Stem cell stories that caught our eye: Prostate cancer and BPA, mini organs and diabetes trial

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Latest mini-organ, a prostate, fingers BPA. A team at the University of Illinois, at Chicago, has added the prostate gland to the growing list of “organoids” that have been grown from stem cells in the lab. The tiny gland that produces semen in men has an unusually high rate of cancer compared to other organs. Prior research has linked that cancerous nature to exposure to the hormone estrogen during fetal growth, including synthetic estrogen mimics like the chemical BPA (bisphenol A) found in many plastics.

Unlike the other organs associated with male gender, which form very early in fetal development, the prostate develops later when stem cells’ roles are more narrowly defined to creating specific tissues. The team, led by Gail Prins, had previously shown that prostate stem cells grown in the presence of BPA formed cells more likely to show signs of cancer. But that did not allow them to determine what really triggered the increase in cancer. So, they decided to grow mini prostates and look at all the cells as they developed in the organoid.

“What we were doing originally with the human prostate stem cells is we were mixing and growing them in vivo,” Prins told Medical Daily. “The idea to generate this organoid came from the first author, Esther Calderon-Gierszal; she was my graduate student. ‘They’ve done it for other organs,’ she thought. ‘Let’s try it for a prostate.’”

The researchers pushed embryonic stem cells to grow into the several different tissues found in a prostate gland using a cocktail of hormones. Although much smaller than a normal prostate the cells did self-organize into structures that resembled the gland. When they grew the organoid in the presence of BPA they found an unusually large number of prostate specific stem cells. So, it appears just the increased number of stem cells increases the likelihood a few will go bad and form cancer.

A round up of all the mini-organs. The journal Nature has written a very accessible wrap up in its news section on all the various organs that have been simulated in a lab dish since a Japanese team reported the phenomenon for the first time in 2008. After a fun lead-in explaining the science, Cassandra Willyard runs through what has been accomplished so far in the stomach, kidney, and liver.

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

The fun in the opening section comes from the fact that given the right environment, stem cells are pretty darn good at self-organizing into the multiple tissue types that become a specific organ. So much so, that the early teams that saw it in the lab were shocked and did not at first know what they had.

Willyard starts with quotes from Madeline Lancaster, a post-doctoral fellow in a lab at the Institute for Molecular Biotechnology in Vienna, Austria. She found milky looking spheres in the lab cultures and when she cut into them she found multiple types of nerves. So she grabbed her mentor and reported:

“I’ve got something amazing. You’ve got to see it.”

She also discusses the work that led Hans Clevers, a researcher at Hubrecht Institute in Utrecht, the Netherlands, to report the creation of mini-guts in 20009. They grew the cells in a gel that resembled the structure that naturally surrounds cells. In this “at-home” environment stem cells formed much more complex tissue than he had hoped.

“The structures, to our total astonishment, looked like real guts,” Clevers said. “They were beautiful.”

The author also lets Clevers talk about taking his work the next step, using the gut organoids to screen for drugs for related diseases. If you have been following this work, Willyard’s piece is a must read.

Second clinical trial site for diabetes. Opening multiple clinical trial sites accelerates the process of determining whether a new therapy is safe and effective. So we were thrilled to get the announcement from ViaCyte that they would begin enrolling patients at a second location for the diabetes trial we helped them launch by funding the first clinical trial site at the University of California, San Diego.

That trial uses pancreatic cells grown from embryonic stem cells that are protected from immune attack by a semi-permeable pouch. The second site, at the University of Alberta Hospitals in Edmonton, Canada, is being funded in part by Alberta Innovates as well as by the JDRF Canadian Clinical Trials Network. JDRF also helps support the San Diego trial through its US office.

The lead researcher for the Alberta trial, James Shapiro, developed the procedure for transplanting pancreatic tissue from cadavers that became known as “the Edmonton Protocol.” That protocol has changed many lives, but because it requires life-long immunosuppression, doctors only recommend it for the most severe diabetics. The small number of donor pancreases also limits its use. Shapiro commented about the value and need for something like the ViaCyte therapy in a company press release picked up by Yahoo Finance, and dozens of other sites:

“The fact remains that new treatments are sorely needed, not only for the high risk patients but for all patients suffering from this life-altering disease.  The remarkable promise of the (ViaCyte) product candidate is that a virtually limitless source of appropriate human cells can be transplanted without the need for lifetime immunosuppression.”

Stem cell stories that caught our eye: fixing defects we got from mom, lung repair and staunching chronic nerve pain

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Two ways to clean up mitochondrial defects. Every student gets it drilled into them that we get half our genes from mom and half from dad, but that is not quite right. Mom’s egg contains a few genes outside the nucleus in the so-called powerhouse of the cell, the mitochondria that we inherit only from mom. The 13 little genes in that tiny organelle that are responsible for energy use can wreak havoc when they are mutated. Now, a multi-center team working in Oregon and California has developed two different ways to create stem cells that match the DNA of specific patients in everyway except those defective mitochondrial genes.

