When someone thinks of machine learning, the first thing that comes to mind might be the technology used by Netflix or Hulu to suggest new shows based on their viewing history. But what if this technology could be applied towards advancing the field of regenerative medicine?
Thanks to a CIRM funded study, a team of scientists lead by Dr. Todd McDevitt at the Gladstone Institutes have found a way to to use machine learning to control the spacial organization of stem cells, a key process that plays a vital role in organ development. This new understanding of how stem cells organize themselves in 3D is an important step towards being able to create functional and/or personalized organs for research or organ transplants.
“We’ve shown how we can leverage the intrinsic ability of stem cells to organize,” said Dr. McDevitt in a news release from Gladstone Institutes. “This gives us a new way of engineering tissues, rather than a printing approach where you try to physically force cells into a specific configuration.”
In their normal environment, stem cells are able to form patterns as they mature and over time morph into the tissues seen in an adult organism. One type of stem cell, called an induced pluripotent stem cell (iPSC), can become nearly every cell type of the body. In fact, researchers have already found ways to direct iPSCs to become various cell types such as those in the heart or brain.
Unfortunately, attempting to replicate the pattern formation of stem cells as they mature has been challenging. Some have used 3D printing to lay out stem cells in a desired shape, but the cells often migrated away from their initial locations.
In the same news release mentioned above, Ashley Libby, a graduate student at Gladstone and co-first author of this study, said that,
“Despite the importance of organization for functioning tissues, we as scientists have had difficulty creating tissues in a dish with stem cells. Instead of an organized tissue, we often get a disorganized mix of different cell types.”
To solve this problem, the scientists used a computational model to learn how to influence stem cells into forming new arrangements, such as those that might be useful in generating personalized organs.
Previous studies conducted by Dr. McDevitt showed that blocking the expression of two genes, called ROCK1 and CDH1, affected the layout of iPS cells grown in a petri dish.
In this current study, the scientists used CRISPR/Cas9 gene editing (you can read about this technology in more detail here) to block expression of ROCK1 and CDH1 at any time by adding a drug to the iPSCs. This was done to see if they could predict stem cell arrangement based on the alterations made to ROCK1 and CDH1 at different drug doses and time periods.
The team carried out various experiments with different doses and timing. Then, the data was input into a machine-learning program designed to identify patterns, something that could take a human months to identify.
The machine-learning program used the data to predict ways that ROCK1 and CDH1 affect iPSC organization. The scientists then began to see whether the program could compute how to make entirely new patterns, like a bull’s-eye or an island of cells. The team says the results were little short of astounding. Machine learning was able to accurately predict conditions that will cause stem cell colonies to form desired patterns.
The full study was published in the journal Cell Systems.
For years CIRM and others in the stem cell community (hello Paul Knoepfler) have been warning people about the dangers of going to clinics offering unproven and unapproved stem cell therapies. Recently the drum beat of people and organizations coming out in support of that stand has grown louder and louder. Mainstream media – TV and print – have run articles about these predatory clinics. And now, Google has joined those ranks, announcing it will restrict ads promoting these clinics.
“We regularly review and revise our
advertising policies. Today, we’re announcing a new Healthcare and
medicines policy to prohibit advertising for unproven or experimental
medical techniques such as most stem cell therapy, cellular (non-stem) therapy,
and gene therapy.”
“Google’s new policy banning
advertising for speculative medicines is a much-needed and welcome step to curb
the marketing of unscrupulous medical products such as unproven stem cell
therapies. While stem cells have great potential to help us understand and
treat a wide range of diseases, most stem cell interventions remain
experimental and should only be offered to patients through well-regulated
clinical trials. The premature marketing and commercialization of unproven stem
cell products threatens public health, their confidence in biomedical research,
and undermines the development of legitimate new therapies.”
Speaking of Deepak – we can use first
names here because we are not only great admirers of him as a physician but also
as a researcher, which is why we have funded
some of his research – he has just published a wonderfully well written
article criticizing these predatory clinics.
The article – in Scientific
American – is titled “Don’t Believe Everything You Hear About Stem Cells”
and rather than paraphrase his prose, I think it best if you read it yourself.
So, here it is.
Don’t Believe Everything You Hear about Stem Cells
The science is progressing rapidly,but bad
actors have co-opted stem cells’ hope and promise by preying on unsuspecting
patients and their families
Stem cell science is moving forward
rapidly, with potential therapies to treat intractable human diseases on the
horizon.Clinical trials are now underway to test the safety
and effectiveness of stem cell–based treatments for blindness,spinal
cord injury,heart disease,Parkinson’s
disease, and more,some with early positive results.A
sense of urgency drives the scientific community, and there is tremendous hope
to finally cure diseases that, to date, have had no treatment.
