Corporate Banner
Satellite Banner
Stem Cells, Cellular Therapy & Biobanking
>
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Study Gives Insight into Subtle Genomic Differences Among our own Cells

Published: Tuesday, November 20, 2012
Last Updated: Tuesday, November 20, 2012
Bookmark and Share
Study also calms concerns about genetic instability of iPS cells.

Stanford University School of Medicine scientists have demonstrated, in a study conducted jointly with researchers at Yale University, that induced-pluripotent stem cells — the embryonic-stem-cell lookalikes whose discovery a few years ago won this year’s Nobel Prize in medicine — are not as genetically unstable as was thought.

The new study, published online Nov. 18 in Nature, showed that what seemed to be changes in iPS cells’ genetic makeup — presumed to be inflicted either in the course of their generation from adult cells or during their propagation and maintenance in laboratory culture dishes — instead are often accurate reflections of existing but previously undetected genetic variations among the cells comprising our bodies.

That’s good news for researchers hoping to use the cells to study disease or, someday, for regenerative medicine. But it raises the question of whether and to what extent we humans are really walking mosaics whose constituent cells differ genetically from one to the next in possibly significant respects, said Alexander Urban, PhD, assistant professor of psychiatry and behavioral sciences. Urban shared senior authorship of the study with bioinformatics professor Mark Gerstein, PhD, and neurobiology professor Flora Vaccarino, MD, both of Yale.

It’s only a few years ago that human iPS cells started becoming available to researchers. These cells hold great promise because they act almost exactly like embryonic stem cells, which can be nudged to differentiate into virtually any of the body’s roughly 200 different cell types. But iPS cells can be derived easily from a person’s skin, alleviating numerous ethical concerns arising from the necessity of obtaining embryonic stem cells from fertilized eggs.

At least in principle, iPS cells’ genetic makeup closely reflects that of the individual from whom they were derived. Today, “heart cells” derived from a heart patient’s skin can be produced in a laboratory dish so scientists can learn more about that particular patient’s condition and to screen drugs that might treat it. Tomorrow, perhaps, such cells could be administered to that patient to restore heart health without being perceived as foreign tissue by the patient’s immune system, which would otherwise reject the implanted cells.

However, Urban said, several previous studies have raised worries regarding iPS cells’ genomic stability. Whether it was the reprogramming procedure researchers use to convert ordinary adult cells into iPS cells or the culturing techniques employed to keep them alive and thriving afterward, something appeared to be inducing an upswing in these cells’ manifestation of copy number variations, or CNVs — the disappearance or duplication of chunks of genetic material at specific locations along the vast stretches of DNA that coil to form the chromosomes residing in all human cells.

CNVs dot everybody’s genomes. They occur naturally because of DNA-copying errors made during cell replication, and accumulate in our genomes over evolutionary time. The human genome, taken as a whole, is a DNA sequence consisting of four varieties of chemical units, strung together like beads on a roughly 3-billion-bead-long necklace. CNVs range in length from under 1,000 DNA units to several million. They account for up to several percent of the entire human genome, making them a major source of genetic differences between people.

But if either iPS cells’ mode of generation or their subsequent maintenance in culture were promoting an increase in CNVs, it would seriously compromise these cells’ utility in research and pose a fatal flaw to their use in regenerative medicine, said Urban. “You would never want to introduce iPS cells into a patient thinking that these cells had the same genome as the rest of the patient’s cells, when in fact they had undergone substantial genetic modifications you knew nothing about, much less their effects,” said Urban. (Similar concerns apply to embryonic stem cells.)

To see how serious a problem CNVs might pose for iPS cells’ use, the collaborators performed tiny skin biopsies on seven volunteers and extracted cells called fibroblasts, which abound in skin and are amenable to cell culture in general and iPS cell generation in particular. From these, the team produced 20 separate iPS cell lines in culture. Using now-standard lab methods, the investigators determined, chemical unit by chemical unit, the full genomic sequence of the cells composing each new iPS cell line.

Urban and his colleagues, who had likewise assessed the fibroblasts from which the lines were derived, compared their genomic sequences with those of the newly generated iPS cells. The scientists were able to pinpoint numerous CNVs in the new cells that hadn’t shown up in the fibroblasts. This raised the possibility that the rigors of reprogramming or life in a dish, or both, had led to new CNVs in the cells.

