For years scientists have been touting the potential of CRISPR, a gene editing tool that allows you to target a specific mutation and either cut it out or replace it with the corrected form of the gene. But like all new tools it had its limitations. One important one was the difficult in delivering the corrected gene to mature cells in large numbers.
Scientists at the Gladstone Institutes and U.C. San Francisco say they think they have found a way around that. And the implications for using this technique to develop new therapies for deadly diseases are profound.
In the past scientists used inactivated viruses as a way to deliver corrected copies of the gene to patients. We have blogged about UCLA’s Dr. Don Kohn using this approach to treat children born with SCID, a deadly immune disorder. But that was both time consuming and expensive.
CRISPR, on the other hand, showed that it could be easier to use and less expensive. But getting it to produce enough cells for an effective therapy proved challenging.
The team at Gladstone and UCSF found a way around that by switching from using CRISPR to deliver a double-stranded DNA to correct the gene (which is toxic to cells in large quantities), and instead using CRISPR to deliver a single stranded DNA (you can read the full, very technical description of their approach in the study they published in the journal Nature Biotechnology).
Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology and the senior author of the study, said this more than doubled the efficiency of the process. “One of our goals for many years has been to put lengthy DNA instructions into a targeted site in the genome in a way that doesn’t depend on viral vectors. This is a huge step toward the next generation of safe and effective cell therapies.”
It has another advantage too, according to Gladstone’s Dr. Jonathan Esensten, an author of the study. “This technology has the potential to make new cell and gene therapies faster, better, and less expensive.”
The team has already used this method to generate more than one billion CAR-T cells – specialized immune system cells that can target cancers such as multiple myeloma – and says it could also prove effective in targeting some rare genetic immune diseases.
So, I reached out to Jackie and asked her some questions about her work and career. She generously put aside keeping the nation healthy to answer them. Enjoy.
What made you decide to move from research into government.
I think if you asked my high school government teacher (shout out to Mr. Bell!), he would be the least surprised person that I have ended up where I am currently. I was always interested in topics and activities beyond science, but at a certain point you have to choose a path. When it came time to deciding my undergraduate major, I figured that if I pursued my interest in biology it would still keep my options open to do something different in my career, but if I chose to be a French major, or Political Science major, or English major – I might close the door in my ability to pursue scientific research. When I got to graduate school, I saw the impact of government (both state and federal) decisions on work in the lab. This takes the form of where funding goes, but also in the rules you have to follow while doing research. Though I liked the pursuit of new knowledge and being the one designing and performing experiments, I was interested in understanding more about how those government decisions are made upstream of the lab bench.
What’s the most surprising thing you have learned in your time at the White House Office of Science and Technology Policy (OSTP).
Maybe not “surprising” but the thing that may not be obvious to outsiders: OSTP’s budget is tiny compared to other Executive Branch agencies (like where I came from previously at NIH). The work we accomplish in this office is solely by forming partnerships and collaborations with others across the government. We are not typically the rowers of the boat, but we can be the steerer or navigator. (Is the term coxswain? I have never been on a crew team obviously.)
Was it hard making the transition from research to advocacy and now policy?
Honestly I feel like my training in research set me up well for the jobs I’ve had in policy. There is often not someone telling you exactly how to do something – you have to do the work yourself to search the literature, talk to other people, find collaborators, and keep at it. And the skills that you hone in research – from keeping an organized lab notebook the whole way through to writing scientific papers – are some of the same skills you need in government.
At a time when so many people seem so skeptical of science how do you get your message out.
We have to meet people where they are. As a government official, I have great respect for messages that come from experts within the government – but that is not the only way the message should be getting out. Scientists and other experts within communities should also be spokespeople for science. I would urge scientists at every level – whether you are a citizen scientist, a medical doctor, a PhD student, or some other kind of expert – to engage with their communities and put the work in to understand how to effectively communicate at levels beyond just speaking to your colleagues.
One of the issues that so many of us, including here at CIRM, are working on is improving our performance in diversity, equity and inclusion. How big an issue is that for you and your colleagues at OSTP and what are you doing to try and address it.
The mission of our office is to “maximize the benefits of science and technology to advance health, prosperity, security, environmental quality, and justice for all Americans.” Those final two words are key: “all Americans.” It is the policy of this Office and our Administration that it is not okay for the benefits of science & technology to only reach a select few – who can afford it or who live in a certain zip code or who know the right people.
