The second Wednesday in October is celebrated as Stem Cell Awareness Day. It’s an event that CIRM has been part of since then Governor Arnold Schwarzenegger launched it back in 2008 saying: ”The discoveries being made today in our Golden State will have a great impact on many around the world for generations to come.”
In the past we would have helped coordinate presentations by scientists in schools and participated in public events. COVID of course has changed all that. So, this year, to help mark the occasion we asked some people who have been in the forefront of making Governor Schwarzenegger’s statement come true, to share their thoughts and feelings about the day. Here’s what they had to say.
What do you think is the biggest achievement so far in stem cell research?
Jan Nolta, PhD., Director of the Stem Cell Program at UC Davis School of Medicine, and directs the new Institute for Regenerative Cures. “The work of Don Kohn and his UCLA colleagues and team members throughout the years- developing stem cell gene therapy cures for over 50 children with Bubble baby disease. I was very fortunate to work with Don for the first 15 years of my career and know that development of these cures was guided by his passion to help his patients.
When people ask you what kind of impact CIRM and stem cell research has had on your life what do you say?
Pawash Priyank and Upasana Thakur, parents of Ronnie,who was born with a life-threatening immune disorder but is thriving today thanks to a CIRM-funded clinical trial at UC San Francisco. “This is beyond just a few words and sentences but we will give it a shot. We are living happily today seeing Ronnie explore the world day by day, and this is only because of what CIRM does every day and what Stem cell research has done to humanity. Researchers and scientists come up with innovative ideas almost every day around the globe but unless those ideas are funded or brought to implementation in any manner, they are just in the minds of those researchers and would never be useful for humanity in any manner. CIRM has been that source to bring those ideas to the table, provide facilities and mechanisms to get those actually implemented which eventually makes babies like Ronnie survive and see the world. That’s the impact CIRM has. We have witnessed and heard several good arguments back in India in several forums which could make difference in the world in different sectors of lives but those ideas never come to light because of the lack of organizations like CIRM, lack of interest from people running the government. An organization like CIRM and the interest of the government to fund them with an interest in science and technology actually changes the lives of people when some of those ideas come to see the light of real implementation.
What are your biggest hopes for the future at UC Davis?
Jan Nolta, PhD: “The future of stem cell and gene therapy research is very bright at UC Davis, thanks to CIRM and our outstanding leadership. We currently have 48 clinical trials ongoing in this field, with over 20 in the pipeline, and are developing a new education and technology complex, Aggie Square, next to the Institute for Regenerative Cures, where our program is housed. We are committed to our very diverse patient population throughout the Sacramento region and Northern California, and to expanding and increasing the number of novel therapies that can be brought to all patients who need them.”
What are your biggest hopes for the future at Cedars-Sinai?
Clive Svendsen, PhD: “That young investigators will get CIRM or NIH funding and be leaders in the regenerative medicine field.”
What do you hope is the future for stem cell research?
Pawash Priyank and Upasana Thakur: “We always have felt good about stem cell therapy. For us, a stem cell has transformed our lives completely. The correction of sequencing in the DNA taken out of Ronnie and injecting back in him has given him life. It has given him the immune system to fight infections. Seeing him grow without fear of doing anything, or going anywhere gives us so much happiness every hour. That’s the impact of stem cell research. With right minds continuing to research further in stem cell therapy bounded by certain good processes & laws around (so that misuse of the therapy couldn’t be done) will certainly change the way treatments are done for certain incurable diseases. I certainly see a bright future for stem cell research.”
On a personal note what is the moment that touched you the most in this journey.
Jan Nolta, PhD: “Each day a new patient or their story touches my heart. They are our inspiration for working hard to bring new options to their care through cell and gene therapy.”
Clive Svendsen, PhD: “When I realized we would get the funding to try and treat ALS with stem cells”
How important is it to raise awareness about stem cell research and to educate the next generation about it?
Pawash Priyank and Upasana Thakur: “Implementing stem cell therapy as a curriculum in the educational systems right from the beginning of middle school and higher could prevent false propaganda of it through social media. Awareness among people with accurate articles right from the beginning of their education is really important. This will also encourage the new generation to choose this as a subject in their higher studies and contribute towards more research to bring more solutions for a variety of diseases popping up every day.”
