Them bones them bones them dry bones – and how to help repair them

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Broken bones

People say that with age comes wisdom, kindness and confidence. What they usually don’t say is that it also comes with aches and pains and problems we didn’t have when we were younger. For example, as we get older our bones get thinner and more likely to break and less likely to heal properly.

That’s a depressing opening paragraph isn’t it. But don’t worry, things get better from here because new research from Germany has found clues as to what causes our bones to become more brittle, and what we can do to try and stop that.

Researchers at the Max Planck Institute for Biology of Ageing and CECAD Cluster of Excellence for Ageing Research at the University of Cologne have identified changes in stem cells from our bone marrow that seem to play a key role in bones getting weaker as we age.

To explain this we’re going to have to go into the science a little, so bear with me. One of the issues the researchers focused on is the role of epigenetics, this is genetic information that doesn’t change the genes themselves but does change their activity. Think of it like a light switch. The switch doesn’t change the bulb, but it does control when it’s on and when it’s off. So this team looked at the epigenome of MSCs, the stem cells found in the bone marrow. These cells play a key role in the creation of cartilage, bone and fat cells.

In a news release, Dr. Andromachi Pouikli, one of the lead researchers in the study, says these MSCs don’t function as well as we get older.

“We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice. We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected.”

So, they took some stem cells from the bone marrow of mice and tested them with a solution of sodium acetate. Now sodium acetate has a lot of uses, including being used in heating pads, hand warmers and as a food seasoning, but in this case the solution was able to make it easier for enzymes to get access to genes and boost their activity.

“This treatment impressively caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells,” Pouikli said.

So far so good. But does this work the same way in people? Maybe so. The team analyzed MSCs from people who had undergone hip surgery and found that they showed the same kind of age-related changes as the cells from mice.

Clearly there’s a lot more work to do before we can even think about using this finding as a solution to aging bones. But it’s an encouraging start.

The study is published in the journal Nature Aging.

Using a stem cell’s journey to teach kids science

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As far as Aldo Pourchet is concerned you are never too young to learn about stem cells. Aldo should know. He’s a molecular and cellular biologist and the co-founder and CEO of Omios Bio, which develops immunotherapies for cancer, infectious and inflammatory diseases.

Aldo Pourchet

And now Aldo is the author of a children’s book about stem cells. The book is “Nano’s Journey! A Little Stem Cell Visits the Heart and Lungs.” It’s the story of Nano, a stem cell who doesn’t know what kind of cell she wants to be when she grows up, so she goes on a journey through the body, exploring all the different kinds of cell she could be.

It’s a really sweet book, beautifully illustrated, and written in a charming way to engage children between the ages of 5 and 8. I asked Aldo what made him want to write a book like this.

“I was interested in providing very general knowledge such as the principle of life, the basic logics of nature and at the same time to entertain. It was very important for it not to be a textbook.

“Why Stem cells? Because it is the most fascinating biology and they are at the origin of an organism and throughout its life play an essential role. They evolve and transform, so they have a story that unfolds. An analogy with children maybe. It’s easy to imagine children are like stem cells, trying to decide who they are, while adults are like differentiated cells because they have already decided.

“For the kids to appropriate the story, I thought that humanizing cells was important.  I wanted children to identify themselves with the cells and especially Nano, the little girl main character. It’s a book written for the children, in the first place. We tell the story at their level. Not try to bring them up to the level of life science.

Aldo says right from the start he had a clear idea of who he wanted the lead character to be.

“I think the world needs more female leaders, more female voices and influence in general and in every domain. So quite early it became natural for me that Nano would be a girl and also would have a strong character, curious and adventurous.

“Blasto came later because I was looking for a companion to share the adventure with Nano. Blasto is a fibroblast so he is not supposed to leave the Bone Marrow but fibroblasts are everywhere in our organism so I thought it was an acceptable stretch.

The drawings in the book are delightful, colorful and fun. Aldo says he had some ideas, rounded shapes for the cells for example and a simple design that reflected the fact that there are no lines in nature. Illustrator Jen Yoon took it from there:

“Based on Aldo’s direction and imagination, I envisioned the style like drawings on a chalkboard. Soft curves with rough textures. After that everything went smoothly. Following Nano’s journey with my iPad pencil, it felt like a boat ride at an amusement park.”

The books are written to be read aloud by parents, adults and teachers to kids. But, spoiler alert, we don’t find out what cell Nano decides to be in this book. She’s going to have more adventures in other books before she makes up her mind.