The various mitochondrial mutations tend to impact one body system more than others. The end goal for the current research is to turn those stem cells into healthy tissue that can be transplanted into the area most impacted by the disease in a specific patient. That remains some years away, but this is a huge step in providing therapies for this group of diseases.

Currently, we have two ways of making stem cells that match the DNA of a patient, which hopefully result in transplantable cells that can avoid immune rejection. One is to reprogram adult tissue into induced pluripotent (iPS type) stem cells and the other uses the techniques called Somatic Cell Nuclear Transfer (SCNT), often called therapeutic cloning. The current research did both.

The team converted the SCNT stem cells into various needed tissues such as these nerve precursor cells.

The team converted the SCNT stem cells into various needed tissues such as these nerve precursor cells.

The iPS work relied on the fact that our tissues are mosaics because of the way mitochondria get passed on when cells divide. So not all cells show mitochondrial mutations in people with “mito disease” —how impacted families tend to refer to it, as I found out through a distant cousin with a child valiantly struggling with one form of the disease. Because each iPS stem cell line arises from one cell, the researchers could do DNA analysis on each cell line and sort for ones with few or no mutations, resulting in healthy stem cells, which could become healthy transplant tissue.

But for some patients, there are just too many mutations. For those the researchers inserted the DNA from the patient into a healthy donor egg containing healthy mitochondria using SCNT. The result: again healthy stem cells.

“To families with a loved one born with a mitochondrial disease waiting for a cure, today we can say that a cure is on the horizon,” explained co-senior author Shoukhrat Mitalipov at the Oregon Stem Cell Center in a story in Genetic Engineering News. “This critical first step toward treating these diseases using gene therapy will put us on the path to curing them and unlike unmatched tissue or organ donations, combined gene and cell therapy will allow us to create the patients’ own healthy tissue that will not be rejected by their bodies.”

ScienceDaily ran the Oregon press release, HealthCanal ran the press release from the Salk Institute in La Jolla home of the other co-senior author Juan Carlos Izpisua Belmonte, whose lab CIRM funds for other projects. And Reuters predictably did a piece with a bit more focus on the controversy around cloning. Nature published the research paper on Wednesday.

Stem cells to heal damaged lungs. Lung doctors dealing with emphysema, cystic fibrosis and other lung damage may soon take a page from the playbook of cancer doctors who transplant bone marrow stem cells. A team at Israel’s Weizmann Institute has tested a similar procedure in mice with damaged lungs and saw improved lung function

Transplanted lung cells continued to grow at six weeks (left) and 16 weeks (right).

Transplanted lung cells continued to grow at six weeks (left) and 16 weeks (right).

Stem cells are homebodies. They tend to hang out in their own special compartments we call the stem cell niche, and if infused elsewhere in the body will return home to the niche. Bone marrow transplants make use of that tendency in two ways. Doctors wipe out the stem cells in the niche so that there is room there when stem cells previously harvested from the patient or donor cells are infused after therapy.

The Weizmann team did this in the lungs by developing a method to clear out the lung stem cell niche and isolating a source of stem cells capable of generating new lung tissue that could be infused. They now need to perfect both parts of the procedure. ScienceDaily ran the institute’s press release.

Stem cells for chronic pain due to nerve damage. Neuropathy, damaged nerves caused by diabetes, chemotherapy or injury tends to cause pain that resists treatment. A team at Duke University in North Carolina has shown that while a routine pain pill might provide relief for a few hours, a single injection of stem cells provided relief for four to five weeks—in mice.

They used a type of stem cell found in bone marrow known to have anti-inflammatory properties called Bone Marrow Stromal Cells (BMSCs). They infused the cells directly into the spinal cavity in mice that had induced nerve damage. They found that one chemical released by the stem cells, TGF Beta1, was present in the spinal fluid of the treated animals at higher than normal levels. This finding becomes a target for further research to engineer the BMSCs so that they might be even better at relieving pain. ScienceNewsline picked up the Duke press release about the research published in the Journal of Clinical Investigation.

Stem cell stories that caught our eye: correcting cystic fibrosis gene, improving IVF outcome, growing bone and Dolly

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Cystic Fibrosis gene corrected in stem cells. A team at the University of Texas Medical School at Houston corrected the defective gene that causes cystic fibrosis in stem cells made from the skin of cystic fibrosis patients. In the long term the advance could make it possible to grow new lungs for patients with genes that match their own—with one life-saving exception—and therefore avoid immune rejection. But, the short-term outcome will be a model for the disease that provides tools for evaluating potential new drug therapies.

“We’ve created stem cells corrected for the cystic fibrosis mutation that potentially could be utilized therapeutically for patients,” said Brian Davis the study’s senior author in a university press release. “While much work remains, it is possible that these cells could one day be used as a form of cell therapy.”

The researchers made the genetic correction in the stem cells using the molecular scissors known as zing finger nucleases. Essentially they cut out the bad gene and pasted in the correct version.