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
CRISPR iPSC colony of human skin cells showing expression of SOX2 and TRA-1-60, markers of human embryonic pluripotent stem cells
Back in 2012, Shinya Yamanaka was awarded the Nobel Prize in Physiology or Medicine for his group’s identification of “Yamanaka Factors,” a group of genes that are capable of turning ordinary skin cells into induced pluripotentent stem cells (iPSCs) which have the ability to become any type of cell within the body. Discovery of iPSCs was, and has been, groundbreaking because it not only allows for unprecedented avenues to study human disease, but also has implications for using a patient’s own cells to treat a wide variety of diseases.
Recently, Timo Otonkoski’s group at the University of Helsinki along with Juha Kere’s group at the Karolinska Institutet and King’s College, London have found a way to program iPSCs from skin cells using CRISPR, a gene editing technology. Their approach allows for the induction, or turning on of iPSCs using the cells own DNA, instead of introducing the previously identified Yamanka Factors into cells of interest.
As detailed in their study, published in the journal Nature Communications, this is the first instance of mature human cells being completely reprogrammed into pluripotent cells using only CRISPR. Instead of using the canonical CRISPR system that allows the CAS9 protein (an enzyme that is able to cut DNA, thus rendering a gene of interest dysfunctional) to mutate any gene of interest, this group used a modified version of the CAS9 protein, which allows them to turn on or off the gene that CAS9 is targeted to.
The robustness of their approach lies in the researcher’s identification of a DNA sequence that is commonly found near genes involved in embryonic development. As CAS9 needs to be guided to genes of interest to do its job, identification of this common motif allows multiple genes associated with pluripotency to be activated in mature human skin cells, and greatly increased the efficiency and effectiveness of this approach.
In a press release, Dr. Otonkoski further highlights the novelty and viability of this approach:
“…Reprogramming based on activation of endogenous genes rather than overexpression of transgenes is…theoretically a more physiological way of controlling cell fate and may result in more normal cells…”
Here are the stem cell stories that caught our eye this week.
Photos of the week
TGIF! We’re so excited that the weekend is here that we are sharing not one but TWO amazing stem cell photos of the week.
Image caption: Cells of a human intestinal lining, after being placed in an Intestine-Chip, form intestinal folds as they do in the human body. (Photo credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute)
Photo #1 is borrowed from a blog we wrote earlier this week about a new stem cell-based path to personalized medicine. Scientists at Cedars-Sinai are collaborating with a company called Emulate to create intestines-on-a-chip using human stem cells. Their goal is to create 3D-organoids that represent the human gut, grow them on chips, and use these gut-chips to screen for precision medicines that could help patients with intestinal diseases. You can read more about this gut-tastic research here.
Image caption: UCLA scientists used four different fluorescent-colored proteins to determine the origin of cardiomyocytes in mice. (Image credit: UCLA Broad Stem Cell Research Center/Nature Communications)
Photo #2 is another beautiful fluorescent image, this time of a cross-section of a mouse heart. CIRM-funded scientists from UCLA Broad Stem Cell Research Center are tracking the fate of stem cells in the developing mouse heart in hopes of finding new insights that could lead to stem cell-based therapies for heart attack victims. Their research was published this week in the journal Nature Communications and you can read more about it in a UCLA news release.
Stem cell injection improves muscle function in muscular dystrophy mice
Another study by CIRM-funded Cedars-Sinai scientists came out this week in Stem Cell Reports. They discovered that they could improve muscle function in mice with muscular dystrophy by injecting cardiac progenitor cells into their hearts. The injected cells not only improved heart function in these mice, but also improved muscle function throughout their bodies. The effects were due to the release of microscopic vesicles called exosomes by the injected cells. These cells are currently being used in a CIRM-funded clinical trial by Capricor therapeutics for patients with Duchenne muscular dystrophy.
How to build a better brain (blob)
For years stem cell researchers have been looking for ways to create “mini brains”, to better understand how our own brains work and develop new ways to repair damage. So far, the best they have done is to create blobs, clusters of cells that resemble some parts of the brain. But now researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have come up with a new method they think can advance the field.
