Stem Cell Profiles in Courage: Brenden Whittaker

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Brenden Whittaker: Photo Colin McGuire

It’s not often you meet someone who says one of their favorite things in the world is mowing the lawn. But then, there aren’t many people in the world like Brenden Whittaker. In fact, as of this writing, he may be unique.

Brenden was born with severe chronic granulomatous disease (x-CGD), a rare genetic disorder that left him with an impaired immune system that was vulnerable to repeated bacterial and fungal infections. Over 22 years Brenden was in and out of the hospital hundreds of times, he almost died a couple of times, and lost parts of his lungs and liver.

Then he became the first person to take part in a clinical trial to treat x-CGD. UCLA researcher Don Kohn had developed a technique that removed Brenden’s blood stem cells, genetically re-engineered them to correct the mutation that caused the disease, and then returned those stem cells to Brenden. Over time they created a new blood system, and restored Brenden’s immune system.

He was cured.

We profiled Brenden for our 2016 Annual Report. Here’s an extended version of the interview we did with him, talking about his life before and after he was cured.

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Brenden with a CIRM Game Ball – signed by everyone at CIRM

Brenden’s story:

I still think about it, my disease, every few days or so and it’s weird because in the past I was sick so often; before this year, I was sick consistently for about 5 years and going to doctor’s appointments 2 or 3 times a week and being in the hospital. So, it’s weird having a cough and not having to be rushed to the ER, not having to call someone every time the smallest thing pops up, and not having to worry about what it means.

It’s been good but it’s been weird to not have to do that.  It’s a nice problem to have.

What are you doing now that you didn’t do before?

Cutting the grass is something I couldn’t do before, that I’ve taken up now. Most people look at me as if I’m crazy when I say it, but I love cutting grass, and I wasn’t able to do it for 22 years of my life.

People will complain about having to pick up after their dog goes to the bathroom and now I can follow my dog outside and can pick up after her. It really is just the little things that people don’t think of. I find enjoyment in the small things, things I couldn’t do before but now I can and not have to worry about them.

The future

I was in the boy scouts growing up so I love camping, building fires, just being outdoors. I hiked on the Appalachian Trail. Now I’ll be able to do more of that.

I have a part time job at a golf course and I’m actually getting ready to go back to school full time in January. I want to get into pre-med, go to medical school and become a doctor. All the experience I’ve had has just made me more interested in being a doctor, I just want to be in a position where I can help people going through similar things, and going through all this just made me more interested in it.

Before the last few months I couldn’t schedule my work more than a week in advance because I didn’t know if I was going to be in the hospital or what was going on. Now my boss jokes that I’m giving him plans for the next month or two. It’s amazing how far ahead you can plan when you aren’t worried about being sick or having to go to the hospital.

I’d love to do some traveling. Right now most of my traveling consists of going to and from Boston (for medical check-ups), but I would love to go to Europe, go through France and Italy. That would be a real cool trip. I don’t need to see everything in the world but just going to other countries, seeing cities like London, Paris and Rome, seeing how people live in other cultures, that would be great.

Advice for others

I do think about the fact that when I was born one in a million kids were diagnosed with this disease and there weren’t any treatments. Many people only lived a few years. But to be diagnosed now you can have a normal life. That’s something all on its own. It’s almost impossible for me to fathom it’s happening, after all the years and doctor’s appointments and illnesses.

So, for people going through anything like this, I’d say just don’t give up. There are new advances being made every day and you have to keep fighting and keep getting through it, and some day it will all work out.


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Stories that caught our eye: frail bones in diabetics, ethics of future IVF, Alzheimer’s

The connection between diabetes and frail bones uncovered
Fundamentally, diabetes is defined by abnormally high blood sugar levels. But that one defect over time carries an increased risk for a wide range of severe health problems. For instance, compared to healthy individuals, type 2 diabetics are more prone to poorly healing bone fractures – a condition that can dramatically lower one’s quality of life.

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Bones of the healthy animals (top) form larger calluses during healing which lead to stronger repaired bones. Bones of the diabetic mice (bottom) have smaller calluses and the healed bones are more brittle. Image: Stanford University

To help these people, researchers are trying to tease out how diabetes impacts bone health. But it’s been a complicated challenge since there are many factors at play. Is it from potential side effects of diabetes drugs? Or is the increased body weight associated with type 2 diabetes leading to decreased bone density? This week a CIRM-funded team at Stanford pinpointed skeletal stem cells, a type of adult stem cell that goes on to make all the building blocks of the bone, as important pieces to this scientific puzzle.