This takes different forms depending on what kind of S&T work we are talking about, but I will give you an example from my own work. I have been leading an effort that aims to explore and act upon how digital health care delivery technologies can be used to increase access to healthcare in community-based health settings. We know that these cutting edge technologies are most likely to get to people who, for example, get their care at academic medical centers, or who have primo health insurance plans, or who are already tech savvy. We feel that as these technologies continue to grow within the healthcare system, that it is an imperative to ensure that they are accessible to practitioners and patients at community health centers, or to people who may not be tech geeks, or that they can be interoperable with the systems used by community health workers.
During a time of Covid and now Monkeypox, what’s it like to have a front row seat and watch how government responds to public health emergencies.
My colleagues who work on outbreaks and pandemic responses are some of the most dedicated public servants I know. They will be the first to admit that we are continually learning and integrating new tools and technologies into our toolbox, and that is a constant effort. Emergent issues like outbreaks force decisions when there may not be a lot of information – that is a hard job.
I’ve always felt that DC would be a fun place to live and work (except during the height of summer!) what do you most like about it.
DC is a city full of people who care deeply (almost to a pathological extent) about the work they do and how to make the world a better place. There’s also incredible diversity here – which means a variety of viewpoints, languages, and food! I love that.
Jackie is not just a good writer. She’s also a great speaker. Here’s a clip of her responding to our Elevator Challenge many years ago, when she was still a fledgling researcher. Her explanation of what she does, is a master class in turning a complex subject into something easy to understand.
An ever-growing array of academic and industry resources are required to rapidly translate scientific discoveries and emerging technologies toward safe and effective regenerative medicine therapies for patients. To help, the California Institute for Regenerative Medicine (CIRM) is creating a network of Industry Resource Partners (IRP) that will make its unique resources available to help accelerate the progression of CIRM-funded Discovery, Translational and Clinical stage research projects toward transformative regenerative medicine therapies for rare and prevalent diseases.
The Industry Resource Partners will offer their services, technologies and expertise to CIRM-funded projects in a cost-effective, stage-appropriate and consistent manner.
For example, Novo Nordisk is making research-grade vials of its Good Manufacturing Practice (GMP)-grade human embryonic stem cell line available for CIRM Discovery Quest stage research projects at no cost. Having access to clinically compatible pluripotent stem cell lines such as this one will help CIRM researchers accelerate the translation of their therapeutic discoveries toward clinical use. Researchers will also have future access to Novo Nordisk’s GMP seed stock as well as opportunities for partnering with Novo Nordisk.
“CIRM is a lender of first resort, supporting projects in the very early stages, long before they are able to attract outside investment,” says Shyam Patel, PhD, the Director of Business Development at CIRM. “With the launch of this program we hope to create a force-multiplier effect by bringing in industry partners who have the resources, experience and expertise to help further accelerate CIRM-funded regenerative medicine research projects.”
This new network builds on work CIRM started in 2018 with the Industry Alliance Program (IAP). The goal of the IAP was to partner researchers and industry to help accelerate the most promising stem cell, gene and regenerative medicine therapy programs to commercialization. Four of the members of the IAP are also founding members or the IRP.
In addition to Novo Nordisk, the IRP includes:
ElevateBio is providing access to high quality, well-characterized induced pluripotent stem cell (iPSC) lines to CIRM Discovery Quest stage research projects for product development in regenerative medicine. CIRM awardees will also have access to ElevateBio’s viral vector technologies, process development, analytical development, and GMP manufacturing services.
Bayer is offering to support the cell therapy process development and GMP manufacturing needs of CIRM Translational and Clinical awardees at its newly built Berkeley facilities. The partnered projects will have access to Bayer’s cell therapy manufacturing facilities, equipment, resources and expertise. Bayer is also open to partnering from fee-based-services to full business development and licensing opportunities.
Resilience is providing access to its GMP manufacturing services for CIRM Translational and Clinical Stage projects. In addition to providing access to its cell therapy manufacturing services and partnering opportunities, Resilience will provide project consultation that could aid CIRM applicants in drafting manufacturing plans and budgets for CIRM applications.
“These partnerships are an important step forward in helping advance not only individual projects but also the field as a whole,” says Dr. Maria T. Millan, President and CEO of CIRM. “One of the biggest challenges facing regenerative medicine right now involves manufacturing. Providing researchers with access to high quality starting materials and advanced manufacturing capabilities is going to be essential in helping these projects maintain high quality standards and comply with the regulatory frameworks needed to bring these therapies to patients.”
While the IRP Network will offer its services to CIRM grantees there is no obligation or requirement that any CIRM awardee take advantage of these services.
