Testing a drug is safe before you give it to a pregnant woman

Pregnant woman holding medicine.

When a doctor gives you a medication you like to think that it’s safe, that it has been tested to make sure it will do you some good or, at the very least, won’t do you any harm. That’s particularly true when the patient is a pregnant woman. You hope the medication won’t harm her or her unborn child. Now scientists in Switzerland have found a new way to do that that is faster and easier than previous methods, and it uses cell cultures instead of animals.

Right now, drugs that are intended for use in pregnant women have to undergo some pretty rigorous testing before they are approved. This involves lots of tests in the lab, and then in animals such as rats and rabbits. It’s time consuming, costly, and not always accurate because animals never quite mimic what happens in people.

In the past researchers tested new medications in the lab on so-called “embryoid bodies”. These are three-dimensional clumps of cells developed from embryonic stem cells from mice. The problem is that even when tested in this way the cells don’t always reflect what happens to a medication as it passes through the body. For example, some medications can seem fine on the surface but after they pass through the liver can take on toxic qualities. 

So, scientists at ETH Zurich in Basel, Switzerland, developed a better way to test for toxicity.

They took a cell-culture chip and created several compartments on it, in some they placed the embryoid bodies and in others they put microtissue samples from human livers.  The different compartments were connected so that fluid flowed freely from the embryoid bodies to the liver and vice versa.

In a news release, Julia Boos, a lead author of the study, says this better reflects what happens to a medication exposed to a human metabolism.

“We’re the first to directly combine liver and embryonic cells in a body-on-a-chip approach. Metabolites created by the liver cells – including metabolites that are stable for just a few minutes – can thus act directly on the embryonic cells. In contrast to tests on mice, in our test, the substances are metabolised by human liver cells – in other words, just as they would be in the human body when the medication is administered.”

To see if this worked in practice the researchers tested their approach on the chemotherapy drug cyclophosphamide, which is turned into a toxic substance after passing through the liver.

They compared results from testing cyclophosphamide with the new liver/embryoid body method to the older method. They found the new approach was far more sensitive and determined that a 400 percent lower concentration of cyclophosphamide was enough to pose a toxic threat.

The team now hope to refine the test even further so it can one day, hopefully, be applied to drug development on a large scale.

Their findings are published in the journal Advanced Science

CIRM-funded study helps unlock some of the genetic secrets behind macular degeneration

Retina affected by age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in people over 60. It affects 10 million Americans. That’s more than cataracts and glaucoma combined. The causes of AMD are not known but are believed to involve a mixture of hereditary and environmental factors. There is no treatment for it.

Now, in a CIRM-funded study, researchers at UC San Diego (UCSD) have used stem cells to help identify genetic elements that could provide some clues as to the cause, and maybe give some ideas on how to treat it.

Before we get into what the researchers did let’s take a look at what AMD does. At a basic level it attacks the retina, the thin layer of tissue that lines the back of the eye. The retina receives light, turns it into electrical signals and sends it to the brain which turns it into a visual image.

The disease destroys the macula, the part of the retina that controls our central vision. At first, sight becomes blurred or fuzzy but over time it progresses to the point where central vision is almost completely destroyed.

To try and understand why this happens the team at UCSD took skin samples from six people with AMD and, using the iPSC method, turned those cells into the kinds of cell found in the retina. Because these cells came from people who had AMD they now displayed the same characteristics as AMD-affected retinal cells. This allowed the researchers to create what is called a “disease-in-a-dish” model that allowed them to see, in real time, what is happening in AMD.

They were able to identify a genetic variant that reduces production of a protein called VEGFA, which is known to promote the growth of new blood vessels.

In a news release Kelly Frazer, director of the Institute for Genomic Medicine at UCSD and the lead author of the study, said the results were unexpected.

Kelly Frazer, PhD, UC San Diego

“We didn’t start with the VEGFA gene when we went looking for genetic causes of AMD. But we were surprised to find that with samples from just six people, this genetic variation clearly emerged as a causal factor.”

Frazer says this discovery, published in the journal Stem Cell Reports, could ultimately lead to new approaches to developing new treatments for AMD.

CIRM already funds one clinical trial-stage project targeting AMD.

The Past, the Present, and the Uncertain Future of Stem Cell Research

Ronnie, a boy who was born without a functioning immune system but who is thriving today because of CIRM funded research

When CIRM was created in 2004 the field of stem cell research was still very much in its infancy. Fast forward 15 years and it’s moving ahead at a rapid pace, probably faster than most scientists would have predicted. How fast? Find out for yourself at a free public event at UC San Diego on May 28th from 12.30 to 1.30p.