But the technique used to determine the full-length genome sequences of iPS cells and the “parental” fibroblasts from which they’d been spawned analyzes not single cells but millions at a time. So a CNV residing in only a minority of cells within this mix could easily be missed, its signal swamped by the noise of the majority report.

Armed with knowledge of the precise locations along the genome where each of the “new” CNVs had popped up in their iPS cell lines, the scientists went back to the fibroblasts. This time, they used an analytical tool that, like a photocopying machine, can generate millions or billions of copies of a single section of DNA — provided that the specific DNA section is present to begin with. For each “new” CNV that had been unearthed in the iPS cells, a different version of this molecular copying machine was employed.

“Lo and behold, in many cases, this technique unearthed CNVs in the fibroblasts that were there all along but had been missed in the earlier, mass analysis,” Urban said. These CNVs had gone undetected because the fibroblasts in which they resided represented as little as a fraction of a percent of the fibroblasts in a biopsy sample. But any CNV in a fibroblast lucky enough to become the “parent” of the billions of iPS cells bearing its identical genomic “face” would now stick out like the proverbial sore thumb. Six out of the 20 different iPS cell lines sported at least one CNV unshared with the other lines, the investigators found. To the extent this reflects differences in parental fibroblasts, it means about 30 percent of the cells in human skin may harbor unique CNVs.

“This is a huge amount of cell-to-cell genetic variation,” said Urban, who also participated in a recent study of human tissues conducted by the laboratory of Michael Snyder, PhD, professor and chair of genetics at Stanford. That study showed there can be distinct CNV patterns in kidney, pancreas and liver. “Rather than monoliths, our bodies may be mosaics composed of cells whose genomes differ. What we do not know is whether or when these differences are dangerous, irrelevant or beneficial.”

That may depend on the organ, said Urban. “The more complicated something is, the more ways there are that something could go wrong with it. The brain is a particularly complicated organ. CNVs affecting cells in particular brain structures or areas could be playing a role in complex neurodevelopmental disorders such as schizophrenia and autism.” Urban intends to find out, he said.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Body May be Able to 'Coach' Transplanted Stem Cells to Differentiate Appropriately
Pluripotent stem cells can develop into a dizzying variety of cell types and tissues, and are a potentially invaluable therapeutic resource.
Thursday, November 22, 2012
Survival of Stage-4 Breast Cancer Patients Improves with Stem Cell Treatment, Study Finds
The study analyze the long-term outcomes of women who received their own stem cells that had undergone purification process.
Tuesday, July 26, 2011
Scientific News
The Mending Tissue - Cellular Instructions for Tissue Repair
NUS-led collaborative study identifies universal mechanism that explains how tissue shape regulates physiological processes such as wound healing and embryo development.
Tissue Bank Pays Dividends for Brain Cancer Research
Checking what’s in the bank – the Brisbane Breast Bank, that is – has paid dividends for UQ cancer researchers.
iPS Cells Discover Drug Target for Muscle Disease
Researchers have designed a model that reprograms fibroblasts to the early stages of their differentiation into intact muscle cells in a step towards a therapeutic for Duchenne muscular dystrophy.
Engineered Hot Fat Implants Reduce Weight Gain
Scientists at UC Berkeley have developed a novel way to engineer the growth and expansion of energy-burning “good” fat, and then found that this fat helped reduce weight gain and lower blood glucose levels in mice.
Transplanted Stem Cells Can Benefit Retinal Disease Sufferers
Tests on animal models show that MSCs secrete growth factors that suppress causes of diabetic retinopathy and macular degeneration.
MRI Scanners Can Steer Therapeutics to Specific Target Sites
Scientists from the University of Sheffield have discovered MRI scanners, normally used to produce images, can steer cell-based, tumour busting therapies to specific target sites in the body.
Team Finds Early Inflammatory Response Paralyzes T Cells
Findings could have enormous implications for immunotherapy, autoimmune disorders, transplants and other aspects of immunity.
Early Detection of Lung Cancer
The University of Manchester has signed a collaboration agreement with Abcodia to perform proteomics studies on a cohort of non-small cell lung cancer cases from the UKCTOCS biobank, with the aim of discovering new blood-based biomarkers for earlier detection of the disease.
Researchers Identify Drug Candidate for Skin, Hair Regeneration
Formerly undiscovered role of protein may lead to the development of new medications that stimulate hair and skin regeneration in trauma or burn victims.
Basis for New Treatment Options for a Fatal Leukemia in Children Revealed
Detailed molecular analyses allow new insights into the function of tumour cells and options for new treatments.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!