But don’t believe everything you hear about stem cells. Advertisements and pseudo news articles promote stem cell treatments for everything from Alzheimer’s disease,autism and ALS, to cerebral palsy and other diseases.The claims simply aren’t true–they’re propagated by people wanting to make money off of a desperate and unsuspecting or unknowing public.Patients and their families can be misled by deceptive marketing from unqualified physicians who often don’t have appropriate medical credentials and offer no scientific evidence of their claims.In many cases, the cells being utilized are not even true stem cells.
Advertisements for stem cell treatments are showing up everywhere, with too-good-to-be-true
claims and often a testimonial or two meant to suggest legitimacy or efficacy.Beware of the following:
• Claims that stem
cell treatments can treat a wide range of diseases using a singular stem cell
type. This is unlikely to be true.
• Claims that stem
cells taken from one area of the body can be used to treat another, unrelated
area of the body. This is also unlikely to be true.
• Patient testimonials used to validate a
particular treatment, with no scientific evidence. This is a red flag.
• Claims that
evidence doesn’t yet exist because the clinic is running a patient-funded
trial. This is a red flag; clinical trials rarely require payment for
• Claims that the
trial is listed on ClinicalTrials.gov and is therefore NIH-approved. This may
not be true. The Web site is simply a listing; not all are legitimate trials.
• The bottom line:
Does the treatment sound too good to be true? If so, it probably is. Look for
concrete evidence that the treatment works and is safe.
Hundreds of clinics offer costly, unapproved and unproven stem cell
interventions, and patients may suffer physical and financial harm as a result.A Multi-Pronged Approach to Deal with
The International Society for Stem Cell Research (ISSCR)has
long been concerned that bad actors have co-opted the hope and promise of stem
cell science to prey on unsuspecting patients and their families.
We read with sadness and disappointment the many stories of people trying unproven therapies and being harmed, including going blind from injections into the eyes or suffering from a spinal tumor after an injection of stem cells.Patients left financially strapped, with no physical improvement in their condition and no way to reclaim their losses, are an underreported and underappreciated aspect of these treatments.
Since late 2017, the Food and Drug Administration has stepped up its
regulatory enforcement of stem cell therapies and provided a framework
for regenerative medicine products that provides guidelines for work in
this space.The agency has alerted many clinics and centers
that they are not in compliance and has pledged to bring additional enforcement
action if needed.
A Multi-Pronged Approach to Deal with Bad Actors The International Society for Stem Cell Research (ISSCR) has long been concerned that bad actors have co-opted the hope and promise of stem cell science to prey on unsuspecting patients and their families.
We read with sadness and disappointment the many stories of people trying
unproven therapies and being harmed, including going
blind from injections into the eyesor suffering from a spinal
tumor after an injection of stem cells.Patients left
financially strapped, with no physical improvement in their condition and no
way to reclaim their losses, are an underreported and underappreciated aspect
of these treatments.
Since late 2017, the Food and Drug Administration has stepped up its
regulatory enforcement of stem cell therapies and provided a framework
for regenerative medicine products that provides guidelines for work in
this space.The agency has alerted many clinics and centers
that they are not in compliance and has pledged to bring additional enforcement
action if needed.
In recent weeks, a federal judge granted the FDA a permanent injunction
against U.S. Stem Cell, Inc. and U.S. Stem Cell Clinic, LLC for adulterating
and misbranding its cellular products and operating outside of regulatory
authority.We hope this will send a strong message to other
clinics misleading patients with unapproved and potentially harmful cell-based
The Federal Trade Commission has also helped by identifying and curtailing
unsubstantiated medical claims in advertising by several clinics. Late in 2018
the FTC won a $3.3-million judgment against two California-based clinics for
deceptive health claims.
The Federal Trade Commission has also
helped by identifying and curtailing unsubstantiated medical claims in
advertising by several clinics. Late in 2018 the FTC won a $3.3-million
judgment against two California-based clinics for deceptive health claims.
These and other actions are needed to stem the tide of clinics offering
unproved therapies and the people who manage and operate them.
Improving Public Awareness
We’re hopeful that the FDA will help improve public awareness of these
issues and curb the abuses on ClinicalTrials.gov,a government-run Web site being misused by rogue clinics looking to
legitimize their treatments. They list pay-to-participate clinical trials on
the site, often without developing, registering or administering a real
The ISSCR Web site A Closer
Look at Stem Cellsincludes patient-focused information
about stem cells,with information written and vetted by stem
cell scientists.The site includes how and where to report
adverse events and false marketing claims by stem cell clinics.I
encourage you to visit and learn about what is known and unknown about stem
cells and their potential for biomedicine.The views expressed are those of the
author(s) and are not necessarily those of Scientific American.
