells, which normally reside in the bone marrow, are collected from the patient and then a normal version of the defective gene is introduced into the cells, where it is incorporated into the chromosomes. Then, the corrected stem cells are transplanted back into the patient’s body, where they can repopulate the blood system with cells expressing the normal copy of the gene, thus curing the disease.
A similar approach could be used to treat sickle cell disease, since it is also caused by a single gene mutation in a gene (beta hemoglobin) that is expressed in blood cells. The same technique would be used as I described for bubble baby disease but would differ in the gene that is introduced into the patient’s blood stem cells.
Is there any concern that CIRM’s lack of support in basic research will hamper the amount of new approaches that can reach clinical stages? Jason
Dr. Kelly Shepard: CIRM always has and continues to believe that basic research is vital to the field of regenerative medicine. Over the past 10 years CIRM has invested $904 million in “discovery stage/basic research”, and about $215 million in training grants that supported graduate students, post docs, clinical fellows, undergraduate, masters and high school students performing basic stem cell research. In the past couple of years, with only a limited amount of funds remaining, CIRM made a decision to invest most of the remaining funds into later stage projects, to support them through the difficult transition from bench to bedside. However, even now, CIRM continues to sponsor some basic research through its Bridges and SPARK Training Grant programs, where undergraduate, masters and even high school students are conducting stem cell research in world class stem cell laboratories, many of which are the same laboratories that were supported through CIRM basic research grants over the past 10 years. While basic stem cell research continues to receive a substantial level of support from the NIH ($1.8 billion in 2018, comprehensively on stem cell projects) and other funders, CIRM believes continued support for basic research, especially in key areas of stem cell research and vital opportunities, will always be important for discovering and developing new treatments.
What is the future of the use of crispr cas9 in clinical trials in california/globally. Art Venegas
Dr. Kelly Shepard: CRISPR/Cas9 is a powerful gene editing tool. In only a few years, CRISPR/Cas9 technology has taken the field by storm and there are already a few CRISPR/Cas9 based treatments being tested in clinical trials in the US. There are also several new treatments that are at the IND enabling stage of development, which is the final testing stage required by the FDA before a clinical trial can begin. Most of these clinical trials involving CRISPR go through an “ex vivo” approach, taking cells from the patient with a disease causing gene, correcting the gene in the laboratory using CRISPR, and reintroducing the cells carrying the corrected gene back into the patient for treatment. Sickle cell disease is a prime example of a therapy being developed using this strategy and CIRM funds two projects that are preparing for clinical trials with this approach. CRISPR is also being used to develop the next generation of cancer T-cell therapies (e.g. CAR-T), where T-cells – a vital part of our immune system – are modified to target and destroy cancer cell populations. Using CRISPR to edit cells directly in patients “in vivo” (inside the body) is far less common currently but is also being developed. It is important to note that any FDA sanctioned “in vivo” CRISPR clinical trial in people will only modify organ-specific cells where the benefits cannot be passed on to subsequent generations. There is a ban on funding for what are called germ line cells, where any changes could be passed down to future generations.
CIRM is currently supporting multiple CRISPR/Cas9 gene editing projects in California from the discovery or most basic stage of research, through the later stages before applying to test the technique in people in a clinical trial.
While the field is new – if early safety signals from the pioneering trials are good, we might expect a number of new CRISPR-based approaches to enter clinical testing over the next few years. The first of these will will likely be in the areas of bone marrow transplant to correct certain blood/immune or metabolic diseases, and cancer immunotherapies, as these types of approaches are the best studied and furthest along in the pipeline.
Explain the differences between gene therapy and stem cell therapy?Renee Konkol
Dr. Stephen Lin: Gene therapy is the direct modification of cells in a patient to treat a disease. Most gene therapies use modified, harmless viruses to deliver the gene into the patient. Gene therapy has recently seen many success in the clinic, with the first FDA approved therapy for a gene induced form of blindness in 2017 and other approvals for genetic forms of smooth muscle atrophy and amyloidosis.
Stem cell therapy is the introduction of stem cells into patients to treat a disease, usually with the purpose of replacing damaged or defective cells that contribute to the disease. Stem cell therapies can be derived from pluripotent cells that have the potential to turn into any cell in the body and are directed towards a specific organ lineage for the therapy. Stem cell therapies can also be derived from other cells, called progenitors, that have the ability to turn into a limited number of other cells in the body. for example hematopoietic or blood stem cells (HSCs), which are found in bone marrow, can turn into other cells of the blood system including B-cells and T-cells: while mesenchymal stem cells (MSCs), which are usually found in fat tissue, can turn into bone, cartilage, and fat cells. The source of these cells can be from the patient’s own body (autologous) or from another person (allogeneic).