Jill Helms is not your average Stanford University faculty member. Yes, she is a professor in the Department of Surgery. Yes, she has published lots of scientific studies. Yes, she is a stem cell scientist (funded by CIRM). And yes, she is playing a leading role in Ankasa Regenerative Therapeutics, a company focused on tissue repair and regeneration. But she is so much more than all that.
She is a brilliant public speaker, a fashionista, and has ridden her horse to work (well, Stanford is referred to as The Farm, so why not!) and she lives on a farm of her own called “Follow Your Bliss.” The name comes from philosopher Joseph Campbell who wrote, “If you follow your bliss, you put yourself on a kind of path that has been there all the while, waiting for you. And the life you ought to be living is the one you are living.”
Dr. Helms says that pretty much sums up her life. She says she feels enormously blessed.
Well, we felt enormously blessed when she agreed to sit down with us and chat about her work, her life and her love of fashion for the California Institute for Regenerative Medicine podcast, Talking ‘Bout (re)Generation.
Surrounded by the cold white walls of a hospital room, my family suddenly found themselves on the other side of medicine. Void of any answers or cures, this new reality was full of doubt. As we witnessed assurance dwindle into a look of angst, the doctor’s lips stiffened as he faltered to say the words that would change my grandmother’s life forever. The spinal cancer they had gone in to extract was a misdiagnosed nothing. Instead, the exploration of his scalpel left her paralyzed from the chest down.
Seemingly simple day-to-day moments of my life became the building blocks of my passion for science today. Early realizations of the hurdles laced throughout my grandmother’s life. Vivid memories of my mother’s weary smile as she read articles on the newest advancements in stem cell research. Collectively, what these fragments of time nurtured was hope. I grew to have a dream that something different awaited us in the future. With purpose, I dove into the world of research as an undergraduate.
Today, I am a CIRM Bridges to Stem Cell Research Intern at the Sanford Consortium for Regenerative Medicine. I received my acceptance into the program about a month after my grandmother’s passing. She never saw a cure, let alone an effective treatment.
My position allows me to understand why stem cell research takes time. The road from the bench to the clinic is a painstakingly deliberate one. And although we seek reason and order from the world of science, what we often find is how imperfect it all can be. At its root, I found that research is truly a human endeavor. That is why, as scientists, we must grapple with our lack of knowledge and failures with humility.
CIRM’s programs that train tomorrow’s scientists, such as Bridges, are important because they do more than simply transfer over skills from one generation to the next. Over the next year, I get the valuable experience of working with scientists who share a common dream. They understand the urgency of their research, value the quality of their findings, and put patient needs first. This mentorship ensures that a sense of responsibility is carried on throughout this field.
I applied to this program because stem cell research gave my family the gift of hope. Now, on the other side of the wait, I wish to serve patients and families like my own. I am incredibly grateful to be a part of the Bridges program and I will devote the full extent of my knowledge towards the advancement of this field.
When I was in high school I spent my summers working in a shoe shop and playing soccer with my mates. It never occurred to me that I could do something really worthwhile with that time. So, when I meet the high school students who took part in the California Institute for Regenerative Medicine’s SPARK program I realized I had wasted a lot of time.
For those not familiar with SPARK, it stands for Summer Program to Accelerate Regenerative Medicine Knowledge. It’s a summer program offering high school students a chance to work in a world-class stem cell and gene therapy research facility. The quality of the work they do is truly remarkable. By the end of the summer they are doing projects that many full-time researchers would be proud of.
As part of that program the students also must write blogs and post photos and videos to Instagram to chart their progress. The quality of that work is equally impressive. Last week we posted items about the two best blogs from the students. But there were so many other fine entries that we thought it would be worthwhile to highlight elements of those.
For instance, Ricardo Rodriguez at Charles R. Drew University had some interesting observations on life, even when it’s not always working out the way you planned:
“Cancer is not life going wrong so much as it is life changing. If mutation is random, then so is life. That beautiful randomness that drives evolution and extinction, change and stagnation, life and death, and for you to think that that part of your body could be simple in any way, whether it be simply evil, simply inconvenient, simply structured, is simply hilarious. There is beauty in your body’s complexity, adaptability, and resilience, and these attributes are not barred from any part of your life.”
Mindy Rodriguez at Beckman City of Hope says she learned valuable lessons from working with mice, creatures she previously considered scary, dirty and vicious, but later came to like:
“The CIRM SPARK program reinforced the value of facing my fears by exploring the unknown and most importantly taught me to be comfortable with the uncomfortable. In both cases, I found that it is our response to fear that shapes who we are. We can either run away from the thing that scares us or take each moment as a learning opportunity, embracing change over comfort.”