Lung cancer, Sherlock Holmes and piano

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Image of lung cancer

When we think of lung cancer we typically tend to think it’s the end result of years of smoking cigarettes. But, according to the Centers for Disease Control and Prevention, between 10 and 20 percent of cases of lung cancer (20,000 to 40,000 cases a year) happen to non-smokers, people who have either never smoked or smoked fewer than 100 cigarettes in their life. Now researchers have found that there are different genetic types of cancer for smokers and non-smokers, and that might mean the need for different kinds of treatment.

A team at the National Cancer Institute did whole genome sequencing on tumors from 232 never-smokers who had lung cancer. In an interview with STATnews, researcher Maria Teresa Landi said they called their research the Sherlock-Lung study, after the famous fictional pipe-smoking detective Sherlock Holmes. “We used a detective approach. By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease.”

They also got quite creative in naming the three different genetic subtypes they found. Instead of giving them the usual dry scientific names, they called them piano, mezzo-forte and forte; musical terms for soft, medium and loud.

Half of the tumors in the non-smokers were in the piano group. These were slow growing with few mutations. The median latency period for these (the time between being exposed to something and being diagnosed) was nine years. The mezzo-forte group made up about one third of the cases. Their cancers were more aggressive with a latency of around 14 weeks. The forte group were the most aggressive, and the ones that most closely resembled smokers’ cancer, with a latency period of just one month.

So, what is the role of stem cells in this research? Well, in the study, published in the journal Nature Genetics the team found that the piano subtype seemed to be connected to genes that help regulate stem cells. That complicates things because it means that the standard treatments for lung cancer that work for the mezzo-forte and forte varieties, won’t work for the piano subtype.

“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Dr. Landi said.

With that in mind, and because early-detection can often be crucial in treating cancer, what can non-smokers do to find out if they are at risk of developing lung cancer? Well, right now there are no easy answers. For example, the U.S. Preventive Services Task Force does not recommend screening for people who have never smoked because regular CT scans could actually increase an otherwise healthy individual’s risk of developing cancer.

A personal reason to develop a better gene therapy

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Credit : Allison Dougherty, Broad Communications

For Sharif Tabebordbar, finding a gene therapy for genetic muscle wasting diseases was personal. When he was a teenager, his father was diagnosed with a rare genetic muscle disease that eventually left him unable to walk.

In an interview with the Broad Institute at MIT he said: “I watched my dad get worse and worse each day. It was a huge challenge to do things together as a family – genetic disease is a burden on not only patients but families. I thought: This is very unfair to patients and there’s got to be a way to fix this. That’s been my motivation during the 10 years that I’ve been working in the field of gene therapy.”

That commitment now seems to be paying off. In a study published in the journal Cell, Tabebordar and his team at MIT and Harvard showed how they have developed a new, safer and easier way to deliver genes to help repair wasting muscles.   

In earlier treatments targeting genetic muscle diseases, researchers used a virus to help deliver the gene that would correct the problem. However, to be effective they had to use high doses of the gene-carrying virus to ensure it reached as many muscles throughout the body as possible. But this meant that more of the payload often ended up in the liver and that led to severe side effects in some patients, even a few deaths.

The usual delivery method of these gene-correcting therapies is something called an adeno-associated virus (AAV), so Dr. Tabebordar set out to develop a new kind of AAV, one that would be safer for patients and more effective at tackling the muscle wasting.

They started by taking an adeno-associated virus called AAV9 and then set out about tweaking its capsid – that’s the outer shell that helps protect the virus and allows it to attach to another cell and penetrate it to deliver the corrected gene. They called this new viral vector MyoAAV and in tests it quickly showed it had an enhanced ability to deliver genes into cells.

The team showed that it not only was around 10 times more efficient at reaching muscle than other AAVs, but that it also reduces the amount that reaches the liver. This meant that MyoAAV could achieve impressive results in doses up to 250 times lower than those previously used.

In animal studies MyoAAV showed encouraging results in diseases like Duchenne Muscular Dystrophy and X-linked myotubular myopathy. Dr. Amy Wagers, a co-senior author of the study, says they are hopeful it will be equally effective in people.

“All of these results demonstrate the broad applicability of the MyoAAV vectors for delivery to muscle. These vectors work in different disease models and across different ages, strains and species, which demonstrates the robustness of this family of AAVs. We have an enormous amount of information about this class of vectors from which the field can launch many exciting new studies.”

Mother and daughter team up to fight bias and discrimination in treatment for people with sickle cell disease

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Adrienne Shapiro and Marissa Cors are a remarkable pair by any definition. The mother and daughter duo share a common bond, and a common goal. And they are determined not to let anyone stop them achieving that goal.

