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: 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.

International stem cell group offers much needed guidance for patients and families

Yesterday the International Society for Stem Cell Research launched a greatly expanded website for the public. While the site, “Closer Look at Stem Cells,” offers a broad overview of stem cell science, the group launched it out of concern stem cell treatments are being marketed by clinics around the world without appropriate oversight and patient protections in place.

closer look webThe design for the new site provides easy navigation that quickly gets you to brief outlines and opportunities for a bit more information one click down. Most important, the detail page often includes a bright yellow warning icon with messages like this:

“View clinics that offer the same cell treatment for a wide variety of conditions or diseases with extreme caution. Be wary of claims that stem cells will somehow just know where to go and what to do to treat a specific condition.”

I could buy several rounds at the pub if I had a dollar for every time I said something like that to a desperate patient or family member who called CIRM with questions.

With quick reads like “Nine things to know about stem cell treatments,” as well as a more in-depth patient handbook the site provides ample opportunities to get the level of information any individual wants. It offers clear explanations for the different phases of clinical trials and what to expect if you enter a clinical trial.

A task force of society members and staff produced the new site. The chair of the task force, Megan Munsie from Stem Cells Australia, noted some of the concerns that triggered the effort in the organization’s press release:

“Promising clinical trials are underway for many diseases and conditions, but most stem cell-based treatments are still in the future. We hope that the website will foster interest and excitement in the science, but also an understanding of the current limitations of stem cells as medicine and a healthy skepticism of clinics selling treatments.”

Hope mixed with a good dose of skepticism is always a good approach to a new field of science. Our web site also offers advice for things to consider if a person is contemplating going to a clinic offering an unproven therapy outside of a clinical trial.

Stem cell stories that caught our eye; viral genes in embryos, underuse of transplants and joint pain clinics

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.

Ancient viral invaders help make us, us. The cells of our ancestors millions of years ago may have found a way to turn viral invasion into a good thing. This genetic lemons-to-lemonade tale comes from a team in Singapore that meticulously looked at 650,000 bits of virus genes that have been left behind in our cells after viral infections.

Retroviruses like HIV can only replicate by integrating their genes into ours and getting our cellular machinery to make new copies of themselves. Biologists have long known that they often leave behind bits of their genes, but had assumed this became part of the “junk DNA” that does not serve any function and that makes up the bulk of the genetic material in our cells. That scenario has started to change over the past few years as teams have reported examples of those retroviral genetic elements playing a role in the regulation—the turning on and off—of our functional genes.
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Jonathan Goke, the lead researcher on the project at the Genome Institute of Singapore, wrote that roughly 1,400 of those viral gene elements were involved in the very early stages of embryo development, helping determine how cells decide to mature into different types of tissue. They seem to be needed for determining who we are.

In an article on the website science 2.0 Goke speculated that these viruses may have been able to speed-up evolution by making changes in gene function faster than random mutation.

Blood stem cell transplants under used. Even as the number of blood stem cell transplants ever performed has passed the one million mark, a new report warns that lives are at risk because too many patients that could benefit are not getting these transplants. Blood stem cell transplants, which started as bone marrow transplants, provide the only shot at life-saving therapy for many patients, mostly those with blood cancers.

An international team, led by Dietger Niederwieser of the University Hospital Leipzig in Germany, found a dramatic under use of donor cells for transplants that varied widely around the world. Writing in the Lancet they reported that just 0.4 people per 10 million in the Philippines get such transplants, but in Israel the number shoots up to 506. The report noted both uneven distribution of resources needed to perform the complex procedure and inconsistent support for and participation in donor registries. Niederwieser was quoted in a press release from the journal picked up by ScienceDaily:

“Patients, many of them children, are facing a life and death situation. Ultimately they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

What is real with stem cells and joint pain? Bethesda Magazine, the local publication for the county that is home to the National Institutes of Health (NIH), produced a good piece giving the perspective of patients wanting to avoid joint replacement surgery as well as scientists leery of cell-based procedures that have very little evidence to back them up.

The magazine reached out to its neighbor, the NIH to provide some perspective. It quotes Pamela Robey, the co-coordinator of the NIH Bone Marrow Stromal Cell Transplantation Center—those stromal cells are one type of cell often touted by clinics offering to treat joint pain.

“There are a huge number of clinical trials, but there has been next to no published information. The bottom line is there’s no real rigorous data showing it is actually repairing the joint.”

