Nuclear reprogramming opened new avenues for pursuing a range of aspects of embryonic and adult stem cell research, understanding inscrutable diseases, and exploring personalized cell-replacement therapies.
Beginning in the mid-1950s, Dr. Gurdon showed that most of the body’s cell types retain all of their genetic information as they specialize and that the right conditions can wake up genes that turn idle during development. Dr. Gurdon’s discoveries in frog eggs ignited the entire field of nuclear reprogramming whereby specialized adult cells turn into stem cells that can then differentiate to form many of the body’s tissues. This line of inquiry with mammalian eggs allowed other work to unfold, including the creation by Scottish scientists of Dolly the sheep in 1997 as the first clone made from the nucleus of a fully specialized mammalian adult cell.
With Dr. Gurdon’s findings in mind but without the need for eggs, Dr. Yamanaka, who is also a senior investigator at the Gladstone Institute of Cardiovascular Disease, reported in 2006 the reprogramming of fully differentiated mouse skin cells into stem cells that can specialize into many fetal and adult types of cells. Subsequent research based on the findings of Drs. Gurdon and Yamanaka has the potential to make reprogrammed cells a source of patient-specific cells for use in medicine that will enable the body to regenerate, repair, replace, and restore diseased or damaged cells, tissues, and organs.
Professor Sir Ian Wilmut, director of the Centre for Regenerative Medicine at the University of Edinburgh and editor of Cloning and Stem Cells, views the induced pluripotent stem (iPS) cell approach as one of the breakthroughs of this decade and that succeeding generations of scientists may judge iPS as a breakthrough of the new century.
“They are comparatively easy to obtain and combine the main advantages of embryonic stem cells and cells from adults,” he explained. “They can form any tissue and multiply many times in culture, but you also know their genotype. Knowing the genotype may be useful in the longer term, because the iPS cells will be an immunological match to the person from whom they were derived.”
The iPS advantage has already been important for a different application, continued Professor Wilmut. “You can use cells from a person who has an inherited disease to study that disease. There are hundreds of different inherited diseases. Projects using iPS cells are already being developed to study diseases as varied as motor neuron disease, some psychiatric diseases, and cancer.”
Graham Parker, Ph.D., assistant professor (research), department of pediatrics, Wayne State University School of Medicine and editor of Stem Cells and Development, calls nuclear reprogramming technology a “very exciting development. Some might say it’s unbelievable that the introduction of just a few genes can turn a somatic cell pluripotent.”
Dr. Parker, however, also raises a cautionary flag. “The problems and issues that have limited progress of embryonic stem cell research will still apply to induced pluripotent stem cells. We are fantastically ignorant of how the programming to pluripotency occurs,” he noted. “The efficiency levels are so low as to defy a clear understanding of which genes/proteins at what concentration are truly required. At the moment we are definitely dealing with a phenomenon that we see works and produces something useful, but the details are still squarely in a black box.”
Linda Powers, cofounder and managing director of Toucan Capital, which has 16 stem cell or regenerative medicine companies in its portfolio, thinks the introduction of the nuclear reprogramming technique is quite important for at least two reasons.
“First, iPS has rapidly moved the whole regen medicine field away from embryonic stem cells. This change of focus will extricate the stem cell field from the ethics issues and controversies, which continue to be a restraining factor, even under the new Obama Administration,” she emphasized.
“Second, iPS is turning the whole field’s focus to autologous (personalized) products and treatments. In recent years, the strong prevailing dogma about clinical applications and commercialization in the regen med field has been that products must be allogeneic (nonpersonalized) in order to be commercially and medically practical. We, at Toucan, believe that there are some uses for which allogeneic cells are appropriate: principally, situations such as acute MI, where there is no time for an autologous product (at least initially), and situations in which the cells are only being asked to perform limited functions such as trophic support or suppression of inflammation.
“However,” she continued, “we believe strongly that for clinical applications where there is time, and where the cells are being asked to perform actual repair functions, that autologous products and treatments are greatly preferable. In essence, we believe the business model should be made to fit the biology, rather than trying to force the biology to fit a convenient business model. So, we think it is quite important that iPS technology is now turning everyone’s thinking toward autologous products and treatments.”