In the last 15 years CIRM has funded 53 clinical trials in everything from heart disease and stroke, to spinal cord injury, vision loss, sickle cell disease and HIV/AIDS.

UCSD was one of the first medical centers chosen to host a CIRM Alpha Stem Cell Clinic – a specialist center with the experience and expertise to deliver stem cell therapies to patients – and to date is running more than a dozen clinical trials for breast cancer, heart failure, leukemia and chronic lower back pain.

Clearly progress is being made. But the field is also facing some challenges. Funding at the federal level for stem cell research is under threat, and CIRM is entering what could be its final phase. We have enough money left to fund new projects through this year (and these are multi-year projects so they will run into 2021 or 2022) but unless there is a new round of funding we will slowly disappear. And with us, may also disappear the hopes of some of the most promising projects underway.

If CIRM goes, then projects that we have supported and nurtured through different phases of research may struggle to make it into a clinical trial because they can’t get the necessary funding.

Clearly this is a pivotal time in the field.

We will discuss all this, the past, the present and the uncertain future of stem cell research at the meeting at UC San Diego on May 28th. The doors will open at noon for registration (snacks and light refreshments will also be available) and the program runs from 12.30p to 1.30p.

The speakers are:

  • Dr. Catriona Jamieson, Director of the UC San Diego Health CIRM Alpha Stem Cell Clinic and Sanford Stem Cell Clinical Center.
  • Dr. Maria Millan, President and CEO of CIRM
  • Dr. David Higgins, CIRM Board member and Patient Advocate for Parkinson’s Disease.

And of course, we want to hear from you, so we’ll leave plenty of time for questions.

Free parking is available.

Go here for more information about the event and how you can register

Free free to share this with anyone you think might be interested in joining us and we look forward to seeing you there.

New model unlocks clues to treating deadly childhood cancer

CIRM-funded research at Sanford Burnham Prebys Medical Discovery Institute in San Diego is identifying compounds that could be used to help children battling a deadly brain cancer.

The cancer is choroid plexus carcinoma (CPC), a rare brain tumor that occurs mainly in children. As it grows the tumor can affect nearby parts of the brain resulting in nausea, vomiting and headaches.

Treatment involves surgery to remove the tumor followed by chemotherapy and radiation. However, many of the children are too young to undergo radiation and only around 40 percent are still alive five years after being diagnosed. Even those who do survive often experience life-long consequences such as developmental disabilities.

One obstacle to developing better therapies has been the lack of a good animal model to enhance our understanding of the disease. That’s where this later research, published in the journal Cancer Research, comes in.

The team at Sanford Burnham developed a new mouse model, by knocking out p53, a gene known to suppress tumor formation, and activating a gene called Myc, which is known to cause cancer.  

Robert Wechsler-Reya

In a news release, Robert Wechsler-Reya, the senior author of the paper, says this new model mirrors the way CPC grows and develops in humans.

“This model is a valuable tool that will increase our understanding of the biology of the cancer and allow us to identify and test novel approaches to therapy. This advance brings us one step closer to a future where every child survives—and thrives—after diagnosis with CPC.”

As proof of that the team tested nearly 8,000 compounds against the mouse tumor cells, to see if they could help stop or slow the progression of the disease. They identified three that showed potential of not just stopping the cancer, but of also not harming healthy surrounding cells.

“These compounds are promising, much-needed leads in the quest for an effective CPC treatment,” says Wechsler-Reya. “Our laboratory plans to evaluate these and additional compounds that can effectively treat this cancer.”

Organoids revolutionize approach to studying a variety of diseases

Organoids

There are limitations to studying cells under a microscope. To understand some of the more complex processes, it is critical to see how these cells behave in an environment that is similar to conditions in the body. The production of organoids has revolutionized this approach.

Organoids are three-dimensional structures derived from stem cells that have similar characteristics of an actual organ. There have been several studies recently published that have used this approach to understand a wide scope of different areas.

In one such instance, researchers at The University of Cambridge were able to grow a “mini-brain” from human stem cells. To demonstrate that this organoid had functional capabilities similar to that of an actual brain, the researchers hooked it up to a mouse spinal cord and surrounding muscle. What they found was remarkable– the “mini-brain” sent electrial signals to the spinal cord that made the surrounding muscles twitch. This model could pave the way for studying neurodegenerative diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

Spinal muscular atrophy

Speaking of SMA, researchers in Singapore have used organoids to come up with some findings that might be able to help people battling the condition.