The author also talked to CIRM grantee Larry Goldstein of the University of California, San Diego, in his role as a member of the Ethics and Public Policy Committee of the International Society for Stem Cell Research. He notes that what clinics are offering is unproven and the author directs readers to the ISSCR web site’s “Closer Look” section to get more information on how to evaluate potential therapies they may be considering.

Stem cell stories that caught our eye: new ways to reprogram, shifting attitudes on tissue donation, and hockey legend’s miracle questioned

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.

Insulin-producing cells produced from skin. Starting with human skin cells a team at the University of Iowa has created iPS-type stem cells through genetic reprogramming and matured those stem cells into insulin-producing cells that successfully brought blood-sugar levels closer to normal when transplanted in mice.

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left). [Credit: University of Iowa]

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left).
[Credit: University of Iowa]

The cells did not completely restore blood-sugar levels to normal, but did point to the possibility of achieving that goal in the future, something the team leader Nicholas Zavazava noted in an article in the Des Moines Register, calling the work an “encouraging first step” toward a potential cure for diabetes.

The Register discussed the possibility of making personalized cells that match the genetics of the patient and avoiding the need for immune suppression. This has long been a goal with iPS cells, but increasingly the research community has turned to looking for options that would avoid immune rejection with donor cells that could be off-the-shelf and less expensive than making new cells for each patient.

Heart cells from reprogramming work in mice. Like several other teams, a group in Japan created beating heart cells from iPS-type stem cells. But they went the additional step of growing them into sheets of heart muscle that when transplanted into mice integrated into the animals own heart and beat to the same rhythm.

The team published the work in Cell Transplantation and the news agency AlianzaNews ran a story noting that it has previously been unclear if these cells would get in sync with the host heart muscle. The result provides hope this could be a route to repair hearts damaged by heart attack.

Patient attitudes on donating tissue. A University of Michigan study suggests most folks don’t care how you use body tissue they donate for research if you ask them about research generically. But their attitudes change when you ask about specific research, with positive responses increasing for only one type of research: stem cell research.

On the generic question, 69 percent said go for it, but when you mentioned the possibility of abortion research more than half said no and if told the cells might lead to commercial products 45 percent said nix. The team published their work in the Journal of the American Medical Association and HealthCanal picked up the university’s press release that quoted the lead researcher, Tom Tomlinson, on why paying attention to donor preference is so critical:

“Biobanks are becoming more and more important to health research, so it’s important to understand these concerns and how transparent these facilities need to be in the research they support.”

CIRM has begun building a bank of iPS-type stem cells made from tissue donated by people with one of 11 diseases. We went through a very detailed process to develop uniform informed consent forms to make sure the donors for our cell bank knew exactly how their cells could be used. Read more about the consent process here.

Mainstream media start to question hockey legend’s miracle. Finally some healthy skepticism has arrived. Hockey legend Gordie Howe’s recovery from a pair of strokes just before the holidays was treated by the general media as a true Christmas miracle. The scientific press tried to layer the coverage with some questions of what we don’t know about his case but not the mainstream media. The one exception I saw was Brad Fikes in the San Diego Union Tribune who had to rely on a couple of scientists who were openly speaking out at the time. We wrote about their concerns then as well.

Now two major outlets have raised questions in long pieces back-to-back yesterday and this morning. The Star in hockey-crazed Canada wrote the first piece and New York Magazine wrote today’s. Both raise serious questions about whether stem cells could have been the cause of Howe’s recovery and are valuable additions to the coverage.

Truth or Consequences: how to spot a liar and what to do once you catch them

Nothing undermines the credibility of science and scientists more than the retraction a high profile paper. Earlier this year there was a prime example of that when researchers at one of Japan’s most prestigious research institutions, the Riken Center for Developmental Biology in Kobe, had to retract a study that had gathered worldwide attention. The study, about a new method for creating embryonic-like stem cells called stimulus triggered acquisition of pluripotency or STAP, was discredited after it was discovered that the lead author had falsified data.

Publication retractions have increased dramatically in recent years [Credit: PMRetract]

Publication retractions have increased dramatically in recent years [Credit: PMRetract]

The STAP incident drew international coverage and condemnation and raised the question, how common is this and what can be done to combat it? A panel discussion at the World Stem Cell Summit in San Antonio, Texas entitled “Reproducibility and rigor in research: What have we learned from the STAP debacle” tackled the subject head on.

Ivan Oransky, medical journalist and the co-founder of the website Retraction Watch posed the question “Does stem cell research have a retraction problem?” He says:

“The answer to my question is yes. But so does everyone else. All of science has a retraction problem, not just stem cells.”