Their approach is explained in a fascinating article in the journal Science News, where lead researcher Bennet Novitch says finding the right method is like being a chef:
“It’s like making a cake: You have many different ways in which you can do it. There are all sorts of little tricks that people have come up with to overcome some of the common challenges.”
Brain cake. Yum.
A more efficient way to make iPS cells
Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)
In 2006 Shinya Yamanaka discovered a way to take ordinary adult cells and reprogram them into embryonic-like stem cells that have the ability to turn into any other cell in the body. He called these cells induced pluripotent stem cells or iPSC’s. Since then researchers have been using these iPSC’s to try and develop new treatments for deadly diseases.
There’s been a big problem, however. Making these cells is really tricky and current methods are really inefficient. Out of a batch of, say, 1,000 cells sometimes only one or two are turned into iPSCs. Obviously, this slows down the pace of research.
Now researchers in Colorado have found a way they say dramatically improves on that. The team says it has to do with controlling the precise levels of reprogramming factors and microRNA and…. Well, you can read how they did it in a news release on Eurekalert.
One of the most famous stem cell scientists in the world said on Monday that the promise of stem cell treatments has in some ways been overstated.
In an interview with the New York Times, Dr. Shinya Yamanaka, one of the recipients of the 2012 Nobel Prize in Medicine for his discovery of induced pluripotent stem cells (iPS cells), said, “we can help just a small portion of patients by stem cell therapy.”
Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)
He explained that there are only 10 target diseases that he believes will benefit directly from stem cell therapies including, “Parkinson’s, retinal and corneal diseases, heart and liver failure, diabetes, spinal cord injury, joint disorders and some blood disorders. But maybe that’s all. The number of human diseases is enormous.”
This is a big statement coming from a key opinion leader in the field of stem cell research, and it’s likely to spur a larger conversation on the future of stem cell treatments.
Yamanaka also touched on another major point in his interview – progress takes time.
In the ten years since his discovery of iPS cells, he and other scientists have learned the hard way that the development of stem cell treatments can be time consuming. While autologous iPS cell treatments (making stem cell lines from a patient and transplanting them back into that patient) have entered clinical trials to treat patients with macular degeneration, a disease that causes blindness, the trials have been put on hold until the safety of the stem cell lines being used are confirmed.
At the World Alliance Forum in November, Yamanaka revealed that generating a single patient iPS cell line can cost up to one million dollars which isn’t feasible for the 1000’s of patients who need them. He admitted that the fate of personalized stem cell medicine, which once seemed so promising, now seems unrealistic because it’s time consuming and costly.
But with any obstacle, there is always a path around it. Under Yamanaka’s guidance, Japan is generating donor iPS cell lines that can be used to treat a large portion of the Japanese population. Yamanaka said that 100 lines would cover 100 million people in Japan and that 200 lines would be enough to cover the US population. iPS cell banks are being generated around the world, meaning that one day the millions of people suffering from the target diseases Yamanaka mentioned could be treated or even cured. Would this not fulfill a promise that was made about the potential of stem cell treatments?
Which brings me to my point, I don’t believe the promise of stem cells has been overstated. I think that it has yet to be realized, and it will take more research and more time to get there. As a community, we need to be understanding, patient, and supportive.
In my opinion (as a scientist aside from my role at CIRM), I believe that Yamanaka’s interview failed to reveal his optimism about the future of stem cell treatments. What I took from Yamanaka’s comments is that stem cell treatments can help a small number of patients with specific diseases right now. That’s not to say that stem cell research won’t produce promising treatments for other diseases in the future.
Retinal diseases and blood disorders are easier to target with stem cell treatments because only one type of cell needs to be replaced. It makes sense to tackle those diseases first and make sure that these stem cell treatments are effective and safe in patients before we focus on more complicated diseases where multiple cell types or organs are involved.
Part of the reason why scientists are unsure whether stem cell treatments can treat complex diseases is because we still don’t know the details of what causes these diseases. After we know more about what’s going wrong, including all the cell types and molecules involved, research might reveal new ways that stem cells could be used to help treat those diseases. Or on the other hand, stem cells could be used to model those diseases to help discover new drug treatments.
