I was a wide-eyed science student when I witnessed a prime-time TV debate between two scientists; the Oxford-styled atheist (not the famous one) vs. the Catholic. They had been my professors and were well-known in the small world of science. Years later, I was thrilled by having one of them refereeing my PhD dissertation.
It was the beginning of the 21st century. Back then people was still shocked by a cloned sheep named Dolly. The debate was about embryonic stem cells (ESCs) and it was hopeless; they could have as well been arguing whether there was a God. Production of ESCs lines required the destruction of human embryos. In the US, president Bush had banned federal agencies from providing funds to groups developing new ESCs lines (ban lifted by president Obama in 2009). Bush administration’s argument was that there were enough embryonic stem cell lines already (around 60) and further destruction of embryos was unnecessary. Should other countries follow suit? Stakes were high: ESCs could become any cell in the body making them an ideal tool not only for research but also for regenerative medicine and cell-based therapies*. That date back in the early 2000s, pro-life and supporting-research-at-all-costs positions remained irreconcilable. No-one could have predicted that in less than a decade a Nobel Prize would be rewarding a discovery that made that debate partially obsolete.The 2012 Nobel Prize in Medicine or Physiology was awarded to Britain’s Sir John Gurdon and Japan’s Shinya Yamanaka.
Gurdon’s seminal work was carried out during the ’60s and ultimately led to the cloning of Dolly the sheep in 1997 by Campbell and Wilmut. Gurdon proved a fundamental principle in biology: Every cell with a nucleus contains the genetic information required to generate the complete organism from which it came from. Furthermore, he showed that there were “factors” in the egg capable of rejuvenating the nucleus of an old cell into the nucleus of an embryonic cell with the potential for developing a complete new organism. Hidden within the egg there was the secret of eternal cellular youth, the philosopher’s stone.
But Gurdon’s “cloning” method was extraordinarily cumbersome and inefficient. The nuclei of both an adult cell and an egg had to be removed and then the nucleus of the adult cell had to be inserted into the enucleated egg. It was like injecting a tennis ball into a football full of custard using a wide pipe as needle without the football exploding or leaking too much. If the nuclear transplant was successful the resulting cell had to develop into an embryo, instead of dying or doing nothing; that embryo could be used to generate stem cells or it could be transferred into a surrogate mother, as it was the case with Dolly the sheep. When trying to generate complete organisms -like Dolly- the most common outcome was natural abortion. Technical difficulties aside -cloning of human cells by nuclear transfer was only achieved in 2013**- the distant possibility of cloning people and using their clones as a source of spare organs generated much anxiety. Even without fully grown up clones the requirement for generating and destroying embryos is ethically unacceptable for many.
To solve this technical and ethical deadlock, Yamanaka decided to chase the elusive factor(s) that could reprogram an adult cell into an embryonic-like cell capable of becoming any other cell type. In 2006 Yamanaka and his assistant Kazutoshi Takahashi were able to transform adult cells into embryonic-like stem cells (now known as induced-pluripotent stem cells or iPSCs). They used genetic engineering to introduce combinations of tens of genes into adult cells studying which of these became stem cell-like. Finally they isolated 4 genes that together were sufficient to rejuvenate adult cells. They had found the philosopher’s stone of cellular biology: the genes Oct4, Sox2, KLF4, and c-Myc. Yamanaka’s reprogramming was so successful that iPSCs not only looked like ESCs, behaved like ESCs and differentiated to other cell types like ESCs but were capable of generating full grown up mice.iPSCs are so practical that their creation and use have spread like wild fire after their invention in 2006. iPSCs provide a plentiful supply of embryonic-like stem cell lines without cumbersome and inefficient nuclear transfers and without the need of destroying embryos. They can be generated even from skin cells, making it easy to produce patient-specific cells to study patient-specific diseases.
Regarding their use in regenerative medicine, these are early days for iPSCs; there are still safety concerns because of the possible long term effects of the genetic manipulations required to produce them. However, as you read new technologies are being developed to make iPSCs safer, avoiding genetic manipulation altogether, and clinical trials to correct macular degeneration using iPSCs are about to start in Japan, their native land.
* It is worthy pointing out that many of the so called “stem cell therapies” advertised these days do not use ESCs, but adult mesenchymal stem cells (MSCs). These therapies have severe limitations since MSCs are far down the line of ESCs and they can’t become any type of cell.
** in May 2013 Mitalipov’s group at Oregon University reported that they had been able to clone human cells generating embryos from which they derived new stem cell lines. However, there are flaws in Mitalipov’s report generating scepticism -in 2004 a group in Korea announced similar results that were later discredited as false in a high profile scientific case. Other labs still have to reproduce Mitalipov’s experiments but it seems likely that they have finally developed a technique to clone human cells by nuclear transfer (7 years too late).