An NIH and foundation-funded postdoctoral fellow position in the Knoepfler Lab at UC Davis School of Medicine is open. The focus of research will be on cancer and stem cell epigenomics. Studies will include functional genomics assays such s ChIP-Seq, chromatin configuration, CRISPR genetics work, and cell biological research.
Qualifications:
Applicants must have a PhD, an MD, or both. Preference will be given to applicants who do not already have postdoctoral experience, but who have a strong track record as graduate students of biological research including publication of their work. Genomics, next generation sequencing, bioinformatics, cancer biology, and/or stem cell experience would be a plus. Excellent written and oral communication skills are required.
To apply: E-mail knoepfler@ucdavis.edu a 1-page overview of research experience and career goals, a CV, and contact information for 3 references.
I was really sad when I heard about John McCain’s diagnosis with a glioblastoma, a particularly nasty type of brain tumor that we study in my lab when it shows up in children. My own battle with prostate cancer starting almost 8 years ago might have sensitized me to this news even though I’m in long-term remission. I also started thinking about whether stem cells could somehow help him fight or even beat the tumor. It turns out that others have been including stem cells in the mix in thinking about McCain’s treatment options.
How might stem cells be of use for patients like McCain with a serious brain tumor?
Many types of brain cancer have their own populations of stem cells that are called “cancer stem cells”, but it turns out that other stem cells in some cases can also home in on brain tumors being somehow attracted to them. This property has inspired researchers for years to consider using stem cells as a delivery mechanism to bring toxic agents right into the tumor, and a variety of clinical trials are ongoing in this area that in theory could be applicable to McCain.
Any such treatment would be highly experimental and have a high risk of failure and even potential harm. However, since most patients with glioblastoma die within about 1 year even with aggressive conventional treatments including surgery (McCain already had that when his tumor was discovered during blood clot removal), brain irradiation and chemo, risky interventions are quite justified.
What would stem cells deliver to the cancer in the way of a therapeutic punch to in theory more specifically work to help a brain tumor patient? A whopping 144studies pop up on Clinicaltrials.gov for a search for “Glioblastoma” and “stem cells”.
Smart b0ms. A number of these involve “loaded” stem cells carrying payloads to attack the tumor, which include a range of factors such as toxins and viruses. For instance, this cool Northwestern University trialmentioned in the Yahoo article cited near the beginning of this post uses viruses delivered by stem cells. Some of the stem cells used as smart b0ms against brain cancer may be loaded with nanoparticles that they deliver to the tumor cells. Interestingly, whatever the “special delivery” of toxicity that the stem cells bring along, they can deliver it to the cancer cells in a variety of ways including via exosomes (little buds off of cell membranes containing small amounts of cellular material inside) or even fusing with the cancer cells to become one bigger cell containing the poison.
Immunotherapy. In a somewhat different approach, stem cells may also have a role to play in immunotherapy against brain tumors, an exciting area that is really taking off where the patient’s immune system is turbo-charged to specifically kill the tumor. The most talked about cancer immunotherapy today is called CAR-T, which is not technically a stem cell therapy but rather a “cell therapy”.
Protection of the good guys. Some of the trials take a different approach of using stem cells to hopefully benefit the patient by potentially protecting the normal cells in their brains from the harsh conventional treatments. In certain cases the stem cells have been genetically modified to be resistant to chemotherapy.
Overall, McCain has quite a battle in front of him with his glioblastoma whether he sticks to conventional therapies or goes into a clinical trial such as one using stem cells or some other new investigational therapy. I wish him the best.
The FDA issued a historic statement today promising to more clearly define its regulatory policies on stem cell therapies and to take strong action on some stem cell clinics that it views as “bad actors”. I’ve never the FDA use such clear-cut language before. I give big kudos to new FDA Commissioner Scott Gottlieb.