Oransky says the number of retractions has doubled from 2001 to 2010. One author has retracted 183 times – the record so far – but to break into the top 5 you need to have at least 50 retractions. These come from all over the world from the US to Germany and Japan and most recently Azerbaijan.

Oransky says part of the problem is the system itself. Getting your research results published is critical to advancing a career in science and those kinds of pressures force people to cut corners, take risks or even just falsify data and manipulate images in order to get a paper into a high profile journal. In most cases, journals charge a fee of several hundred to thousands of dollars to publish studies, so they have no incentive to dig too deeply into findings looking for flaws, as it might undermine their own business model.

“Some authors, more than 100, have been caught reviewing their own papers. When the journal they were submitting their paper to asked for the names of recommended reviewers they would submit the names of people who are legitimate reviewers in the field but instead of giving real email addresses they would give fake email addresses, ones they controlled so they could submit their own reviews under someone else’s name.”

What gave them away is that all the potential “reviewers” didn’t first reply and say “yes, I’ll review”, instead they responded by sending back a full review of the paper, raising suspicions and ultimately to detection.

Graham Parker, a researcher at Wayne State University School of Medicine and the editor of Stem Cell and Development says spotting the problem is not always easy:

“As an editor I regard scientific misconduct as fabrication, falsification or plagiarism of data but there are lots of other areas where it’s not always so clear – there are often shades of gray”

He says researchers may make an honest mistake, or include duplicative images and in those cases should be allowed to fix the problems without any stigma attached. But when serious cases of falsification of data are uncovered they can have a big impact by retarding scientific progress and sapping public confidence in the field as a whole.

Jeanne Loring, a stem cell scientist at The Scripps Research Institute and a recipient of funding from CIRM, says the STAP incident was actually a sign of progress in this area. Ten years ago when a Korean researcher named Hwang Woo-Suk claimed to have cloned human embryos it took more than a year before he was found to have falsified the data. But in the STAP case it took a little over a week for other researchers to start raising red flags:

“One of the real heroes in this story is Paul Knoepfler (a CIRM-funded researcher at UC Davis) who takes on difficult issues in his blog. It took Paul just 8 days to post a request for people to crowdsource this study, asking people who were trying to replicate the findings to report their results – and they did, showing they failed over and over again”

Parker said it’s getting easier for editors and others in the field to double check data in studies. For example new software programs allow him to quickly check submitted manuscripts for plagiarism. And he says there is a growing number of people who enjoy looking for problems.

“Nowadays it’s so easy for people to dig very deeply into papers and check up on every aspect of it, from the content to the methodology to the images they use and whether those images were in any way manipulated to create a false impression. Once they find a problem with one paper they’ll dig back through papers in that scientist’s past to see if they can find other problems dating back years that were never found at the time.”

He says that in most cases researchers caught falsifying data or deliberately misleading journals faced few consequences:

“Often the consequences of misconduct are very mild, the equivalent of a slap on the wrist, which does not discourage others from trying to do the same.”

Each panel member says that tougher penalties are needed. For example, in extreme cases a threat of criminal action could be warranted, if the falsified research could lead to serious consequences for patients.

But the panel ended on an encouraging note. Oransky says, for example, that medical journals are now paying more attention and imposing stricter rules and he says there’s even scientific evidence that “doing the right thing might pay off.”

“One study recently showed that if you made an honest error and corrected it publicly not only does the stigma of retraction not apply to you, you don’t get a decrease in your citations—you actually get an increase. So we’d like to think that doing the right thing is a good thing and might actually be a positive thing.”

Policy Matters: Stem Cells and the Public Interest

Guest Author Geoff Lomax is CIRM’s Senior Officer for Medical and Ethical Standards.

In the spirit of Stem Cell Awareness Day, Cell Stem Cell has compiled a “Public Interest” collection of articles covering ethical, legal, and social implications of stem cell research and made it freely available. The collection may be found here.

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The collection covers issues ranging from research involving human embryos to the use of stem cell therapies in patients. For those of you interested in a good primer on the history of stem cell controversies, Herbert Gottweis provides a detailed review of the federal policy debate in the United States. This debate has resulted in inconsistent policy and disrupted research. Gottweis uses this history to support his message that a “comprehensive, and proactive policy approach in this field beyond the quick legal fix” is needed for patients to ultimately benefit from the science.