I’ve heard Yamanaka talk many times and recently I heard him speak at the World Alliance Forum in November, where he said that the two biggest hurdles we are facing for stem cell treatments to be successful is time and cost. After we overcome these hurdles, his outlook was optimistic that stem cell treatments could improve people’s lives. But he stressed that these advances will take time.
He shared a similar sentiment at the very end of the NY Times interview by referencing his father’s story and the decades it took to cure hepatitis C,
“You know, my father had a small factory. He injured his leg in the factory when I was in junior high. He had a transfusion, and he got hepatitis C. He passed away in 1989. Twenty-five years later, just two years ago, scientists developed a very effective cure. We now have a tablet. Three months and the virus is gone — it’s amazing. But it took 25 years. iPS cells are only 10 years old. The research takes time. That’s what everybody needs to understand.”
Yamanaka says more time is needed for stem cell treatments to become effective cures, but CIRM has already witnessed success. In our December Board meeting, we heard from two patients who were cured of genetic blood diseases by stem cell treatments that CIRM funded. One of them was diagnosed with severe combined immunodeficiency (SCID) and the other had chronic granulomatous disease (CGD). Both had their blood stem cells genetically engineered to removed disease-causing mutations and then transplanted back into their body to create a healthy immune system and cure them of their disease.
Hearing how grateful these patients and their families were to receive life-saving stem cell treatments and how this research brings new hope to other patients suffering from the same diseases, in my mind, fulfills the promise of stem cell research and makes funding stem cell treatments worth it.
I believe we will hear more and more of these success stories in the next decade and CIRM will most certainly play an important role in this future. There are others in the field who share a similar optimism for the future of stem cell treatments. Hank Greely, the Director for Law and the Biosciences at Stanford University, said in an interview with the Sacramento Bee about the future of CIRM,
Hank Greely, Stanford University
“The next few years should determine just how good California’s investment has been. It is encouraging to see CIRM supporting so many clinical trials; it will be much more exciting when – and I do expect ‘when’ and not ‘if’ – one of those trials leads to an approved treatment.”
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.
Telomeres and stem cell stability: too much of a good thing
Just like those plastic tips at the end of shoelaces (fun fact: they’re called aglets), telomeres form a protective cap on the end of chromosomes. Because of the way DNA replication works, the telomeres shorten each time a cell divides. Trim away enough of the telomere over time and, like a frayed shoelace, the chromosomes become unstable and an easy target for damage which eventually leads to cell death.
Telomeres (white dots) form a protective cap on chromsomes (gray). (Wikimedia)
Stem cells are unique in that they contain an enzyme called telomerase that lengthens telomeres. Telomerase activity and telomere lengthening are critical for a stem cell’s ability to maintain virtually limitless cell divisions. So you’d assume the longer the telomere, the more stable the cell. But Salk Institute scientists reported this week that too much telomere can be just as bad, if not worse, than too little.
The CIRM-funded work, which was published in Nature Structural & Molecular Biology, used genetic engineering to artificially vary telomerase activity in human embryonic stem cells. Cells with low telomerase activity had shorter telomeres and died. This result wasn’t a surprise since the short telomeres-cell death observation has been well documented. Based on those results, the team was expecting cells with boosted telomerase activity and, in turn, extended telomeres would be especially stable. But that’s not what happened as senior author Jan Karlseder mentioned in a Salk press release:
“We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer. These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism.”
The researchers also examined induced pluripotent stem (iPS) cells in the study and found that the cells contain “footprints” of telomere trimming. So the team is in a position to study how a cell’s telomere history relates to how well it can be reprogrammed into iPS cells. First author Teresa Rivera pointed out the big picture significance of this finding:
“Stem cell reprogramming is a major scientific breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the promise of stem cell therapies and regenerative medicine.”
Jan Karlseder and Teresa Rivera
Lego set of gene activators takes trial and error out of cellular reprogramming
To convert one cell type into another, stem cell researchers rely on educated guesses and a lot of trial and error. In fact, that’s how Shinya Yamanaka identified the four Yamanaka Factors which, when inserted into a skin cell, reprogram it into the embryonic stem cell-like state of an iPS cell. That ground-breaking discovery ten years ago has opened the way for researchers worldwide to specialize iPS cells into all sorts of cell types from nerve cells to liver cells. While some cell types are easy to generate this way, others are much more difficult.
