Researcher claims to have made first gene-edited baby. But did it really happen?

Raelians

Claude Vorilhorn, founder of Raelism; Photo: courtesy thoughtco.com

Remember the Raelians? Probably not. But way back in 2002 the group, some described them as a cult, claimed it had created the world’s first cloned baby. The news made headlines all around the world raising fears we were stepping into uncharted scientific territory. Several weeks later the scientist brought in by the Raelians to verify their claims called it an “elaborate hoax.”

hejiankui

He Jiankui: Photo courtesy MIT Technology Review

Fast forward 16 years and a Chinese scientist named He Jiankui of Shenzhen claims he has created the first genetically modified humans. Again, it is generating headlines around the world and alarming people. In an interview with CNBC, Hank Greely, a bioethicist at Stanford, said if it happened it was “criminally reckless and I unequivocally condemn the experiment.”

The question now is did it happen, or is this just another “elaborate hoax”?

The concerns about this story are real. The scientist claims he used CRISPR to modify embryos during fertility treatments, resulting in the birth of twin girls.

CRISPR has been making headlines all of its own in the last few years as a fast, cheap and efficient way of editing genes. CIRM supports research using CRISPR for problems such as sickle cell disease. The difference being that our research works with adults so any changes in their genes are just for them. Those changes are not passed on to future generations.

The work making headlines around the world used CRISPR on embryos, meaning a child born from one of those embryos would pass those changes on to future generations. In effect, creating a new kind of human being.

This approach raises all sorts of serious issues – scientific, ethical and moral – not the least of which is that the technique could create unknown mutations down the road that would be passed on to future generations.  That’s why in the US the editing of embryos for pregnancy is banned.

But almost as soon as the news was announced there were questions raised about it. The research was not published anywhere. A hospital that the researchers named in their ethical approval documents is denying any involvement.

If it did happen, it could open a new, and potentially frightening chapter in science. In an interview on CNN, Julian Savulescu, director of the Oxford Uehiro Centre for Practical Ethics at the University of Oxford, called the use of CRISPR in this manner as “genetic Russian Roulette.”

“If true, this experiment is monstrous. Gene editing itself is experimental and is still associated with off-target mutations, capable of causing genetic problems early and later in life, including the development of cancer.”

And in an interview on the BBC, Prof Robert Winston, Professor of Science and Society at Imperial College London, said: “If this is a false report, it is scientific misconduct and deeply irresponsible. If true, it is still scientific misconduct.”

Our best hope right now is that this is just a repeat of the Raelians. Our worst fear, is that it’s not.

Japanese scientists implant first Parkinson’s patient with replacement neurons derived from stem cells

Parkinsons

Neurons derived from stem cells.Credit: Silvia Riccardi/SPL

Currently, more than 10 million people worldwide live with Parkinson’s disease (PD). By 2020, in the US alone, people living with Parkinson’s are expected to outnumber the cases of multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined.

There is no cure for Parkinson’s and treatment options consist of medications that patients ultimately develop tolerance to, or surgical therapies that are expensive. Therefore, therapeutic options that offer long-lasting treatment, or even a cure, are essential for treating PD.

Luckily for patients, Jun Takahashi’s team at Kyoto University has pioneered a stem cell based therapy for PD patients.

To understand their treatment strategy, however, we first have to understand what causes this disease. Parkinson’s results from decreased numbers of neurons that produce dopamine, a molecule that helps control muscle movements. Without proper dopamine production, patients experience a wide range of movement abnormalities, including the classic tremors that are associated with PD.

The current treatment options only target the symptoms, as opposed to the root cause of the disease. Takashi’s group decided to go directly to the source and improve dopamine production in these patients by correcting the dopaminergic neuron shortage.

The scientists harvested skin cells from a healthy donor and reprogrammed them to become induced pluripotent stem cells (iPSCs), or stem cells that become any type of cell. These iPSCs were then turned into the precursors of dopamine-producing neurons and implanted into 12 brain regions known to be hotspots for dopamine production.

The procedure was carried out in October and the patient, a male in his 50s, is still healthy. If his symptoms continue to improve and he doesn’t experience any bad side effects,  he will receive a second dose of dopamine-producing stem cells. Six other patients are scheduled to receive this same treatment and Takashi hopes that, if all goes well, this type of treatment can be ready for the general public by 2023.

This treatment was first tested in monkeys, where the researchers saw that not only did the implanted stem cells improve Parkinson’s symptoms and survive in the brain for at least two years, but they also did not cause any negative side effects.

This is only the third time iPSCs have been used as a treatment option in humans. The first was for macular degeneration in 2014.

CIRM is funding a similar, albeit earlier-stage program, with Jeanne Loring at Scripps.