Stem cell researchers boost IVF. Given all the ethical issues raised in the early years of embryonic stem cell research it is nice to be able to report on work in the field that can boost the chances of creating a new life through in vitro fertilization (IVF). Building on earlier work at Stanford a CIRM-funded team there has developed a way to detect chromosome abnormalities in the embryo within 30 hours of fertilization.

Chromosomal abnormalities account for a high percent of the 60 to 70 percent of implanted embryos that end up in miscarriage. But traditional methods can’t detect those chromosomal errors until day five or six and clinicians have found that embryos implant best three to four days post fertilization. This new technique should allow doctors to implant only the embryos most likely to survive.

“A failed IVF attempt takes an emotional toll on a woman who is anticipating a pregnancy as well as a financial toll on families, with a single IVF treatment costing thousands and thousands of dollars per cycle. Our findings also bring hope to couples who are struggling to start a family and wish to avoid the selection and transfer of embryos with unknown or poor potential for implantation,” explained Shawn Chavez who led the team and has since moved to Oregon Health Sciences University.

The study, which used recent advanced technology in non-invasive imaging, was described in a press release from Oregon.

Fun TED-Ed video shows how to grow bone. Medical Daily published a story this week about a team that had released a TED-Ed video earlier this month on how to grow a replacement bone on the lab. The embedded video provides a great primer on how we normally grow and repair bone in our bodies and how that knowledge can inform efforts to grow bone in the lab.

In particular, the story walks through a scenario of a patient with a bone defect too large for our normal repair mechanisms to patch up. It describes how scientist can take stem cells from fat, use 3D printers to mold a scaffold the exact shape of the defect, and culture the stem cells on the scaffold in the lab to create the needed bone.

The video and story reflect the work of New York-based company EpiBone and its tissue engineer CEO Nina Tandon.

Happy birthday Dolly (the sheep). July 5 marked the 19th anniversary of the first cloned mammal, Dolly the sheep in Scotland. For fans of the history of science, MotherBoard gives a good brief history of the resulting kerfuffle and a reminder that Dolly was not very healthy and the procedure was not and is not ready to produce cloned human.

Dolly's taxidermied remains are in a museum in Scotland. She died after only six years, about half the normal life expectancy.

Dolly’s taxidermied remains are in a museum in Scotland. She died after only six years, about half the normal life expectancy.

Stem cell stories that caught our eye: Immune therapy for HIV, nerves grown on diamonds and how stem cells talk

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Trendy CAR T therapy tried on HIV.  The hottest trend in cancer therapy today is using CAR-T cells to attack and rid the body of cancer. Technically called chimeric antigen receptors the technology basically provides our own immune system with directions to cancer cells and keys to get inside them and destroy them. A CIRM-funded team at the University of California, Los Angeles, has now tried that same scheme with HIV.

Jerome Zack (left) and Scott Kitchen, found that the technique decreased HIV levels in mice by 80 to 95 percent.

Jerome Zack (left) and Scott Kitchen, found that the technique decreased HIV levels in mice by 80 to 95 percent.

The researchers worked with mice bred to have a human immune system so that HIV affects them similarly to humans. They harvested their blood-forming stem cells and inserted a CAR that recognized HIV. After giving the stem cells back to the mice they produced T cells capable of seeking out and destroying about 90 percent of the virus. The technique has a ways to go, but the study’s lead author noted their ultimate goal in a University press release picked up by HealthCanal:

“We hope this approach could one day allow HIV-positive individuals to reduce or even stop their current HIV drug regimen and clear the virus from the body altogether,” said Scott Kitchen. “We also think this approach could possibly be extended to other diseases.”

Nerves grown on diamonds. Diamonds are so chemically non-reactive our bodies would not recognize them as foreign. But they can also be made to conduct electricity, which could make nerves grown on their surface able to be turned on and off with electrical impulses. When developing cell therapy for several neurologic diseases the ability to control the activity of replacement cells could be critical to success—making new research by a team in Britain and Ireland intriguing, if very preliminary.

They doped diamonds with boron to make them able to conduct electricity and then used them as a surface for growing nerve stem cells that could later be turned into nerves. They then succeeded in growing nerves long term on the diamonds.

“We still have a lot more fundamental studies of the neuron/diamond interface to perform,” said Paul May of the University of Bristol. “[But] the long term possibilities for this work are exciting.  Long-lifetime diamond bio-implants may offer treatments for Parkinson’s, Alzheimer’s, stroke or even epilepsy.”

Materials Today wrote a piece explaining the work.

Some stem cells talk over “land lines.” Most cellular communication works through chemical signals that get dispatched by one cell and received by others. It turns out that some types of stem cells communicate by sending out tiny nanotubes, sort of a cellular land line.

A team at the University of Michigan and the University of Texas Southwestern Medical Center found the new form of communication working with fruit flies. Yukiko Yamashita, a senior author of the paper from Michigan explained why it is so important to get a better understanding of cell-to-cell communication in a university press release picked up by ScienceNewsline:

“There are trillions of cells in the human body, but nowhere near that number of signaling pathways. There’s a lot we don’t know about how the right cells get just the right messages to the right recipients at the right time.”