One of the favorite
events of the year for the team here at CIRM is our annual SPARK (Summer Program to Accelerate
Regenerative Medicine Knowledge) conference.
This is where high school students, who spent the summer interning at world
class stem cell research facilities around California, get to show what they
learned. It’s always an engaging, enlightening, and even rather humbling
The students, many
of whom are first generation Californians, start out knowing next to nothing
about stem cells and end up talking as if they were getting ready for a PhD.
Most say they went to their labs nervous about what lay ahead and half
expecting to do menial tasks such as rinsing out beakers. Instead they were
given a lab coat, safety glasses, stem cells and a specific project to work on.
They learned how to handle complicated machinery and do complex scientific
But most importantly
they learned that science is fun, fascinating, frustrating sometimes, but also
fulfilling. And they learned that this could be a future career for them.
We asked all the
students to blog about their experiences and the results were extraordinary.
All talked about their experiences in the lab, but some went beyond and tied their
internship to their own lives, their past and their hopes for the future.
Judging the blogs
was a tough assignment, deciding who is the best of a great bunch wasn’t easy.
But in the end, we picked three students who we thought captured the essence of
the SPARK program. This week we’ll run all those blogs.
We begin with our
third place blog by Dayita Biswas from UC Davis.
Personal Renaissance: A Journey from
Scientific Curiosity to Confirmed Passions
As I poured over the pages of my
battered Campbell textbook, the veritable bible for any biology student, I saw
unbelievable numbers like how the human body is comprised of over 30 trillion
cells! Or how we have over 220 different types of cells— contrary to my mental picture of
a cell as a circle. Science, and biology in particular, has no shortage of these
seemingly impossible Fermi-esque statistics that make one do a
My experience in science had always been studying from numerous textbooks in preparation for a test or competitions, but textbooks only teach so much. The countless hours I spent reading actually demotivated me and I constantly asked myself what was the point of learning about this cycle or that process — the overwhelming “so what?” question. Those intriguing numbers that piqued my interest were quickly buried under a load of other information that made science a static stream of words across a page.
That all changed this summer when I
had the incredible opportunity to work in the Nolta lab under my mentor,
Whitney Cary. This internship made science so much more tangible and fun to be
a part of. It was such an amazing
environment, being in the same space with people who all have the same goals
and passion for science that many high school students are not able to truly
experience. Everyone was so willing to explain what they were doing, and even
went out of their way to help if I needed papers or had dumb questions.
This summer, my project was to create embryoid bodies and characterize induced pluripotent stem cells (iPSCs) from children who had Jordan’s Syndrome, an extremely rare neurodevelopmental disease whose research has applications in Alzheimer’s and autism.
I had many highs and lows during this research
experience. My highs were seeing that my iPSCs were happy and healthy. I
enjoyed learning lab techniques like micro-pipetting, working in a biological
safety hood, feeding, freezing, and passaging cells. My lows were having to
bleach my beloved iPSCs days after they failed to survive, and having
unsuccessful protocols. However, while my project consistently failed, these
failures taught me more than my successes.
I learned that there is a large gap
between being able to read about techniques and being “book smart” and actually
being able to think critically about science and perform research. Science,
true science, is more than words on a page or fun facts to spout at a party.
Science is never a straight or easy answer, but the mystery and difficulty is
part of the reason it is so interesting. Long story short: research is hard and
it takes time and patience, it involves coming in on weekends to feed cells,
and staying up late at night reading papers.
The most lasting impact that this
summer research experience had was that everything we learn in school and the
lab are all moving us towards the goal of helping real people. This internship
renewed my passion for biology and cemented my dream of working in this field.
It showed me that I don’t have to wait to be a part of dynamic science and that
I can be a small part of something that will change, benefit, and save lives.
This internship meant being a part of something bigger than myself, something meaningful. We must always think critically about what consequences our actions will have because what we do as scientists and researchers— and human beings will affect the lives of real people. And that is the most important lesson anyone can hope to learn.
And here’s a bonus, a video put together by the SPARK students at Cedars-Sinai Medical Center.
The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.
In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.
“This sequencing technique allowed us
to see all the different types of cells present at various stages of heart development
and helped us identify which genes are activated and suppressed along the way. We
were not only able to uncover the existence of unknown cell types, but we also
gained a better understanding of the function and behavior of individual
cells—information we could never access before.”
Then they partnered with a team at Luxembourg Centre for Systems
Biomedicine (LCSB) of the University of Luxembourg which ran a
computational analysis to identify which genes were involved in creating
different cell types. This highlighted one specific gene, called Hand2, that controls
the activity of thousands of other genes. They found that a lack of Hand2 in
mice led to an inability to form one of the heart’s chambers, which in turn led
to impaired blood flow to the lungs. The embryo was creating the cells needed
to form the chamber, but not a critical pathway that would allow those cells to
get where they were needed when they were needed.