Reporting in Science Translational Medicine, the team, led by Michael Longaker – co-director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine – found that, compared to healthy animals, type 2 diabetic mice have a reduced number of skeletal stem cells after bone fracture. A study of the local cellular “neighborhood” of these stem cells showed that the diabetic mice also had a reduction in the levels of a protein called hedgehog. Blocking hedgehog activity in healthy mice led to the slow bone healing seen in the diabetic mice. More importantly, boosting hedgehog levels near the site of the fracture in diabetic mice lead to bone healing that was just as good as in the healthy mice.

To see if this result might hold up in humans, the team analyzed hedgehog levels in bone samples retrieved from diabetics and non-diabetics undergoing joint replacement surgeries. Sure enough, hedgehog was depleted in the diabetic bone exactly reflecting the mouse results.

Though more studies will be needed to develop a hedgehog-based treatment in humans, Longaker talked about the exciting big picture implications of this result in a press release:

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Michael Longaker

“We’ve uncovered the reason why some patients with diabetes don’t heal well from fractures, and we’ve come up with a solution that can be locally applied during surgery to repair the break. Diabetes is rampant worldwide, and any improvement in the ability of affected people to heal from fractures could have an enormously positive effect on their quality of life.”

 

Getting the ethics ahead of the next generation of fertility treatments
The Business Insider ran an article this week with a provocative title, “Now is the time to talk about creating humans from stem cells.” I initially read too much into that title because I thought the article was advocating the need to start the push for the cloning of people. Instead, author Rafi Letzter was driving at the importance for concrete, ethical discussion right now about stem cell technologies for fertility treatments that may not be too far off.

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These mice were born from artificial eggs that were made from stem cells in a dish.
It’s great news for infertility specialist but carries many ethical dilemmas. 
(Image: K. Hayashi, Kyushu University)

In particular, he alludes to a paper from October (read our blog about it) that reported the creation of female mouse eggs from stem cells. These eggs were fertilized, implanted into the mother and successfully developed into living mice. What’s more, one set of stem cells were derived from mouse skin samples via the induced pluripotent stem cell method. This breakthrough could one day make it possible for an infertile woman to simply go through a small skin biopsy or mouth swab to generate an unlimited number of eggs for in vitro fertilization (IVF). Just imagine how much more efficient, less invasive and less costly this procedure could be compared to current IVF methods that require multiple hormone injections and retrieval of eggs from a woman’s ovaries.

But along with that hope for couples who have trouble conceiving a child comes a whole host of ethical issues. Here, Letzter refers to a perspective letter published on Wednesday in Science Translation Medicine by scientists and ethicists about this looming challenge for researchers and policymakers.

It’s an important read that lays out the current science, the clinical possibilities and regulatory and ethical questions that must be addressed sooner than later. In an interview with Letzter, co-author Eli Adashi, from the Alpert Medical School at Brown University, warned against waiting too long to heed this call to action:

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Eli Adashi

“Let’s start the [ethical] conversation now. Like all conversations it will be time consuming. And depending how well we do it, and we’ve got to do it well, it will be demanding. It will not be wise to have that conversation when you’re seeing a paper in Science or Nature reporting the complete process in a human. That would not be wise on our collective part. We should be as much as possible ready for that.”

 

 

Tackling Frontotemporal dementia and Alzheimer’s by hitting the same target.
To develop new disease therapies, you usually need to understand what is going wrong at a cellular level. In some cases, that approach leads to the identification of a specific protein that is either missing or in short supply. But this initial step is just half the battle because it may not be practical to make a drug out of the protein itself. So researchers instead search for other proteins or small molecules that lead to an increase in the level of the protein.

A CIRM-funded project at the Gladstone Institutes has done just that for the protein called progranulin. People lacking one copy of the progranulin gene carry an increased risk for  frontotemporal dementia (FTD), a degenerative disease of the brain that is the most common cause of dementia in people under 60 years of age. FTD symptoms are often mistaken for Alzheimer’s. In fact, mutations in progranulin are also associated with Alzheimer’s.