In a classic example of the beauty of young minds in science, prior images of these stem cells had shown the nanotubes, but they had been overlooked until a graduate student asked what they were.

Phase 3 melanoma trial explained. When a new therapy gets into its third and final phase of testing it is make or break for the company developing the therapy and for patients who hope it will become broadly available. CIRM recently provided funding to our first phase three clinical trial, one aimed at metastatic melanoma being conducted by Caladrius Biosciences.

The CEO of the company, David Mazzo, gave an interview with The New Economy this week that does a nice job of explaining the goal of the therapy and how it is different from other therapies currently used or being developed. The therapy’s main difference is its ability to target the cancer-inducing cells thought to responsible for the spread of the disease.

Stem cell stories that caught our eye: Parkinson’s in a dish, synthetic blood, tracking Huntington’s and cloning

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

3D nerve model for Parkinson’s. The wave of successes in making more complex tissues in three dimensional lab cultures continues this week with a team in Luxembourg creating nerves from stem cells derived from Parkinson’s patients that assembled into complex connections in the lab.

Nerve cells made from skin cells. Credit: Luxembourg Centre for Systems Biomedicine (LCSB), 2015

Nerve cells made from skin cells. Credit: Luxembourg Centre for Systems Biomedicine (LCSB), 2015

The name of the journal where the group published their results, Lab on a Chip, says a lot about where the field is going. While many have grown the dopamine-producing nerves lost in Parkinson’s disease in two dimensional cultures, the new technique better replicates the disease state and does it about 10-fold cheaper because the 3D bioreactors used can be automated and use less of the reagents needed to grow the cells and to tell them to become the right nerves.

They started with skin samples from patients and reprogrammed them into iPS-type stem cells. After those cells are placed in the vessel, they are matured into 90 percent pure dopamine-nerves. At that point they are ideal for testing potential drugs for any impact on the disease. The senior researcher, Ronan Fleming, explained the benefit in a press release from the University of Luxembourg, picked up by ScienceDaily:

“In drug development, dozens of chemical substances can therefore be tested for possible therapeutic effects in a single step. Because we use far smaller amounts of substances than in conventional cell culture systems, the costs drop to about one tenth the usual.”

Synthetic blood from stem cells. Making synthetic blood, particularly for people with rare blood types for which there are few donors, has long been a goal of science. Now, the British National Health Service (NHS) says it expects to begin giving patients at least one component of lab-made blood—red cells—by 2017.

Starting with adult stem cells grown in just the right solution they hope to produce large quantities of red blood cells. Initially they plan to give only small quantities to healthy individuals with rare blood types to compare them to donor blood.

“These trials will compare manufactured cells with donated blood,” said Nick Warkins of the NHS. “The intention is not to replace blood donation but provide specialist treatment for specific patient groups.”

The story got wide pick up in the British press including in the Daily Mail and in several web portals including Rocket News.

Tracking Huntington’s spread in the brain. A CIRM-funded team at the University of California, Irvine, has developed a way to track the spread of the mutant protein responsible for progression of Huntington’s disease. They were able to accurately detect the mutant protein in cerebrospinal fluid and distinguish between people who carried the mutation but were pre-symptomatic from those that had advanced disease.

The protein appears to be released by diseased cells and migrates to other cells, seeding additional damage there. Measuring levels of the protein should allow physicians to monitor progression of the disease ahead of symptoms.

“Determining if a treatment modifies the course of a neurodegenerative disease like Huntington’s or Alzheimer’s may take years of clinical observation,” said study leader Dr. Steven Potkin. “This assay that reflects a pathological process can play a key role in more rapidly developing an effective treatment. Blocking the cell-to-cell seeding process itself may turn out to be an effective treatment strategy.”

Medical News Today wrote up the research that the team published in the journal Molecular Psychiatry.

Good overview of cloning. Writing for Medical Daily, Dana Dovey has produced a good overview of the history of cloning, and more important, the reasons why reproductive cloning of human is not likely to happen any time soon.

She describes the important role a number of variations on cloning play in scientific research, and the potential to create personalized cells for patients through a process known as therapeutic cloning. But she also describes the many problems with reproductive cloning as it is practiced in animals. It is very inefficient with dozens of eggs failing to mature and often results in animals that have flaws. She quotes Robert Lanza of Advanced Cell Technologies (now Ocata Therapeutics):

“It’s like sending your baby up in a rocket knowing there’s a 50-50 chance it’s going to blow up. It’s grossly unethical.”

 

Hed: Stem cell stories that caught our eye: the why’s of heart failure, harnessing stem cells’ repair kits and growing organs

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Stem cell model sheds light on heat failure. Pretty much everyone who has heart failure due to cardiomyopathy—where the heart muscle doesn’t work as effectively as it should—or has a condition that could lead there, is taking a beta blocker. The beta-andrenergic pathway, a key molecular pathway in the heart, dysfunctions in patients with cardiomyopathy and we have never known exactly why. We just know these drugs help.