Manvi Ketireddy at UC Davis had a similar experience, learning to accept things not working out.
“A researcher must be persistent and have the ability to endure lots of failures. I think that is what I love about research: the slight possibility of discovery and answers amid constant defeat is one of the greatest challenges to exist. And boy, do I love challenges.”
Ameera Ali at Sanford Burnham Prebys says she had struggled for years to decide on a career direction, but the internship gave her a fresh perspective on it all.
“Growing up, I never really knew what I wanted to do for a living, and I think that’s because I wanted to do everything. In kindergarten I wanted to be a paleontologist. In 5th grade I wanted to be the CEO of The San Diego Union Tribune, and in 9th grade I wanted to be a physicist at NASA. By 10th grade I was having an existential crisis about what to do with my life, and so began the search for my purpose at the ripe old age of 15.
So now, writing this blog, I never thought I’d end up spending so much of my time in a room filled floor to ceiling with fish tanks. You might be wondering, how does one end up going from physicist to fish farmer? Well, I’m not completely sure to be honest, but it’s been a very fun and interesting experience nonetheless.”
She says by the end she says what initially felt like mundane chores were actually moments worth celebrating.
“These aquatic friends have taught me a lot of valuable life lessons, like being appreciative of the little things in life, caring for others and see things from a different perspective, and realizing that
working in a biology lab allows me to explore my passions, be creative, and be a mother to hundreds of fish children on the side.”
SPARK attracts students from all over California, and it’s that diversity that makes it so important.
My name is Alexa Gastelum and I am from a small border town called Calexico. It is located in the Imperial Valley around two hours away from San Diego. I found out about this Internship from my Math teacher and Mesa Coordinator. They discussed what it was about, and I immediately knew that I wanted to apply. I have always been interested in doing labs and researching so I knew that it would be the perfect opportunity for me. It is not normal to be presented with an opportunity like this from where I’m from because it is a small and low-income town. When I told my family about this internship they were very supportive. They agreed that I needed to apply for it since it was an extremely good opportunity. Even though I would need to spend my summer away from my hometown, they were okay with it because they knew that I could not miss out on the opportunity. I decided to write my personal statement on a disease that hit close to home with my family which was Alzheimer’s. It is a disease that runs in my family and my uncle passed from it. I believe that this is what sparked my interest because I wanted to understand how it worked and how it affects the brain.
At the SPARK event Alexa told me her grandmother was so proud of her for being accepted at the program that she was going around town telling everyone about it. Her grandmother, and all the other grandmothers and mothers and fathers, had every reason to be proud of these students. They are remarkable young people and we look forward to following their careers in the years to come.
We had a wonderful time meeting so many energetic and enthusiastic high school students at the 2022 SPARK Program annual conference hosted by UCSF at the MLK Research Building. The SPARK program is one of the California Institute for Regenerative Medicine’s(CIRM) many programs dedicated to building a diverse and highly-skilled workforce to support the growing regenerative medicine economy right here in California.
Held in-person for the first time since 2019, the event hosted students and program directors from all over California, allowing them the opportunity to share their research through oral and poster presentations. This year, students also attended talks about new approaches to sickle cell disease curative therapies, anti-racism in STEM, and patient advocacy.
The SPARK Program—also known as the Summer Program to Accelerate Regenerative Medicine Knowledge—provides California high school students with summer research internships at leading stem cell institutes in California. To date, there have been 530 SPARK alumni, and another 110 high school interns are completing their training this summer.
The SPARK program specifically selects students who represent the diversity of California’s population, particularly those who might not otherwise have opportunities to take part in research internships due to socioeconomic constraints.
“I really enjoyed being a part of this program, and I feel like I understand so much better what it’s like to be a researcher,” said Brighton C., a student in the SPARK program at Charles R. Drew University of Medicine and Science (pictured below). “I also feel more confident in the subject of stem cells and I might want to dedicate my future to it.”
We’ll be sharing more stories from CIRM’s SPARK Program throughout the year, including blog submissions from students that summarize their summer experiences. Stay tuned for more and be sure to follow CIRM on Instagram, where we will share more photos and fun content created by the students.
There are currently 11 active SPARK programs throughout California, each with its own eligibility criteria and application process. If you are interested in learning more, please visit this web page for more details about each program. If you have questions about CIRM’s education programs, please email Dr. Kelly Shepard at firstname.lastname@example.org.
