Small DNA changes, life or death consequences

Two recent papers by CIRM grantees highlight the importance of understanding basic stem cell biology while developing new cures. Both have to do with chemical modifications to the DNA – called epigenetics.

One of the two papers shows that an epigenetic change in DNA, called methylation, changes dramatically as human embryonic stem cells mature into specific cell types; the other shows that even subtle DNA methylation differences alter the way a cell behaves.

The first paper, by Jeanne Loring at The Scripps Research Institute, working with scientists in Singapore and New York, provides detailed maps of DNA methylation over the entire 3 billion “letters” that make up our DNA. By comparing methylation patterns of human embryonic stem cells and more mature cells, the scientists tracked the large number of epigenetic changes, many of them surprises, that occur when cells differentiate.

A press release quotes first author Louise Laurent as saying:

"The data are publicly available, and we are looking forward to learning what other scientists discover from using this information for their own studies on individual genes, embryonic development, and stem cells."

The second paper, from UCLA, focuses on epigenetic differences in pancreatic cancers, showing that differences in these modifications translate to different responses to chemotherapy. This means that a few DNA modifications here or there could mean life or death.

In a press release the authors say the next step is to develop a test doctors can use to figure out which patients will respond well to standard chemotherapy and which need an alternative treatment.

Taken together, the papers make a compelling case for how basic biology research such as understand DNA modifications can inform scientists who are actively pursuing cures.

Genome Research, February 4, 2010
CIRM funding: Jeanne Loring (RT1-1108 and TR1-01250)

Journal of Clinical Oncology, February 8, 2010
CIRM funding: Siavash Kurdistani (RN1-005505)

A.A.

Virus-free Technique Yields Pluripotent Stem Cells

Stem cells in fat hold intrigue for scientists because most of us have excess to spare, and the cells seem to be quite versatile. Now a team at Stanford has found a way to transform them into induced pluripotent stem (iPS) cells without using potentially dangerous viruses to carry the reprogramming genes into the cells.

This paper marks another step toward the holy grail of reprogramming, which is to find a safe, efficient way of returning adult cells to their embryonic-like state, called pluripotency. So far, most techniques are either not efficient or require inserting genes that may make the cells unsafe for therapeutic use.

The team used so-called minicircles of DNA to reprogram the cells into pluripotency. These minicircles contain just the four genes needed to transform the cells along with a fluorescence gene that allows the cells to be tracked. The minicricles are about half the size of naturally occurring plasmid rings that have been used in some other iPS transformations, and unlike integrating viruses, the minicircles do not get replicated as the cells multiply so the extra genes are lost over time, making the cells safer for therapy.

A press release from Stanford University quoted co-author Michael Longaker saying:

“This technique is not only safer, it’s relatively simple. It will be a relatively straightforward process for labs around the world to begin using this technique. We are moving toward clinically applicable regenerative medicine.”

Another co-author, Mark Kay, developed the minicircle technology a few years ago for use in gene therapy trials. This paper provides a great example of discoveries in one field impacting another, and moving them both forward.

Nature Methods, February 7, 2010
CIRM funding: Michael Longaker (RL1-00662-1); (T1-00001)

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