Previous studies have shown that increasing levels of progranulin in animals with diseases that mimic FTP and Alzheimer’s symptoms can reverse symptoms. But little was known how progranulin protein levels were regulated in the cells. Amanda Mason, the lead author on the Journal of Biological Chemistry report, explained in a press release how they tackled this challenge:

“We wanted to know what might regulate the levels of progranulin. Many processes in biology are controlled by adding or removing a small chemical group called phosphate, so we started there.”

These phosphate groups hold a lot of energy in their chemical bonds and can be harnessed to activate or turn off the function of proteins and DNA. The team systematically observed the effects of enzymes that add and remove phosphate groups and zeroed in on one called Ripk1 that leads to increases in progranulin levels. Now the team has set their sights on Ripk1 as another potential target for developing a therapeutic that could be effective against both FTP and Alzheimer’s. Steve Finkbeiner, the team lead, gave a big picture perspective on these promising results:

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Steve Finkbeiner

“This is an exciting finding. Alzheimer’s disease was discovered over 100 years ago, and we have essentially no drugs to treat it. To find a possible new way to treat one disease is wonderful. To find a way that might treat two diseases is amazing.”

 

Stem cell stories that caught our eye: designer socks for cancer patients, stem-cell derived stomachs and fighting off bone infections

Inspiring cancer patients with designer socks. (Karen Ring)
Here’s a motivating story we found in the news this week about a cancer survivor who’s bringing inspiration to other cancer patients with designer socks. Yes, you read that correctly, socks.

Jake Teitelbaum is a student at Wake Forest University and suffers from a rare form of blood cancer called Refractory Hodgkin’s lymphoma. Since his diagnosis, Jake has been admitted to hospitals multiple times. Each time he received a welcome package of a gown and a pair of beige, “lifeless” socks. After his fifth welcome package, this time to receive a life-saving stem cell treatment, Jake had had enough of the socks.

He explained in a story by USA Today College,

“[Those socks] represented chemotherapy and being in isolation. They were the embodiment of that experience.”

Jake ditched the hospital socks and started bringing his own to prove that his cancer didn’t define him. Even though his cancer kept coming back, Jake wanted to prove he was just as resilient.

Jake Teitelbaum

Jake Teitelbaum

Feeling liberated and in control, Jake decided to share his socks with other patients by starting the Resilience Project. Patients can go to the Resilience website and design their own socks that represent their experiences with cancer. The Resilience project also raises money for cancer patients and their families.

“We provide tangible benefits and create fun socks, but what we’re doing comes back to the essence of resilience,” said Jake. “These terrible circumstances where we’re at our most vulnerable also give us the unique opportunity to grow.”

Jake was declared cancer free in October of 2016. You can learn more about the Resilience project on their website and by watching Jake’s video below.

 

Feeding disease knowledge with stem cell-derived stomach cells.
Using educated guess work and plenty of trial and error in the lab, researchers around the world have successfully generated many human tissues from stem cells, including heart muscle cells, insulin-producing cells and nerve cells to name just a few. Reporting this week in Nature, stem cell scientists at Cincinnati’s Children Hospital have a new cell type under their belt. Or maybe I should say above their belt, because they have devised a method for coaxing stem cells to become stomach mini organs that can be studied in a petri dish.

Confocal microscopic image shows tissue-engineered human stomach tissues from the corpus/fundus region, which produce acid and digestive enzymes. Image: Cincinnati Children’s Hospital Medical Center

Confocal microscopic image shows tissue-engineered human stomach tissues from the corpus/fundus region, which produce acid and digestive enzymes. Image: Cincinnati Children’s Hospital Medical Center

With this method in hand, the team is poised to make new discoveries about how the stomach forms during human development and to better understand stomach diseases. In a press release, team lead Jim Wells pointed out the need to find new therapies for stomach disease:

“Diseases of the stomach impact millions of people in the United States and gastric [stomach] cancer is the third leading cause of cancer-related deaths worldwide.”

The cells they generated are those found in the corpus/fundus area of the stomach which releases enzymes and hydrochloric acid to help us break down and digest the food we eat. The team is particularly interested to use the mini organs to study the impact of H. pylori infection, a type of bacteria that causes ulcers and has been linked to stomach cancers.

