Clocks & stem cells: Time and tinkering to develop the best embryonic stem cells

Geoff Lomax is CIRM's Senior Officer to the Standards Working Group

The history of technology tells us that the first strategy is rarely the one that sticks. One of my favorite examples involves the English clock maker John Harris, whose many iterations of marine chronometers revolutionized sea travel. (His story is recounted in Dava Sobel’s excellent book Longitude: The True Story of a Lone Genius Who Solved the Greatest Scientific Problem of His Time.) My English grandfather also worked on clocks and marine guidance systems so I have a soft spot for the guild.

In 1730, Harris sought to produce a clock, called the H1, which could maintain accurate time on a lengthy, rough sea voyage with widely varying conditions of temperature, pressure and humidity – a great challenge in his day. This initial prototype performed well but there was a desire for a more rugged and compact design. After several iterations and another 23 years, he produced the H4, which kept time within 39 seconds during a trans Atlantic sea trial. A subsequent design, H5, was accurate within one-third of a second – revolutionary for its time.

Fast forward to 2011, in the world of human embryonic stem cell research, the cell line H9 has been revolutionary for its time – used in thousand of published studies. In a recent article, Rohun Patel and I illustrate how it is also the most widely utilized human embryonic stem cell (hESC) line by CIRM researchers. However, we also found that CIRM grantees were carrying out research with 137 other lines including 17 that had been recently derived with CIRM funding.

A recent study in Human Molecular Genetics authored by Amander Clark at University of California, Los Angeles suggests the newly derived CIRM lines may have several improvements over the earlier models. The study compared the X chromosomes of older lines, including H9, to recently derived lines. The UCLA team found that the X chromosomes in the newer lines were more active than those in the older lines, which tended to have more of the X chromosome shut down. Furthermore, the way in which those older lines shut down portions of the X chromosome deviated from how cells normally de-activate portions of the X chromosome – called “X inactivation”. In a press release from UCLA Clark said:

“The classic signature is gone, so something else is regulating X chromosome inactivation in the established cell lines,” Clark said. “It will be important not only to find out what that is, but also to discover what else is changing in the nucleus that we cannot see.”

Clark’s paper shows that in stem cell research—as in other areas of innovation—it takes time and tinkering to develop the best model. The ability of CIRM-funded researchers to develop and then investigate 17 new human embryonic stem cell lines and access hundreds of others would not be possible under federal guidelines alone. Federal agencies like the NIH can’t fund research to create new stem cell lines. Clark’s paper shows the clear need for these efforts to continue under CIRM and other agencies that fund cell line derivation. In the press release she said:

“Our data highlights the importance of maintaining hESC derivation efforts. Gold standard hESC lines should be the benchmark for human pluripotent stem cell research.”

Unlike Harris, stem cell researchers don’t have 23 years to tinker with their design. Patients need therapies soon, and therapy development will be bolstered by having optimal tools available to all researchers. Clark’s work shows the value to patients in those 17 lines derived by CIRM grantees, and by all those other new lines that have been and will continue to be created through sources other than federal funding.

Human Molecular Genetics, November 30, 2011
CIRM Funding: Amander Clark (RL1-00636-1)

G.L.

New disease-specific embryonic stem cell lines from Michigan

Stem cell scientists at the University of Michigan and in Detroit have created two embryonic stem cell lines that contain disease-causing mutations: Hemophilia B, a hereditary condition in which the blood does not clot properly and Charcot-Marie-Tooth disease, an inherited disorder leading to degeneration of muscles in the foot, lower leg and hand.

For the first time, scientists will have a way of studying cells that carry the causing mutation and understanding how the disease arises. When the mutation is in embryonic stem cells, it is then carried by any cell type emerging from that line. Maturing the hemophilia line into blood cells, for example, could provide insights into genetic factors associated with disease. These cells also provide a way to test possible therapies in human cells rather than in animals that mimic the disease.

The cells came from embryos created through in vitro fertilization that were determined by preimplantation genetic testing to carry a disease mutation. A few cells from the 3-5 day old IVF embryo are sent to the clinic, and the parents can choose which embryos to implant based on the results. Embryos with possibly lethal disease mutations are generally destroyed as medical waste. Donating t research gives couples an option other than simply destroying the embryos.

The Detroit News wrote about the new lines:

U-M will soon be submitting these disease-specific lines to the National Institutes of Health to be placed on the Human Embryonic Stem Cell Registry. Researchers across the country will be able to use the lines for federally funded research. Of the 91 lines currently on the registry, three are disease-specific stem cell lines submitted by Harvard and Stanford universities.

In the story, Bernard Seigal, executive director of the Florida-based Genetics Policy Institute that hosts the World Stem Cell Summit (to be co-hosted this year by CIRM) said this discovery is a direct result of the passage of Proposal 2, a constitutional amendment that allowed for embryonic stem cell research in Michigan.

The passage of Proposal 2 wasn't just a political statement," Siegel said. "This has been followed up with real, tangible research and real results that have the potential to impact human health. It portends very well for the future of stem cell research in Michigan."

CIRM funds several awards to grantees who are developing embryonic stem cell lines that were found to carry disease-causing mutations through preimplantation genetic testing. These include Julie Baker at Stanford University and Amander Clark at UCL.

- A.A.

NIH accepts new human embryonic stem cell lines

By Geoff Lomax

The NIH has accepted three new human embryonic stem cell lines, created by CIRM grantee Amander Clark at UCLA. According to the UCLA press release:

“The addition of the three human embryonic stem cells lines to the registry brings the total number of lines available for federal funding to 64, NIH officials said. Another 100 lines are pending approval. UCLA is one of only nine institutions in the world with stem cell lines admitted to the NIH registry.”

All lines were created from blastocysts left over from IVF treatments and would otherwise have been discarded. (You can read more about how the lines are created in this CIRM Stem Cell Basics page.)

In this video, Clark describes the process of creating new lines:


It is reassuring to know that the standards CIRM developed in 2006 for hESC derivation are acceptable in the rigorous NIH policy context. This approval is important because it signals that our grantees are well positioned to support research nationally by registering cell lines derived with CIRM funding.

Geoff Lomax is Senior Officer to the CIRM Standards Working Group, which developed CIRM’s stem cell derivation regulations.