Stories that caught our eye: FDA grants orphan drug status to CIRM-funded therapy; stunning discovery upends ideas of cell formation; and how tadpoles grow new tails

Gut busting discovery

Intestinal stem cells: Photo courtesy Klaus Kaestner, Penn Institute for Regenerative Medicine

It’s not often you read the word “sensational” in a news release about stem cells. But this week researchers at the University of Copenhagen released findings that are overturning long-held ideas about the development of cells in our stomachs. So perhaps calling it “sensational” is not too big a stretch.

In the past it was believed that the development of immature cells in our stomachs, before a baby is born, was predetermined, that the cells had some kind of innate sense of what they were going to become and when. Turns out that’s not the case. The researchers say it’s the cells’ environment that determines what they will become and that all cells in the fetus’ gut have the potential to turn into stem cells.

In the “sensational” news release lead author, Kim Jensen, says this finding could help in the development of new therapies.

“We used to believe that a cell’s potential for becoming a stem cell was predetermined, but our new results show that all immature cells have the same probability for becoming stem cells in the fully developed organ. In principle, it is simply a matter of being in the right place at the right time. Here signals from the cells’ surroundings determine their fate. If we are able to identify the signals that are necessary for the immature cell to develop into a stem cell, it will be easier for us to manipulate cells in the wanted direction’.

The study is published in the journal Nature.                             

A tale of a tail

African clawed frog tadpole: Photo courtesy Gary Nafis

It’s long been known that some lizards and other mammals can regrow severed limbs, but it hasn’t been clear how. Now scientists at the University of Cambridge in the UK have figured out what’s going on.

Using single-cell genomics the scientists were able to track which genes are turned on and off at particular times, allowing them to watch what happens inside the tail of the African clawed frog tadpole as it regenerates the damaged limb.

They found that the response was orchestrated by a group of skin cells they called Regeneration-Organizing Cells, or ROCs. Can Aztekin, one of the lead authors of the study in the journal Science, says seeing how ROCs work could lead to new ideas on how to stimulate similar regeneration in other mammals.

“It’s an astonishing process to watch unfold. After tail amputation, ROCs migrate from the body to the wound and secrete a cocktail of growth factors that coordinate the response of tissue precursor cells. These cells then work together to regenerate a tail of the right size, pattern and cell composition.”

Orphan Drug Designation for CIRM-funded therapy

Poseida Therapeutics got some good news recently about their CIRM-funded therapy for multiple myeloma. The US Food and Drug Administration (FDA) granted them orphan drug designation.

Orphan drug designation is given to therapies targeting rare diseases or disorders that affect fewer than 200,000 people in the U.S. It means the company may be eligible for grant funding toward clinical trial costs, tax advantages, FDA user-fee benefits and seven years of market exclusivity in the United States following marketing approval by the FDA.

CIRM’s President and CEO, Dr. Maria Millan, says the company is using a gene-modified cell therapy approach to help people who are not responding to traditional approaches.

“Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”

Poseida’s CEO, Eric Ostertag, said the designation is an important milestone for the company therapy which “has demonstrated outstanding potency, with strikingly low rates of toxicity in our phase 1 clinical trial. In fact, the FDA has approved fully outpatient dosing in our Phase 2 trial starting in the second quarter of 2019.”

Stem cell stories that caught our eye: CIRM-funded scientist wins prestigious prize and a tooth trifecta

CIRM-grantee wins prestigious research award

Do we know how to pick ‘em or what? For a number of years now we have been funding the work of Stanford’s Dr. Marius Wernig, who is doing groundbreaking work in helping advance stem cell research. Just how groundbreaking was emphasized this week when he was named as the winner of the 2018 Ogawa-Yamanaka Stem Cell Prize.

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Marius Wernig, MD, PhD. [Photo: Stanford University]

The prestigious award, from San Francisco’s Gladstone Institutes, honors Wernig for his innovative work in developing a faster, more direct method of turning ordinary cells into, for example, brain cells, and for his work advancing the development of disease models for diseases of the brain and skin disorders.