 

Stem Cell Agency Invests in New Immunotherapy Approach to HIV, Plus Promising Projects Targeting Blindness and Leukemia

HIV AIDS

While we have made great progress in developing therapies that control the AIDS virus, HIV/AIDS remains a chronic condition and HIV medicines themselves can give rise to a new set of medical issues. That’s why the Board of the California Institute for Regenerative Medicine (CIRM) has awarded $3.8 million to a team from City of Hope to develop an HIV immunotherapy.

The City of Hope team, led by Xiuli Wang, is developing a chimeric antigen receptor T cell or CAR-T that will enable them to target and kill HIV Infection. These CAR-T cells are designed to respond to a vaccine to expand on demand to battle residual HIV as required.

Jeff Sheehy

CIRM Board member Jeff Sheehy

Jeff Sheehy, a CIRM Board member and patient advocate for HIV/AIDS, says there is a real need for a new approach.

“With 37 million people worldwide living with HIV, including one million Americans, a single treatment that cures is desperately needed.  An exciting feature of this approach is the way it is combined with the cytomegalovirus (CMV) vaccine. Making CAR T therapies safer and more efficient would not only help produce a new HIV treatment but would help with CAR T cancer therapies and could facilitate CAR T therapies for other diseases.”

This is a late stage pre-clinical program with a goal of developing the cell therapy and getting the data needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial.

The Board also approved three projects under its Translation Research Program, this is promising research that is building on basic scientific studies to hopefully create new therapies.

  • $5.068 million to University of California at Los Angeles’ Steven Schwartz to use a patient’s own adult cells to develop a treatment for diseases of the retina that can lead to blindness
  • $4.17 million to Karin Gaensler at the University of California at San Francisco to use a leukemia patient’s own cells to develop a vaccine that will stimulate their immune system to attack and destroy leukemia stem cells
  • Almost $4.24 million to Stanford’s Ted Leng to develop an off-the-shelf treatment for age-related macular degeneration (AMD), the leading cause of vision loss in the elderly.

The Board also approved funding for seven projects in the 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.

Application Title Institution CIRM Committed Funding
DISC2-10979 Universal Pluripotent Liver Failure Therapy (UPLiFT)

 

Children’s Hospital of Los Angeles $1,297,512

 

DISC2-11105 Pluripotent stem cell-derived bladder epithelial progenitors for definitive cell replacement therapy of bladder cancer

 

Stanford $1,415,016
DISC2-10973 Small Molecule Proteostasis Regulators to Treat Photoreceptor Diseases

 

U.C. San Diego $1,160,648
DISC2-11070 Drug Development for Autism Spectrum Disorder Using Human Patient iPSCs

 

Scripps $1,827,576
DISC2-11183 A screen for drugs to protect against chemotherapy-induced hearing loss, using sensory hair cells derived by direct lineage reprogramming from hiPSCs

 

University of Southern California $833,971
DISC2-11199 Modulation of the Wnt pathway to restore inner ear function

 

Stanford $1,394,870
DISC2-11109 Regenerative Thymic Tissues as Curative Cell Therapy for Patients with 22q11 Deletion Syndrome

 

Stanford $1,415,016

Finally, the Board approved the Agency’s 2019 research budget. Given CIRM’s new partnership with the National Heart, Lung, Blood Institute (NHLBI) to accelerate promising therapies that could help people with Sickle Cell Disease (SCD) the Agency is proposing to set aside $30 million in funding for this program.

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Congresswoman Barbara Lee (D-CA 13th District)

“I am deeply grateful for organizations like CIRM and NHLBI that do vital work every day to help people struggling with Sickle Cell Disease,” said Congresswoman Barbara Lee (D-CA 13th District). “As a member of the House Appropriations Subcommittee on Labor, Health and Human Services, and Education, I know well the importance of this work. This innovative partnership between CIRM and NHLBI is an encouraging sign of progress, and I applaud both organizations for their tireless work to cure Sickle Cell Disease.”

Under the agreement CIRM and the NHLBI will coordinate efforts to identify and co-fund promising therapies targeting SCD.  Programs that are ready to start an IND-enabling or clinical trial project for sickle cell can apply to CIRM for funding from both agencies. CIRM will share application information with the NHLBI and CIRM’s Grants Working Group (GWG) – an independent panel of experts which reviews the scientific merits of applications – will review the applications and make recommendations. The NHLBI will then quickly decide if it wants to partner with CIRM on co-funding the project and if the CIRM governing Board approves the project for funding, the two organizations will agree on a cost-sharing partnership for the clinical trial. CIRM will then set the milestones and manage the single CIRM award and all monitoring of the project.