Now, a team at Stanford led by Joseph Wu has used skin samples from patients and normal subjects to create reprogrammed iPS type stem cells, grown them into heart muscle, and compared them at a very fine-tuned molecular level.

Some patients have a mutation in a protein called TNNT2 in heart muscle fibers, which regulates muscle contraction. So, one thing they looked at was the impact of that mutation. Wu’s team followed the actions triggered by this mutation and found they lead to the beta-andrenergic pathway. Wu explained the value he sees in this fundamental understanding of the disease in a Stanford press release:

“As a cardiologist, I feel this basic research study is very clinically relevant. The beta-andrenergic pathway is a major pharmaceutical target for many cardiac conditions. This study confirms that iPS-cell-derived cardiomyocytes can help us understand biologically important pathways at a molecular level, which can aid in drug screening.”

CIRM did not fund this project but we do fund other projects in Wu’s lab including one to advance the use of iPS cells as models of heart disease, one using tissue engineering to repair damaged areas of the heart and one using embryonic stem cells to generate new heart muscle.

Harnessing stem cells’ repair kits. Stem cells repair tissue in multiple ways, but primarily by maturing into cells that replace damaged ones or by excreting various chemicals that give marching orders to neighboring cells to get busy and make the repairs. Those chemicals, collectively called paracrine factors, get excreted by the stem cells in vessels known as exosomes. So, a team at Temple University in Philadelphia decided to try injecting just the exosomes, rather than whole stem cells to repair heart damage. It seemed to work pretty well in mice.

Stem cells release exosomes, tiny vessels that act as repair kits.

Stem cells release exosomes, tiny vessels that act as repair kits.


After treatment with the exosomes, mice with induced heart attacks showed fewer heart cells dying, less scar tissue, more development of new blood vessels and a stronger heart function. The head of the Temple team, Raj Kishore, described the result in a university press release distributed by EuekaAlert:

“You can robustly increase the heart’s ability to repair itself without using the stem cells themselves. Our work shows a unique way to regenerate the heart using secreted vesicles from embryonic stem cells.”

The team went on to isolate a specific regulatory chemical that was among the most abundant in the exosomes. That compound, a type of RNA, produced much of the same results when administered by itself to the mice—intriguing results for further study.

Good primer on using stem cells to grow organs. The Wisconsin State Journal ran a nice primer in both video and prose about what would theoretically go into building a replacement organ from stem cells and some of the basic stem cell principals involved. The piece is part of a series the paper produces with the Morgridge Institute at the University of Wisconsin. This one features an interview with Michael Treiman of Epic Systems:

“The biggest challenge right now is that we can push a stem cell to be a particular type of cell, but in a tissue there’s multiple cells. And an organ like your heart or brain isn’t just made of one cell type; it’s made of many cell types working together.”

Stem cell stories that caught our eye: Parkinson’s trial revived, aspirin kills cancer stem cells and a stem cell role in mother-child obesity

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Parkinson’s clinical trials back on track.
After nearly 20 years of being stuck on the clinical trial “bookshelf”, an international team from Cambridge, UK revived a cell therapy for Parkinson’s disease.

In an announcement picked up this week by the Genetic Literacy Project, the team reported they had treated their first patient. Specifically, fetal brain cells were injected into the brain of a man in his mid-50’s with the disease.

Neurons derived from human embryonic stem cells

A fluorescent microscopic image of numerous dopaminergic neurons (the type of neurons that are degenerated in Parkinson’s disease patients) generated from human embryonic stem cells. Image courtesy of the Xianmin Zeng lab at the Buck Institute for Age Research.

In Parkinson’s, nerve cells controlling movement die for poorly understood reasons. An accumulation of data through the 60’s and 70’s suggested transplantation of fetal brain cells into the Parkinson’s brain would replace the lost nerve cells and restore movement control. After initial promising results in the 80’s and 90’s, larger clinical trials showed no significant benefit and even led to a worsening of symptoms in some patients.

Due to these outcomes, the research community shelved the approach. Insights gained in the interim pointed to more ideal brain injection sites in order to help avoid side effects. Also, follow up on patients beyond the two-year run of those early trials suggested that positive effects of the cell therapy may not emerge for at least three to five years. So this latest trial will run longer to capture this time window.

One remaining snag for this therapeutic strategy is the limited number of available cells for each transplant. So in the meantime, scientists including some of our grantees are working hard at getting embryonic stem cell- or iPS cell-based therapies to the clinic. Since stem cells divide indefinitely, this approach could provide an off-the-shelf, limitless supply of the nerve cells. Stay tuned.

Targeting cancer stem cells with the Wonder Drug.
Aspirin: it’s the wonder drug that may turn out to be even more wonderful.

Ball and stick model of aspirin, the wonder drug: relieves pain and prevents cancer

Ball and stick model of aspirin, the wonder drug: relieves pain and prevents cancer

Famous for relieving pain and preventing heart attacks, aspirin may add breast cancer-killer to its resume. This week a cancer research team at the Kansas City (Mo.) Veteran Affairs Medical Center published experiments picked up by Eureka Alert showing a daily dose of aspirin could put the brakes on breast cancer.