Thank you to UCSF for hosting the event, and to all the SPARK program directors for supporting this year’s bright interns!
Check out some of the photos from this year’s SPARK conference below.
The news that a stem cell transplant at City of Hope helped a man with HIV go into long-term remission made banner headlines around the world. As it should. It’s a huge achievement, particularly as the 66-year-old man had been living with HIV since 1988.
First the news. In addition to living with HIV the man was diagnosed with acute leukemia. Doctors at City of Hope found a donor who was not only a perfect match to help battle the patient’s leukemia, but the donor also had a rare genetic mutation that meant they were resistant to most strains of HIV.
In transplanting blood stem cells from the donor to the patient they were able to send both his leukemia and HIV into remission. The patient stopped taking all his antiretroviral medications 17 months ago and today has no detectable levels of HIV.
“This patient had a high risk for relapsing from AML [acute myeloid leukemia], making his remission even more remarkable and highlighting how City of Hope provides excellent care treating complicated cases of AML and other blood cancers.”
It’s a remarkable achievement and is only the fifth time that a patient with both HIV and leukemia has been put into remission after a transplant from an HIV-resistant donor.
So, what does that have to do with CIRM? Well, CIRM’s Alpha Clinics Network helped City of Hope get this case approved by an Institutional Review Board (IRB) and also helped in collecting and shipping the donor blood. In addition, part of the Alpha Clinics team at University of California San Diego helped with the reservoir analysis of blood and gut biopsies to check for any remaining signs of HIV.
It’s a reminder that this kind of achievement is a team effort and CIRM is very good at creating and supporting teams. The Alpha Clinics Network is a perfect example. We created it because there was a need for a network of world-class medical facilities with the experience and expertise to deliver a whole new kind of therapy. The Network has been remarkably successful in doing that with more than 200 clinical trials, taking care of more than 1,000 patients, and treating more than 40 different diseases.
This year our Board approved expanding the number of these clinics to better serve the people of California.
While the role of the Alpha Clinics Network in helping this one patient may seem relatively small, it was also an important one. And we are certainly not stopping here. We have invested more than $79 million in 19 different projects targeting HIV/AIDS, include four clinical trials.
We are in this for the long term and results like the man who had HIV and is now in remission are a sign we are heading in the right direction.
A urethral stricture is scarring of the tube that carries urine out of the body. If left untreated it can be intensely painful and lead to kidney stones and infections. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) is investing more than $3.8 million in a Phase 1 clinical trial to create a stem cell-based therapy for the condition.
When a scar, or stricture, forms along the urethra it impedes the flow of urine and causes other complications. James Yoo, M.D., Ph.D., and his team at Wake Forest University Health Sciences will use epithelial and smooth muscle cells, taken from the patient’s bladder, and layer them on to a synthetic tubular scaffold. The tube will then be surgically implanted inside the urethra.
The goal is for the progenitor cells to support self-renewal of the tissue and for the entire structure to become integrated into the surrounding tissue and become indistinguishable from it, restoring normal urinary function. Dr. Yoo and his team believe their approach has the potential to be effective for at least a decade.
“While not immediately life-threatening, urethral strictures lead to multiple health complications that impair quality of life and predispose to kidney dysfunction,” says Dr. Maria T. Millan, President and CEO of CIRM. “Developing an effective and durable treatment would significantly impact lives and has the potential to decrease the cumulative healthcare costs of treating recurrent kidney stones, infections and downstream kidney complications, especially of long-segment urethral strictures.”
The word “miraculous” gets tossed around a lot in the world of medicine, mostly by people who have made an unexpected recovery from a deadly or life-threatening condition. In Sean Entin’s case calling his recovery from an almost-fatal stroke could be called miraculous, but I think you would also have to say it’s due to hard work, determination, and an attitude that never even considered giving up.
Sean had a stroke in 2011. Doctors didn’t think he’d survive. He was put into a coma and underwent surgery to create an opening in his skull to give his brain time and space to heal. When he woke he couldn’t walk or talk, couldn’t count. Doctors told him he would never walk again.
They didn’t know Sean. Fast forward to today. Sean is active, has completed two 5k races – that’s two more than me – and has created Stroke Hacker, a program designed to help others going through what he did.
Sean is a remarkable man, which is why I sat down to chat with him for the latest episode of the California Institutes for Regenerative Medicine’s podcast, ‘Talking ‘Bout (re)Generation’.