Dr. Deepak Srivastava, the President of Gladstone, announced the award in a news release:

“Dr. Wernig is a leader in his field with extraordinary accomplishments in stem cell reprogramming. His team was the first to develop neuronal cells reprogrammed directly from skin cells. He is now investigating therapeutic gene targeting and cell transplantation–based strategies for diseases with mutations in a single gene.”

Wernig was understandably delighted at the news:

“It is a great honor to receive this esteemed prize. My lab’s goal is to discover novel biology using reprogrammed cells that aids in the development of effective treatments.”

Wernig will be presented with the award, and a check for $150,000, at a ceremony on Oct. 15 at the Gladstone Institutes in San Francisco.

A stem cell trifecta for teeth research

It was a tooth trifecta among stem cell scientists this week. At Tufts University School of Medicine, researchers made an important advance in the development of bioengineered teeth. The current standard for tooth replacement is a dental implant. This screw-shaped device acts as an artificial tooth root that’s inserted into the jawbone. Implants have been used for 30 years and though successful they can lead to implant failure since they lack many of the properties of natural teeth. By implanting postnatal dental cells along with a gel material into mice, the team demonstrated, in a Journal of Dental Research report, the development of natural tooth buds. As explained in Dentistry Today, these teeth “include features resembling natural tooth buds such as the dental epithelial stem cell niche, enamel knot signaling centers, transient amplifying cells, and mineralized dental tissue formation.”

Another challenge with the development of a bioengineered tooth replacement is reestablishing nerve connections within the tooth, which plays a critical role in its function and protection but doesn’t occur spontaneously after an injury. A research team across the “Pond” at the French National Institute of Health and Medical Research, showed that bone marrow-derived mesenchymal stem cells in the presence of a nerve fiber can help the nerve cells make connections with bioengineered teeth. The study was also published in the Journal of Dental Research.

And finally, a research report about stem cells and the dreaded root canal. When the living soft tissue, or dental pulp, of a tooth becomes infected, the primary course of action is the removal of that tissue via a root canal. The big downside to this procedure is that it leaves the patient with a dead tooth which can be susceptible to future infections. To combat this side effect, researchers at the New Jersey Institute of Technology report the development of a potential remedy: a gel containing a fragment of a protein that stimulates the growth of new blood vessels as well as a fragment of a protein that spurs dental stem cells to divide and grow. Though this technology is still at an early stage, it promises to help keep teeth alive and healthy after root canal. The study was presented this week at the National Meeting of the American Chemical Society.

Here’s an animated video that helps explain the research:

New Study on Humans Shows Promise for Sepsis Therapy

A new study published in STEM CELLS, conducted by researchers at the University of Amsterdam, shows how mesenchymal stem cells (MSCs) can restore the health and improve the function of the immune system,  which could benefit the treatment of sepsis. Sepsis is a life-threatening complication from an infection that can lead to multiple organ failure. It is a major cause of illness and death worldwide and despite the use of antibiotics it kills about one in every four patients who contract it.

Since early studies done on animals have shown that treating sepsis with MSCs can reduce the mortality rate by as much as 73 percent, a group of researchers from University of Amsterdam sought to answer this question:  could humans realize the same benefits?

So, the team conducted an experiment by taking a group of healthy volunteers and inducing endotoxemia in them, where bacterial toxins can build up and cause fever, nausea and vomiting but do not cause long-term harm to the participants (?).  The idea was that by inducing endotoxemia, which exhibits some of the key characteristics of sepsis, that they could model the condition in people.

One hour prior to the initial dose, each person was given an infusion of either adipose (fat) mesenchymal stem cells (ACSs) taken from a donor,  or a placebo as a control. Those receiving the ASCs were divided into three groups, with each group receiving a consecutively higher dose of cells.

In a news release, Desiree Perlee, senior author of the study, said the study provided some valuable insights and information:

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Desirée Perlee

“The results showed that the ASCs were well tolerated…We realize that there is a limitation with the endotoxemia model. Although in a qualitative way it resembles responses seen in patients with sepsis, it differs in that sepsis-associated alterations are more severe and sustained, while in the endotoxemia model responses occur in a very rapid, short-lived and transient way. But despite these limitations, some of our findings confirm the earlier studies on animals. We believe they show further testing of ASCs in actual sepsis patients is warranted.”