In an earlier study, Wells’ group devised stem cell recipes for making cells from an area of the stomach, called the antrum, that produces hormones that affect digestion and appetite. Wells thinks having both tissue types recreated in a petri dish may help provide a complete picture of stomach function:

James Wells

James Wells

“Now that we can grow both antral- and corpus/fundic-type human gastric mini-organs, it’s possible to study how these human gastric tissues interact physiologically, respond differently to infection, injury and react to pharmacologic treatments.”

 

 

A silver bullet for antibiotic-resistant bone infections?
Alexander Fleming’s discover of penicillin in the 1920’s marked the dawn of antibiotics – drugs which kill off bacteria and help stop infections. Rough estimates suggest that over 200 million lives have been saved by these wonder drugs. But over time there’s been a frightening rise in bacteria that are resistant to almost all available antibiotics.

These super resistant “bugs” are particularly scary for people with chronic bone infections because the intense, long term antibiotic medication required to keep the infection in check isn’t effective. But based on research published this week in Tissue Engineering, the use of stem cells and silver may provide a new treatment option.

Scanning Electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, brown spheres) surrounded by cellular debris. MRSA, the bacteria examined in this study, is resistant by many antibiotics

Scanning Electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, brown spheres) surrounded by cellular debris. MRSA, the bacteria examined in this study, is resistant by many antibiotics. (Wikimedia)

It’s been known for many years that silver in liquid form can kill bacteria and scientists have examined ways to deliver a controlled release of silver nanoparticles at the site of the bone infection. But there has been a lot of concern, including by the Food and Drug Administration (FDA), about the toxicity of silver nanoparticles to human cells.

In this study, a team led by Elizabeth Loboa from the University of Missouri instead looked at the use of silver ions which are safer than the nanoparticles. The team developed a three-dimensional cell culture system that resembles bone by growing human bone-forming stem cells on a tissue engineered scaffold, which also slowly releases silver ions.

The researchers stimulated the stem cells within the scaffold to specialize into bone cells and included a strain of bacteria that’s resistant to multiple antibiotics. They found that the silver ions effectively killed the bacteria and at the same time did not block the bone-forming stem cells. If this work holds up, doctors may one day use this silver ion-releasing, biodegradable scaffold to directly treat the area of bone infection. And to help prevent infection after joint replacement procedures, surgeons may rely on implants that are coated with these scaffolds.

Cured by Stem Cells

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To get anywhere you need a good map, and you need to check it constantly to make sure you are still on the right path and haven’t strayed off course. A year ago the CIRM Board gave us a map, a Strategic Plan, that laid out our course for the next five years. Our Annual Report for 2016, now online, is our way of checking that we are still on the right path.

I think, without wishing to boast, that it’s safe to say not only are we on target, but we might even be a little bit ahead of schedule.

The Annual Report is chock full of facts and figures but at the heart of it are the stories of the people who are the focus of all that we do, the patients. We profile six patients and one patient advocate, each of whom has an extraordinary story to tell, and each of whom exemplifies the importance of the work we support.

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Brenden Whittaker: Cured

Two stand out for one simple reason, they were both cured of life-threatening conditions. Now, cured is not a word we use lightly. The stem cell field has been rife with hyperbole over the years so we are always very cautious in the way we talk about the impact of treatments. But in these two cases there is no need to hold back: Evangelina Padilla Vaccaro and Brenden Whittaker have been cured.

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Evangelina: Cured

 

In the coming weeks we’ll feature our conversations with all those profiled in the Annual Report, giving you a better idea of the impact the stem cell treatments have had on their lives and the lives of their family. But today we just wanted to give a broad overview of the Annual Report.

The Strategic Plan was very specific in the goals it laid out for us. As an agency we had six big goals, but each Team within the agency, and each individual within those teams had their own goals. They were our own mini-maps if you like, to help us keep track of where we were individually, knowing that every time an individual met a goal they helped the Team get closer to meeting its goals.

As you read through the report you’ll see we did a pretty good job of meeting our targets. In fact, we missed only one and we’re hoping to make up for that early in 2017.

But good as 2016 was, we know that to truly fulfill our mission of accelerating treatments to patients with unmet medical needs we are going to have do equally well, if not even better, in 2017.

That work starts today.