The analysis attributed this anti-cancer effect to aspirin’s capacity to reduce the growth of cancer stem cells. These cells make up a tiny portion of a tumor but if chemotherapy or radiation treatment leaves any behind, it’s thought the cells’ stem cell-like ability for unlimited growth drives cancer relapse and spread (metastasis).

In the study, mice with tumors given a daily low dose of aspirin for 15 days had, on average, tumors nearly 50% smaller than the aspirin-free mice. In another set of experiments, the team showed aspirin could prevent tumors as well. Mice were given aspirin for 10 days before exposing them to cancer cells. After another 15 days, the aspirin treated animals had significantly less tumor growth compared to an untreated group.

Senior author Sushanta Banerjee stands behind these findings: he’s been taking an aspirin a day for three years but stresses that you should consult with your doctor before trying it yourself.

A stem cell link to the passing on of obesity from mom to child?
It’s been observed that children of obese moms have a high risk for obesity and diabetes. You might conclude that genetics are the culprit as well as lifestyle habits passed down from parent to child. But research published this week by researchers at the University of Colorado School of Medicine suggests another mechanism: they conclude the mere presence of the growing embryo in the uterus of an obese mother may instruct the child’s cells to take on more fat.

The team’s reasoning is based on an analysis of umbilical cord blood stem cells collected from babies born to 12 obese mothers and 12 normal weight mothers. In the lab, the stem cells were specialized into fat and muscle cells. The cells from babies of obese mothers showed increased fat accumulation and a lower production of proteins important for uptake of blood sugar (a state that could eventually tip the scales towards diabetes).

Certainly it’s a leap to link the property of cells in a dish to the eventual health of a child. But the results are intriguing enough that the researchers intend to follow the children as they get older to look for more connections between the state of the kids’ stem cells and their health profile.

Stem cell stories that caught our eye: regenerating limbs on scaffolds, self regeneration via a drug, mood stem cells, CRISPR

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Regenerating a limb, or at least part of it. Many teams have generated organs or parts of organs in animals by starting with a dead one. They literally wash away all the cells from the donor organ using a detergent so that they are left with a framework of the cells’ connective tissue. Then they seed that scaffold with stem cells or other cells to grow a new organ. A team at Massachusetts General Hospital has now used the same process to generate at least part of a rat limb.

The news cells growing on the donor limb scaffold in a bioreactor

The news cells growing on the donor limb scaffold in a bioreactor

It took a week to get the tiny little leg fully cleaned up and then another two weeks for the seeded cells to repopulate the scaffold left behind. That cellular matrix seems to send signals to the seeded cells on what type of tissue to become and how to arrange themselves. The team succeeded in creating an artificial limb with muscle cells aligned into appropriate fibers and blood vessels in the right places to keep them nourished. The researchers published their work in the journal Biomaterials and the website Next Big Future wrote up the procedure and provided some context on the limitations of current prosthetic limbs. The author also notes that the researchers have a lot more work to do, notably to prove they can get nerves to grow and connect at the point of transplantation to the “patient” animal. Discover also wrote a version of the story.

Getting the body to regenerate itself. A strain of mice discovered 20 years ago has led a multi-institution team to a possible way to get the body to regenerate damaged tissue, something the mouse discovered two decades ago can do and other mammals cannot. The researchers found that those mice have one chemical pathway, HIF-1a, that is active in the adult mice but is normally only active in the developing embryo. When they pushed that chemical path to work in normal mice those mice, too, gained the power to regenerate tissue. Ellen Heber-Katz from the Lankenau Institute for Medical Research outside of Philadelphia was quoted in the institute’s press release on Health Medicine Network.

“We discovered that the HIF-1a pathway–an oxygen regulatory pathway predominantly used early in evolution but still used during embryonic development–can act to trigger healthy regrowth of lost or damaged tissue in mice, opening up new possibilities for mammalian tissue regeneration.”

Heber-Katz led the team that included researchers from the company Allergan and the University of California, Berkeley. In order to activate the HIF-1a pathway they basically took the natural brakes off it. Another cellular chemical, PHD normally inhibits the action of HIF-1a in adults. The researcher turned the table on PHD and inhibited it instead. The result, after three injections of the PHD inhibitor over five days the mice who had a hole punched in their ear healed over the hole complete with cartilage and new hair.

Regulating memory and mood. It turns out your brain’s hippocampus, the section responsible for both memory and mood, has not one type of stem cell replenishing nerves, but two. And those two types of stem cells give rise to different types of nerves, which may account for the highly varied function of this part of the brain. Researchers at the University of Queensland in Australia isolated the two types of stem cells and then let them grow into nerves but the nerves from each expressed different genes, which means they have different functions. The lead researcher on the study, Dhanisha Jhaveri, discussed the findings in a press release picked up by Science Daily:

“The two cell groups are located in different regions of the hippocampus, which suggests that distinct areas within the hippocampus control spatial learning versus mood.”