Dr. Jan Nolta, Editor-in-Chief of STEM CELLS (and a CIRM-grantee), said, “This novel clinical trial provides important insight into the mechanism of action of MSCs in inflammation and provides human safety data in support of treatment of sepsis using MSCs.

 

The Five Types of Stem Cells

When I give an “Intro to Stem Cells” presentation to, say, high school students or to a local Rotary Club, I begin by explaining that there are three main types of stem cells: (1) embryonic stem cells (ESCs) (2) adult stem cells and (3) induced pluripotent stem cells (iPSCs). Well, like most things in science, it’s actually not that simple.

To delve a little deeper into the details of characterizing stem cells, I recommend checking out a video animation produced by BioInformant, a stem cell market research company. The video is introduced in a blog, “Do you know the 5 types of stem cells?” by Cade Hildreth, BioInformant’s founder and president.

Stem-Cell-Types

Image credit: BioInformant

Hildreth’s list categorizes stem cells by the extent of each type’s shape-shifting abilities. So while we sometimes place ESCs and iPSCs in different buckets because the methods for obtaining them are very different, in this list, they both belong to the pluripotent stem cell type. Pluri (“many”) – potent (“potential”) refers to the ability of both stem cell types to specialize into all of the cell types in the body. They can’t, though, make the cells of the placenta and other extra-embryonic cells too. Those ultimate blank-slate stem cells are called toti (“total”) – potent (“potential”).

When it comes to describing adult stem cells in my talks, I often lump blood stem cells together with muscle stem cells because they are stem cells that are present within us throughout life. But based on their ability to mature into specialized cells, these two stem cell types fall into two different categories in Hildreth’s list:  blood stem cells which can specialize into closely related cell types – the various cell types found in the blood – are considered “oligopotent” while muscle stem cells are “unipotent” because the can only mature into one type of cell, a muscle cell.

For more details on the five types of stem cells based on their potential to specialize, head over to the BioInformant blog. And scroll to the very bottom for the video animation which can also viewed on FaceBook.

Starving stem cells of oxygen can help build stronger bones

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J. Kent Leach: Photo courtesy UC Davis

We usually think that starving something of oxygen is going to make it weaker and maybe even kill it. But a new study by J. Kent Leach at UC Davis shows that instead of weakening bone defects, depriving them of oxygen might help boost their ability to create new bone or repair existing bone.

Leach says in the past the use of stem cells to repair damaged or defective bone had limited success because the stem cells often didn’t engraft in the bone or survive long if they did. That was because the cells were being placed in an environment that lacked oxygen (concentration levels in bone range from 3% to 8%) so the cells found it hard to survive.

However, studies in the lab had shown that if you preconditioned mesenchymal stem cells (MSCs), by exposing them to low oxygen levels before you placed them on the injury site, you helped prolong their viability. That was further enhanced by forming the MSCs into three dimensional clumps called spheroids.

Lightbulb goes off

In the  current study, published in Stem Cells, Leach says the earlier spheroid results  gave him an idea:

“We hypothesized that preconditioning MSCs in hypoxic (low oxygen) culture before spheroid formation would increase cell viability, proangiogenic potential (ability to create new blood vessels), and resultant bone repair compared with that of individual MSCs.”

So, the researchers placed one group of human MSCs, taken from bone marrow, in a dish with just 1% oxygen, and another identical group of MSCs in a dish with normal oxygen levels. After three days both groups were formed into spheroids and placed in an alginate hydrogel, a biopolymer derived from brown seaweed that is often used to build cellular cultures.

Seaweed

Brown seaweed

The team found that the oxygen-starved cells lasted longer than the ones left in normal oxygen, and the longer those cells were deprived of oxygen the better they did.

Theory is great, how does it work in practice?