Gene therapy is often used in combination with cell therapies when cells are taken from the patient and, in the lab, modified genetically to correct the mutation or to insert a correct form of the defective gene, before being returned to patients. Often referred to as “ex vivo gene therapy” – because the changes are made outside the patient’s body – these therapies include Chimeric Antigen Receptor T (CAR-T) cells for cancer therapy and gene modified HSCs to treat blood disorders such as severe combined immunodeficiency and sickle cell disease. This is an exciting area that has significantly improved and even cured many people already.
Currently, how can the outcome of CIRM stem cell medicine projects and clinical trials be soundly interpreted when their stem cell-specific doses are not known?James L. Sherley, M.D., Ph.D., Director. Asymmetrex, LLC
Dr. Stephen Lin: Stem cell therapies that receive approval to conduct clinical trials must submit a package of data to the FDA that includes studies that demonstrate their effectiveness, usually in animal models of the disease that the cell therapy is targeting. Those studies have data on the dose of the cell therapy that creates the therapeutic effect, which is used to estimate cell doses for the clinical trial. CIRM funds discovery and translational stage awards to conduct these types of studies to prepare cell therapies for clinical trials. The clinical trial is also often designed to test multiple doses of the cell therapy to determine the one that has the best therapeutic effect. Dosing can be very challenging with cell therapies because of issues including survival, engraftment, and immune rejection, but CIRM supports studies designed to provide data to give the best estimate possible.
Is there any research on using stem cells to increase the length of long bones in people?” For example, injecting stem cells into the growth plates to see if the cells can be used to lengthen limbs.Sajid
Dr. Kelly Shepard: There is quite a lot of ongoing research seeking ways to repair bones with stem cell based approaches, which is not the same but somewhat related. Much of this is geared towards repairing the types of bone injuries that do not heal well naturally on their own (large gaps, dead bone lesions, degenerative bone conditions). Also, a lot of this research involves engineering bone tissues in the lab and introducing the engineered tissue into a bone lesion that need be repaired. What occurs naturally at the growth plate is a complex interaction between many different cell types, much of which we do not fully understand. We do not fully understand how to use the cells that are used to engineer bone tissue in the lab. However, a group at Stanford, with some CIRM support, recently discovered a “skeletal stem cell” that exists naturally at the ends of human bones and at sites of fracture. These are quite different than MSCs and offer a new path to be explored for repairing and generating bone.
In honor of brain awareness week, our featured stem cell photo is of the brain! Scientists at the Massachusetts General Hospital and Harvard Stem Cell Institute identified a genetic switch that could potentially improve memory during aging and symptoms of PTSD. Shown in this picture are dentate gyrus cells (DGC) (green) and CA3 interneurons (red) located in the memory-forming area of the brain known as the hippocampus. By reducing the levels of a protein called abLIM3 in the DGCs of older mice, the researchers were able to boost the connections between DGCs and CA3 cells, which resulted in an improvement in the memories of the mice. The team believes that targeting this protein in aging adults could be a potential strategy for improving memory and treating patients with post-traumatic stress disorder (PTSD). You can read more about this study in The Harvard Gazette.
New target for obesity. Fat cells typically get a bad rap, but there’s actually a type of fat cell that is considered “healthier” than others. Unlike white fat cells that store calories in the form of energy, brown fat cells are packed with mitochondria that burn energy and produce heat. Babies have brown fat, so they can regulate their body temperature to stay warm. Adults also have some brown fat, but as we get older, our stores are slowly depleted.
In the fight against obesity, scientists are looking for ways to increase the amount of brown fat and decrease the amount of white fat in the body. This week, CIRM-funded researchers from the Salk Institute identified a molecule called ERRg that gives brown fat its ability to burn energy. Their findings, published in Cell Reports, offer a new target for obesity and obesity-related diseases like diabetes and fatty liver disease.
The team discovered that brown fat cells produce the ERRg molecule while white fat cells do not. Additionally, mice that couldn’t make the ERRg weren’t able to regulate their body temperature in cold environments. The team concluded in a news release that ERRg is “involved in protection against the cold and underpins brown fat identity.” In future studies, the researchers plan to activate ERRg in white fat cells to see if this will shift their identity to be more similar to brown fat cells.
Mice that lack ERR aren’t able to regulate their body temperature and are much colder (right) than normal mice (left). (Image credit Salk Institute)
Tale of two nanomedicine stories: making gene therapies more efficient with a bit of caution (Todd Dubnicoff). This week, the worlds of gene therapy, stem cells and nanomedicine converged for not one, but two published reports in the journal American Chemistry Society NANO.
The first paper described the development of so-called nanospears – tiny splinter-like magnetized structures with a diameter 5000 times smaller than a strand of human hair – that could make gene therapy more efficient and less costly. Gene therapy is an exciting treatment strategy because it tackles genetic diseases at their source by repairing or replacing faulty DNA sequences in cells. In fact, several CIRM-funded clinical trials apply this method in stem cells to treat immune disorders, like severe combined immunodeficiency and sickle cell anemia.