Marissa was born with sickle cell disease (SCD) a life-threatening genetic condition where normally round, smooth red blood cells are instead shaped like sickles. These sickle cells are brittle and can clog up veins and arteries, blocking blood flow, damaging organs, and increasing the risk of strokes. It’s a condition that affects approximately 100,000 Americans, most of them Black.

Adrienne became a patient advocate, founding Axis Advocacy, after watching Marissa get poor treatment in hospital Emergency Rooms.  Marissa often talks about the way she is treated like a drug-seeker simply because she knows what medications she needs to help control excruciating pain on her Sickle Cell Experience Live events on Facebook.

Now the two are determined to ensure that no one else has to endure that kind of treatment. They are both fierce patient advocates, vocal both online and in public. And we recently got a chance to sit down with them for our podcast, Talking ‘Bout (re) Generation. These ladies don’t pull any punches.

Enjoy the podcast.

CIRM is funding four clinical trials aimed at finding new treatments and even a cure for sickle cell disease.

Creating a better way to treat type 1 diabetes

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The cell encapsulation device (right) that is being developed by Encellin, a San Francisco–based biotechnology company. Photo courtesy of Encellin

Type 1 diabetes (t1d) affects every aspect of a person’s life, from what they eat and when they eat, to when they exercise and how they feel physically and emotionally. Because the peak age for being diagnosed with t1d is around 13 or 14 years of age it often hits at a time when a child is already trying to cope with big physical and emotional changes. Add in t1d and you have a difficult time made a lot more challenging.

There are ways to control the disease. Regular blood sugar monitoring and insulin injections can help people manage their condition but those come with their own challenges. Now researchers are taking a variety of different approaches to developing new, innovative ways of helping people with t1d.

One of those companies is Encellin. They are developing a pouch-like device that can be loaded with stem cells and then implanted in the body. The pouch acts like a mini factory, releasing therapies when they are needed.

This work began at UC San Francisco in the lab of Dr. Tejal Desai – with help from CIRM funding – that led to the creation of Encellin. We recently sat down – virtually of course – with Dr. Grace Wei, the co-founder of the company to chat about their work, and their hopes for the future.

Dr. Grace Wei

She said the decision to target t1d was an easy one:

Type 1 diabetes is an area of great need. It’s very difficult to manage at any age but particularly in children. It affects what they can eat, what they can do, it’s a big burden on the family and can become challenging to manage when people get older.

“It’s an autoimmune disease so everyone’s disease progression is a bit different. People think it’s just a matter of you having too much blood sugar and not enough insulin, but the problem with medicines like insulin is that they are not dynamic, they don’t respond to the needs of your body as they occur. That means people can over-regulate and give themselves too much insulin for what their body needs and if it happens at night, it can be deadly.

Dr. Wei says stem cell research opens up the possibility of developing dynamic therapies, living medicines that are delivered to you by cells that respond to your dynamic needs. That’s where their pouch, called a cell encapsulation device (CED) comes in.

The pouch is tiny, only about the size of a quarter, and it can be placed just under the skin. Encellin is filling the pouch with glucose-sensitive, insulin producing islet cells, the kind of cells destroyed by t1d. The idea is that the cells can monitor blood flow and, when blood sugar is low, secrete insulin to restore it to a healthy level. 

Another advantage of the pouch is that it may eliminate the need for the patient to take immunosuppressive medications.

“The pouch is really a means to protect both the patient receiving the cells and the cells themselves. Your body tends to not like foreign objects shoved into it and the pouch in one respect protects the cells you are trying to put into the person. But you also want to be able to protect the person, and that means knowing where the cells are and having a means to remove them if you need to. That’s why it’s good to have a pouch that you can put in the body, take it out if you need, and replace if needed.”

Dr. Wei says it’s a little like making tea with a tea bag. When the need arises the pouch can secrete insulin but it does so in a carefully controlled manner.

“These are living cells and they are responsive, it’s not medicine where you can overdose, these cells are by nature self-regulating.”

They have already tested their approach with a variety of different kinds of islets, in a variety of different kinds of model.

“We’ve tested for insulin production, glucose stimulation and insulin response. We have tested them in a number of animal models and those studies are supporting our submission for a first-in-human safety clinical trial.”

Dr. Wei says if this approach works it could be used for other metabolic conditions such as parathyroid disorders. And she says a lot of this might not be possible without the early funding and support from CIRM.