“This is an extraordinary opportunity to create a first-of-its-kind partnership with the NHLBI to accelerate the development of curative cell and gene treatments for patients suffering with Sickle Cell Disease” says Maria T. Millan, MD, President & CEO of CIRM. “This allows us to multiply the impact each dollar has to find relief for children and adults who battle with this life-threatening, disabling condition that results in a dramatically shortened lifespan.  We are pleased to be able to leverage CIRM’s acceleration model, expertise and infrastructure to partner with the NHLBI to find a cure for this condition that afflicts 100,000 Americans and millions around the globe.”

The budget for 2019 is:

Program type 2019
CLIN1 & 2

CLIN1& 2 Sickle Cell Disease

$93 million

$30 million

TRANSLATIONAL $20 million
DISCOVER $0
EDUCATION $600K

 

 

Using biological “codes” to generate neurons in a dish

BrainWavesInvestigators at the Scripps Research Institute are making brain waves in the field of neuroscience. Until now, neuroscience research has largely relied on a variety of animal models to understand the complexities of various brain or neuronal diseases. While beneficial for many reasons, animal models do not always allow scientists to understand the precise mechanism of neuronal dysfunction, and studies done in animals can often be difficult to translate to humans. The work done by Kristin Baldwin’s group, however, is revolutionizing this field by trying to re-create this complexity in a dish.

One of the primary hurdles that scientists have had to overcome in studying neuronal diseases, is the impressive diversity of neuronal cell types that exist. The exact number of neuronal subtypes is unknown, but scientists estimate the number to be in the hundreds.

While neurons have many similarities, such as the ability to receive and send information via chemical cues, they are also distinctly specialized. For example, some neurons are involved in sensing the external environment, whereas others may be involved in helping our muscles move. Effective medical treatment for neuronal diseases is contingent on scientists being able to understand how and why specific neuronal subtypes do not function properly.

In a study in the journal Nature, partially funded by CIRM, the scientists used pairs of transcription factors (proteins that affect gene expression and cell identity), to turn skin stem cells into neurons. These cells both physically looked like neurons and exhibited characteristic neuronal properties, such as action potential generation (the ability to conduct electrical impulses). Surprisingly, the team also found that they were able to generate neurons that had unique and specialized features based on the transcription factors pairs used.

The ability to create neuronal diversity using this method indicates that this protocol could be used to recapitulate neuronal diversity outside of the body. In a press release, Dr. Baldwin states:

KristinBaldwin

Kristin Baldwin, PhD

“Now we can be better genome detectives. Building up a database of these codes [transcription factors] and the types of neurons they produce can help us directly link genomic studies of human brain disease to a molecular understanding of what goes wrong with neurons, which is the key to finding and targeting treatments.”

These findings provide an exciting and promising tool to more effectively study the complexities of neuronal disease. The investigators of this study have made their results available on a free platform called BioGPS in the hopes that multiple labs will delve into the wealth of information they have opened up. Hopefully, this system will lead to more rapid drug discovery for disease like autism and Alzheimer’s

Celebrating Exciting CIRM-Funded Discovery Research on World Parkinson’s Day

April 11th is World Parkinson’s Disease Awareness Day. To mark the occasion, we’re featuring the work of CIRM-funded researchers who are pursuing new, promising ideas to treat patients with this debilitating neurodegenerative disease.


Birgitt Schuele, Parkinson’s Institute

CIRM Grant: Quest Award – Discovery Stage Research

Research: Birgitt and her team at the Parkinson’s Institute in Sunnyvale, California, are using CRISPR gene editing technology to reduce the levels of a toxic protein called alpha synuclein, which builds up in the dopaminergic brain cells affected by Parkinson’s disease.

Birgitt Schuele

“My hope is that I can contribute to stopping disease progression in Parkinson’s. If we can develop a drug that can get rid of accumulated protein in someone’s brain that should stop the cells from dying. If someone has early onset PD and a slight tremor and minor walking problems, stopping the disease and having a low dose of dopamine therapy to control symptoms is almost a cure.”

Parkinson’s disease in a dish. Dopaminergic neurons made from Parkinson’s patient induced pluripotent stem cells. (Image credit: Birgitt Schuele)


Jeanne Loring, Scripps Research Institute

CIRM Grant: Quest Award – Discovery Stage Research

Research: Jeanne Loring and her team at the Scripps Research Institute in La Jolla, California, are deriving dopaminergic neurons from the iPSCs of Parkinson’s patients. Their goal is to develop a personalized, stem cell-based therapy for PD.