What I found most interesting about this collection was the focus on stem cell treatments and “tourism.” A majority of the articles address the use of stem cells in patients. This focus is an indicator of how far the field has progressed. Stem cells clinical trials are now a reality and this results in two separated but related considerations. First, is how to make sure prospective patients are well informed should they participate in a clinical trial. Second, how to avoid stem cell “snake oil” where someone is pitching an unproven procedure. These issues are related by their solution that involves empowerment and education of patients and their support networks.

For example, in Stem Cell Tourism and Public Education: The Missing Elements, Master writes:

“It is important for the scientific, medical, ethics, and policy communities to continue to promote accurate patient and public information on stem cell research and tourism and to ensure that it is effectively disseminated to patients by working alongside patient advocacy groups.”

Master’s team found that groups committed to the advancement of good science, including patient advocates and researchers, often lacked basic information about clinical trials and other options for patients. This lack of information may contribute to patients being wooed by those pitching unproven procedures. Thus, the research community should continue to work with patients and advocacy organizations to identity options for treatment.

Another aspect of patient empowerment is what Insoo Huyn refers to as “therapeutic hope” in his piece: Therapeutic Hope, Spiritual Distress, and the Problem of Stem Cell Tourism. Huyn suggests that a supportive system for delivering cell therapies should includes nurturing hope. He writes, “patients might understand when an intervention’s chances of success are extremely remote at best, but may still want to ‘‘give it a shot’’ as long as a beneficial outcome cannot be ruled out as categorically impossible.” Huyn recognizes that well developed early-stage clinical trials are not expected to provide a benefit to patients (they are designed to evaluate safety), but the nature of the therapeutic (often cells) means there may be some real effect.

A third piece by the ISSCR Ethics Taskforce titled Patients Beware: Commercialized Stem Cell Treatments on the Web presents a guide to evaluating therapies. They present five principles that patients, researchers and advocates can rally around to identify credible interventions. The taskforce states:

The guiding principles for the development of the recommended process were that (1) the standards for identifying and reviewing clinics and suppliers should be objective and clear; (2) the inquiry and review process should be publicly transparent and relatively straight- forward for any clinic or practitioner to comply with; (3) conflicts of interest, if any, of the declarant ought to be disclosed to the ISSCR; (4) there should be no actual or apparent conflicts of interest of staff or others involved in the inquiry or review process for any particular matter; and (5) any findings that a clinic fails to meet standards should be communicated in a specific factual way, rather than with broad conclusions of fraudulent practices.

While the Cell Stem Cell Public Interest series covers a range of issues related to stem cells and society, the emphasis on treatments and patients is a reminder of how far the field has come. There is broad consensus that patients, researchers and advocates have roles to play in advancing safe and effective cell therapies.

Geoff Lomax

DISCUSSing iPSC Derivation

Geoff Lomax is CIRM’s Senior Officer for Medical and Ethical Standards. He has been working in the implementation of CIRM’s iPSC Banking Program.

The ability to create high-quality stem cell lines depends, in part, on the generosity of donors. For example, CIRM is sponsoring an induced pluripotent stem cell bank (iPSC bank) that will eventually contain 9,000 stem cell lines. Each of these lines will be generated from tissue donated by 3,000 people suffering from known diseases such as Alzheimer’s disease, autism, hepatitis, blindness, heart disease—and many more. You can learn more about this important initiative here.

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In other countries there are similar initiatives like the one sponsored by CIRM.

We also believe that our donors should have accurate information about how their donated materials will be used, so CIRM has developed variety of tools designed to educate donors. For example, each donor must go through a process called “informed consent” where they are told the details of how iPSC’s are derived and preserved in a bank. We discuss this effort here. In the context of the CIRM bank, new donors are being recruited under ethically and scientifically optimal conditions—where they can be fully informed as to how their cells will be used and how their contribution will spur stem cell research.

There are, however, existing libraries of cell and tissues that have inherent scientific value. For example, they may represent a rare or “orphan” disease. Or, they may be essential for tracking the progress of a patient’s disease over time. These collections have also been developed with the consent of the donor or patient, but, at the time of collection, iPSCs may not have even existed. One question that frequently arises is: can these cells be used for iPSC derivation, research and banking? It is not an abstract concern; CIRM and others often get questions about the adequacy of donor consent for precisely this purpose.

In 2013, CIRM, the NIH and the International Stem Cell Forum (ISCF)/McGill University formed the DISCUSS Project (Deriving Induced Stem Cells Using Stored Specimens) to engage the boarder research community on this issue. Rosario Isasi, a project collaborator from ISCF/McGill University, said that her research tells us that investigators around the world are asking the same questions about use of existing cell lines. To help inform researchers, we started by publishing a report on this very subject. The report included nine points to consider when answering the question of whether existing cell libraries can be used for iPSC research.

