Ethical Stem Cells Provide Model for Progress in Down Syndrome Research

Researchers using ethically uncontroversial induced pluripotent stem cells (iPSCs) have achieved what appears to be a major breakthrough in understanding the origin and development of Down syndrome, according to a new study recently published in Nature Communications.

Working at the University of California, Davis, the researchers created a new cellular model for studying Down syndrome by taking skin cells from patients with Down syndrome and inducing them into a pluripotent state.  They then coaxed these induced pluripotent stem cells, which are genetically identical to the patients’ cells, to develop into two separate groups of nerve cells: neurons and what are called astroglial cells.

Astroglial cells are a type of “helper” cell in that they assist in the development of neurons.  The researchers found that the astroglial cells derived from the patients with Down syndrome produced a certain protein in amounts larger than normal.  This increase in the amount of protein produced by the astroglial cells in turn had a negative effect on the development of neurons, causing them to die outright or to develop abnormally.

To further test this finding, the researchers then injected one group of mice with the iPSC-derived astroglial cells and another group with the iPSC-derived neurons.  Those mice injected with the astroglial cells displayed markers for Down syndrome, while those injected with the neurons did not.

This led the researchers to conclude that the abnormal functioning of the astroglial cells plays a key role in the occurrence of Down syndrome.  According to lead researcher Wenbin Deng, “[A]lthough neurons are regarded as our ‘thinking cells,’ the astroglia have an extremely important supportive role.  Astroglial function is increasingly recognized as a critical factor in neuronal dysfunction in the brain, and this is the first study to show its importance in Down syndrome.”

The researchers further treated the iPSC-derived astroglial cells with a common antibiotic that is routinely used to treat infections, arthritis and acne.  These treated cells began to show corrections in their abnormalities, allowing them to interact more normally with the neuron cells.

While cautioning that more research is needed, Deng noted the prospects of future treatments. “[I]t is exciting to consider that pharmacological intervention in these cellular processes might help slow or even prevent disease progression.”

Disease modeling and iPSCs

In addition to the importance of this research for understanding and possibly treating Down syndrome, the method by which it was conducted shows how important ethically non-contentious iPSCs are in advancing medical research.

“The advent of induced pluripotent stem cell technology has created exciting new approaches to model neurodevelopmental and neurodegenerative diseases for the study of pathogenesis and for drug screening,” said Prof. David Pleasure a co-author of the study. “Using this technology, the study is the first to discover the critical role of astroglial cells in Down syndrome as well as identify a promising pathway for exploring how a drug such as minocycline may offer an effective way to help treat it.”

Traditionally, this type of research would be conducted in animal models, most often mice. Here researchers were able to work with a human cellular model genetically identical to that of the patients.

Noting that animal models are not adequate as the human brain is more complicated, Deng characterized the iPSC-derived model as “more realistic than traditional animal models because it is derived from a patient’s own cells.”

Prior to the advent of iPSCs in 2007 the only method researchers may have had to produce a genetically matched stem cell line from a patient’s own cells was Somatic Cell Nuclear Transfer (SCNT), i.e., cloning.  “May have had” because it was only in 2013 that researchers finally succeeded in creating a cloned human embryo that was then destroyed to produce a stem cell line.  In 2014, two more teams succeeded in doing this.  One of those teams created a cloned embryo from the somatic cells of a diabetic patient; this embryo was then destroyed in order to generate an insulin-producing embryonic stem cell line.

In addition to the ethical problems surrounding it, human cloning presents other concerns as well.  Compared to the process for generating iPSCs, the SCNT process is highly inefficient.  SCNT requires a large number of eggs and produces very few stem cell lines.  The team that generated the insulin-producing embryonic stem cell line, e.g., had a success rate of under six percent, using 71 eggs to produce four stem cell lines from the embryos they created and destroyed.  Moreover, the process of harvesting the eggs can present risks for women, some serious.

In contrast, the process of producing iPSCs has improved since 2007 and continues to do so.  In addition, iPSCs present no ethical issues as eggs are not needed and embryos are not created and destroyed.  The relative efficiency and ease of the iPSC process for producing patient-specific stem cells, compared to the SCNT process, is likely among the reasons that MIT professor Rudolf Jaenish, who supports cloning for research, nonetheless said that the 2013 success in cloning a human embryo “has no clinical relevance.”  John Gearhart, one of the first scientists to isolate, in 1998, human embryonic stem cells, also downplayed the therapeutic value of human cloning, saying “the more we learn about reprogramming, the more I think IPS will be the one of choice.”

Not so long ago, human embryonic stem cell (hESC) research and SCNT were being hailed as the future of regenerative medicine, capable of generating cures and therapies for any number of diseases and conditions.  Adult and other avenues of non-embryonic stem cell research were at best considered somewhat flawed alternatives to the “gold standard” presented by hESCs.

But as this research into the origins and possible treatment of Down syndrome and other developments shows (e.g., here, here, and here), the non-embryonic “alternative” is fast outpacing the much-hyped human embryonic stem cell research in advancing the field of regenerative medicine.

Gene Tarne is a Senior Analyst with the Charlotte Lozier Institute.