Jeanne Loring

“We are working toward a patient-specific neuron replacement therapy for Parkinson’s disease.  By the time PD is diagnosed, people have lost more than half of their dopamine neurons in a specific part of the brain, and loss continues over time.  No drug can stop the loss or restore the neurons’ function, so the best possible option for long term relief of symptoms is to replace the dopamine neurons that have died.  We do this by making induced pluripotent stem cells from individual PD patients and turning them into the exact type of dopamine neuron that has been lost.  By transplanting a patient’s own cells, we will not need to use potentially dangerous immunosuppressive drugs.  We plan to begin treating patients in a year to two years, after we are granted FDA approval for the clinical therapy.”

Skin cells from a Parkinson’s patient (left) were reprogrammed into induced pluripotent stem cells (center) that were matured into dopaminergic neurons (right) to model Parkinson’s disease. (Image credit: Jeanne Loring)


Justin Cooper-White, Scaled BioLabs Inc.

CIRM Grant: Quest Award – Discovery Stage Research

Research: Justin Cooper-White and his team at Scaled Biolabs in San Francisco are developing a tool that will make clinical-grade dopaminergic neurons from the iPSCs of PD patients in a rapid and cost-effective manner.

Justin Cooper-White

“Treating Parkinson’s disease with iPSC-derived dopaminergic neuron transplantation has a strong scientific and clinical rationale. Even the best protocols are long and complex and generally have highly variable quality and yield of dopaminergic neurons. Scaled Biolabs has developed a technology platform based on high throughput microfluidics, automation, and deep data which can optimize and simplify the road from iPSC to dopaminergic neuron, making it more efficient and allowing a rapid transition to GMP-grade derivation of these cells.  In our first 6 months of CIRM-funded work, we believe we have already accelerated and simplified the production of a key intermediate progenitor population, increasing the purity from the currently reported 40-60% to more than 90%. The ultimate goal of this work is to get dopaminergic neurons to the clinic in a robust and economical manner and accelerate treatment for Parkinson’s patients.”

High throughput differentiation of dopaminergic neuron progenitors in  microbioreactor chambers in Scaled Biolabs’ cell optimization platform. Different chambers receive different differentiation factors, so that optimal treatments for conversion to dual-positive cells can be determined (blue: nuclei, red: FOXA2, green: LMX1A).


Xinnan Wang, Stanford University

CIRM Grant: Basic Biology V

Research: Xinnan Wang and her team at Stanford University are studying the role of mitochondrial dysfunction in the brain cells affected in Parkinson’s disease.

Xinnan Wang

“Mitochondria are a cell’s power plants that provide almost all the energy a cell needs. When these cellular power plants are damaged by stressful factors present in aging neurons, they release toxins (reactive oxygen species) to the rest of the neuron that can cause neuronal cell death (neurodegeneration).  We hypothesized that in Parkinson’s mutant neurons, mitochondrial quality control is impaired thereby leading to neurodegeneration. We aimed to test this hypothesis using neurons directly derived from Parkinson’s patients (induced pluripotent stem cell-derived neurons).”

Dopaminergic neurons derived from human iPSCs shown in green, yellow and red. (Image credit: Atossa Shaltouki, Stanford)


Related Blogs:

Stem Cell RoundUp: CIRM Clinical Trial Updates & Mapping Human Brain

It was a very CIRMy news week on both the clinical trial and discovery research fronts. Here are some the highlights:

Stanford cancer-fighting spinout to Genentech: ‘Don’t eat me’San Francisco Business Times

Ron Leuty, of the San Francisco Business Times, reported this week on not one, but two news releases from CIRM grantee Forty Seven, Inc. The company, which originated from discoveries made in the Stanford University lab of Irv Weissman, partnered with Genentech and Merck KGaA to launch clinical trials testing their drug, Hu5F9-G4, in combination with cancer immunotherapies. The drug is a protein antibody that blocks a “don’t eat me” signal that cancer stem cells hijack into order to evade destruction by a cancer patient’s immune system.

Genentech will sponsor two clinical trials using its FDA-approved cancer drug, atezolizumab (TECENTRIQ®), in combination with Forty Seven, Inc’s product in patients with acute myeloid leukemia (AML) and bladder cancer. CIRM has invested $5 million in another Phase 1 trial testing Hu5F9-G4 in AML patients. Merck KGaA will test a combination treatment of its drug avelumab, or Bavencio, with Forty-Seven’s Hu5F9-G4 in ovarian cancer patients.

In total, CIRM has awarded Forty Seven $40.5 million in funding to support the development of their Hu5F9-G4 therapy product.