 

Stem cell heroes: patients who had life-saving, life-changing treatments inspire CIRM Board

 

It’s not an easy thing to bring an entire Board of Directors to tears, but four extraordinary people and their families managed to do just that at the last CIRM Board meeting of 2016.

The four are patients who have undergone life-saving or life-changing stem cell therapies that were funded by our agency. The patients and their families shared their stories with the Board as part of CIRM President & CEO Randy Mill’s preview of our Annual Report, a look back at our achievements over the last year.

The four included:

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Jake Javier, whose life changed in a heartbeat the day before he graduated high school, when he dove into a swimming pool and suffered a spinal cord injury that left him paralyzed from the chest down. A stem cell transplant is giving him hope he may regain the use of his arms and hands.

 

 

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Karl Trede who had just recovered from one life-threatening disease when he was diagnosed with lung cancer, and became the first person ever treated with a new anti-tumor therapy that helped hold the disease at bay.

 

brenden_stories_of_hopeBrenden Whittaker, born with a rare immune disorder that left his body unable to fight off bacterial or fungal infections. Repeated infections cost Brenden part of his lung and liver and almost killed him. A stem cell treatment that gave him a healthy immune system cured him.

 

 

evangelinaEvangelina Padilla Vaccaro was born with severe combined immunodeficiency (SCID), also known as “bubbly baby” disease, which left her unable to fight off infections. Her future looked grim until she got a stem cell transplant that gave her a new blood system and a healthy immune system. Today, she is cured.

 

 

Normally CIRM Board meetings are filled with important, albeit often dry, matters such as approving new intellectual property regulations or a new research concept plan. But it’s one thing to vote to approve a clinical trial, and a very different thing to see the people whose lives you have helped change by funding that trial.

You cannot help but be deeply moved when you hear a mother share her biggest fear that her daughter would never live long enough to go to kindergarten and is now delighted to see her lead a normal life; or hear a young man who wondered if he would make it to his 24th birthday now planning to go to college to be a doctor

When you know you played a role in making these dreams happen, it’s impossible not to be inspired, and doubly determined to do everything possible to ensure many others like them have a similar chance at life.

You can read more about these four patients in our new Stories of Hope: The CIRM Stem Cell Four feature on the CIRM website. Additionally, here is a video of those four extraordinary people and their families telling their stories:

We will have more extraordinary stories to share with you when we publish our Annual Report on January 1st. 2016 was a big year for CIRM. We are determined to make 2017 even bigger.

Pregnant women’s stem cells could help battle brittle bone diseases like osteoporosis

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Sometimes I wonder how a scientist ever came up with an idea for a potential treatment. Case in point is a study in the journal Scientific Reports, where researchers use stem cells from the amniotic fluid of a pregnant woman to cure osteoporosis in mice! What researcher, seeing a pregnant woman, thought to her or himself “I wonder if…..”

Regardless of how they came up with the idea, we might be glad they did because this study showed that those stem cells could reduce the number of fractures in mice with brittle bone disease by 78 percent. And that’s raising hopes they might one day be able to do the same for people.

Researchers at University College London took mesenchymal stem cells (MSCs) that had been shed by babies into the amniotic fluid of their mother, and injected them into mice with brittle bone disease. Previous studies had suggested that MSCs, taken at such an early age, might be more potent than similar cells taken from adults. That certainly seems to have been the case here where the treated mice had far fewer fractures than untreated mice.

Pascale Guillot, the lead researcher of the study, told the Guardian newspaper:

“The stem cells we’ve used are excellent at protecting bones. The bones become much stronger and the way the bone is organised internally is of much higher quality.”

 

What was also interesting was not just what they did but how they did it. You might think that the injected stem cells helped reduce fractures by forming new bones. You might think that, but you’d be wrong. Instead, the stem cells seem to have worked by releasing growth factors that stimulated the mouse’s own bone cells to kick into a higher gear, and help build stronger bones.

In the study the researchers say using MSCs from amniotic fluid has a number of distinct advantages over using MSCs from adults:

  • They are easier to expand into large numbers needed for therapies
  • They don’t create tumors
  • The body’s immune system won’t attack them
  • They are smaller and so can move around with greater ease
  • They are easier to reprogram into different kinds of cells

Next Guillot and his team want to explore if this approach could be used to treat children and adults with brittle bone disease, and to help adults with osteoporosis, a problem that affects around 44 million people in the US.