Gifford says this has given us a deeper insight into how
cells are formed, knowledge we didn’t have before.
“Single-cell technologies can inform us about how organs
form in ways we couldn’t understand before and can provide the underlying cause
of disease associated with genetic variations. We revealed subtle differences
in very, very small subsets of cells that actually have catastrophic
consequences and could easily have been overlooked in the past. This is the
first step toward devising new therapies.”
These therapies are needed to help treat congenital heart
defects, which are the most common and deadly birth defects. There are more
than 2.5 million Americans with these defects. Deepak Srivastava, President of
Gladstone and the leader of the study, said the knowledge gained in this study
could help developed strategies to help address that.
to see the long-term consequences in adults, and right now, we don’t really
have any way to treat them. My hope is that if we can understand the genetic
causes and the cell types affected, we could potentially intervene soon after
birth to prevent the worsening of their state over time.
Students present their research finding at the 2016 CIRM Bridges conference
One of the programs people here at CIRM love is our Bridges to Stem Cell Research Awards. These are given to undergraduate and master’s level college students, to train the next generation of stem cell scientists. How good a program is it? It’s terrific. You don’t have to take my word for it. Just read this piece by a great stem cell champion, Don Reed. Don is the author of two books about CIRM, Stem Cell Battles and California Cures! so he clearly knows what he’s talking about.
ADVENTURES ON “BRIDGES”: Humboldt State Stem Cell Research
By Don C. Reed
Imagine yourself as a California college student, hoping to become a stem cell researcher. Like almost all students you are in need of financial help, and so (let’s say) you asked your college counselor if there were any scholarships available.
To your delight, she said, well, there is this wonderful internship program called Bridges, funded by the California Institution for Regenerative Medicine (CIRM) which funds training in stem cell biology and regenerative medicine — and so, naturally, you applied…
After doing some basic training at the college, you would receive a grant (roughly $40,000) for a one-year internship at a world-renowned stem cell research facility. What an incredible leap forward in your career, hands-on experience (essentially a first job, great “experience” for the resume) as well an expert education.
Where are the 14 California colleges participating in this program? Click below:
Let’s take a look at one of these college programs in action: find out what happened to a few of the students who received a Bridges award, crossing the gap between studying stem cell research and actually applying it.
HSU information is courtesy of Dr. Amy Sprowles, Associate Professor of Biological Sciences and Co-Director of the Bridges program at Humboldt State University (HSU), 279 miles north of San Francisco.
“The HSU Bridges program”, says Dr. Sprowles, “was largely developed by four people: Rollin Richmond, then HSU President, who worked closely with Susan Baxter, Executive Director of the CSU Program for Education and Research in Biotechnology, to secure the CIRM Bridges initiative; HSU Professor of Biological Sciences Jacob Varkey, who pioneered HSU’s undergraduate biomedical education program”, and Sprowles herself, at the time a lecturer with a PhD in Biochemistry.
The program has two parts: a beginning course in stem cell research, and a twelve-month internship in a premiere stem cell research laboratory. For HSU, these are at Stanford University, UC Davis, UCSF, or the Scripps Research Institute.
Like all CIRM Bridges programs, the HSU stem cell program is individually designed to suit the needs of its community.
Each of the 15 CIRM Bridges Programs fund up to ten paid internships, but the curriculum and specific activities of each are designed by their campus directors. The HSU program prepares Bridges candidates by requiring participation in a semester-long lecture and stem cell biology laboratory course before selection for the program: a course designed and taught by Sprowles since its inception.
She states, “The HSU pre-internship course ensures our students are trained in fundamental scientific concepts, laboratory skills and professional behaviors before entering their host laboratory. We find this necessary since, unlike the other Bridges campuses, we are 300+ miles away from the internship sites and are unable to fully support this kind of training during the experience. It also provides additional insights about the work ethic and mentoring needs of the individuals we select that are helpful in placing and supporting our program participants”.
How is it working?
Ten years after it began, 76 HSU students have completed the CIRM Bridges program at HSU. Of those, the overwhelming majority (over 85%) are committed to careers in regenerative medicine: either working in the field already, or continuing their education toward that goal.