Novel regenerative drug for osteoarthritis entering clinical trialsThe Scripps Research Institute

The California Institute for Biomedical Research (Calibr), a nonprofit affiliate of The Scripps Research Institute, announced on Tuesday that its CIRM-funded trial for the treatment of osteoarthritis will start treating patients in March. The trial is testing a drug called KA34 which prompts adult stem cells in joints to specialize into cartilage-producing cells. It’s hoped that therapy will regenerate the cartilage that’s lost in OA, a degenerative joint disease that causes the cartilage that cushions joints to break down, leading to debilitating pain, stiffness and swelling. This news is particularly gratifying for CIRM because we helped fund the early, preclinical stage research that led to the US Food and Drug Administration’s go-ahead for this current trial which is supported by a $8.4 million investment from CIRM.


And finally, for our Cool Stem Cell Image of the Week….

Genetic ‘switches’ behind human brain evolutionScience Daily

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This artsy scientific imagery was produced by UCLA researcher Luis del la Torre-Ubieta, the first author of a CIRM-funded studied published this week in the journal, Cell. The image shows slices of the mouse (bottom middle), macaque monkey (center middle), and human (top middle) brain to scale.

The dramatic differences in brain size highlights what sets us humans apart from those animals: our very large cerebral cortex, a region of the brain responsible for thinking and complex communication. Torre-Ubieta and colleagues in Dr. Daniel Geschwind’s laboratory for the first time mapped out the genetic on/off switches that regulate the growth of our brains. Their results reveal, among other things, that psychiatric disorders like schizophrenia, depression and Attention-Deficit/Hyperactivity Disorder (ADHD) have their origins in gene activity occurring in the very earliest stages of brain development in the fetus. The swirling strings running diagonally across the brain slices in the image depict DNA structures, called chromatin, that play a direct role in the genetic on/off switches.

Scientists find switch that targets immunotherapies to solid tumors

Cancer immunotherapies harness the power of the patient’s own immune system to fight cancer. One type of immunotherapy, called adoptive T cell therapy, uses immune cells called CD8+ Killer T cells to target and destroy tumors. These T cells are made in the spleen and lymph nodes and they can migrate to different locations in the body through a part of our circulatory system known as the lymphatic system.

CD8+ T cells can also leave the circulation and travel into the body’s tissues to fight infection and cancer. Scientists from the Scripps Research Institute and UC San Diego are interested in learning how these killer T cells do just that in hopes of developing better immunotherapies that can specifically target solid tumors.

In a study published last week in the journal Nature, the teams discovered that a gene called Runx3 acts as a switch that programs CD8+ T cells to set up shop within tissues outside of the circulatory system, giving them access to solid tumors.

“Runx3 works on chromosomes inside killer T cells to program genes in a way that enables the T cells to accumulate in a solid tumor,” said Matthew Pipkin, co-senior author and Associate Professor at The Scripps Research Institute.

Study authors Adam Getzler, Dapeng Wang and Matthew Pipkin of The Scripps Research Institute collaborated with scientists at the University of California, San Diego.

They discovered Runx3 by comparing what genes were expressed in CD8+ T cells found in the lymphatic system to CD8+ T cells that were found in tissues outside of the circulation. They then screened thousands of potential factors for their ability to influence CD8+ T cells to infiltrate solid tumors.

“We found a distinct pattern,” Pipkin said. “The screens showed that Runx3 is one at the top of a list of regulators essential for T cells to reside in non-lymphoid tissues.”

The team then set out to prove that Runx3 was a key factor in getting CD8+ T cells to localize at the site of solid tumors. To do this, they took T cells that either overexpressed Runx3 or did not express Runx3 in these cells. The T cells were then transplanted into mice with melanoma through a process known as adoptive cell transfer. Overexpression of Runx3 in T cells not only reduced tumor size but also extended lifespan in the mice. On the other hand, removing Runx3 expression had a negative impact on their survival rate.

This research, which was supported in part by CIRM funding, offers a new strategy for developing better cancer immunotherapies for solid tumors.

Pipkin concluded in a Scripps Research Institutes News Release,

“Knowing that modulating Runx3 activity in T cells influences their ability to reside in solid tumors opens new opportunities for improving cancer immunotherapy. We could probably use Runx3 to reprogram adoptively transferred cells to help drive them to amass in solid tumors.”

CIRM-funded scientists discover a new way to make stem cells using antibodies

Just as learning a new skill takes time to hone, scientific discoveries take time to perfect. Such is the case with induced pluripotent stem cells (iPSCs), the Nobel Prize winning technology that reprograms mature adult cells back into a pluripotent stem cell state. iPSCs are a powerful tool because they can develop into any cell found in the body. Scientists use iPSCs to model diseases in a dish, screen for new drugs, and to develop stem cell-based therapies for patients.

iPSCs grown in a cell culture dish.

