Researchers create stem cells from schizophrenia patients

Mar 17, 2011

Using skin cells from adult siblings with schizophrenia and a genetic mutation linked to major mental illnesses, Johns Hopkins researchers have created induced pluripotent stem cells (iPS cells) using a new and improved "clean" technique.

Reporting online February 22 in , the team confirms the establishment of two new lines of iPS with mutations in the gene named Disrupted In Schizophrenia 1, or DISC1. They made the cells using a nonviral "epiosomal vector" that jumpstarts the reprogramming machinery of cells without modifying their original genetic content with foreign DNA from a virus.

The stem cells from these two new lines, the scientists say, can be coaxed to become such as neurons. Because they have the DISC1 mutation, they stand to play an important role in the screening of drugs for treatments of major mental illnesses such as schizophrenia, bipolar disorder and , as well as provide clues about the causes of these diseases.

"Most people think of stem cells only as potential transplant therapy to replace damaged cells or tissue, but for psychiatric diseases, which have proven a challenge to scientific understanding just as a sheer cliff challenges a climber, these cells provide a toehold," says Russell L. Margolis, M.D., professor of psychiatry and neurology, and director of the Johns Hopkins Schizophrenia Program. "Nature put in only a few little grab holds, and now we are generating our own so we can scale the cliff of mental illness faster."

The benefit of maintaining the original genome of cells being reprogrammed outweighs the fact that the episomal vector approach is both time- and labor-intensive, says Guo-li Ming, Ph.D., associate professor of neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine.

"The efficiency of the new technique is very, very low," Ming reports, citing a rate of 0.0006 percent or less and comparing it to the rate of efficiency of virally infected reprogrammed cells, which hovers at about 0.001 percent. "Human cells grow slowly, and this kind of reprogramming takes time."

However, the episomal vector method solves tricky problems associated with the more efficient viral approach, which involves inserting foreign genes into the cell's genome and potentially interrupting or influencing other genes that can change cell behavior. It also relieves worry about weird cell behavior later due to reactivation of introduced genes that remain in the genome, the researchers say.

The skin biopsy samples used in the study came from an American family first reported 25 years ago to have multiple family members affected with schizophrenia. A genetic analysis conducted by Margolis and colleagues six years ago discovered that a mutation in the DISC1 gene was common to all members of the family with severe mental illness. Two years ago, Margolis and Christopher A. Ross, M.D., Ph.D., director of the division of neurobiology, collected the skin samples and delivered them to Ming's team, which thus far has successfully reprogrammed two of those samples into the new iPS cell lines. Skin cell samples from the remaining family members, as well as from unrelated individuals with schizophrenia, are still works in progress in the Ming lab, potentially becoming additional stem cell lines, according to Ming.

First, using the cultured skin cells, the team delivered a package of so-called reprogramming factors into the cytoplasm — as opposed to the nucleus, where the cell's genetic material resides — via bits of DNA (episomal vectors) that are serially diluted during cell division after making their special delivery. These cells then were grown in culture while the scientists monitored them for changes.

It took a wildly variable window of time — anywhere between three weeks and three months — for the elongated and single-layered to begin to change shape and cluster together, a telling sign that they were on the path to becoming stem cells, Ming explains.

"Seeing the colonies was heartening evidence of reprogramming, but not proof of ground state of ," Ming says. "We had to go through a series of characterization process, which generally takes about six months or more, depending on your rigor, to prove that.

The team then conducted a series of tests to verify not only that the genes they used to introduce the reprogramming factors were undetectable from the transformed cells, but also to prove their pluripotency. First, they confirmed that these cells could generate differentiated cells from all three germ layers — the endoderm, mesoderm and ectoderm — which eventually give rise to all of an animal's tissues and organs. By changing the recipe of the culture media in which the cells were growing, the team coaxed the cells to become not only neurons, but also fat cells and bone and muscle tissue, for instance. To confirm these were bona fide iPS cells with the ability to differentiate into all different cells types, the researchers performed a stringent test that involved injecting the presumed into mice whose immune systems were suppressed and noted that cells from three germ layers were present in the tumors that formed.

"The hard work of generating and characterizing these iPS cells is a prelude for future studies," Ming says. "Now, we can look at neural cells differentiated from these iPS cells in order to investigate the mechanisms and functions of the DISC1 gene in the nervous system, and understand the role it may play in diseases such as schizophrenia. These future studies may lead to the identification of new molecules that might serve as drug targets."

Explore further: Bioengineering study finds two-cell mouse embryos already talking about their future

More information: Molecular Psychiatry: www.nature.com/mp/index.html

Provided by Johns Hopkins Medical Institutions

not rated yet

Related Stories

Researchers piggyback to safer reprogrammed stem cells

Feb 27, 2009

Austin Smith and his research team at the Centre for Stem Cell Research in Cambridge have just published in the journal Development a new and safer way of generating pluripotent stem cells - the stem cells that can give r ...

Recommended for you

New button mushroom varieties need better protection

3 hours ago

A working group has recently been formed to work on a better protection of button mushroom varieties. It's activities are firstly directed to generate consensus among the spawn/breeding companies to consider ...

Cataloguing 10 million human gut microbial genes

Nov 25, 2014

Over the past several years, research on bacteria in the digestive tract (gut microbiome) has confirmed the major role they play in our health. An international consortium, in which INRA participates, has developed the most ...

New device could make large biological circuits practical

Nov 24, 2014

Researchers have made great progress in recent years in the design and creation of biological circuits—systems that, like electronic circuits, can take a number of different inputs and deliver a particular ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.