Next was to see how those two groups did in actually repairing bones in rats. Leach says the results were encouraging:

“Once again, the oxygen-deprived, spheroid-containing gels induced significantly more bone healing than did gels containing either preconditioned individual MSCs or acellular gels.”

The team say this shows the use of these oxygen-starved cells could be an effective approach to repairing hard-to-heal bone injuries in people.

“Short‐term exposure to low oxygen primes MSCs for survival and initiates angiogenesis (the development of new blood vessels). Furthermore, these pathways are sustained through cell‐cell signaling following spheroid formation. Hypoxic (low oxygen) preconditioning of MSCs, in synergy with transplantation of cells as spheroids, should be considered for cell‐based therapies to promote cell survival, angiogenesis, and bone formation.”

CIRM & Dr. Leach

While CIRM did not fund this study we have invested more than $1.8 million in another study Dr. Leach is doing to develop a new kind of imaging technology that will help us see more clearly what is happening in bone and cartilage-targeted therapies.

In addition, back in March of 2012, Dr. Leach spoke to the CIRM Board about his work developing new approaches to growing bone.

 

A Cowboys Fan’s Take on The Catch and Dwight Clark’s Passing Due to ALS

I grew up in Dallas in the 80’s. Needless to say, I was a diehard fan of the Dallas Cowboys National Football League (NFL) team and January 10, 1982 will forever be seared into my memory. Late in the fourth quarter, the Cowboys were leading the San Francisco 49ers 27-21 in the conference championship with the winner moving on to the Super Bowl. But then, with less than a minute remaining, The Catch happened. Dwight Clark of the 49ers sailed over the Cowboys’ Everson Walls to catch Joe Montana’s game-winning pass in the end zone. I was crushed and had a dark cloud over my head for many days afterward.

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Dwight Clark sails over Everson Walls for The Catch

Though I’ve lived in the Bay Area for the past twenty years and become a 49ers fan, it’s still hard for me to watch video clips of The Catch which is arguably this region’s greatest moment in the history of professional sports. Over the years of listening to sports talk radio, I heard interviews with and about Dwight Clark and have come to realize what a terrific person he was. So, I may hate that play, but I certainly can’t hate the man. That’s why I was as heartbroken as everyone else around here with yesterday’s news that Clark had succumbed, at only 61 years of age, to his battle with amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s disease, an incurable neurodegenerative disorder that is usually fatal within 2 to 5 years after diagnosis.

Not surprisingly, the ALS Association’s Golden West Chapter, which covers the entire West Coast, was contacted by every Bay Area TV station about Clark’s death. In her KTVU news segment, TV reporter Deborah Villalon explained what Clark meant to ALS patient advocates who often feel invisible:

“To the ALS community he is a hero for raising awareness in the very public way he faced the disease. Clark faced the terminal illness head-on, speaking publicly of his challenges, even appearing on the big screen at Levi’s Stadium last fall, to thank fans for their support.”

At CIRM, we are funding two clinical trials run by Cedars-Sinai and BrainStorm Cell Therapeutics testing stem cell-based treatments for ALS. In Clark’s memory and for everyone in the ALS community, we hope these trials one day lead to new treatment options for the 5,000 thousand newly diagnosed cases each year in the U.S.

Can stem cells help people recover from a stroke? Join us for a Facebook Live event this Thursday, May 31 for the answers

AskExpertsMAY2018[1]

Stroke is one of the leading causes of death in the US and the leading cause of serious, long-term disability. But could stem cell therapies change that and help people who’ve had a brain attack?  Could stem cells help repair the damage caused by a stroke and restore a person’s ability to speak normally, to be able to walk without a limp or regain strength in their hands and arms?

To find out the answers to these and other questions joins us for “Ask the Expert”, a special Facebook Live event this Thursday, May 31, from noon till 1pm PDT

 The event will feature Dr. Gary Steinberg, the Chair of Neurosurgery at Stanford University. Dr. Steinberg is currently running a CIRM-funded clinical trial targeting stroke.

We will also be joined by CIRM Senior Science Officer Lila Collins, PhD who can talk about the broad range of other projects using stem cells to help people recover from a stroke.