The research provides fodder for future work looking into the treatment of learning and mood disorders. Review of the now celebrity tool, CRISPR. I don’t think I have ever seen so much ink and so many electrons spilled over a science tool as I have seen for CRISPR, particularly for one few scientists can tell you what the acronym stands for: Clustered Regularly Interspaced Short Palindromic Repeats. It is basically a fluke in the genes of several bacteria in which some of the base pairs that make up their DNA get repeated at regular intervals. Their configuration confers the ability for CRISPR segments to be used to disrupt or change specific genes in other organisms. Heidi Ledford writing for Nature in the journal’s news section provides a great wrap-up of what the technology is and what it can do, but also provides some caveats about its efficiency, accuracy, ethical concerns, and occasionally just not understanding how it works. The Nature team provides some valuable infographics showing the history of the science and on the rapid adoption of the technology as shown in publications, patents and funding. They also published an infographic on using CRISPR for “gene drive,” a way to push a modified trait through a population quickly, such as a mutation that could stop mosquitos from transmitting malaria. This potential drives much of the concern about misuse of the tool. But scientists quoted in the piece also provide more mundane reasons for moving slowly in thinking about using the therapy for patients. One of those is that it can sometime cause a high rate of “off-target” gene edits; simply put, cutting DNA in the wrong place. But as a research tool, there is no doubt it has revolutionized the field of gene modification. It is so much faster and so much cheaper than earlier gene editing tools; it is now possible for almost any lab to do this work. The piece starts out with an anecdote from CIRM-grantee Bruce Conklin of the Gladstone Institutes, talking about how it completely changed the way his lab works.

“It was a student’s entire thesis to change one gene,” Conklin said, adding “CRISPR is turning everything on its head.”

Stem cell stories that caught our eye: Spinal cord injury, secret of creating complex tissue, mini brains in a dish and funding

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Monkey trial provides some hope for spinal cord injury. Stem cell treatments have made many mice and rats walk again after spinal cord injury, but moving from those rodents to human has been a slow process. Their immune systems and nervous systems are very different from ours. So, it was good to read this week that a team at Japan’s Keio University reported success in monkeys with systems much more like ours.

The experiment was “controlled.” They compared treated and non-treated animals and saw a significant difference in mobility between the two groups. Bloomberg picked up the release from the journal that published the work Stem Cells Translational Medicine, which quoted the study author Hideyuki Okano:

“An animal in the control group, for example, could not raise her hands up to head height at 12 weeks after injury when motor function almost plateaus. On the other hand, at the same point in time a transplanted animal was able to jump successfully and run so fast it was difficult for us to catch her. She could also grip a pen at 3 cm. above head-height.”

But the work requires some caveats. They treated all animals at exactly 14-days post injury, a window considered optimal for having initial inflammation subside and scar tissue not yet formed. Also, the researchers inflicted bruises not more severe damage to the spinal cord. Most patients with spinal cord injury are chronic, long past the 14-day window, and have damage to their spinal cords more severe than these animals.

The researchers started with embryonic stem cells and matured them into nerve progenitor cells, which they injected into the monkeys. While this process can yield plentiful cells for therapy the researchers acknowledged that much more research is needed before they can help the vast majority of spinal cord injuries with more severe and older injuries. CIRM funds a clinical trial using cells derived from embryonic stem cells to treat more complex spinal injuries, but it is just getting underway.

Clues to creating complex tissues. These days getting stem cells to form a single type of tissue, nerve or skin for example, is almost routine, with the remaining hurdle being purity. But getting stem cells to form complex tissues with multiple types of cells, while done a few times, still gets folks attention. For the most part, this is because we don’t know the cell-to-cell interactions required to form complex tissues. A CIRM-funded team at the University of California, San Diego, thinks they have part of the answer.

They studied something called the neurovascular unit, made up of blood vessels, smooth muscle and nerves that regulate heart rate, blood flow and breathing, among other basic functions. Using a lab model they showed how the different cell types come together to form the vital regulatory tissue. San Diego Newscape posted a piece on the work, quoting the study’s senor author David Cheresh:

“This new model allows us to follow the fate of distinct cell types during development, as they work cooperatively, in a way that we can’t in intact embryos, individual cell lines or mouse models. And if we’re ever going to use stem cells to develop new organ systems, we need to know how different cell types come together to form complex and functional structures such as the neurovascular unit.”

And a brainy example.   Prior research has created small brain “organoids” that started with stem cells and self assembled in a lab dish to create layers of nerves and support cells, but the cells did not interact much like normal brain tissue. Now, a team at Stanford has developed “cortex-like spheroids” with different types of cells that talk to each other.

Nerves and supporting cells form layers and organize like in the developing brain

Nerves and supporting cells form layers and organize like in the developing brain

In the new cortex spheres the nerves are healthier with a better network of the natural supporting cells called glial cells. The cells form layers that interact with each other like in our brains as we are developing.