It already took some action too on clinics in Florida and in California. So today we heard about both a bold statement of vision on how the FDA will deal with stem cell clinics and also it took real action. For instance, the FDA issued a warning letterto Kristin Comella of US Stem Cell Clinic (a subsidiary of US Stem Cell Inc) in Florida, an organization linked to negative outcomes in patients including blindness. It also apparently raided a stem cell business in San Diego, StemImmune Inc.
This taken together is a very big deal. For me as someone who has been following and trying to make a difference about the stem cell clinic duduk kasus for more than 7 years, I find today very encouraging. Better late than never?
The FDA also indicated today and has suggested before in a blog postby Gottlieb, that it may soften some regulations of stem cell treatments. We’ll have to wait and see how that plays out and what impact it has.
Overall, what does this all mean and what happens next? This story is still breaking so there’s a lot to think about, but on my first run through of it I’ve got 6 major thoughts and questions on today’s development.
How much further will the FDA go with actual enforcement actions? What we heard about today is a major positive step, but it’s just one step out of many needed along the path toward reining in the out of control stem cell clinic industry. With around 600 stem cell clinics in the U.S., FDA action on just 2 is positive but not enough. More to come?
Will the FDA define fat stem cells as a drug (or not) in upcoming guidances? If yes, how will it handle the fact that there are hundreds of clinics using fat stem cells without proper licensing and approval of the product/treatment as a drug? If not and fat stem cells are viewed as not necessarily drug products, will the FDA then narrow the scope of permitted applications of fat stem cells used not as a drug to only include homologous use? I.e., “fat stem cells are drugs if used on non-fat-related health problems”? May there be exceptions to that limitation?
How will the FDA handle non-homologous use of bone marrow cells in the commercial sector? This kind of use is pretty common out there too by clinics. To be clear, some clinics use bone marrow cells in a homologous fashion and without more than minimal manipulation, but I’m not referring here to those.
Amniotics? Will the FDA work to deal with the growing duduk kasus of unapproved, amniotic stem cell offerings? If so, what steps will it take?
What about networks of stem cell businesses? How will the new FDA under Gottlieb view networks of stem cell businesses such as Cell Surgical Network? This comes to mind because the FDA in its PR mentioned key member of that network as where StemImmune’s unapproved product was administered to patients: “California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, California. ” The founders of Cell Surgical Network are listed on its own website as part of the StemImmune Inc. leadership team.
Will other entities like state medical boards use this FDA action as a spring-board to get off the sidelines and take positive action too? After all, some of the providers at stem cell clinics I’ve talked to over the years often recite a similar mantra that it isn’t the FDA that regulates them, but rather state medical boards. So, state medical boards and other governmental bodies, are you watching and willing to do something? So far state medical boards have mainly stood on the sidelines on the stem cell clinic problem, but that may be changing.
The Knoepfler lab has formed a team to raise research funds to try to find new treatments and hopefully cures for kids facing a type of mostly fatal brain tumors. Here’s the team page.If you can give us a hand by joining the team or making a donation that’d be wonderful. Any help would be appreciated.
The way it works is that this great pediatric cancer foundation called Alex’s Lemonade Stand Foundation, from whom I recently got a 2-year grant, will match all the money we raise dollar for dollar to give the funding a further boost. So for every $1 we raise, our lab’s Alex’s Lemonade Stand Foundation-supported children’s brain tumor research gets $2 more of support beyond the grant.
As part of the team, we simply indicate that we will walk, run, or bike (or some combo of the three) a certain number of miles by December 31. Participants can self-record mileage or you can do it via an App like Fitbit or others.
Here’s more info from the UC Davis Comprehensive Cancer Center about the specific childhood cancer research & the cool back story of Alex’s Lemonade Stand Foundation 🍋🍋🍋🍋🍋🍋.
Screenshot from publicly available US Stem Cell Inc. Facebook video of talk by Kristin Comella
What if it seemed based on the public statements of its leader that a business was using an unapproved and unproven, genetically-modified, stem cell-based ‘cancer vaccine’ on patients?
Is that possible?