The original iPSC technology, discovered by Dr. Shinya Yamanaka in 2006, requires viral delivery of four transcription factor genes, Oct4, Sox2, Klf4, and c-Myc, into the nucleus of an adult cell. These genes are inserted into the genome where they are activated to churn out their respective proteins. The combined expression of these four factors (OSKM) turns off the genetic programming of an adult cell and turns on the programming for a pluripotent stem cell.

The technology is pretty neat and allows scientists to make iPSCs from patients using a variety of different tissue sources including skin, blood, and even urine. However, there is a catch. Inserting reprogramming genes into a cell’s genome can be disruptive if the reprogramming genes fail to switch off or can cause cancer if nefarious oncogenes are turned on.

In response to this concern, scientists are developing alternative methods for making iPSCs using non-invasive methods. A CIRM-funded team from The Scripps Research Institute (TSRI) published such a study yesterday in the journal Nature Biotechnology.

Led by senior author and CIRM grantee Dr. Kristin Baldwin, the TSRI team screened a large library of antibodies – proteins that recognize and bind to specific molecules – to identify ones that could substitute for the OSKM reprogramming factors. The hope was that some of these antibodies would bind to proteins on the surface of cells and turn on a molecular signaling cascade from the outside that would turn on the appropriate reprogramming genes from the inside of the cell.

The scientists screened over 100 million antibodies and found ones that could replace three of the four reprogramming factors (Oct4, Sox2, and c-Myc) when reprogramming mouse skin cells into iPSCs. They were unable to find an antibody to replace Klf4 in the current study but have it on their to-do list for future studies.

Dr. Baldwin explained how her team’s findings improve upon previous reprogramming methods in a TSRI news release,

Kristen Baldwin

“This result suggests that ultimately we might be able to make IPSCs without putting anything in the cell nucleus, which potentially means that these stem cells will have fewer mutations and overall better properties.”

 

Other groups have published other non-invasive iPSC reprogramming methods using cocktails of chemicals, proteins or microRNAs in place of virally delivering genes to make iPSCs. However, Baldwin’s study is the first (to our knowledge) to use antibodies to achieve this feat.

An added benefit to antibody reprogramming is that the team was able to learn more about the signaling pathways that were naturally activated by the iPSC reprogramming antibodies.

“The scientists found that one of the Sox2-replacing antibodies binds to a protein on the cell membrane called Basp1. This binding event blocks Basp1’s normal activity and thus removes the restraints on WT1, a transcription factor protein that works in the cell nucleus. WT1, unleashed, then alters the activity of multiple genes, ultimately including Sox2’s, to promote the stem cell state using a different order of events than when using the original reprogramming factors.”

iPSCs made by antibody reprogramming could address some of the long-standing issues associated with more traditional reprogramming methods and could offer further insights into the complex signaling required to turn adult cells back into a pluripotent state. Baldwin and her team are now on the hunt for antibodies that will reprogram human (rather than mouse) cells into iPSCs. Stay tuned!

Crossing the Grad School Bridge of Self and Scientific Discovery

Since 2010, the CIRM Bridges Program has provided paid stem cell research internships to students at California colleges and universities that don’t have major stem cell research programs. In order to keep in touch with these interns, The Stem Cellar has an ongoing CIRM Scholars blog series, inviting alumni from our training programs to reflect on the importance of their internships, to update readers on their career path and to give career advice to the current interns.

The blog below, written by Mimi Krutein from the 2011 Bridges program at Cal State University San Marcos, is based on a presentation she gave in late July at the 2017 Annual CIRM Bridges Trainee Meeting in San Diego. 

Mimi Krutein

The science graduate school experience is not at all what I was expecting. I imagined it as a mentally stimulating flurry of discoveries and training; before I started I pictured a cross between Harry Potter and The Magic School Bus.  What I got, and what most graduate students get, is a vaguely escorted slog into a land of uncertainty and imposter syndrome, sprinkled with fleeting moments of clarity and excitement.  But don’t get me wrong; it is worth it.

My personal road to graduate school was quite unorthodox.  I entered California State University San Marcos (CSUSM) as a nursing major, because I had a genuine interest in medicine and was fascinated by the complexity of the human body.

 It also didn’t require calculus level math, so I was sold.
I generally enjoyed my courses but everything changed for me when I took microbiology.  It was my first introduction to basic science.  Disease mechanisms of microorganisms blew my mind, sparked my curiosity, and catalyzed a shift in focus that never readjusted.

It was then I decided to add a biology minor to feed the beast, but didn’t have the confidence to switch majors completely.  The pre-nursing program actually advised me not to add the minor; my grades at that point were good but not stellar, and they thought that the new load would be too difficult.  That summer I formally applied to the CSUSM nursing program and was rejected, missing the cutoff by one point.  Chalking it up to fate, I turned gracefully on my heels and belly flopped into a molecular biology major with open arms, calculus and all.