We followed this initial effort with a series of meetings and workshops to get reactions to our proposed points to consider. The process culminated with a workshop in March where researchers from around world provided recommendations to the DISCUSS team. Sara Hull, a project collaborator from the NIH, noted that the international perspectives were key to producing a greatly improved product. A major workshop theme was the importance of having an effective management system in place, making sure that the cells are used in a way that is consistent with the donor consent. Participants described a number of specific mechanisms that should be used by the research community to ensure cells are used appropriately. Participants emphasized that having effective systems in place to manage cells and iPSC lines in accordance with donors wishes serves to build trust.

Our workshop report elaborates on specific steps researchers and stem cell banks should take to ensure cell lines are used appropriately. The report also includes a revised set of points to consider based on comments received from meetings and workshops.

The DISCUSS Team looks forward to working with the research community to develop consensus for the responsible use of donated materials in stem cell research.

Geoff Lomax

When Hope Runs up against Reality: Balancing Patient Optimism with Medical Evidence

One of the big concerns among scientists – including many at the International Society for Stem Cell Research (ISSCR) conference in Vancouver, Canada – is that patient expectations about stem cells are often greater than researchers are able to deliver today. That can result in patients in search of a cure heading to overseas clinics that offer unproven therapies.

Megan Munsie – head of the Education, Ethics, Law and Community Awareness Unit at the University of Melbourne in Australia – wanted to find out what happens when patients’ hopes for new treatments come into conflict with scientific views on medical evidence. So she started with a small survey of 16 Australians, patients and patient-caretakers, who had travelled outside Australia for stem cell treatments for a variety of diseases including MS and cerebral palsy.

She says there were a number of interesting findings:

  • They all considered themselves pro-active and well-informed
  • They rejected advice from their own doctor but instead relied on the overseas doctor selling them the treatment for advice
  • They felt they had no choice but to travel overseas because they were running out of time and options in Australia
  • They didn’t consider the health risks, believing that the worst that would happen is that the “treatment” wouldn’t work and they would have spent a lot of money for nothing

Perhaps the most surprising finding was that all of them talked about the “benefits” they gained from going abroad for the treatment, that it gave them a sense of hope even if there was no evidence of medical benefit.

What happens when patients’ hopes for new treatments come into conflict with scientific views on medical evidence?

What happens when patients’ hopes for new treatments come into conflict with scientific views on medical evidence?

This led to a bigger study where Munsie surveyed patients and patient advocates but also stem cell scientists and physicians. Not surprisingly the researchers had a very different view of the subject than the patients.

Researchers/doctors said they felt that patients don’t understand science and don’t appreciate the subtleties of clinical trials

  • They said patients were basing their decisions not on science but desperation
  • They considered overseas providers as dubious, selling hope and taking advantage of a vulnerable patient population

What was interesting, however, is that many doctors said they didn’t try to persuade their patients not to go, instead they chose to respect their autonomy but did at least try to give them the facts so that they could make a decision based on knowledge not ignorance.

When asked why they didn’t tell patients not to go, they said they respected the patients’ need for hope and didn’t want to take that away from them because they had nothing they could offer to replace it.

Munsie says recently some doctors have started offering these kinds of unproven therapies in Australia. She talked to four of them asking how they could justify it. All four said there is a huge unmet medical need and it was better to offer these therapies in Australia than have patients travel to other countries for them. They also said that they felt competent to provide treatment because they had undergone some kind of training or had a license to use equipment needed for the therapy.

Ironically while they all considered themselves legitimate providers of a needed medical therapy – albeit an unproven one – and only interested in the science, they regarded others doing the same as “cowboys” and only interested in the money.

When asked if they would support more regulation of the kinds of therapies they were already offering they said yes, saying that the other doctors who claimed they were “self-regulating” is like “giving the keys to the asylum to the lunatics.”

Munsie says it’s clear that it’s not just patients who could benefit from some guidance on expectations about stem cell therapies.

She says we need to do a better job of managing patient expectations without robbing them of a sense of hope, perhaps by offering them information that is more tailored to their particular needs.

We also need to manage what she called “the unbridled enthusiasm of providers” who are offering speculative treatments as “medical practice”. That might take regulatory change by the government.

She says it’s difficult to strike a balance between hope and scientific evidence, in maintaining a patient’s sense of optimism while acknowledging the reality of the science and the risks posed by unproven treatments.

Kevin McCormack