This technique requires getting DNA into diseased cells to make the genetic fix. Current methods have low efficiency and can be very damaging to the cells. The UCLA research team behind the study tested the nanospear-delivery of DNA encoding a gene that causes cells to glow green. They showed that 80 percent of treated cells did indeed glow green, a much higher efficiency than standard methods. And probably due to their miniscule size, the nanospears were gentle with 90 percent of the green glowing cells surviving the procedure.
As Steve Jonas, one of the team leads on the project mentions in a press release, this new method could bode well for future recipients of gene therapies:
“The biggest barrier right now to getting either a gene therapy or an immunotherapy to patients is the processing time. New methods to generate these therapies more quickly, effectively and safely are going to accelerate innovation in this research area and bring these therapies to patients sooner, and that’s the goal we all have.”
While the study above describes an innovative nanomedicine technology, the next paper inserts a note of caution about how experiments in this field should be set up and analyzed. A collaborative team from Brigham and Women’s Hospital, Stanford University, UC Berkeley and McGill University wanted to get to the bottom of why the many advances in nanomedicine had not ultimately led to many new clinical trials. They set out looking for elements within experiments that could affect the uptake of nanoparticles into cells, something that would muck up the interpretation of results.
imaging of female human amniotic stem cells incubated with nanoparticles demonstrated a significant increase in uptake compared to male cells. (Green dots: nanoparticles; red: cell staining; blue: nuclei) Credit: Morteza Mahmoudi, Brigham and Women’s Hospital.
In this study, they report that the sex of cells has a surprising, noticeable impact on nanoparticle uptake. Nanoparticles were incubated with human amniotic stem cells derived from either males or females. The team showed that the female cells took up the nanoparticles much more readily than the male cells. Morteza Mahmoudi, PhD, one of the authors on the paper, explained the implications of these results in a press release:
“These differences could have a critical impact on the administration of nanoparticles. If nanoparticles are carrying a drug to deliver [including gene therapies], different uptake could mean different therapeutic efficacy and other important differences, such as safety, in clinical data.”
Laurel Barchas is an old and dear friend of the communications team here at CIRM. As a student at U.C. Berkeley she helped us draft our education portal – putting together a comprehensive curriculum to help high schools teach students about stem cells in a way that met all state and federal standards. But a funny thing happened on her way to her Ph.D., she realized she had changed her mind about research, and so she changed her career direction.
Stem cell parental advice—you can grow up to be anything!
I was one of those students who, since high school, knew I was destined for the lab. Throughout some of high school, and all of college and graduate school, I had internships or positions in amazing labs that warmly took me in and trained me how to be a scientist. I loved designing and carrying out experiments on my stem cells, presenting at lab meetings, writing theses, and teaching others about my work through undergraduate lectures and high school presentations. My participation in the Student Society for Stem Cell Research hugely supported all of my efforts; it even enabled me to get one of my first jobs as a contract curriculum writer (a project manager role) with the California Institute for Regenerative Medicine, which launched my writing career.
Four years into my biology PhD program, things became clear that I didn’t want to do research anymore. I couldn’t handle the failure inherent in doing research. I wasn’t able to put in the time and focus necessary to do big experiments—then repeat them over and over. Although I loved science, I wasn’t meant to be a career scientist like many of my colleagues. I was a science communicator. Realizing this, and taking into account my personal struggles, my advisers and I decided the best thing was to get a terminal master’s degree.**
Differentiation—finding the right path
I struggled for a while finding a job that suited me. I worked as an education consultant, writing materials directed at teachers and students. I worked as a marketing, communications and operations assistant for a real estate group. I looked for jobs as a teacher, curriculum developer, and science education program coordinator, but none felt quite right for me. Although I had extensive experience in school developing materials for teachers and giving presentations to students, and I knew education could be a rewarding career path, I wasn’t sure I wanted to be in the academic world anymore.
Finally, I found some listings looking for technical writers. I didn’t even know what that was at the time. Various biotech companies had their feelers out for entry level writers with advanced degrees in biology or STEM fields—and a master’s degree was just fine. It turns out I was a perfect fit. Surprisingly, many people in the “tech com” (technical communications) and “mar com” (marketing communications) departments at my company had a similar experience; they didn’t want careers in research or the medical professions, so they chose communications.
Life as a technical writer—feeling like a glial cell
As a technical writer at my company, I have many responsibilities beyond writing and editing user manuals, application notes, and diagrams. Tech writers are much like the oft-forgotten glial cells that “glue the brain together.” I manage each project from start to finish, and I get to work on all types of technical documentation and marketing collateral with a team of company scientists (R&D), graphic designers, marketing specialists, coders, product managers, and other writers. Often, I have major creative input on the content, design, and development of marketing campaigns. I enjoy starting with ideas—maybe a few bullet points or a rough draft—and building colorful, captivating content. It feels like solving a complex puzzle.