Reporting this week in PNAS, a University of Wisconsin–Madison research team has developed a nifty systematic, high-throughput method for identifying the factors necessary to convert a cell from one type to another. Their strategy promises to free researchers from the costly and time consuming trial and error approach still in use today.
The centerpiece of their method is artificial transcription factors (ATFs). Now, natural transcription factors – Yamanaka’s Factors are examples – are proteins that bind DNA and activate or silence genes. Their impact on gene activity, in turn, can have a cascading effects on other genes and proteins ultimately causing, say a stem cell, to start making muscle proteins and turn into a muscle cell.
Transcription factors are very modular proteins – one part is responsible for binding DNA, another part for affecting gene activity and other parts that bind to other proteins. The ATFs generated in this study are like lego versions of natural transcription factors – each are constructed from combinations of different transcription factor parts. The team made nearly 3 million different ATFs.
As a proof of principle, the researchers tried reproducing Yamanaka’s original, groundbreaking iPS cell experiment. They inserted the ATFs into skin cells that already had 3 of the 4 Yamanaka factors, they left out Oct4. They successfully generated iPS with this approach and then went back and studied the makeup of the ATFs that had caused cells to reprogram into iPS cells. Senior author Aseem Ansari gave a great analogy in a university press release:
“Imagine you have millions of keys and only a unique key or combination of keys can turn a motor on. We test all those keys in parallel and when we see the motor fire up, we go back to see exactly which key switched it on.”
Micrograph of induced pluripotent stem cells generated from artificial transcription factors. The cells express green fluorescent protein after a key gene known as Oct4 is activated. (ASUKA EGUCHI/UW-MADISON)
The analysis showed that these ATFs had stimulated gene activity cascades which didn’t directly involve Oct4 but yet ultimately activated it. This finding is important because it suggests that future cell conversion experiments could uncover some not so obvious cell fate pathways. Ansari explains this point further:
“It’s a way to induce cell fate conversions without having to know what genes might be important because we are able to test so many by using an unbiased library of molecules that can search nearly every corner of the genome.”
This sort of brute force method to accelerate research discoveries is music to our ears at CIRM because it ultimately could lead to therapies faster.
Search for clues to treat deadly lung disease
When researchers don’t understand what causes a particular disease, a typical strategy is to compare gene activity in diseased vs healthy cells and identify important differences. Those differences may lead to potential paths to developing a therapy. That’s the approach a collaborative team from Cincinnati Children’s Hospital and Cedars-Sinai Medical took to tackle idiopathic pulmonary fibrosis (IPF).
IPF is a chronic lung disease which causes scarring, or fibrosis, in the air sacs of the lung. This is the spot where oxygen is taken up by tiny blood vessels that surround the air sacs. With fibrosis, the air sacs stiffen and thicken and as a result less oxygen gets diffused into the blood and starves the body of oxygen. IPF can lead to death within 2 to 5 years after diagnosis. Unfortunately, no cures exist and the cause is unknown, or idiopathic.
The transfer of oxygen from air sacs to blood vessels is an intricate one with many cell types involved. So pinpointing what goes wrong in IPF at a cellular and molecular level has proved difficult. In the current study, the scientists, for the first time, collected gene sequencing data from single cells from healthy and diseased lungs. This way, a precise cell by cell analysis of gene activity was possible.
One set of gene activity patterns found in healthy sample were connected to proper formation of a particular type of air sac cell called the aveolar type 2 lung cell. Other gene patterns were linked to abnormal IPF cell types. With this data in hand, the researchers can further investigate the role of these genes in IPF which may open up new therapy approaches to this deadly disease.
The study funded in part by CIRM was published this week in Journal of Clinical Investigation Insight and a press release about the study was picked up by PR Newswire.
If Forest Gump were a scientist, I’d like to think he would have said his iconic line a little differently. Dr. Gump would have said, “scientific research is like a box of chocolates – you never know what you’re gonna get.”