We are also delighted to welcome Sonia Coontz, who suffered a devastating stroke several years ago and made a remarkable recovery after getting a stem cell therapy.

To join us for the event, all you have to do is go to our Facebook page on Thursday at noon (PDT) and you should see a video playing, which you can watch on mobile or desktop. Click the video to enter viewing mode.

Also, make sure to “like” our page before the event to receive a notification that we’ve gone live.

And we want to hear from you, so you will be able to post questions for the experts to answer or, you can email them directly to us at info@cirm.ca.gov

We look forward to seeing you there.

 

‘Ask The Expert’ on Facebook Live about the power of stem cells to reverse damage caused by a stroke.

facebook-live-brand-awarenessIt’s not often you get a chance to ask a world class stem cell expert a question about their work, and how it might help you or someone you love. But on Thursday, May 31 you can do just that.

CIRM is hosting a special ‘Ask the Expert’ event on Facebook Live. The topic is Strokes and Stem Cells. Just head over to our Facebook Page on May 31st from noon till 1pm PST to experience it live. You can also re-watch the event any time after the broadcast has ended from our Facebook videos page.

Steinberg

We will be joined by Dr. Gary Steinberg, chair of neurosurgery at Stanford University, who will talk to us about his work in helping reverse the damage caused by a stroke, even for people who experienced a brain attack several years ago.

CIRM Senior Science Officer, Dr. Lila Collins, will talk about other stem cell research targeting stroke, its promise and some of the problems that still need to be overcome.

You will have a chance to ask questions of both our experts, either live on the day or by sending us questions in advance at info@cirm.ca.gov.

We’ll post reminders on Facebook so make sure to follow us. But for now, mark the date and time on your diary and please feel free to share this information with anyone you think might be interested.

It promises to be a fascinating event.

 

 

Cold temps nudge stem cells to boost “good” fat, may point to obesity remedies

Newborn babies may not be able to walk or talk but they can do something that makes adults very jealous: burn extra calories without exercising. This feat is accomplished with the help of brown fat which is abundant in infants (and hibernating animals) but barely detectable in adults. However, a new study in Scientific Reports shows that cold temperatures can nudge mesenchymal stem cells – found in the bone marrow – toward a brown fat cell fate, a finding that may uncover new strategies for combating obesity and other metabolic diseases.

Brown-and-White-adipose-tissue

Side by side comparision of brown fat, or adipose, cells and white fat cells.
Image: AHAJournals.org

So, what’s so magical about cells that carry brown fat, the so-called “good” fat? Like the more common “bad’ white fat cells, brown fat cells store energy in the form of fat droplets and can burn that energy to meet the demands of the body’s functions like pumping the heart and moving the limbs. But brown fat can also burn calories independent of the body’s energy needs. It’s like stepping on a car’s clutch and gas pedal at the same time: the body burns the fuel but doesn’t do any usable work, so those calories just dissipate as heat. This source of heat is critical for babies because they are not yet able to regulate their own body temperature and lose heat rapidly.

Scientists have known for quite some time that cold temperatures stimulate the production of brown fat but didn’t know exactly why (a CIRM-funded study we blogged about last week identified a protein that also boosts brown fat production). In the current study, a team at the University of Nottingham in the U.K., examined the effect of cold temperature on the fate of bone marrow-derived mesenchymal stem cells which give rise to both white and brown fat tissue as well as bone, cartilage and muscle. Petri dishes containing the cells were placed in incubators at 89°F (32°C) and stimulated to become fat cells. That may not seem cold, but if your core body temperature went that low (instead of the normal 98.6F) you would be beyond shivering, close to collapsing and in need of an emergency room.

With that temperature drop, the researcher observed a “browning” of the stem cells towards a brown fat cell fate. The brown color, in case you’re interested, is cause by the increased number of mitochondria within the cells. These “power factories” of the cell are the source of the heat generation. This result has promising implications for adults struggling with their body weight.

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Virginie Sottile

“The good news from these results is that our cells are not pre-programmed to form bad fat and our stem cells can respond if we apply the right change in lifestyle,” explained Dr Virginie Sottile, one of the team leaders on the project, in a press release.