 “The discovery could have a profound effect on the lives of patients who have fragile bones and could stop a large number of their painful fractures.”

A single protein can boost blood stem cell regeneration

Today, CIRM-funded scientists from the UCLA Broad Stem Cell Research Center reported  in Nature Medicine that hematopoietic stem cells (HSCs) – blood stem cells that generate the cell in your blood and immune system – get a helping hand after injury from cells in the bone marrow called bone progenitor cells. By secreting a protein called dickkopf-1 (Dkk1), bone progenitor cells improve the recovery and survival of blood stem cells in a culture dish and in mice whose immune systems are suppressed by irradiation.

These findings build upon a related study published by the same UCLA team last month showing that deleting a single gene in HSCs boosts blood stem cell regeneration. We covered this initial story previously on the Stem Cellar, and you can refer to it for background on the importance of stimulating the regenerative capacity of HSCs in patients that need bone marrow transplants or have undergone radiation therapy for cancer.

Dkk1 boost blood stem cell regeneration

Senior author on the study, UCLA Professor Dr. John Chute, wanted to understand how the different cell types in the bone marrow environment, or niche, interact with HSCs to enhance their ability to recover from injury and regenerate the immune system. As mentioned earlier, he and his team found that bone progenitor cells secrete Dkk1 protein in response to injury caused by exposing mice to full body irradiation. Dkk1 promoted blood stem cell regeneration in the mice and increased their survival rates.

I inquired with Dr. Chute about this seemingly beneficial relationship between HSCs and cells in the bone marrow niche.

Dr. John Chute, UCLA

Dr. John Chute, UCLA

“The precise functions of bone cells, stromal cells and endothelial cells in regulating blood stem cell fate are not completely understood,” said Dr. Chute. “Our prior studies demonstrated that endothelial cells are necessary for blood stem cell regeneration after irradiation.  The current study suggests that bone progenitor cells are also necessary for normal blood stem cell regeneration after irradiation, and that this activity is mediated by secretion of Dkk1 by the bone progenitor cells.”

He further commented in a UCLA press release:

“The cellular niche is like the soil that surrounds the stem cell ‘seed’ and helps it grow and proliferate. Our hypothesis was that the bone progenitor cell in the niche may promote hematopoietic stem cell regeneration after injury.”

Not only did Dkk1 improve HSC regeneration in irradiated mice, it also boosted the regeneration of HSCs that were irradiated in a culture dish. On the other hand, when Dkk1 was deleted from HSCs in irradiated mice, the HSCs did not recover and regenerate. Diving in deeper, the team found that Dkk1 promotes blood stem cell regeneration by direct action on the stem cells and by indirectly increasing the secretion of the stem cell growth factor EGF by bone marrow blood vessels. Taken together, the team concluded that Dkk1 is necessary for blood stem cell recovery following injury/irradiation.

After radiation, blood cells (purple) regenerated in bone marrow when mice were given DKK1 intravenously (left), but not in those that received saline solution (right). (UCLA/Nature Medicine)

After radiation, blood cells (purple) regenerated in bone marrow when mice were given DKK1 (left), but not in those that received saline solution (right). (UCLA/Nature Medicine)

Future applications for blood stem cell regeneration

When I asked Dr. Chute how his current study on Dkk1 and HSCs relates to his previous study on boosting HSC regeneration by deleting a gene called Grb10, he explained:

“In this paper we discovered the role of a niche cell-derived protein, Dkk1, and how it promotes blood stem cell regeneration after myelosuppression in mice.  In the Cell Reports paper, we described our discovery of an adaptor protein, Grb10, which is expressed by blood stem cells and the inhibition of which also promotes blood stem cell regeneration after myelosuppression. So, these are two novel molecular mechanisms that regulate blood stem cell regeneration that could be therapeutically targeted.”

Both studies offer new strategies for promoting blood stem cell regeneration in patients who need to replenish their blood and immune systems following radiation treatments or bone marrow transplants.

Dr. Chute concluded:

“We are very interested in translating our observations into the clinic for the purpose of accelerating hematologic recovery in patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation.”