“CIRM had the foresight to invest in groups that are looking ahead and said it would be great to have renewable cells to transplant into the body  (that function properly. We are grateful that groundwork that has been laid and are looking forward to advancing this work.”

And we are looking forward to working with them to help advance that work too.

Feds hit predatory stem cell clinics with a one-two punch

Federal Trade Commission

Stem cells have a number of amazing properties and tremendous potential to heal previously untreatable conditions. But they also have the potential to create a financial windfall for clinics that are more focused on lining their wallets than helping patients. Now the federal government is cracking down on some of these clinics in a couple of different ways.

The Food and Drug Administration (FDA) sent a warning letter to the Utah Cord Bank LLC and associated companies warning them that the products it sold – specifically “human umbilical cord blood, umbilical cord, and amniotic membrane derived cellular products” – were violating the law.

At the same time the Federal Trade Commission and the Georgia Office of the Attorney General began legal proceedings against Regenerative Medicine Institute of America. The lawsuit says the company claims its products can rebuild cartilage and help treat joint and arthritis pain, and is charging patients thousands of dollars for “treatments” that haven’t been shown to be either safe or effective.

Bloomberg Law reporter Jeannie Baumann recently wrote a fine, in-depth article on these latest steps against predatory stem cell clinics.

CIRM has been a fierce opponents of bogus stem cell clinics for years and has worked with California lawmakers to try and crack down on them. We’re delighted to see that the federal government is stepping up its efforts to stop them marketing their snake oil to unsuspecting patients and will support them every step along the way.

CIRM has produced a short video and other easy to digest information on questions people should ask before signing up for any clinical trial. You can find those resources here.

CIRM has also published findings in Stem Cells Translational Medicine that discuss the three R’s–regulated, reliable, and reputable–and how these can help protect patients with uniform standards for stem cell treatments .

CIRM funds clinical trials targeting heart disease, stroke and childhood brain tumors

Gary Steinberg (Jonathan Sprague)

Heart disease and stroke are two of the leading causes of death and disability and for people who have experienced either their treatment options are very limited. Current therapies focus on dealing with the immediate impact of the attack, but there is nothing to deal with the longer-term impact. The CIRM Board hopes to change that by funding promising work for both conditions.

Dr. Gary Steinberg and his team at Stanford were awarded almost $12 million to conduct a clinical trial to test a therapy for motor disabilities caused by chronic ischemic stroke.  While “clot busting” therapies can treat strokes in their acute phase, immediately after they occur, these treatments can only be given within a few hours of the initial injury.  There are no approved therapies to treat chronic stroke, the disabilities that remain in the months and years after the initial brain attack.

Dr. Steinberg will use embryonic stem cells that have been turned into neural stem cells (NSCs), a kind of stem cell that can form different cell types found in the brain.  In a surgical procedure, the team will inject the NSCs directly into the brains of chronic stroke patients.  While the ultimate goal of the therapy is to restore loss of movement in patients, this is just the first step in clinical trials for the therapy.  This first-in-human trial will evaluate the therapy for safety and feasibility and look for signs that it is helping patients.

Another Stanford researcher, Dr. Crystal Mackall, was also awarded almost $12 million to conduct a clinical trial to test a treatment for children and young adults with glioma, a devastating, aggressive brain tumor that occurs primarily in children and young adults and originates in the brain.  Such tumors are uniformly fatal and are the leading cause of childhood brain tumor-related death. Radiation therapy is a current treatment option, but it only extends survival by a few months.

Dr. Crystal Mackall and her team will modify a patient’s own T cells, an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called chimeric antigen receptor (CAR), which will give the newly created CAR-T cells the ability to identify and destroy the brain tumor cells.  The CAR-T cells will be re-introduced back into patients and the therapy will be evaluated for safety and efficacy.

Joseph Wu Stanford

Stanford made it three in a row with the award of almost $7 million to Dr. Joe Wu to test a therapy for left-sided heart failure resulting from a heart attack.  The major issue with this disease is that after a large number of heart muscle cells are killed or damaged by a heart attack, the adult heart has little ability to repair or replace these cells.  Thus, rather than being able to replenish its supply of muscle cells, the heart forms a scar that can ultimately cause it to fail.  

Dr. Wu will use human embryonic stem cells (hESCs) to generate cardiomyocytes (CM), a type of cell that makes up the heart muscle.  The newly created hESC-CMs will then be administered to patients at the site of the heart muscle damage in a first-in-human trial.  This initial trial will evaluate the safety and feasibility of the therapy, and the effect upon heart function will also be examined.  The ultimate aim of this approach is to improve heart function for patients suffering from heart failure.