I’ve gotten the chance to write articles on human induced pluripotent stem cell-derived beta cells for a drug discovery publication and to create portals for our website. I’ve helped make booth panels and printed resources for conferences like the International Society for Stem Cell Research. Most importantly (to me), I’ve managed to stay within the field of stem cell research/regenerative medicine. I am the main writer for that product and service line, so I can use my expertise and experience (plus, knowledge of my audience) to present products that advance my audience’s basic, translational and clinical research.
I love my job. It pays well, has regular hours, and gives me a sense of belonging to a team. It’s fast paced, I’m working on a new thing every day, and I get to learn and write about the latest advancements from our R&D teams around the world. I could go on and on, but suffice it to say that the job fits like a glove, and I can see myself doing this long term. Also…I get to live in Silicon Valley! (Pros: great food, culture, people. Cons: cost of living, traffic.)
I hope you can get encouragement from the retelling of my experience that there is a space for you in this field. This is the first post in a series of articles about careers in regenerative medicine. I aim to take you through a tour of the vocational landscape—its ups, its downs—and am looking forward to hearing from you with any jobs/roles/scenarios you are curious about. Please comment on what you’d like to learn about next!
Remember: there are plenty of options and ways for you to apply your talent and experience to pushing our field forward. SSSCR is here to help!
*I want to thank everyone who serves in the research and medical areas. Without you our field would stop in its tracks. However, not everyone is cut out for such positions. Luckily, there are other options.
**Some reading this might say “awwwww, too bad, she was so close to that PhD” and some might say “that’s a major accomplishment and you can do a lot with that degree!” Both are right, but I choose to believe the latter, as I am so much happier now that I released myself from the allure of lab research and went into science communications. We tend to hold science and medicine up on pedestals; however, science communication facilitates almost all interactions between academic and industry scientists, clinicians, and the public. An understanding of and engagement with new science is critical to promoting a healthy democracy with citizens who can make informed decisions about their society’s future.
Laurel is a co-founder of SSSCR, the current Associate Director, and a member of the SSSCR International executive committee. She has been involved in SSSCR since 2004, when she helped start UC Berkeley’s chapter. Her main contributions are educating various communities about stem cell research and building career development opportunities for students. Along with a team of SSSCR members, Laurel created the California Institute for Regenerative Medicine’s stem cell education portal to provide teachers with the materials they need to engage students with the field. Currently, Laurel is a Senior Technical Writer focused on stem cell products and services.
How smelling your food could cause weight gain (Karen Ring).
Here’s the headline that caught my eye this week: “Smelling your food first can make you fat…”
It’s a bizarre statement, but the claim is backed by scientific research coming from a new study in Cell Metabolism by researchers at the University of California Berkeley. The team found that obese mice who smelled their food before eating it were more likely to gain weight compared to obese mice that couldn’t smell their food.
Their experiments revealed a connection between the olfactory system, which is responsible for our sense of smell, and how the mice metabolize food into energy. Obese mice that lost their ability to smell actually lost weight on a high-fat diet, burned more fat, and became more sensitive to the hormone insulin. Insulin regulates how much glucose, or sugar, is in the blood by facilitating the absorption of glucose by fat, liver and muscle cells. In obese individuals, insulin resistance can occur where their cells are no longer sensitive to the hormone and therefore can’t regulate how much glucose is in the blood.
Both mice in this picture were fed the same high-fat diet. The only difference: the lower mouse’s sense of smell was temporarily blocked. Image: UC Berkeley
For obese mice that could smell their food, the same high fat diet given to the “no-smellers” resulted in massive weight gain in the “smellers” because their metabolism was impaired. Even more interesting is the fact that other types of smells unrelated to food, such as the scent of other mice, influenced weight gain in the “smellers”.
The authors concluded that the centers in our brain that are responsible for smell (the olfactory system) and metabolism (the hypothalamus) are connected and that manipulating smell could be a future strategy to influence how the brain controls the balance of energy during food consumption.
In an interview with Tech Times, senior author on the study, Dr. Andrew Dillin, explained how their research could potentially lead to a new strategy to promote weight loss,
“Sensory systems play a role in metabolism. Weight gain isn’t purely a measure of the calories taken in; it’s also related to how those calories are perceived. If we can validate this in humans, perhaps we can actually make a drug that doesn’t interfere with smell but still blocks that metabolic circuitry. That would be amazing.”
A link between colorectal cancer and a Western diet identified
Weight gain isn’t the only concern of a eating a high-fat diet. It’s thought that 80% of colorectal cases are associated with a high-fat, Western diet. The basis for this connection hasn’t been well understood. But this week, researchers at the Cleveland Clinic report in Stem Cell Reports that they’ve pinpointed a protein signaling network within cancer stem cells as a possible source of the link.