But what happened to their lives? Take a brief look at the ongoing careers of a “Magnificent Seven” HSU Bridges scientists:
CARSTEN CHARLESWORTH: “Spurred by the opportunity to complete a paid internship at a world class research institution in Stem Cell Biology, I applied to the Humboldt CIRM Bridges program, and was lucky enough to be accepted. With a keen interest in the developing field of genome editing and the recent advent of the CRISPR-Cas9 system I chose to intern in the lab of a pioneer in the genome editing field, Dr. Matthew Porteus at Stanford, who focuses in genome editing hematopoietic stem cells to treat diseases such as sickle cell disease. In August of 2018 I began a PhD in Stanford’s Stem Cell and Regenerative Medicine program, where I am currently a second-year graduate student in the lab of Dr. Hiro Nakauchi, working on the development of human organs in interspecies human animal chimeras. The success that I’ve had and my acceptance into Stanford’s world class PhD program are a direct result of the opportunity that the CIRM Bridges internship provided me and the excellent training and instruction that I received from the Humboldt State Biology Program.”
ELISEBETH TORRETTI: “While looking for opportunities at HSU, I stumbled upon the CIRM Bridges program. It was perfect- a paid internship at high profile labs where I could expand my research skills for an entire year… the best fit (was) Jeanne Loring’s Lab at the Scripps Research Institute in La Jolla, CA. Dr. Loring is one of the premiere stem cell researchers in the world… (The lab’s) main focus is to develop a cure for Parkinson’s disease. (They) take skin cells known as fibroblasts and revert them into stem cells. These cells, called induced pluripotent stem cells (iPSCs) can then be differentiated into dopaminergic neurons and transplanted into the patient…. My project focused on a different disease: adenylate-cyclase 5 (ADCY5) — related dyskinesia. During my time at Dr. Loring’s lab I learned incredibly valuable research skills. I am now working in a mid-sized biotch company focusing on cancer research. I don’t think that would be possible in a competitive area like San Diego without my experience gained through the CIRM Bridges program.”
BRENDAN KELLY: “After completing my CIRM internship in Dr. Marius Wernig’s lab (in Stanford), I began working at a startup company called I Peace. I helped launch this company with Dr. Koji Tanabe, whom I met while working in my host lab. I am now at Cardiff University in Wales working on my PhD. My research involves using patient iPSC derived neurons to model Huntington’s disease. All this derived from my opportunity to partake in the CIRM-Bridges program, which opened doors for me.”
SAMANTHA SHELTON: “CIRM Bridges provided invaluable hands-on training in cell culture and stem cell techniques that have shaped my future in science. My CIRM internship in John Rubenstein’s Lab of Neural Development taught me amazing laboratory techniques such as stem cell transplantation as well as what goes into creating a harmonious and productive laboratory environment. My internship projects led to my first co-first author publication.
After my Bridges internship, I joined the Graduate Program for Neuroscience at Boston University. My PhD work aims to discover types of stem cells in the brain and how the structure of the brain develops early in life. During this time, I have focused on changes in brain development after Zika virus infection to better understand how microcephaly (small skulls and brains, often a symptom of Zika-DR) is caused. There is no doubt that CIRM not only made me a more competitive candidate for a doctoral degree but also provided me with tools to progress towards my ultimate goal of understanding and treating neurological diseases with stem cell technologies.”
DU CHENG: “Both my academic and business tracks started in the CIRM-funded…fellowship (at Stanford) where I invented the technology (the LabCam Microscope adapter) that I formed my company on (iDU Optics LLC). The instructor of the class, Dr. Amy Sprowles, encouraged me to carry on the idea. Later, I was able to get in the MD-PhD program at Weill Cornell Medical College because of the invaluable research experiences CIRM’s research program provided me. CIRM initiated the momentum to get me where I am today. Looking back, the CIRM Bridges Program is an instrumental jump-starter on my early career… I would not remotely be where I am without it.…”
CODY KIME: “Securing a CIRM grant helped me to take a position in the Nobel Prize winning Shinya Yamanaka Lab at the Gladstone Institutes, one of the most competitive labs in the new field of cell reprogramming. I then explored my own reprogramming interests, moving to the Kyoto University of Medicine, Doctor of Medical Sciences Program in Japan, and building a reprogramming team in the Masayo Takahashi Lab at RIKEN. My studies explore inducing cells to their highest total potential using less intrusive means and hacking the cell program. My systems are designed to inform my hypotheses toward a true お好みの細胞 (okonomi no cybo) technology, meaning ‘cells as you wish’ in Japanese, that could rapidly change any cell into another desired cell type or tissue.”
SARA MILLS: “The CIRM Bridges program was the key early influencer which aided in my hiring of my first industry position at ViaCyte, Inc. Also a strongly CIRM funded institution, I was ultimately responsible for the process development of the VC-01™ fill, finish processes and cGMP documentation development. Most recently, with over two years at the boutique consulting firm of Dark Horse Consulting, Inc., I have been focusing on aseptic and cGMP manufacturing process development, risk analysis, CMC and regulatory filings, facility design and project management to advise growing cell and gene therapy companies, worldwide.”