A new CIRM-funded study coming out of the Gladstone Institutes certainly proves this point. Published yesterday in the Proceedings of the National Academy of Sciences, the study found that a specific genetic mutation known to cause a rare disease called fibrodysplasia ossificans progressiva (FOP) makes it easier to reprogram adult skin cells into induced pluripotent stem cells (iPSCs).
Shinya Yamanaka received the Nobel Prize in medicine in 2012 for his seminal discovery of the iPSC technology, which enabled scientists to generate patient specific pluripotent stem cell lines from adult cells like skin and blood. These iPSC lines are useful for modeling disease in a dish, identifying new therapeutic drugs, and potentially for clinical applications in patients. However, one of the rate-limiting steps to this technology is the inefficient process of making iPSCs.
Yamanaka, a senior investigator at Gladstone, knows this problem all too well. In a Gladstone news release he commented, “inefficiency in creating iPSCs is a major roadblock toward applying this technology to biomedicine. Our study identified a surprising way to increase the number of iPSCs that we can generate.”
So how did Yamanaka and his colleagues discover this new trick for making iPSCs more efficiently? Originally, their intentions were to model a rare genetic disease called FOP. It’s commonly known as “stone man syndrome” because the disease converts normal muscle and connective tissue into bone either spontaneously or spurred by injury. Bone growth begins at a young age starting at the neck and progressively moving down the body. Because there is no treatment or cure, patients typically have a lifespan of only 40 years.
The Gladstone team wanted to understand this rare disease better by modeling it in a dish using iPSCs generated from patients with FOP. These patients had a genetic mutation in the ACVR1 gene, which plays an important role in the development of the embryo. FOP patients have a mutant form of ACVR1 that overstimulates this developmental pathway and boosts the activity of a protein called BMP (bone morphogenic protein). When BMP signaling is ramped up, they discovered that they could produce significantly more iPSCs from the skin cells of FOP patients compared to normal, healthy skin cells.
First author on the study, Yohei Hayashi, explained their hypothesis for why this mutation makes it easier to generate iPSCs:
“Originally, we wanted to establish a disease model for FOP that might help us understand how specific gene mutations affect bone formation. We were surprised to learn that cells from patients with FOP reprogrammed much more efficiently than cells from healthy patients. We think this may be because the same pathway that causes bone cells to proliferate also helps stem cells to regenerate.”
To be sure that enhanced BMP signaling caused by the ACVR1 mutation was the key to generating more iPSCs, they blocked this signal and discovered that much fewer iPSCs were made from FOP patient skin cells.
Senior Investigator Bruce Conklin, who was a co-author on this study, succinctly summarized the importance of their findings:
“This is the first reported case showing that a naturally occurring genetic mutation improves the efficiency of iPSC generation. Creating iPSCs from patient cells carrying genetic mutations is not only useful for disease modeling, but can also offer new insights into the reprogramming process.”
Gladstone investigators Bruce Conklin and Shinya Yamanaka. (Photo courtesy of Chris Goodfellow, Gladstone Institutes)
A decade has passed since Dr. Shinya Yamanaka and his colleagues discovered the Nobel Prize-winning technology called induced pluripotent stem cells (iPSCs). These stem cells can be derived from adult tissue and can develop into any cell type in the body. They are an extremely useful tool to model disease in a dish, screen for new drug therapeutics, and have the potential to replace lost or damaged tissue in humans.
In honor of this amazing scientific discovery, we’re launching a new blog series about iPSCs and their impact on CIRM since we started funding stem cell research in 2007. It will be a four-part series over the course of September ending with a blog highlighting the 10 Years of iPSCs Cell Symposium that will be hosted in Berkeley, CA in late September.
Here are the topics:
CIRM jumps on the iPSC bandwagon before it had wheels.
Expanding the CIRM iPSC bank, how individuals are making a difference.
Spotlight on CIRM-funded iPSC research, interviews with CIRM-funded scientists.
What the experts have to say, recap of the 10 Years of iPSCs Cell Symposium.
