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

Stem Cell Stories that Caught our Eye: Multiple Sclerosis, Diabetes, Cornea Repair and of Course, New Stem Cells too Good to be True

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.

Buddy system gets stem cells to stick around. The type of stem cell most likely to be used in a clinical trial today is the mesenchymal stem cell (MSC) found in fat and bone marrow. It is also the type of stem cell most likely to produce vaguely positive or downright disappointing results. In most situations they die within a few days of being transplanted, so the only impact they can have is from the various protein signals they secrete that may trigger the body’s own natural healing processes. They never live up to their stem cell potential to form new adult tissue. A team at Harvard looked at their natural environment and found they most often live near a second type of cell called an endothelial colony-forming cell. When the team transplanted the two cells together they found the MSCs survived for weeks and matured into appropriate adult tissue. Genetic Engineering & Biotechnology News had a nice interview with members of the team about their work that appeared this week in the Proceedings of the National Academy of Sciences.

Fat cells (yellow) descended from transplanted stem cells (green) inside a mouse 28 days after co-transplantation with “buddy cells”  [Courtesy Children’s Hospital]

Fat cells (yellow) descended from transplanted stem cells (green) inside a mouse 28 days after co-transplantation with “buddy cells”
[Courtesy Children’s Hospital]


Master switch for creating brain insulation.
Researchers know how to take a skin cell from a patient, turn it into an iPS type stem cell and then turn those cells into the type of intermediate cell that can become the myelin that insulates our nerves and is lost in Multiple Sclerosis. The problem: the process takes way too long to be a feasible therapy. To get enough of these middleman cells called oligodendrocyte progenitors for a therapy can take as much as a year. Neural stem cells naturally mature into multiple intermediate cells, but prefer to become the progenitors for neurons, which would not help an MS patient. A team at the University of Buffalo looked to see what genetic switches were active in neuron progenitors versus those for myelin. They found that just one of these switches could push the early nerve stem cells to the myelin middlemen. That genetic factor, SOX10, instantly becomes a candidate for a path to a more efficient therapy. Again, Genetic Engineering & Biotechnology News did the best of several write-ups of this work that was published in the Proceedings of the National Academy of Sciences.

You can read about CIRM’s projects working on a cure for MS on our Multiple Sclerosis Fact Sheet.

Can gut be taught to make insulin. Earlier work at Columbia University had shown that in mice you can turn off a single gene and get normal gut cells to secrete insulin and to do so in response to sugar in the bloodstream. Now the team has made the often difficult transition of moving from mouse results to humans, or in this case human gut cells in a dish. They matured human stem cells into gut tissue and then shut down the one gene. The resulting cells produced insulin in response to sugar in their environment. The research published in Nature Communication got coverage on a few sites including HealthDay.

Early success in cornea repair poised to get even better. One of the stem cell field’s early successes has been work pioneered in Italy using a type of stem cell found in the cornea of the eye. When a patient has the cornea of one eye damaged they harvest these cells, called limbal stem cells, from the healthy eye and transplant them to the damaged eye. It often works quite well, but not always and the success has been correlated with how many actual limbal stem cells are among the cells transplanted. It has been difficult to sort out and purify the stem cells until now. A team from three Harvard affiliated hospitals has found a marker that let them transplant purer human limbal stem cells into mice and they saw consistent regrowth of damaged corneas. RedOrbit wrote up the research that was published in Nature.

STAP stem cell retraction everywhere. When Japanese and American researchers published a new, simple method for creating stem cells in January it got way more news coverage than an unconfirmed and unconventional piece of research should have. Most of that coverage failed to include the caveat that the work needed to be replicated to confirm the findings. In less than six months, the research community quickly reported repeated failures to replicate the work and more recently found outright errors in the published papers. When the journal that published the work, Nature, formally retracted the papers this week it was good to see that this “oops-ignore-our-first-article” seemed to get equal play. To show the reach of this news, I have included the Associated Press version from the tiny Logansport Pharos Tribune, which averages about 12 pages a day and is the closest real newspaper to the tiny Indiana town where I grew up.

Don Gibbons