SMA is a neurodegenerative disease caused by a protein deficiency that results in nerve degeneration, paralysis and even premature death. The fact that it mainly affects children makes it even worse. Not much is known how SMA develops and even less how to treat or prevent it.

That’s where the research from the A*STAR’s Institute of Molecular and Cell Biology (IMCB) comes in. Using the iPSC method they turned tissue samples from healthy people and people with SMA into spinal organoids.

They then compared the way the cells developed in the organoids and found that the motor nerve cells from healthy people were fully formed by day 35. However, the cells from people with SMA started to degenerate before they got to that point.

They also found that the protein problem that causes SMA to develop did so by causing the motor nerve cells to divide, something they don’t normally do. So, by blocking the mechanism that caused the cells to divide they were able to prevent the cells from dying.

In an article in Science and Technology Research News lead researcher Shi-Yan Ng said this approach could help unlock clues to other diseases such as ALS.

“We are one of the first labs to report the formation of spinal organoids. Our study presents a new method for culturing human spinal-cord-like tissues that could be crucial for future research.”

Just yesterday the CIRM Board awarded almost $4 million to Ankasa Regenerative Therapeutics to try and develop a treatment for another debilitating back problem called degenerative spondylolisthesis.

And finally, organoid modeling was used to better understand and study an infectious disease. Scientists from the Max Planck Institute for Infection Biology in Berlin created fallopian tube organoids from normal human cells. Fallopian tubes are the pair of tubes found inside women along which the eggs travel from the ovaries to the uterus. The scientists observed the effects of chronic infections of Chlamydia, a sexually transmittable infection. It was discovered that chronic infections lead to permanent changes at the DNA level as the cells age. These changes to DNA are permanent even after the infection is cleared, and could be indicative of the increased risk of cervical cancer observed in women with Chlamydia or those that have contracted it in the past.

Of Mice and Men, and Women Too; Stem cell stories you might have missed

Mice brains can teach us a lot

Last week’s news headlines were dominated by one big story, the use of a stem cell transplant to effectively cure a person of HIV. But there were other stories that, while not quite as striking, did also highlight how the field is advancing.

A new way to boost brain cells (in mice!)

It’s hard to fix something if you don’t really know what’s wrong in the first place. It would be like trying to determine why a car is not working just by looking at the hood and not looking inside at the engine. The human brain is far more complex than a car so trying to determine what’s going wrong is infinitely more challenging. But a new study could help give us a new option.

Researchers in Luxembourg and Germany have developed a new computer model for what’s happening inside the brain, identifying what cells are not operating properly, and fixing them.

Antonio del Sol, one of the lead authors of the study – published in the journal Cell – says their new model allows them to identify which stem cells are active and ready to divide, or dormant. 

“Our results constitute an important step towards the implementation of stem cell-based therapies, for instance for neurodegenerative diseases. We were able to show that, with computational models, it is possible to identify the essential features that are characteristic of a specific state of stem cells.”

The work, done in mice, identified a protein that helped keep brain stem cells inactive in older animals. By blocking this protein they were able to help “wake up” those stem cells so they could divide and proliferate and help regenerate the aging brain.

And if it works in mice it must work in people right? Well, that’s what they hope to see next.

Deeper understanding of fetal development

According to the Mayo Clinic between 10 and 20 percent of known pregnancies end in miscarriage (though they admit the real number may be even higher) and our lack of understanding of fetal development makes it hard to understand why. A new study reveals a previously unknown step in this development that could help provide some answers and, hopefully, lead to ways to prevent miscarriages.

Researchers at the Karolinska Institute in Sweden used genetic sequencing to follow the development stages of mice embryos. By sorting those different sequences into a kind of blueprint for what’s happening at every stage of development they were able to identify a previously unknown phase. It’s the time between when the embryo attaches to the uterus and when it begins to turn these embryonic stem cells into identifiable parts of the body.

Qiaolin Deng, Karolinska Institute

Lead researcher Qiaolin Deng says this finding provides vital new evidence.

“Being able to follow the differentiation process of every cell is the Holy Grail of developmental biology. Knowledge of the events and factors that govern the development of the early embryo is indispensable for understanding miscarriages and congenital disease. Around three in every 100 babies are born with fetal malformation caused by faulty cellular differentiation.”

The study is published in the journal Cell Reports.

Could a new drug discovery reduce damage from a heart attack?

Every 40 seconds someone in the US has a heart attack. For many it is fatal but even for those who survive it can lead to long-term damage to the heart that ultimately leads to heart failure. Now British researchers think they may have found a way to reduce that likelihood.