A Conference Dedicated to 10 Years of iPSCs
Cell Press is hosting a Symposium on September 25th dedicated to the 10th anniversary of Yamanaka’s iPSC discovery. The symposium is featuring famous scientists in biology, medicine, and industry and is sure to be one of the best stem cell conferences this year. The speakers will cover topics from discovery research to technology development and clinical applications of iPSCs.
More details about the Symposium can be found here.
Here are a few of the talks and events we’re excited about:
Keynote by Gladstone’s Shinya Yamanaka: Recent progress in iPSC research and application
Panel on ethical considerations for clinical translation of iPSC research
Organized run with Shinya Yamanaka (I can finally say that I’ve run with a Nobel Prize winner!)
Advances in modeling ALS with iPSCs by Kevin Eggan, Harvard University
Cellular reprogramming approaches for cardiovascular disease by Deepak Srivastava, Director of the Roddenberry (named after Star Trek’s Gene Roddenberry) Stem Cell Center at the Gladstone Institutes in San Francisco
Keynote by MIT’s Rudolf Jaenisch: Stem cells, iPSCs and the study of human development and disease
CIRM will be attending and covering the conference through our blog and on Twitter (@CIRMnews).
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.
Is fasting the fountain of youth?
Among the many insults our bodies endure in old age is a weakened immune system which leaves the elderly more susceptible to infection. Chemotherapy patients also face the same predicament due to the immune suppressing effects of their toxic anticancer treatments. While many researchers aim to develop drugs or cell therapies to protect the immune system, a University of Southern California research report this week suggests an effective alternative intervention that’s startlingly straightforward: fasting for 72 hours.
The study published in Cell Stem Cell showed that cycles of prolonged fasting in older mice led to a decrease in white blood cells which in turn set off a regenerative burst of blood stem cells. This restart of the blood stem cells replenished the immune system with new white blood cells. In a pilot Phase 1 clinical trial, cancer patients who fasted 72 hours before receiving chemotherapy maintained normal levels of white blood cells.
A look at the molecular level of the process pointed to a decrease in the levels of a protein called PKA in stem cells during the fasting period. In a university press release carried by Science Daily, the study leader, Valter Longo, explained the significance of this finding:
“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system. And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”
In additional to necessary follow up studies, the team is looking into whether fasting could benefit other organ systems besides the immune system. If the data holds up, it could be that regular fasting or direct targeting of PKA could put us on the road to a much more graceful and healthier aging process.
Faster, cheaper, safer way to use iPS cells
Science, like traffic in any major city, never moves quite as quickly as you would like, but now Japanese researchers are teaming up to develop a faster, and cheaper way of using iPSC’s , pluripotent stem cells that are reprogrammed from adult cells, for transplants.
Part of the beauty of iPSCs is that because those cells came from the patient themselves, there is less risk of rejection. But there are problems with this method. Taking adult cells and turning them into enough cells to treat someone can take a long time. It’s expensive too.
But now researchers at Kyoto University and three other institutions in Japan have announced they are teaming up to change that. They want to create a stockpile of iPSCs that are resistant to immunological rejection, and are ready to be shipped out to researchers.
Having a stockpile of ready-to-use iPSCs on hand means researchers won’t have to wait months to develop their own, so they can speed up their work.
Shinya Yamanaka, who developed the technique to create iPSCs and won the Nobel prize for his efforts, say there’s another advantage with this collaboration. In a news article on Nikkei’s Asian Review he said these cells will have been screened to make sure they don’t carry any potentially cancer-causing mutations.
“We will take all possible measures to look into the safety in each case, and we’ll give the green light once we’ve determined they are sound scientifically. If there is any concern at all, we will put a stop to it.”
Any article that has an opening sentence that says “Cancer stem cells are like zombies” has to be worth reading. And a report in ScienceMag that explains how pre-leukemia white blood cell precursors become leukemia cancer stem cells is definitely worth reading.
The article is about a study in the journal Cell Stem Cell by researchers at UC San Diego. The senior author is Catriona Jamieson:
“In this study, we showed that cancer stem cells co-opt an RNA editing system to clone themselves. What’s more, we found a method to dial it down.”
An enzyme called ADAR1 is known to spur cancer growth by manipulating small pieces of genetic material known as microRNA. Jamieson and her team wanted to track how that was done. They discovered it is a cascade of events, and that once the first step is taken a series of others quickly followed on.