Cancer stem cells have properties that resemble embryonic stem cells and are thought to be the source of a cancer’s unlimited growth and spread. A cancer stem cell maintains its properties by exploiting various cell signaling processes that when functioning abnormally can lead to inappropriate cell division and tumor growth. In this study, the team focused on one cell signaling process carried out by a protein called STAT3, known to promote tumor growth in a mouse model of colon cancer. When the team blocked STAT3 activity, high fat diet-induced cancer stem cell growth subsided.
In a press release, Dr. Matthew Kalady, a colorectal surgeon at the Cleveland Clinic and an author on this study, explained how this new insight can open new therapeutic avenues:
“We have known the influence of diet on colorectal cancer. However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk.”
Scientists connect dots between diabetes and broken bones. Type 2 diabetes carries a whole host of long-term complications including heart disease, nerve damage, kidney dysfunction and even an increased risk for bone fractures. The connection between diabetes and fragile bones has not been well understood. But this week, researchers at New York University of Dentistry, Stanford University and China’s Dalian Medical University published a report, funded in part by CIRM, in this week’s Nature Communications showing a biochemical basis for this connection. The new insight may lead to treatment options to prevent fractures.
Fundamentally, diabetes is a disease that causes hyperglycemia, or abnormally high levels of blood sugar. The team ran a systematic analysis of hyperglycemia’s effects on bone metabolism using bone marrow samples from diabetic and healthy mice. They found that the levels of succinate, a key molecule involved in energy production, are over 20 times higher in the diabetic mice. In turns out that succinate also acts as a stimulator of bone breakdown. Now, bone is continually in a process of turnover and, in a healthy state, the breakdown of old bone is balanced with the formation of new bone. So, it appears that the huge increase of succinate is tipping the balance of bone turnover. In fact, the team found that the porous, yet strong inner region of bone, called trabecular bone, was significantly reduced in the diabetic mice, making them more susceptible to fractures.
“The results are important because diabetics have a significantly higher fracture risk and their healing process is always delayed. In our study, the hyperglycemic mice had increased bone resorption [the breakdown and absorption of old bone], which outpaced the formation of new bone. This has implications for bone protection, as well as for the treatment of diabetes-associated collateral bone damage.”
Here are the stem cell stories that caught our eye this week. Enjoy!
LAPD officer in search of the perfect match.
LAPD Officer Matthew Medina with his wife, Angelee, and their daughters Sadie and Cassiah. (Family photo)
This week, the San Diego Union-Tribune featured a story that tugs at your heart strings about an LAPD officer in desperate need of a bone marrow transplant. Matthew Medina is a 40-year-old man who was diagnosed earlier this year with aplastic anemia, a rare disorder that prevents the bone marrow from producing enough blood cells and platelets. Patients with this disorder are prone to chronic fatigue and are at higher risk for infection and uncontrolled bleeding.
Matthew needs a bone marrow transplant to replace his diseased bone marrow with healthy marrow from a donor, but so far, he has yet to find a match. Part of the reason for this difficulty is the lack of diversity in the national bone marrow registry, which has over 25 million registered donors, the majority of which are white Americans of European decent. As a Filipino, Matthew has a 40% chance of finding a perfect match in the national registry compared to a 75% chance if he were white. An even more unsettling fact is that Filipinos make up less than 1% of donors on the national registry.
Matthew has a sister, but unfortunately, she wasn’t a match. For now, Matthew is being kept alive with blood transfusions at his home in Bellflower while he waits for good news. With the support of his family and friends, the hope is that he won’t have to wait for long. Already 1000 people in his local community have signed up to be bone marrow donors.
On a larger scale, organizations like A3M and Mixed Marrow are hoping to help patients like Matthew by increasing the diversity of the national bone marrow registry. A3M specifically recruits Asian donors while Mixed Match focuses on people with multi-ethnic backgrounds. Ayumi Nagata, a recruitment manager at A3M, said their main challenge is making healthy people realize the importance of being a bone marrow donor.
“They could be the cure for someone’s cancer or other disease and save their life. How often do we have that kind of opportunity?”
An algorithm that makes it easier to see stem cell development.
To understand how certain organs like the brain develop, scientists rely on advanced technologies that can track individual stem cells and monitor their fate as they mature into more specialized cells. Scientists can observe stem cell development with fluorescent proteins that light up when a stem cell expresses specific transcription factors that help decide the cell’s fate. Using a time-lapse microscope, these fluorescent stem cells can easily be identified and tracked throughout their lifetime.
But the pictures don’t always come out crystal clear. Just as a dirty camera lens makes for a dirty picture, images produced by time-lapse microscopy images can be plagued by shadows, artifacts and lighting inconsistencies, making it difficult to observe the orchestrated expression of transcription factors involved in a stem cell’s development.
This week in the journal Nature Communications, a team of scientists from Germany reported a solution that gives a clear view of stem cell development. The team developed a computer algorithm called BaSiC that acts like a filter and removes the background noise from time-lapse images of individual cells. Unlike previous algorithms, BaSiC requires fewer reference images to make its corrections.