A few semesters passed and I desperately craved more lab time so I applied to 12 summer undergraduate research programs and was swiftly rejected due to lack of experience.  The only position I was offered was a 100-hour, unpaid internship at a tiny biotech composed of 5 people, where we utilized bioluminescent phytoplankton to monitor water toxicity.  Then I joined the only research lab at CSUSM with an opening, and under Dr. Betsy Read I studied the metabolic pathways of the model organism Emiliania huxleyi, also a phytoplankton.

As much as I loved the lab and industry training I was receiving, I wanted to integrate my fascination of human medicine with my passion for laboratory science.  Betsy pulled me into her office one day and asked the very obtuse question “what do you want to do in science?”  To her surprise –and slight disappointment I’m sure- I told her that I didn’t want to stay in phytoplankton, but rather explore medically relevant research, and study human disease.  Happily she lit up and frantically told me about the CIRM Bridges internship that would be perfect, the caveat being that applications were due that very day.  I received a 24-hour extension, and was later accepted for the 2011 program.

I was equal parts inspired and terrified
For my CIRM internship I joined Tobin Dickerson’s lab in the department of chemistry at The Scripps Research Institute.  I received excellent one-on-one training in a small lab studying highly infectious agents, primarily botulinum toxin.  Now, botulinum toxin has an extremely simple mechanism of action, however, it is also the most potent neurotoxin known to man.  Approximately 1 gram of aerosolized toxin can kill 1 million people; and the bacteria that produces it, Clostridium botulinum, is relatively easy to propagate, making it a potential bioterrorist agent.

iPSC-derived motor neurons. Image courtesey of Mimi Kreitin/The Scripps Research Institute

For this reason, The Department of Defense gave us a grant to pursue high-throughput screening of small molecule inhibitors that could block the effects of this toxin.  I assisted in the screening and follow up tests on individual inhibitors.  At the same time, I established a robust method for generating motor neurons from human embryonic and induced pluripotent stem cells.  This work provided us with a virtually endless pool of boltulinum-sensitive cells for the use of cellular studies with prospective inhibitors found in our initial screens.  Deriving the neurons from stem cells also eliminated the need for expensive and tiresome motor neuron harvests from animals.  The cells I produced in the lab presented as bonafide motor neurons because they produced an appropriate dose response to live toxin.

I finally felt like a real scientist
After my internship, I was formally hired by the lab as a part time technician while I finished my last year of classes as CSUSM.  My two years of work in the lab resulted in three publications, one of which was accepted for the cover of ACS Combinatorial Science.  More importantly though, the years I spent in the Dickerson lab provided room for me to grow into myself as a scientist, receive unparalleled training, and gain perspective on what it meant to be in the thick of academic research.

After many discussions with my peers and mentors, I decided graduate school, ideally a PhD track, was the next step for my scientific career.  I knew I loved research, but I wanted to learn how to think, how to approach unanswered questions in a productive manner.  I wanted to be trained by everyone who could provide me with knowledge.

I was just plain hungry.
And like most 20-somethings on the edge of graduation, my passion was mixed in equal parts with indecisiveness.  I really didn’t know what I wanted to study, but I knew I wanted to utilize my stem cell training, and I knew what made my mind light up; I was -and still am- fascinated by how diseases work on a cellular and molecular level.  So, after months of searching, digging, and crosschecking, I applied to a dozen translational research programs across the US.

And then the news arrived
While running late to a class, I got the acceptance email from my dream school; the University of Washington. After reading the subject line I was frozen with disbelief, I called my mom, forgot where I was going and took a stroll the other direction until I realized I had a test waiting for me.  It never occurred to me that I could actually do this for real.

My first day of grad school was one I will never forget.  After a lukewarm five minutes of awkwardly chatting with my new postdoc lab members, we go out to get coffee and I proceed to faceplant in the middle of a puddle-filled crosswalk directly in front of a truck.  I skinned my knee and sliced my hand open, but magically managed to keep my coffee upright.  Understandably, my newly acquired lab members didn’t let me touch anything of real importance for 2 weeks.  Even after being considered a ‘seasoned’ graduate student I still knock over racks of pipette tips or spill liters of E. coli cultures on my new jeans.  Such is the grad school life.  Part of me hopes once I earn those fancy three letters after my name, I’ll evolve to the perfect scientist, but I won’t bet on it.