“We are pleased to add these clinical trials to CIRM’s portfolio,” says Maria T. Millan, M.D., President and CEO of CIRM.  “Because of the reauthorization of CIRM under Proposition 14, we have now directly funded 75 clinical trials.  The three grants approved bring forward regenerative medicine clinical trials for brain tumors, stroke, and heart failure, debilitating and fatal conditions where there are currently no definitive therapies or cures.”

Building a better brain (model) in the lab

Leica Picture of a brain organoid: courtesy National Institute of Allergy and Infectious Diseases, NIH

One of the biggest problems with trying to understand what is happening in a disease that affects the brain is that it’s really difficult to see what is going on inside someone’s head. People tend to object to you trying to open their noggin while they are still using it.

New technologies can help, devices such as MRI’s – which chart activity and function by measuring blood flow – or brain scans using electroencephalograms (EEGs), which measure activity by tracking electrical signaling and brain waves. But these are still limited in what they can tell us.

Enter brain organoids. These are three dimensional models made from clusters of human stem cells grown in the lab. They aren’t “brains in a dish” – they can’t function or think independently – but they can help us develop a deeper understanding of how the brain works and even why it doesn’t always work as well as we’d like.

Now researchers at UCLA’s Broad Center of Regenerative Medicine have created brain organoids that demonstrate brain wave activity similar to that found in humans, and even brain waves found in particular neurological disease.

The team – with CIRM funding – took skin tissue from healthy individuals and, using the iPSC method – which enables you to turn these cells into any other kind of cell in the body – they created brain organoids. They then studied both the physical structure of the organoids by examining them under a microscope, and how they were functioning by using a probe to measure brain wave activity.

In a news release Dr. Ranmal Samarasinghe, the first author of the study in the journal Nature Neuroscience, says they wanted to do this double test for a very good reason: “With many neurological diseases, you can have terrible symptoms but the brain physically looks fine. So, to be able to seek answers to questions about these diseases, it’s very important that with organoids we can model not just the structure of the brain but the function as well.”

Next, they took skin cells from people with a condition called Rhett syndrome. This is a rare genetic disorder that affects mostly girls and strikes in the first 18 months of life, having a severe impact on the individual’s ability to speak, walk, eat or even breathe easily. When the researchers created brain organoids with these cells the structure of the organoids looked similar to the non-Rhett syndrome ones, but the brain wave activity was very different. The Rhett syndrome organoids showed very erratic, disorganized brain waves.

When the team tested an experimental medication called Pifithrin-alpha on the Rhett organoids, the brain waves became less erratic and more like the brain waves from the normal organoids.

“This is one of the first tangible examples of drug testing in action in a brain organoid,” said Samarasinghe. “We hope it serves as a stepping stone toward a better understanding of human brain biology and brain disease.”

Celebrating a young life that almost wasn’t

Often on the Stem Cellar we feature CIRM-funded work that is helping advance the field, unlocking some of the secrets of stem cells and how best to use them to develop promising therapies. But every once in a while it’s good to remind ourselves that this work, while it may often seem slow, is already saving lives.

Meet Ja’Ceon Golden. He was one of the first patients treated at U.C. San Francisco, in partnership with St. Jude Children’s Hospital in Memphis, as part of a CIRM-funded study to treat a rare but fatal disorder called Severe Combined Immunodeficiency (SCID). Ja’Ceon was born without a functioning immune system, so even a simple cold could have been fatal.

At UCSF a team led by Dr. Mort Cowan, took blood stem cells from Ja’Ceon and sent them to St. Jude where another team corrected the genetic mutation that causes SCID. The cells were then returned to UCSF and re-infused into Ja’Ceon.  

Over the next few months those blood stem cells grew in number and eventually helped heal his immune system.

He recently came back to UCSF for more tests, just to make sure everything is OK. With him, as she has been since his birth, was his aunt and guardian Dannie Hawkins. She says Ja’Ceon is doing just fine, that he has just started pre-K, is about to turn five years old and in January will be five years post-therapy. Effectively, Ja’Ceon is cured.

SCID is a rare disease, there are only around 70 cases in the US every year, but CIRM funding has helped produce cures for around 60 kids so far. A recent study in the New England Journal of Medicine showed that a UCLA approach cured 95 percent of the children treated.

The numbers are impressive. But not nearly as impressive, or as persuasive of the power of regenerative medicine, as Ja’Ceon and Dannie’s smiles.

Ja’Ceon on his first day at pre-K. He loved it.