“Contrary to other programs, BaSiC can correct changes in the background of time-lapse videos. This makes it a valuable tool for stem cell researchers who want to detect the appearance of specific transcription factors early on.”
The team proved that BaSiC is an effective image correcting tool by using it to study the development of hematopoietic or blood stem cells. They took time-lapse videos of blood stem cells over six days and observed that the stem cells chose between two developmental tracks that produced different types of mature blood cells. Using BaSiC, they found that blood stem cells that specialized into white blood cells expressed the transcription factor Pu.1 while the stem cells that specialized into red blood cells did not. Without the algorithm, they didn’t see this difference.
Senior author on the study, Dr. Nassir Navab, concluded by highlighting the importance of their technology and sharing his team’s vision for the future.
“Using BaSiC, we were able to make important decision factors visible that would otherwise have been drowned out by noise. The long-term goal of this research is to facilitate influencing the development of stem cells in a targeted manner, for example to cultivate new heart muscle cells for heat-attack patients. The novel possibilities for observation are bringing us a step closer to this goal.”
Silenced vs active genes: it’s like oil and water (Todd Dubicoff)
The DNA from just one of your cells would be an astounding six feet in length if stretched out end to end. To fit into a nucleus that is a mere 4/10,000th of an inch in diameter, DNA’s double helical structure is organized into intricate twists within twists with the help of proteins called histones.
Together the DNA and histones are called chromatin. And it turns out that chromatin isn’t just for stuffing all that genetic material into a tiny space. The amount of DNA folding also affects the regulation of genes. Areas of chromatin that are less densely packed are more accessible to DNA-binding proteins called transcription factors that activate gene activity. Other regions, called heterochromatin, are compacted which leads to silencing of genes because transcription factors are shut out.
But there’s a wrinkle in this story. More recently, scientists have shown that large proteins are able to wriggle their way into heterochromatin while smaller proteins cannot. So, there must be additional factors at play. This week, a CIRM-funded research project published in Nature provides a possible explanation.
Liquid-like fusion of heterochromatin protein 1a droplets is shown in the embryo of a fruit fly. (Credit: Amy Strom/Berkeley Lab)
Examining the nuclei of fruit fly embryos, a UC Berkeley research team report that various regions of heterochromatin coalesce into liquid droplets which physically separates them from regions where gene activity is high. This phenomenon, called phase-phase separation, is what causes oil droplets to fuse together when added to water. Lead author Dr. Amy Strom explained the novelty of this finding and its implications in a press release:
“We are excited about these findings because they explain a mystery that’s existed in the field for a decade. That is, if compaction [of chromatin] controls access to silenced [DNA] sequences, how are other large proteins still able to get in? Chromatin organization by phase separation means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners.”
Phase-phase separation can also affect other cell components, and problems with it have been linked to neurological disorders like dementia. In diseases like Alzheimer’s and Huntington’s, proteins aggregate causing them to become more solid than liquid over time. Strom is excited about how phase-phase separation insights could lead to novel therapeutic strategies:
“If we can better understand what causes aggregation, and how to keep things more liquid, we might have a chance to combat these types of disease.”
Imilce Rodriguez-Fernandez likes to talk trash. No, really, she does. In her case it’s cellular trash, the kind that builds up in our cells and has to be removed to ensure the cells don’t become sick.
Imilce was one of several stem cell researchers who took part in a couple of public events over the weekend, on either side of San Francisco Bay, that served to span both a geographical and generational divide and create a common sense of community.
The first event was at the Buck Institute for Research on Aging in Marin County, near San Francisco. It was titled “Stem Cell Celebration” and that’s pretty much what it was. It featured some extraordinary young scientists from the Buck talking about the work they are doing in uncovering some of the connections between aging and chronic diseases, and coming up with solutions to stop or even reverse some of those changes.
One of those scientists was Imilce. She explained that just as it is important for people to get rid of their trash so they can have a clean, healthy home, so it is important for our cells to do the same. Cells that fail to get rid of their protein trash become sick, unhealthy and ultimately stop working.
Imilce is exploring the cellular janitorial services our bodies have developed to deal with trash, and trying to find ways to enhance them so they are more effective, particularly as we age and those janitorial services aren’t as efficient as they were in our youth.
Unlocking the secrets of premature aging
Chris Wiley, another postdoctoral researcher at the Buck, showed that some medications that are used to treat HIV may be life-saving on one level, preventing the onset of full-blown AIDS, but that those benefits come with a cost, namely premature aging. Chris said the impact of aging doesn’t just affect one cell or one part of the body, but ripples out affecting other cells and other parts of the body. By studying the impact those medications have on our bodies he’s hoping to find ways to maintain the benefits of those drugs, but get rid of the downside.
The list of speakers was a Who’s Who of CIRM-funded scientists from U.C. Davis’ Jan Nolta and Paul Knoepfler, to U.C. Irvine’s Henry Klassen and U.C. Berkeley’s David Schaffer. The talks ranged from progress in fighting blindness, to how advances in stem cell gene editing are cause for celebration, and concern.