Like warriors fighting to save lives, these young scientists are engaged in an effort to study and defeat chronic disease. It is to be hoped the California stem cell program will have its funding renewed, so the “Bridges” program can continue.
For more information on the Bridges program, which might help a young scientist (perhaps yourself) cut and paste the following URL:
One closing paragraph perhaps best sums up the Bridges experience:
“During my CIRM Bridges training in Stanford University, I was fortunate to work with Dr. Jill Helms, who so patiently mentored me on research design and execution. I ended up publishing 7 papers with her during the two-year CIRM internship and helped making significant progress of turning a Stem Cell factor into applicable therapeutic form, that is currently in preparation for clinical trial by a biotech company in Silicon Valley. I also learned from her how to write grants and publications, but more importantly, (to) never limit your potential by what you already know.” — Du Cheng
The news that President Trump’s administration has told scientists employed by the National Institutes of Health (NIH) that they can’t buy any new human fetal tissue for research has left many scientists frustrated and worried.
The news has also highlighted the reason why voters created CIRM in the first place and the importance of having an independent source of funding for potentially life-saving research such as this.
The Trump administration imposed the suspension of all new acquisitions saying it wants to review all fetal tissue research funded by the federal government. The impact was felt immediately.
In an article on ScienceMag.com, Warner Greene, director of the Center for HIV Cure Research at the Gladstone Institutes in San Francisco, said the decision derailed collaboration between his lab and one at Rocky Mountain Laboratories in Hamilton, Montana. The research focused on an antibody that previous studies showed might prevent HIV from establishing reservoirs in the human body.
“We were all poised to go and then the bombshell was dropped. The decision completely knocked our collaboration off the rails. We were devastated.”
Right now, it’s not clear if the “halt” is temporary or permanent, or if it will ultimately be expanded beyond scientists employed by the NIH to all scientists funded by the NIH who use fetal tissue.
In 2001, President George W. Bush’s decision to impose restrictions on federal funding for embryonic stem cell research helped generate support for Proposition 71, the voter-approved initiation that created CIRM. People felt that stem cell research had potential to develop treatments and cures for deadly diseases and that if the federal government wasn’t going to support it then California would.
CIRM Board member, and Patient Advocate for HIV/AIDS, Jeff Sheehy says the current actions could have wide-reaching impact.
“While the initial focus of the emerging ban on the use of fetal tissue has been on projects related to HIV, this action undermines a spectrum of vital research initiatives that seek to cure multiple life-threatening diseases and conditions. Many regenerative medicine cell-based or gene therapies require pre-clinical safety studies in humanized mice created with fetal tissue. These mice effectively have human immune systems, which allows researchers to examine the effects of products on the immune system. Work to prevent and treat infectious diseases, including vaccine efforts, require this animal model to do initial testing. Development of vaccines to respond to actual threats requires use of this animal model. This action could have damaging effects on the health of Americans.”
Do we know how to pick ‘em or what? For a number of years now we have been funding the work of Stanford’s Dr. Marius Wernig, who is doing groundbreaking work in helping advance stem cell research. Just how groundbreaking was emphasized this week when he was named as the winner of the 2018 Ogawa-Yamanaka Stem Cell Prize.
Marius Wernig, MD, PhD. [Photo: Stanford University]
The prestigious award, from San Francisco’s Gladstone Institutes, honors Wernig for his innovative work in developing a faster, more direct method of turning ordinary cells into, for example, brain cells, and for his work advancing the development of disease models for diseases of the brain and skin disorders.
Dr. Deepak Srivastava, the President of Gladstone, announced the award in a news release:
“Dr. Wernig is a leader in his field with extraordinary accomplishments in stem cell reprogramming. His team was the first to develop neuronal cells reprogrammed directly from skin cells. He is now investigating therapeutic gene targeting and cell transplantation–based strategies for diseases with mutations in a single gene.”
Wernig was understandably delighted at the news:
“It is a great honor to receive this esteemed prize. My lab’s goal is to discover novel biology using reprogrammed cells that aids in the development of effective treatments.”
Wernig will be presented with the award, and a check for $150,000, at a ceremony on Oct. 15 at the Gladstone Institutes in San Francisco.
A stem cell trifecta for teeth research
It was a tooth trifecta among stem cell scientists this week. At Tufts University School of Medicine, researchers made an important advance in the development of bioengineered teeth. The current standard for tooth replacement is a dental implant. This screw-shaped device acts as an artificial tooth root that’s inserted into the jawbone. Implants have been used for 30 years and though successful they can lead to implant failure since they lack many of the properties of natural teeth. By implanting postnatal dental cells along with a gel material into mice, the team demonstrated, in a Journal of Dental Research report, the development of natural tooth buds. As explained in Dentistry Today, these teeth “include features resembling natural tooth buds such as the dental epithelial stem cell niche, enamel knot signaling centers, transient amplifying cells, and mineralized dental tissue formation.”