Sometimes I think I’ve seen and heard it all when it comes to companies marketing non-FDA approved, scientifically unproven stem cell ‘therapies’ to patients after 8+ years blogging here, but then I run across something new each year that still surprises me.
For example, in a mind-blowing video that the company posted on Facebook the leader of U.S. Stem Cell, Inc. ($USRM, a publicly traded stem cell clinic firm), Katolik Comella, seems to be indicating to an audience that her firm might already be administering some kind of stem cell-based “cancer vaccine” to patients. This possibly genetically-modified product would almost certainly not have been approved by the FDA nor tested first in rigorous preclinical studies in animals.
The video as a whole provides many other striking insights into USRM and the stem cell clinic industry (which I’ll cover in a separate follow-up post), but if you go to about the 43.5-minute mark in this video, you can see the cancer-related thing that struck me as so concerning. Comella begins talking about how her company has a cancer “protocol.” She also mentions electroporation and a “cancer vaccine” mechanism suggested to involve antigen presentation.
What’s the deal here? It’s difficult to be sure.
I got no reply to an email that I sent to Comella a month or so back via which I was trying to get some more clarity on what USRM was doing with cancer through asking some straightforward questions. Even without further specifics, in my opinion as a stem cell and cancer researcher as well as a cancer survivor myself, there is plenty in the video to be deeply concerned about regarding the possible cancer “vaccine” protocol mentioned.
Here are some key points that stood out and questions that came to mind as I’ve been pondering this.
Genetically modifying stem cells for clinical use? Electroporation is typically something we do in a lab to insert DNA (or much less often RNA) into cells for in vitro studies. It is an electric jolt to cells in a special glass tube called a cuvette generally used to get DNA into them so it is a form of genetic modification. It can be tricky to get right so as to get the DNA in without killing all of the cells. For instance, I accidentally killed my cells a few times as a postdoc when there was an arc of electricity. I don’t have a clear picture of the exact details of what USRM is doing on this front, but if they are in fact genetically modifying stem cells via DNA electroporation and then giving the cells to cancer patients without pre-clinical science to back it up and without FDA approval, this could be extremely dangerous. I hope the company will clarify this situation.
What is going into the cells and how risky is this? Then there’s the question of what specific DNA (RNA?) that USRM might be electroporating into the stem cells prior to use. She mentions a protein from the patients’ own cancer in the video. If USRM is electroporating in the DNA to express cancer-related proteins in patients’ stem cells and then infusing the genetically modified MSCs back into the patients, that potentially could cause new cancers and could also spark dangerous immune reactions as a side effect. It seems to me more generally like this might be an effort potentially trying to build on the excitement in the field over CAR-T cells, but these wouldn’t be CAR-T cells.
Where would the electroporated material come from? I also wonder about the source of whatever they are electroporating into the stem cells to make their “vaccine” as such materials intended for clinical use in patients would have to be made in a very particular, rigorous kind of laboratory facility with strict environmental controls and equipment dedicated to only being used for processing drug products. For instance, you can’t just make a regular old prep of DNA (or RNA or whatever is being electroporated) like we do in the lab for in vitro studies if you are going to use it for a clinical protocol. It would further increase risk.
Would the cells be cultured in a lab? Typically to electroporate cells, one would first grow them, then zap them, and then put them in culture again for some period of time to recover prior to the end use. If indeed that is happening, the step(s) with the cells in a dish in the lab not only raises risks, but also add to other multiple factors here making this a case of a product seeming to me at least to be almost certainly a drug requiring pre-approval.
Efficacy? I also am skeptical about efficacy of this kind of approach, especially as done without peer-reviewed pre-clinical data to back it up. In addition, some cancer patients who might get this hypothetical ‘cancer vaccine’-like intervention, may end up choosing to stop other therapeutic approaches that are more likely to have beneficial results.
Maybe this is just an idea and not actually an active protocol? Perhaps I got the wrong impression from this video? Maybe USRM isn’t already infusing modified stem cells into cancer patients, but it’s just an idea of theirs? I guess that’s possible, but instead it sure sounds like this has already been done on patients. Again, I hope USRM can clarify.