A program at the National Institutes of Health (NIH) focusing on using stem cells to create models of disease in the lab funded the work. Thomas Insel, Director of the NIH’s National Institute of Mental Health described the importance of the current work in a press release from the institute picked up by HealthCanal:

 

“There’s been amazing progress in this field over the past few years. The cortex spheroids grow to a state in which they express functional connectivity, allowing for modeling and understanding of mental illnesses. They do not even begin to approach the complexity of a whole human brain. But that is not exactly what we need to study disorders of brain circuitry.“

The release starts with a fun lede imagining the day when a patient tormented by mental illness could have a model of their disease grown in a dish and researchers could genetically engineer better brain circuits for the patient. Certainly not just around the corner, but not far fetched.

States economic gain from funding research. The very niched web cite Governing posted a piece that appears to be largely from a conference in Washington D.C. hosted by the Greater Phoenix Economic Council. It quotes several experts speaking about the opportunity for states to gain economic advantage by funding research.

The piece notes some well documented examples of federal government spending on research spawning industries—think Silicon Valley. Then it talks about some more recent state examples including the California initiative that created CIRM.

One speaker, Mark Muro of the Brookings Institute said that we are in a new era now and states may not be able to fund research through their general tax revenue. He said:

“It may be the state becoming part of a consortium or working with Fortune 500 companies, or going to voters with a general obligation bond vote. I think we’re heading for a new complexity.”

Since CIRM was created through a vote for bonds, guess we have to agree.

Stem cell stories that caught our eye: sickle cell patient data, vaccine link to leukemia protection, faster cell analysis

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Good news from sickle cell clinical trial. It is always satisfying to report positive results from human clinical trials using stem cells even when we don’t fund the work. Bluebird Bio released the first data on a patient treated for sickle cell anemia using the same procedure the company had earlier used to get good outcomes for two patients with beta thalassemia.

Both diseases result from defects—though different defects—in the gene for hemoglobin, the protein our red blood cells use to carry needed oxygen. So, in both cases they use a modified, deactivated virus to carry a correct version of the gene into patients’ own blood-forming stem cells in the lab. They then re-infused those cells into the patients to provide a ready supply of cells able to make the needed protein.

In the sickle cell patient, after the transplant a third of his red cells were making the right protein and that was enough to wean him off blood transfusions that had been keeping him alive and prevented any further hospitalizations due to the disease. The company also announced that the two previously reported patients treated for beta thalassemia had continued to improve. Reuters ran a story on the new data.

CIRM funds a similar project about to begin treating patients for sickle cell disease (link to video), also using a viral vector but a somewhat different one, so it is reassuring to see viral gene carriers working without side effects.

Another reason to vaccinate, prevent leukemia. While it has been known for some time that infant vaccination seems to have driven down the rate of childhood leukemia, no one has known why. A CIRM-funded team at the University of California, San Francisco, thinks they have figured it out. Viral infections trigger inflammation and the production of enzymes in cells that cause genetic mutations that lead to the cancer.

They worked with Haemophilus influenza Type b (Hib) vaccine but suggest a similar mechanism probably applies to other viral infections, and correspondingly, protection from other vaccines. The senior author on the paper, Marcus Muschen, explained the process in a university press release posted at Press-News.org

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy. Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

Barcoding individual cells. Our skin cells all pretty much look the same, but in the palm of your hand there are actually several different types of cells, even a tiny scratch of the fingernail. As scientist work to better understand how cells function, and in particular how stem cells mature, they increasingly need to know precisely what genes are turned on in individual cells.

Both techniques use tiny channels to isolate individual cells and introduce beads with "bar codes."

Both techniques use tiny channels to isolate individual cells and introduce beads with “bar codes.”

Until recently, all this type of analysis blended up a bunch of cells and asked what is in the collective soup. And this did not get the fine-tuned answers today’s scientists are seeking. Numerous teams over the past couple years have reported on tools to get down to single-cell gene analysis. Now, two teams at Harvard have independently developed ways to make this easier. They both use a type of DNA barcode on tiny beads that gets incorporated into individual cells before analysis.

Allan Klein, part of one team based at the Harvard Medical School’s main campus, described why the work is needed in a detailed narrative story released by the school:

“Does a population of cells that we initially think is uniform actually have some substructure. What is the nature of an early developing stem cell? . . . How is [a cell’s] fate determined? “

Even Macosko who worked with the other team centered at the Broad Institute of Harvard and MIT, noted the considerable increase in ease and decrease in cost with the new methods compared to some of the early methods of single cell gene analysis:

“If you’re a biologist with an interesting question in mind, this approach could shine a light on the problem without bankrupting you. It finally makes gene expression profiling on a cell-by-cell level tractable and accessible. I think it’s something biologists in a lot of fields will want to use.”

The narrative provides a good example of what we called the “bump rate” when I was at Harvard Med. Good science often moves forward when scientists bump into each other, and with Harvard Medical faculty scattered at 17 affiliated hospitals and research institutes scattered across Boston and Cambridge we were always looking for ways to increase the bump rate with conferences and cross department events. Macosko and Klein found out they were both working on similar systems at a conference.