To those of you considering graduate school
I’ll end with these parting thoughts. Obviously, I’m still not on the other end of this whole grad school thing, but I can tell you from the four years I’ve spent doing this so far, there has been no experience more rewarding and humbling than pursuing a PhD.  If you find yourself interested in taking the leap in a similar direction, know that if you choose this path, it’s a marathon, not a sprint so take care of yourself through the process.  Maintain a strong support system, both for your personal and professional well-being.  Foster relationships with your peers to gain strength in numbers and build mentorships with individuals you admire to perpetuate curiosity.  Choose your home lab thoughtfully; the Principal Investigator to Student dynamic is the cornerstone of the graduate school experience; you can’t be on different pages with the lab’s leader and expect to write the same story.

Imposter syndrome is the greatest barrier to your success
I spent 22 years wholeheartedly believing I couldn’t do the thing I’m currently doing, and I’ll tell you guys a secret, some days I still feel that way. But it’s vital to recognize that you are worthy of success and not defined by your failures.  Lastly, find humor where you can and stay hungry for opportunities that you believe are just outside of your reach. And stay hungry for knowledge, it’s one of few things that doesn’t expire.

Stories that caught our eye: stem cell transplants help put MS in remission; unlocking the cause of autism; and a day to discover what stem cells are all about

multiple-sclerosis

Motor neurons

Stem cell transplants help put MS in remission: A combination of high dose immunosuppressive therapy and transplant of a person’s own blood stem cells seems to be a powerful tool in helping people with relapsing-remitting multiple sclerosis (RRMS) go into sustained remission.

Multiple sclerosis (MS) is an autoimmune disorder where the body’s own immune system attacks the brain and spinal cord, causing a wide variety of symptoms including overwhelming fatigue, blurred vision and mobility problems. RRMS is the most common form of MS, affecting up to 85 percent of people, and is characterized by attacks followed by periods of remission.

The HALT-MS trial, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), took the patient’s own blood stem cells, gave the individual chemotherapy to deplete their immune system, then returned the blood stem cells to the patient. The stem cells created a new blood supply and seemed to help repair the immune system.

Five years after the treatment, most of the patients were still in remission, despite not taking any medications for MS. Some people even recovered some mobility or other capabilities that they had lost due to the disease.

In a news release, Dr. Anthony Fauci, Director of NIAID, said anything that holds the disease at bay and helps people avoid taking medications is important:

“These extended findings suggest that one-time treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS. These encouraging results support the development of a large, randomized trial to directly compare HDIT/HCT to standard of care for this often-debilitating disease.”

scripps-campus

Scripps Research Institute

Using stem cells to model brain development disorders. (Karen Ring) CIRM-funded scientists from the Scripps Research Institute are interested in understanding how the brain develops and what goes wrong to cause intellectual disabilities like Fragile X syndrome, a genetic disease that is a common cause of autism spectrum disorder.

Because studying developmental disorders in humans is very difficult, the Scripps team turned to stem cell models for answers. This week, in the journal Brain, they published a breakthrough in our understanding of the early stages of brain development. They took induced pluripotent stem cells (iPSCs), made from cells from Fragile X syndrome patients, and turned these cells into brain cells called neurons in a cell culture dish.

They noticed an obvious difference between Fragile X patient iPSCs and healthy iPSCs: the patient stem cells took longer to develop into neurons, a result that suggests a similar delay in fetal brain development. The neurons from Fragile X patients also had difficulty forming synaptic connections, which are bridges that allow for information to pass from one neuron to another.

Scripps Research professor Jeanne Loring said that their findings could help to identify new drug therapies to treat Fragile X syndrome. She explained in a press release;

“We’re the first to see that these changes happen very early in brain development. This may be the only way we’ll be able to identify possible drug treatments to minimize the effects of the disorder.”

Looking ahead, Loring and her team will apply their stem cell model to other developmental diseases. She said, “Now we have the tools to ask the questions to advance people’s health.”

A Day to Discover What Stem Cells Are All about.  (Karen Ring) Everyone is familiar with the word stem cells, but do they really know what these cells are and what they are capable of? Scientists are finding creative ways to educate the public and students about the power of stem cells and stem cell research. A great example is the University of Southern California (USC), which is hosting a Stem Cell Day of Discovery to educate middle and high school students and their families about stem cell research.

The event is this Saturday at the USC Health Sciences Campus and will feature science talks, lab tours, hands-on experiments, stem cell lab video games, and a resource fair. It’s a wonderful opportunity for families to engage in science and also to expose young students to science in a fun and engaging way.

Interest in Stem Cell Day has been so high that the event has already sold out. But don’t worry, there will be another stem cell day next year. And for those of you who don’t live in Southern California, mark your calendars for the 2017 Stem Cell Awareness Day on Wednesday, October 11th. There will be stem cell education events all over California and in other parts of the country during that week in honor of this important day.