Stem cell clinics get more interested in cancer overall. There is other stem cell clinic activity on the cancer front. A California-based stem cell clinic firm, California Stem Cell Treatment Center (part of Cell Surgical Network) along with a second firm were subject to FDA action last year related to an unapproved cancer-related product reportedly seized by US Marshalls. It apparently involved mixing stem cells with smallpox vaccine, which to me at least seems like another very high-risk, unapproved ‘cancer vaccine’ kind of idea. More broadly, over the years I’ve also seen some other stem cell clinics claim that various kinds of unproven stem cells can work for cancer.
Overall, I’m extremely skeptical that unproven stem cell clinics can help cancer patients by wading into the cancer arena generally without strong preclinical data, lacking FDA-approval, often with no medical oncology experience, etc.
In my opinion it is far more likely that already hurting cancer patients would get hurt more.
For patients. For these reasons, if you are a cancer patient or a loved one of a patient reading this, I would strongly caution against getting an unapproved cancer therapy outside of a proper clinical trial. Even traditional clinical trials have risks, but they are typically based on extensive preclinical animal model data and are conducted in a very careful manner following FDA guidelines.
If you or a loved one are in a particularly desperate situation with a potentially lethal cancer such as one that has metastasized or recurred and there’s no available approved treatment nor active clinical trial available for you/your family member, instead of going to a stem cell clinic, consider applying to the FDA for a compassionate use exemption with the particular company/sponsor developing the new experimental cancer product of interest, if the company is willing. The FDA approves almost 100% of these, does so quickly these days, the company presumably would have oncology expertise, and at least there would be some vetting of data even via this still relatively risky route.
As a person who has faced a potentially lethal cancer, I get what you might be feeling and I understand that risk has to balanced with the nature of a particular health situation. Also to be clear, I’m not a medical doctor and am not giving medical advice, but these suggestions to use caution are just based on my experience as a stem cell and cancer researcher and cancer patient as well as common sense. Talk to your oncologist(s) and primary cancer physician for expert medical advice.
Marketing unproven CRISPR to patients? Much more broadly, there is some concern that well beyond the scope of stem cell clinics, other firms may start selling unapproved and unproven genetic modification services such as via CRISPR directly to patients. I hope in future years we won’t be seeing a major duduk perkara of unproven, for-profit “CRISPR clinics” in the way we have now with stem cell clinics.
Again, I’m going to do a second post on this USRM video, which had some other notable statements.
Could potential associated cancer risks claw into CRISPR’s potential?
The short answer from both previous and new data is that while CRISPR gene editing impacts the P53 pathway, which is involved in cancer along with having many other functions, this news is neither too surprising nor a fatal flaw, but some caution is warranted.
CRISPR is many things including an exciting technology that my own lab uses a lot, but it isn’t and never will be perfect or somehow magical. When this week’s story (e.g. in STAT here with arguably an over-the-top headline “A serious new hurdle for CRISPR: Edited cells might cause cancer, two studies find”) about a cancer connection came up, it required some reading and thinking to really see what all the buzz was about.
Part of the challenge here is that people have been so enamored of gene editing that some folks hyped it a ton. Investors in gene editing-related companies have also pushed things into the over-exuberance zone too. This all of course set this technology up for a fall or multiple falls back toward rationale reality.
The initial gene editing “don’t panic” moment came when first oneand then another paper came out indicating that the human body may have, to put it simply, some immunity to the key CRISPR protein component for standard gene editing, the nuclease Cas9. This is a real, sizable issue, but there are possible workarounds and in a way that news brought a needed taste of reality to the gene editing arena. The path ahead is not a smooth, linear one, but that’s OK.
Now two new research papers in Nature Medicine (hereand here) are being portrayed as being some big new “bad news” connection between CRISPR and cancer. The first paper is “CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response”, by a Swedish-UK team led by Jussi Taipale. The second paper is, “p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells” from a team led by Ajamete Kaykas at Novartis.