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Stem cell agency funds clinical trials in three life-threatening conditions

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A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

As Randy Mills, our President and CEO, said in a news release:

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

Deleting a single gene can boost blood stem cell regeneration

A serious side effect that cancer patients undergoing chemotherapy experience is myelosuppression. That’s a big word for a process that involves the decreased production of the body’s immune cells from hematopoietic stem cells (HSCs) or blood stem cells in the bone marrow. Without these important cells that make up the immune system, patients are at risk for major infections and even death.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Scientists are trying to find ways to treat cancer patients that have undergone myelosuppressive therapies, as well as patients that need bone marrow transplants to replace their own bone marrow that’s been damaged or removed. One possible solution is boosting the regenerative capacity of HSCs. Transplanting HSCs that are specially primed to reproduce rapidly into cells of the immune system could improve the outcome of bone marrow transplants in patients.

Deleting Grb10 boost blood stem cell regeneration

A CIRM-funded team from the UCLA Broad Stem Cell Research Center and the Jonsson Comprehensive Cancer Center has identified a single gene that can be manipulated to boost HSC regeneration in mice. The study, which was published in Cell Reports, found that deleting or turning off expression of an imprinted gene called Grb10 in HSCs caused these blood stem cells to reproduce more robustly after being transplanted into mice that had their bone marrow removed.

I just used another big word in that last paragraph, so let me explain. An imprinted gene is a gene that is expressed or activated based on which parent it was inherited from. Typically, you receive one copy of a gene from your mother and one from your father and both are expressed – a process called Mendelian inheritance. But imprinted genes are different – they are marked with specific epigenetic tags that silence their expression in the sperm or egg cells of the parents. Thus if you inherited an imprinted gene from your mother, the other copy of that gene from your father would be expressed and vice versa.

Scientists have discovered that imprinted genes are important for human development and also for directing what cell types adult stem cells like HSCs develop into. The team from UCLA led by senior author Dr. John Chute, was interested in answering a different question: are imprinted genes involved in determining the function of HSCs? They compared two different populations of HSCs derived from mouse bone marrow: a normal, healthy population and HSCs exposed to total body irradiation (TBI), which destroys the immune system. They discovered that the expression of an imprinted gene called Grb10 was dramatically higher in HSCs exposed to TBI compared to healthy HSCs.

Cell Reports

Deleting Grb10  increases blood stem cell regeneration in the bone marrow of irradiated mice (bottom) compared to normal mice (top). Cell Reports

Because Grb10 is an imprinted gene, the scientists deleted either the paternal or maternal copy of that gene in mice. While deleting the paternal Grb10 gene had no effect on the function of HSCs, maternal deletion dramatically boosted the capacity of HSCs to divide and make more copies of themselves. Without the maternal copy of Grb10, HSCs were able to regenerate at a much faster scale than normal HSCs.

To further prove their point, the team transplanted normal HSCs and HSCs that lacked Grb10 into TBI or fully irradiated mice. HSCs that lacked Grb10 were able to regenerate themselves and produce other immune cells more robustly 20 weeks after transplantation compared to normal HSCs.

Potential applications and future studies

This study offers two important findings. First, they discovered that Grb10 plays an important role “in regulating HSC self-renewal following transplantation and HSC regeneration in response to injury.” Second, they found that inhibiting Grb10 function in HSCs could have potential therapeutic applications for boosting “hematopoietic regeneration in the setting of HSC transplantation or following myelosuppressive injury.” Patients in need of bone marrow transplants could potentially receive more benefit from transplants of HSCs that don’t express the Grb10 gene.

In my opinion, further studies should be done to further understand the role of Grb10 in regulating HSC self-renewal and regeneration. What is the benefit of having this gene expressed in HSCs if inhibiting its expression leads to an increased regenerative capacity? Is it to prevent cancer from forming? Additionally, the authors will need to address the potential long-term side effects of inhibiting Grb10 expression in HSCs. They did report that mice that lacked the Grb10 gene did not develop blood cancers at one year of age which is good news. They also suggested that instead of deleting Grb10, new drugs could be identified that inhibit Grb10 function in HSCs.