What struck me most about both meetings was the age divide. At the Buck those presenting were young scientists, millennials; the audience was considerably older, baby boomers. At UC Berkeley it was the reverse; the presenters were experienced scientists of the baby boom generation, and the audience were keen young students representing the next generation of scientists.
Bridging the divide
But regardless of the age differences there was a shared sense of involvement, a feeling that regardless of which side of the audience we are on we all have something in common, we are all part of the stem cell community.
All communities have a story, something that helps bind them together and gives them a sense of common purpose. For the stem cell community there is not one single story, there are many. But while those stories all start from a different place, they end up with a common theme; inspiration, determination and hope.
To all you stem cell lovers out there, today is your day! The second Wednesday of October is Stem Cell Awareness Day (SCAD), which brings together organizations and individuals that are working to ensure the general public realizes the benefits of stem cell research.
For patients in desperate need of treatments for diseases without cures, this is also a day to recognize their struggles and the scientific advances in the stem cell field that are bringing us closer to helping these patients.
Induced pluripotent stem cells.
How are people celebrating SCAD?
This year, a number of institutes in California are hosting events in honor of Stem Cell Awareness Day. Members of the CIRM team will be speaking on Saturday about “The Power of Stem Cells” at the Buck Institute for Research on Aging in Novato (RSVP on Facebook) and at the Berkeley Student Society for Stem Cell Research Conference in Berkeley (RSVP on Eventbrite). There are also a few SCAD events going on this week in Southern California. You can learn more about these all events on our website.
You can also find out about other SCAD celebrations and events on social media by following the hashtag #StemCellAwarenessDay and #StemCellDay on Twitter.
Super Cells: The Power of Stem Cells
Super Cells exhibit at the Lawrence Hall of Science
This is a REALLY COOL interactive exhibit that explains what stem cells are, what they do, and how we can harness their power to treat disease and injury. CIRM was one of the partners that helped create this exhibit, so we were especially excited to see it in person.
Super Cells has four “high-tech interactive zones and a comprehensive educational guide for school children ages 6-14”. You can read more details about the exhibit in this promotional handout. Based on my visit to the exhibit, I can easily say that Super Cells will be interesting and informative to any age group.
The exhibit was unveiled on September 28th, and the Hall told us that they have already heard positive reviews from their visitors. We had the opportunity to talk further with Susan Gregory, the Deputy Director of the Hall, and Adam Frost, a marketing specialist, about the Super Cells exhibit. We asked them a few questions and will share their interview below followed by a few fun pictures we took of the exhibit.
Q: Why did the Lawrence Hall of Science decide to host the Super Cells exhibit?
The Lawrence Hall of Science has a history of bringing in exciting and engaging traveling exhibitions, and we were looking for something new to excite our visitors in the Fall season. When the opportunity presented itself to host Super Cells, we thought it would be a good fit for our audience. Additionally, the Hall is increasing its programming and exhibits in the fields of biology, chemistry and bioengineering.
Q: What aspects of the Super Cells exhibit do you think are valuable to younger kids?
We strive to make our exhibit experiences hands-on and interactive. The Hall believes that the best way for kids to learn science is for them to be active in their learning. Super Cells offers a variety of elements that speak to our philosophy of learning and make learning science more fun.
Q: How is exhibit similar or unique to other exhibits you’ve hosted previously?
The Hall hosts and develops exhibits across a broad range of scientific, engineering, technology and mathematical topics. We are always looking for exhibits that address recent scientific advances, and also try to showcase cutting edge research.
Super Cells presents both basic cell biology and information about recent medical and scientific advances, so it fits. Also, as mentioned in our behind the scenes story about the exhibit install, in the past many of our traveling exhibits were very large experiences that tended to take up a lot of space on the museum floor. One thing that is great about Super Cells is that it packs a lot of information into a relatively small space, allowing us to keep a number of experiences and activities that our audience has come to love on the floor, instead of removing them to make room.
Q: Will there be any special events at the Hall featuring this exhibit?
On November 11, the Hall will host a fun day of activities centered around DNA and the exhibit. Younger visitors will make DNA bracelets based on the unique traits in their genome, while older kids will isolate their own DNA using a swab from inside their cheek. We are still finalizing the details of this event, but it will definitely happen.
Q: Why do you think it’s important for younger students and the general public to learn about stem cells and stem cell research?
As UC Berkeley’s public science center, the Hall is committed to providing a window into cutting edge research and the latest scientific information. We think it’s really important for people and kids to learn about the skills and science behind current research so they can be prepared for a future of incredible scientific challenges and opportunities that we can’t foresee.
Super Cells will be open at the Lawrence Hall of Science until November 27th, so be sure to check it out before then. If you don’t live in California, don’t worry, Super Cells will be traveling around the U.S., Europe and Canada. You can find out where Super Cells is touring next on their website.