What’s the deal with these papers? How worried should we be?
First, it’s not surprising that using a nuclease system for genetic modification would activate P53 (and some data was already out on this last year), which would in turn stimulate apoptosis. After all, Cas9 creates double-strand DNA breaks. Also, it’s not a shocker that the specific cells that do successfully get gene edited might often find a way around P53-induced apoptosis triggered by Cas9.
Yes, in theory that would then make them more susceptible to oncogenic transformation, but it’s not a given. Furthermore, such events might be made much less frequent in fact by chemically inhibiting P53 transiently during gene editing. Such P53 inhibition may improve gene editing attempts for non-clinical research purposes as well.
P53 pathway status should be monitored both for certain in vitro studies and especially for potential clinical applications. For translational studies that should probably have already been on the to-do checklist, but these papers just reinforce the need. Remember that there’s another “reliable” way to relatively frequently generate individual cells in mixed populations having P53 or other cancer-related mutations: just culturing them for long enough in vitro. in other words, I believe that for cell therapies of any kind P53 pathway status and that of other oncogene-related pathways should always be monitored.
Finally, to say that CRISPR-Cas9 gene editing might “cause cancer” seems premature to me so there probably were and are better ways for people to phrase the big-picture meaning of these new papers and others like them that may pop up in the future. However, to be clear safety is crucial so this is an important development and risks of any potential therapy including gene editing-based approaches should be carefully weighed against potential benefits as trials are designed and then progress.
Graphical abstract of van der Kant, et al. Cell Stem Cell 2019. Article mentioned at the bottom of this blog post.
There’s nothing like stem cell good news and interesting publications to perk one up on a Monday. Enjoy.
What recent papers have struck you as exciting?
Novel stem cell-based cancer approaches (Part 1)
It was exciting when Fate Therapeutics got the first induced pluripotent stem cell (IPSC) IND in the U.S. for their IPSC-derived natural killer cell (NK) product. Now in another milestone the first patient has received the investigational NK therapy at UC San Diego. From UCSD, “After 10 years in remission, Derek Ruff’s cancer returned, this time as stage IV colon cancer. Despite aggressive rounds of chemotherapy, palliative radiotherapy and immunotherapy, his disease progressed. In February 2019, as part of a phase I clinical trial at Moores Cancer Center at UC San Diego Health, Ruff became the first patient in the world to be treated for cancer with a human-induced pluripotent stem cell (iPSC)-derived cell therapy called FT500.” This is very good news!
Novel stem cell-based cancer approach (Part 2)
On another IPSC front, a big biotech development also is encouraging on the cancer fight. From the PR, “Leaps by Bayer, the investment arm of the global life sciences company Bayer, and Khloris Biosciences, a biotechnology company, announced today that they have joined forces to develop novel, first-in-class anti-cancer vaccines based on human induced pluripotent stem cells (iPSCs). This technology has the potential to address one of today’s biggest issues in human health: to prevent and cure cancer.”
A tale of two new positive California stem cell bills.
Our state passed Roman Reed Spinal Cord Injury Research Act of 1999, which pioneered stem cell research for spinal cord injury. A new bill, AB214, would give this unique research jadwal $5 million in additional funding. I predict it will pass. Roman is one of the top stem cell advocates in the world and was the first recipient of The Niche’s Stem Cell Person of the Year Award.
California is a leader in a stem cell research in the U.S. and the world, but it is also leading the way on stem cell-related legislation. We were the first state to pass a law aiming to help patients better understand what they are getting into with stem cell clinics. Now a new bill, AB617, would more rigorously oversee stem cell clinics in our state. Hopefully, this legislation will become law and California can continue to lead the way amongst states trying to deal with stem cell clinics.
The FDA issued a 
The Knoepfler lab has formed a team to raise research funds to try to find new treatments and hopefully cures for kids facing a type of mostly fatal brain tumors. 
Could potential associated cancer risks claw into CRISPR’s potential?