They found that when white blood cells have a genetic mutation that is linked to leukemia, they are prone to inflammation. That inflammation then activates ADAR1, which in turn slows down a segment of microRNA called let-7 resulting in increased cell growth. The end result is that the white blood cells that began this cascade become leukemia stem cells and spread an aggressive and frequently treatment-resistant form of the blood cancer.
Having uncovered how ADAR1 works Jamieson and her team then tried to find a way to stop it. They discovered that by blocking the white blood cells susceptibility to inflammation, they could prevent the cascade from even starting. They also found that by using a compound called 8-Aza they could impede ADAR1’s ability to stimulate cell growth by around 40 percent.
Catriona Jamieson – definitely not a zombie
Jamieson says the findings open up all sorts of possibilities:
“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed.”
This wasn’t a CIRM-funded study but we have supported other projects by Dr. Jamieson that have led to clinical trials.
Ever since 2006 when Japanese researcher Shinya Yamanaka showed that you could take an adult cell, such as those in your skin, and reprogram it to act like an embryonic stem cell, the scientific world has looked at these induced pluripotent stem (iPS) cells as a potential game changer. They had the ability to convert a person’s own cells into any other kind of cell in the body, potentially offering a way of creating personalized treatments for a wide variety of diseases.
Fears that this reprogramming method might create some cancer-causing genetic mutations seemed to have been eased when two recent studies suggested this approach is relatively safe and unlikely to lead to any tumors in patients. We funded one of those studies and blogged about it.
Reason for caution
But now a new study in the journal Cell Stem Cell says “not so fast”. The study says the older the person is, the greater the chance that any iPS cells derived from their tissue could contain potentially harmful mutations, but not in the places you would normally think.
A team at Oregon Health and Science University, led by renowned scientist Shoukhrat Mitalipov, took skin and blood samples from a 72-year-old man. The scientists examined the DNA from those samples, then reprogrammed those cells into iPS cells, and examined the DNA from the new stem cells.
Shoukhrat Mitalipov: photo courtesy Oregon Health and Science University
When they looked at the cells collectively the levels of mutations in the new iPS cells appeared to be quite low. But when they looked at individual cells, they noticed a wide variety of mutations in the mitochondria in those cells.
Now, mitochondria play an important role in the life of a cell. They act as a kind of battery, providing the power a cell needs to perform a variety of functions such as signaling and cell growth. But while they are part of the cell, mitochondria have their own genomes. It was here that the researchers found the mutations that raised questions.
Older cells have more problems
Next they repeated the experiment but this time took skin and blood samples from 14 people between the ages of 24 and 72. They found that older people had more genetic mutations in their mitochondrial DNA that were then transferred to the iPS cells derived from those people. In some cases up to 80 percent of the iPS cell lines generated showed mitochondrial mutations. That’s really important because the greater the amount of mutated mitochondrial DNA in a cell, the more its ability to function is compromised.
In a news release, Mitalipov says this should cause people to pause before using iPS cells derived from an older person for therapeutic purposes:
“Pathogenic mutations in our mitochondrial DNA have long been thought to be a driving force in aging and age-related diseases, though clear evidence was missing. Now with that evidence at hand, we know that we must screen stem cells for mutations or collect them at younger age to ensure their mitochondrial genes are healthy. This foundational knowledge of how cells are damaged in the natural process of aging may help to illuminate the role of mutated mitochondria in degenerative disease.”
To be clear, the researchers are not saying these iPS cells from older people should never be used, only that they need to be carefully screened to ensure they are not seriously damaged before being transplanted into a patient.
A possible solution
Mitalipov suggests a simple way around the problem would be to identify the iPS cell with the best mitochondria, and then use that as the basis for a new cell line that could then be used to create a new therapy.
Taosheng Huang, a researcher at the Mitochondrial Disorders Program at Cincinnati Children’s Hospital Medical Center, is quoted in the news release saying the lesson is clear:
“If you want to use iPS cells in a human, you must check for mutations in the mitochondrial genome. Every single cell can be different. Two cells next to each other could have different mutations or different percentages of mutations.”