We hope you enjoy our photos of the Super Cells exhibit!
Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.
Stem cells heal diabetic foot ulcers in pilot study Foot ulcers are one of the many long-term complications that diabetics face. About 15 percent of patients develop these open sores which typically appear at the bottom of the foot. In a quarter of these cases, the ulcers lead to serious infection requiring amputation.
Diabetic foot ulcers are open sores that don’t heal and in many cases leads to amputation. Image source: Izunpharma
But help may be on the horizon in the form of stem cells. Researchers at Mansoura University in Egypt recently presented results of a small study in which 10 patients with diabetic foot ulcers received standard care and another 10 patients received standard care plus injections of mesenchymal stem cells that had been collected from each patient’s own bone marrow. After just six weeks, the stem cell treated group showed a 50% reduction in the foot ulcers while the group with only standard care had a mere 7% reduction.
These superior results with the stem cells were observed even though the group receiving the stem cells had larger foot ulcers to begin with compared to the untreated patients. There are many examples of mesenchymal stem cells’ healing power which make them an extremely popular cell source for hundreds of on-going clinical trials. Mesenchymal stem cells are known to reduce inflammation and increase blood vessel formation, two properties that may be at work to give diabetic foot ulcers the chance to get better.
Suppressing nerve signals to help spinal cord injury victims Losing the use of one’s limbs is a profound life-altering change for spinal cord injury victims. But their quality of life also suffers tremendously from the loss of bladder control and chronic pain sensations. So much so, victims often say that just improving these secondary symptoms would make a huge improvement in their lives.
While current stem cell-based clinical trials, like the CIRM-funded Asterias study, aim to reverse paralysis by restoring loss nerve signals, recent CIRM-funded animal data published in Cell Stem Cell from UC San Francisco suggest that nerve cells that naturally suppress nerve signals may be helpful for these other symptoms of spinal cord injury.
Mature inhibitory neuron derived from human embryonic stem cells is shown after successfully migrated and integrated into the injured mouse spinal cord. Photo by Jiadong Chen, UCSF
It turns out that the bladder control loss and chronic pain may be due to overactive nerve signals. So the lab of Arnold Kriegstein transplanted inhibitory nerve cells – derived from human embryonic stem cells – into mice with spinal cord injuries. The scientists observed that these human inhibitory nerve cells, or interneurons, successfully made working connections in the damaged mouse spinal cords. The rewiring introduced by these interneurons also led to reduced pain behaviors in the mice as well as improvements in bladder control.
In a Yahoo Finance interview, Kreigstein told reporters he’s eager to push forward with these intriguing results:
Arnold Kriegstein, UCSF
“As a clinician, I’m very aware of the urgency that’s felt among patients who are often very desperate for treatment. As a result, we’re very interested in accelerating this work toward clinical trials as soon as possible, but there are many steps along the way. We have to demonstrate that this is safe, as well as replicating it in other animals. This involves scaling up the production of these human interneurons in a way that would be compatible with a clinical product.”
Expanding the CRISPR toolbox If science had a fashion week, the relatively new gene editing technology called CRISPR/Cas9 would be sure to dominate the runway. You can think of CRISPR/Cas9 as a protein and RNA complex that acts as a molecular scissor which directly targets and cuts specific sequences of DNA in the human genome. Scientists are using CRISPR/Cas9 to develop innovative biomedical techniques such as removing disease-causing mutations in stem cells in hopes of developing potential treatments for patients suffering from diseases that have no cures.
What’s particularly interesting about the CRISPR/Cas9 system is that the Cas9 protein responsible for cutting DNA is part of a family of CRISPR associated proteins (Cas) that have similar but slightly different functions. Scientists are currently expanding the CRISPR toolbox by exploring the functions of other CRISPR associated proteins for gene editing applications.
A CIRM-funded team at UC Berkeley is particularly interested in a CRISPR protein called C2c2, which is different from Cas9 in that it targets and cuts RNA rather than DNA. Led by Berkeley professor Jennifer Doudna, the team discovered that the CRISPR/C2c2 complex has not just one, but two, distinct ways that it cuts RNA. Their findings were published this week in the journal Nature.
The first way involves creation: C2c2 helps make the guide RNAs that are used to find the RNA molecules that it wants to cut. The second way involves destruction: after the CRISPR/C2c2 complex finds it’s RNAs of choice, C2c2 can then cut and destroy the RNAs.
Doudna commented on the potential applications for this newly added CRISPR tool in a Berkeley News release:
Jennifer Doudna: Photo courtesy of iPSCell.com
“This study expands our molecular understanding of C2c2 to guide RNA processing and provides the first application of this novel RNase. C2c2 is essentially a self-arming sentinel that attacks all RNAs upon detecting its target. This activity can be harnessed as an auto-amplifying detector that may be useful as a low-cost diagnostic.”