 

Ok, I know what you’re thinking: moving to Antarctica to lose weight is not my idea of a doable lifestyle change! That’s a point well taken. But the ultimate goal for the researchers is to use this cell system to more carefully study the cellular events that occur under reduced temperatures. This type of inquiry could help identify drug targets that mimic the effects of colder temperatures:

“The next step in our research is to find the actual switch in the cell that makes it respond to the change of temperature in its environment,” said Dr Sottile. “That way, we may be able to identify drugs or molecules that people could swallow that may artificially activate the same gene and trick the body into producing more of this good fat.”

Inspiring Video: UC Irvine Stem Cell Trial Gives Orange County Woman Hope in Her Fight Against ALS

Stephen Hawking

Last week, we lost one of our greatest, most influential scientific minds. Stephen Hawking, a famous British theoretical physicist and author of “A Brief History of Time: From the Big Bang to Black Holes”, passed away at the age of 76.

Hawking lived most of his adult life in a wheelchair because he suffered from amyotrophic lateral sclerosis (ALS). Also known as Lou Gehrig’s disease, ALS causes the degeneration of the nerve cells that control muscle movement.

When Hawking was diagnosed with ALS at the age of 21, he was told he only had three years to live. But Hawking defied the odds and went on to live a life that not only revolutionized our understanding of the cosmos, but also gave hope to other patients suffering from this devastating degenerative disease.

A Story of Hope

Speaking of hope, I’d like to share another story of an Orange County woman name Lisa Wittenberg who was recently diagnosed with ALS. Her story was featured this week on KTLA5 news and is also available on the UC Irvine Health website.

VIDEO: UCI Health stem cell trial helps Orange County woman fight neurodegenerative disease ALS. Click on image to view video in new window.

In this video, Lisa describes how quickly ALS changed her life. She was with her family sledding in the snow last winter, and only a year later, she is in a wheelchair unable to walk. Lisa got emotional when she talked about how painful it is for her to see her 13-year-old son watch her battle with this disease.

But there is hope for Lisa in the form of a stem cell clinical trial at the UC Irvine CIRM Alpha Stem Cell Clinic. Lisa enrolled in the Brainstorm study, a CIRM-funded phase 3 trial that’s testing a mesenchymal stem cell therapy called NurOwn. BrainStorm Cell Therapeutics, the company sponsoring this trial, is isolating mesenchymal stem cells from the patient’s own bone marrow. The stem cells are then cultured in the lab under conditions that convert them into biological factories secreting a variety of neurotrophic factors that help protect the nerve cells damaged by ALS. The modified stem cells are then transplanted back into the patient where they will hopefully slow the progression of the disease.

Dr. Namita Goyal, a neurologist at UC Irvine Health involved in the trial, explained in the KTLA5 video that they are hopeful this treatment will give patients more time, and optimistic that in some cases, it could improve some of their symptoms.

Don’t Give Up the Fight

The most powerful part of Lisa’s story to me was the end when she says,

“I think it’s amazing that I get to fight, but I want everybody to get to fight. Everybody with ALS should get to fight and should have hope.”

Not only is Lisa fighting by being in this ground-breaking trial, she is also participated in the Los Angeles marathon this past weekend, raising money for ALS research.

More patients like Lisa will get the chance to fight as more potential stem cell treatments and drugs enter clinical trials. Videos like the one in this blog are important for raising awareness about available clinical trials like the Brainstorm study, which, by the way, is still looking for more patients to enroll (contact information for this trial can be found on the clinicaltrials.gov website here). CIRM is also funding another stem cell trial for ALS at the Cedars-Sinai Medical Center. You can read more about this trial on our website.

Lisa’s powerful message of fighting ALS and having hope reminds me of one of Stephen Hawking’s most famous quotes, which I’ll leave you with:

“Remember to look up at the stars and not down at your feet. Try to make sense of what you see and wonder about what makes the Universe exist. Be curious. And however difficult life may seem, there is always something you can do and succeed at. It matters that you don’t just give up.”


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