Stem cell stories that caught our eye: relief for jaw pain, vitamins for iPSCs and Alzheimer’s insights

Jaw bone stem cells may offer relief for suffers of painful joint disorder
An estimated 10 million people in the US – mostly women –  suffer from problems with their temporomandibular joint (TMJ) which sits between the jaw bone and skull. TMJ disorders can lead to a number of symptoms such as intense pain in the jaw, face and head; difficulty swallowing and talking; and dizziness.

ds00355_im00012_mcdc7_tmj_jpgThe TMJ is made up of fibrocartilage which, when healthy, acts as a cushion to enable a person to move their jaw smoothly. But this cartilage doesn’t have the capacity to heal or regenerate so treatments including surgery and pain killers only mask the symptoms without fixing the underlying damage of the joint.

Reporting this week in Nature Communications, researchers at Columbia University’s College of Dental Medicine identified stem cells within the TMJ that can form cartilage and bone – in cell culture studies as well as in animals. The research team further showed that the signaling activity of a protein called Wnt leads to a reduction of these fibrocartilage stem cells (FSCSs) in animals and as a result causes deterioration of cartilage. But injecting a known inhibitor of Wnt into the animals’ damaged TMJ spurred growth and healing of the joint.

The team is now in search of other Wnt inhibitors that could be used in a clinical setting. In a university press release, Jeremy Mao, a co-author on the paper, talked about the implications of these results:

“They suggest that molecular signals that govern stem cells may have therapeutic applications for cartilage and bone regeneration. Cartilage and certain bone defects are notoriously difficult to heal.”

Take your vitamins: good advice for people and iPS cells
From a young age, we’re repeatedly told how getting enough vitamins each day is important for a healthy life. Our bodies don’t produce these naturally occurring chemicals but they carry out critical biochemical activities to keep our cells and organs functioning properly.

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Carrots: a great source of vitamin A. Image source: Wikimedia Commons

Well, it turns out that vitamins are also an important ingredient in stem cell research labs. Results published the Proceedings of the National Academy of Sciences (PNAS) this week by scientists in the UK and New Zealand show that vitamin A and C work together synergistically to improve the efficiency of reprogramming adult cells, like skin or blood, into the embryonic stem cell-like state of induced pluripotent stem cells (iPSCs).

By the time a stem cell has specialized into, let’s say, a skin cell, only skin cell-specific genes are active while others genes, like those needed for liver function, are shut down. Those non-skin genes are silenced through the attachment of chemical tags on the DNA, a process called methylation. It essentially provides the DNA with the means of maintaining a skin cell “memory”. To convert a skin cell back into a stem cell-like state, researchers in the lab must erase this “memory” by adding factors which demethylate, or remove the methylation tags on the silenced, non-skin related genes.

In the current research picked up by Science Daily, the researchers found that both vitamin A and C increase demethylation but in different ways. The study showed that vitamin A acts to increase the production of proteins that are important for demethylation while vitamin C acts to enhance the enzymatic activity of demethylation.

These insights may help add to the growing knowledge on how to most efficiently reprogram adult cells into iPSCs. And they may prove useful for a better understanding of certain cancers which contain cells that are essentially reprogrammed into a stem cell-like state.

New angles for dealing with the tangles in the Alzheimer’s brain
The memory loss and overall degradation of brain function seen in people with Alzheimer’s Disease (AD) is thought to be caused by the accumulation of amyloid and tau proteins which form plaques and tangles in the brain. These abnormal structures are toxic to brain cells and ultimately lead to cell death.

But other studies of post-mortem AD brains suggest a malfunction in endocytosis – a process of taking up and transporting proteins to different parts of the cell – may also play a role. While follow up studies corroborated this initial observation, they didn’t look at endocytosis in nerve cells so it remained unclear how much of a role it played in AD.

In a CIRM-funded study published this week in Cell Reports, UC San Diego researchers made nerve cells from human iPSCs and used the popular CRISPR and TALEN gene editing techniques to generate mutations seen in inherited forms of AD. One of those inherited mutations is in the PS1 gene which has been shown to play a role in transporting amyloid proteins in nerve cells. The research confirmed that this mutation as well as a mutation in the amyloid precursor protein (APP) led to a breakdown in the proper trafficking of APP within the mutated nerve cells. In fact, they found an accumulation of APP in a wrong area of the nerve cell. However, blocking the action of a protein called secretase that normally processes the APP protein helped restore proper protein transport. In a university press release, team leader Larry Goldstein, explained the importance of these findings:

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Larry Goldstein.
Image: UCSD

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD. But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”