Another challenge with the development of a bioengineered tooth replacement is reestablishing nerve connections within the tooth, which plays a critical role in its function and protection but doesn’t occur spontaneously after an injury. A research team across the “Pond” at the French National Institute of Health and Medical Research, showed that bone marrow-derived mesenchymal stem cells in the presence of a nerve fiber can help the nerve cells make connections with bioengineered teeth. The study was also published in the Journal of Dental Research.
And finally, a research report about stem cells and the dreaded root canal. When the living soft tissue, or dental pulp, of a tooth becomes infected, the primary course of action is the removal of that tissue via a root canal. The big downside to this procedure is that it leaves the patient with a dead tooth which can be susceptible to future infections. To combat this side effect, researchers at the New Jersey Institute of Technology report the development of a potential remedy: a gel containing a fragment of a protein that stimulates the growth of new blood vessels as well as a fragment of a protein that spurs dental stem cells to divide and grow. Though this technology is still at an early stage, it promises to help keep teeth alive and healthy after root canal. The study was presented this week at the National Meeting of the American Chemical Society.
Here’s an animated video that helps explain the research:
A program hoping to supercharge a patient’s own immune system cells to attack and kill a treatment resistant form of prostate cancer was today awarded $3.99 million by the governing Board of the California Institute for Regenerative Medicine (CIRM)
In the U.S., prostate cancer is the second most common cause of cancer deaths in men. An estimated 170,000 new cases are diagnosed each year and over 29,000 deaths are estimated in 2018. Early stage prostate cancer is usually managed by surgery, radiation and/or hormone therapy. However, for men diagnosed with castrate-resistant metastatic prostate cancer (CRPC) these treatments often fail to work and the disease eventually proves fatal.
Poseida Therapeutics will be funded by CIRM to develop genetically engineered chimeric antigen receptor T cells (CAR-T) to treat metastatic CRPC. In cancer, there is a breakdown in the natural ability of immune T-cells to survey the body and recognize, bind to and kill cancerous cells. Poseida is engineering T cells and T memory stem cells to express a chimeric antigen receptor that arms these cells to more efficiently target, bind to and destroy the cancer cell. Millions of these cells are then grown in the laboratory and then re-infused into the patient. The CAR-T memory stem cells have the potential to persist long-term and kill residual cancer calls.
“This is a promising approach to an incurable disease where patients have few options,” says Maria T. Millan, M.D., President and CEO of CIRM. “The use of chimeric antigen receptor engineered T cells has led to impressive results in blood malignancies and a natural extension of this promising approach is to tackle currently untreatable solid malignancies, such as castrate resistant metastatic prostate cancer. CIRM is pleased to partner on this program and to add it to its portfolio that involves CAR T memory stem cells.”
Poseida Therapeutics plans to use the funding to complete the late-stage testing needed to apply to the Food and Drug Administration for the go-ahead to start a clinical trial in people.
The CIRM Board also voted to approve investing $10 million for eight projects under its Discovery Quest Program. The Quest program promotes the discovery of promising new stem cell-based technologies that will be ready to move to the next level, the translational category, within two years, with an ultimate goal of improving patient care.
Among those approved for funding are:
Eric Adler at UC San Diego is using genetically modified blood stem cells to treat Danon Disease, a rare and fatal condition that affects the heart
Li Gan at the Gladstone Institutes will use induced pluripotent stem cells to develop a therapy for a familial form of dementia
Saul Priceman at City of Hope will use CAR-T therapy to develop a treatment for recurrent ovarian cancer
Because the amount of funding for the recommended applications exceeded the money set aside, the Application Subcommittee voted to approve partial funding for two projects, DISC2-11192 and DISC2-11109 and to recommend, at the next full Board meeting in October, that the projects get the remainder of the funds needed to complete their research.
The successful applications are:
CIRM COMMITTED FUNDING
Genetically Modified Hematopoietic Stem Cells for the
Treatment of Danon Disease
U.C San Diego
Preclinical Development of An HSC-Engineered Off-
The-Shelf iNKT Cell Therapy for Cancer
U.C. Los Angeles
Non-viral reprogramming of the endogenous TCRα
locus to direct stem memory T cells against shared
neoantigens in malignant gliomas
U.C. San Francisco
Therapeutic immune tolerant human islet-like
organoids (HILOs) for Type 1 Diabetes
Chimeric Antigen Receptor-Engineered Stem/Memory
T Cells for the Treatment of Recurrent Ovarian Cancer
City of Hope
Develop iPSC-derived microglia to treat progranulin-
In need of an extra dose of inspiration? You might read a great book or listen to that podcast your friend recommended. You might even take a stroll along the beach. But I can do you one better: go to a conference poster session where young stem cell scientists describe their research.