Using stem cells to create human heart muscle tissue in the lab, they identified a protein that is activated after a heart attack or when exposed to stress chemicals. They then identified a drug that can block that protein and, when tested in mice that had experienced a heart attack, they found it could reduce damage to the heart muscle by around 60 percent.

Prof Michael Schneider, the lead researcher on the study, published in Cell Stem Cell, said this could be a game changer.

“There are no existing therapies that directly address the problem of muscle cell death and this would be a revolution in the treatment of heart attacks. One reason why many heart drugs have failed in clinical trials may be that they have not been tested in human cells before the clinic. Using both human cells and animals allows us to be more confident about the molecules we take forward.”

Breakthrough for type 1 diabetes: scientist discovers how to grow insulin-producing cells

Matthias Hebrok, PhD, senior author of new study that transformed human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.

More often than not, people don’t really think about their blood sugar levels before sitting down to enjoy a delicious meal, partake in a tasty dessert, or go out for a bicycle ride. But for type 1 diabetes (T1D) patients, every minute and every action revolves around the readout from a glucose meter, a device used to measure blood sugar levels.

Normally, the pancreas contains beta cells that produce insulin in order to maintain blood sugar levels in the normal range. Unfortunately, those with T1D have an immune system that destroys their own beta cells, thereby decreasing or preventing the production of insulin and in turn the regulation of blood sugar levels. Chronic spikes in blood sugar levels can lead to blindness, nerve damage, kidney failure, heart disease, stroke, and even death.

Those with T1D manage their condition by injecting themselves with insulin anywhere from two to four times a day. A light workout, slight change in diet, or even an exciting event can have a serious impact that requires a glucose meter check and an insulin injection.

There are clinical trials involving transplants of pancreatic “islets”, clusters of cells containing healthy beta cells, but these rely on pancreases from deceased donors and taking immune suppressing drugs for life.

But what if there was a way to produce healthy beta cells in a lab without the need of a transplant?

Dr. Matthias Hebrok, director of the UCSF diabetes center, and Dr. Gopika Nair, postdoctoral fellow, have discovered how to transform human stem cells into healthy, insulin producing beta cells.

In a news release written by Dr. Nicholas Weiler of UCSF, Dr. Hebrok is quoted as saying “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”

For the longest time, scientists could only produce cells at an immature stage that were unable to respond to blood sugar levels and secrete insulin properly. Dr. Hebrok and Dr. Nair discovered that mimicking the “islet” formation of cells in the pancreas helped the cells mature. These cells were then transplanted into mice and found that they were fully functional, producing insulin and responding to changes blood sugar levels.

Dr. Hebrok’s team is already in collaboration with various colleagues to make these cells transplantable into patients.

Gopika Nair, PhD, postdoctoral fellow that led the study for transforming human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.

Dr. Nair in the article is also quoted as saying “Current therapeutics like insulin injections only treat the symptoms of the disease. Our work points to several exciting avenues to finally finding a cure.”

“We’re finally able to move forward on a number of different fronts that were previously closed to us,” Hebrok added. “The possibilities seem endless.” 

Dr. Hebrok, who is also a member of the CIRM funded UCSF Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, was senior author of the new study, which was published February 1, 2019 in Nature Cell Biology.

CIRM has funded three separate human clinical trials for T1D that total approximately $37.8 million in awards. Two of these trials are being conducted by ViaCyte, Inc. and the third trial is being conducted by Caladrius Biosciences.

Targeted treatment for pediatric brain tumors shows promising results

Image of medulloblastoma

Imagine sitting in the doctor’s office and being told the heartbreaking news that your child has been diagnosed with a malignant brain tumor. As one might expect, the doctor states that the most effective treatment option is typically a combination of chemotherapy and radiation. However, the doctor reveals that there are additional risks to take into account that apply to children. Since children’s tiny bodies are still growing and developing, chemotherapy and radiation can cause long-term side effects such as intellectual disabilities. As a parent, it is painful enough to have to watch a child go through chemotherapy and radiation without adding permanent damage into the fold.

Sadly, this scenario is not unique. Medulloblastoma is the most prevalent form of a pediatric brain tumor with more than 350 children diagnosed with cancer each year. There are four distinct subtypes of medulloblastoma, with the deadliest being known as Group 3.

Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) are trying to minimize the collateral damage by finding personalized treatments that reduce side effects while remaining effective. Scientists at SBP are working with an inhibitor known as LSD1 that specifically targets Group 3 medulloblastoma in a mouse model. The study, published in Nature Communications, showed that the drug dramatically decreased the size of tumors grown under the mouse’s skin by shrinking the cancer by more than 80 percent. This suggested that it could also be effective against patients’ tumors if it could be delivered to the brain. The LSD1 inhibitor has shown promise in clinical trials, where it has been tested for treating other types of cancer.

According to Robert Wechsler-Reya, Ph.D., senior author of the paper and director of the Tumor Initiation and Maintenance Program at SBP: “Our lab is working to understand the genetic pathways that drive medulloblastoma so we can find better ways to intervene and treat tumors. This study shows that a personalized treatment based upon a patient’s specific tumor type might be within our reach.”

Dr. Wechsler-Reya’s work on medulloblastoma was, in part, funded by the CIRM (LA1-01747) in the form of a Research Leadership Award for $5,226,049.

Stem Cells make the cover of National Geographic

clive & sam

Clive Svendsen, PhD, left, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, and Samuel Sances, PhD, a postdoctoral fellow at the institute, with the January 2019 special edition of National Geographic. The magazine cover features a striking image of spinal cord tissue that was shot by Sances in his lab. Photo by Cedars-Sinai.

National Geographic is one of those iconic magazines that everyone knows about but few people read. Which is a shame, because it’s been around since 1888 and has helped make generations of readers aware about the world around them. And now, it’s shifting gears and helping people know more about the world inside them. That’s because a special January edition of National Geographic highlights stem cells.

The issue, called ‘The Future of Medicine’, covers a wide range of issues including stem cell research being done at Cedars-Sinai by Clive Svendsen and his team (CIRM is funding Dr. Svendsen’s work in a clinical trial targeting ALS, you can read about that here). The team is using stem cells and so-called Organ-Chips to develop personalized treatments for individual patients.

Here’s how it works. Scientists take blood or skin cells from individual patients, then using the iPSC method, turn those into the kind of cell in the body that is diseased or damaged. Those cells are then placed inside a device the size of an AA battery where they can be tested against lots of different drugs or compounds to see which ones might help treat that particular problem.

This approach is still in the development phase but if it works it would enable doctors to tailor a treatment to a patient’s specific DNA profile, reducing the risk of complications and, hopefully, increasing the risk it will be successful. Dr. Svendsen says it may sound like science fiction, but this is not far away from being science fact.

“I think we’re entering a new era of medicine—precision medicine. In the future, you’ll have your iPSC line made, generate the cell type in your body that is sick and put it on a chip to understand more about how to treat your disease.”

Dr. Svendsen isn’t the only connection CIRM has to the article. The cover photo for the issue was taken by Sam Sances, PhD, who received a CIRM stem cell research scholarship in 2010-2011. Sam says he’s grateful to CIRM for being a longtime supporter of his work. But then why wouldn’t we be. Sam – who is still just 31 years old – is clearly someone to watch. He got his first research job, as an experimental coordinator, with Pacific Ag Research in San Luis Obispo when he was still in high school.

 

 

 

 

 

 

Performance, Passion and Progress: and that’s just page one of our 2018 Annual Report

2018_ar_webimage

It’s hard to sum up the activities and achievements of a year in a single document, let alone one that’s just 24 pages. But that’s what we have done in putting together our 2018 Annual Report.

It’s a look back at the year just gone, the highlights, the low lights (spoiler alert – there weren’t any) and the impact we had on the field of stem cell research. But it’s far more than that. It’s also a look ahead. A look at the challenges we face, and profiles of the people who are going to help us overcome those challenges and maintain our progress.

And people are truly at the heart of this report, from UC San Francisco’s Dr. Tippi MacKenzie who is on the front cover for her work in developing an in-utero treatment for the almost always fatal disorder alpha thalassemia major (and the photo of the baby and mom whose lives were changed by that therapy) to Rich Lajara on the back cover, the first person ever treated in a CIRM-funded clinical trial.

Inside are an array of simple images designed to reflect how we as a state agency have performed this year. The numbers themselves tell a powerful story:

  • 50 clinical trials funded to date, 7 this year alone
  • $2.6 billion in CIRM grants has been leveraged to bring in an additional $3.2 billion in matching funds and investments from other sources.
  • 1,180 patients have been involved in CIRM clinical trials

We know people don’t have a lot of time to read Annual Reports so we have made this as visually engaging and informative as possible. We want you to get a real sense of who we are, what we have done and who has helped us do that without you having to wade through a document the size of War and Peace (great book by the way – the Russians beat Napoleon).

We think we have a great story to tell. This Annual Report is one chapter in that story. We hope you like it.