That’s what I did last week at the City College of San Francisco’s (CCSF) Bioscience Symposium held at UC San Francisco’s Genentech Hall. It’s a day-long conference that showcases the work of CCSF Bioscience interns and gives them a chance to present the results of their research projects, network with their peers and researchers, hear panelists talk about careers in biotechnology and participate in practice job interviews.
CCSF’s CIRM Bridges Scholars (clockwise from top left): Vanessa Lynn Herrara, Viktoriia Volobuieva, Christopher Nosworthy and Sofiana E. Hamama.
CCSF’s CIRM Bridges Scholars (clockwise from top left): Seema Niddapu, Mark Koontz, Karolina Kaminska and Iris Avellano
Eight of the dozens of students in attendance at the Symposium are part of the CIRM-funded Bridges Stem Cell Internship program at CCSF. It’s one of 14 CIRM Bridges programs throughout the state that provides paid stem cell research internships to students at universities and colleges that don’t have major stem cell research programs. Each Bridges internship includes thorough hands-on training and education in stem cell research, and direct patient engagement and outreach activities that engage California’s diverse communities.
In the CCSF Bridges Program, directed by Dr. Carin Zimmerman, the students do a 9-month paid internship in top notch labs at UCSF, the Gladstone Institutes and Blood System Research Institute. As I walked from poster to poster and chatted with each Bridges scholar, their excitement and enthusiasm for carrying out stem cell research was plain to see. It left me with the feeling that the future of stem cell research is in good hands and, as I walked into the CIRM office the next day, I felt re-energized to tackle the Agency’s mission to accelerate stem cell treatment for patients with unmet medical needs. But don’t take my word for it, listen to the enthusiastic perspectives of Bridges scholars Mark Koontz and Iris Avellano in this short video.
With a clinical trial failure rate of 99% over the past 15 years or so, the path to a cure for Alzheimer’s disease is riddled with disappointment. In many cases, candidate therapies looked very promising in pre-clinical animal studies, only to flop when tested in people. Now, a CIRM-funded Nature Medicine study by researchers at the Gladstone Institutes sheds some light on a source of this discrepancy. And more importantly, the study points to a potential treatment strategy that can remove the hallmarks of Alzheimer’s in human brain cells.
For several decades, researchers have known the ApoE gene can influence the risk for an Alzheimer’s diagnosis in individuals 65 years and older. The gene comes in a few flavors with ApoE3 and ApoE4 differing in only one spot in their DNA sequences. Though nearly identical, the resulting ApoE3 and E4 proteins have very different shapes with differing function. In fact, people who inherit two copies of the ApoE4 gene have a twelve times higher risk for Alzheimer’s compared to those with the more common ApoE3.
To better understand what’s happening at the cellular level, Yadong Huang, PhD and his team at the Gladstone Institutes obtained skin samples from Alzheimer’s donors carrying two copies of the ApoE4 gene and healthy donors with two copies of ApoE3. The skin cells were reprogrammed into induced pluripotent stem cells (iPSCs) and then matured into nerve cells, or neurons.
Compared to ApoE3 cells, the researchers observed that the ApoE4 neurons accumulated higher levels of proteins called p-tau and amyloid beta, which are hallmarks of Alzheimer’s disease. Repeating this same experiment in iPSC-derived mouse neurons showed no difference in the production of amyloid beta levels between the ApoE3 and E4 neurons. This result points to the importance of studying human disease in human cells, as first author Chengzhong Wang, PhD, points out in a press release:
“There’s an important species difference in the effect of apoE4 on amyloid beta. Increased amyloid beta production is not seen in mouse neurons and could potentially explain some of the discrepancies between mice and humans regarding drug efficacy. This will be very important information for future drug development.”
Further experiments aimed to answer a long sought-after question: is it the absence of ApoE3 or the presence of ApoE4 that causes the damaging effects on neurons? Using gene-editing techniques, the team removed both ApoE forms from the donor-derived neurons. The resulting cells appeared healthy but when ApoE4 was added back in, Alzheimer’s-associated problems emerged. This finding points to the toxicity of ApoE4 to neurons.
With this new insight in hand, the team examined what would happen if they converted the ApoE4 form into the ApoE3 form. The team had previously designed molecules, they dubbed “structure correctors”, that physically interact with the ApoE4 protein and cause it to take on the shape of the ApoE3 form found in healthy individuals. When these correctors were added to the ApoE4 neurons, it brought back normal function to the cells.
Given that the structure corrector is a chemical compound that works in human brain cells, it’s tantalizing to think about its possible use as a novel Alzheimer’s drug. And you can bet Dr. Huang and his group are eagerly embarking on that new path.