The CSIR Department of Biological Sciences’ Gene Expression and Biophysics Group, led by Dr Musa Mhlanga, success- fully generated the first induced pluripotent stem (iPS) cells in Africa, in December last year.
The iPS cell technology involves inducing adult cells (like skin cells) to revert back to stem cells that can differentiate into specialised cell types. This means that the early stem cells can be programmed to become any type of adult cell, such as skin, heart, brain and blood cells.
Dr Janine Scholefield, one of the key researchers involved in generating iPS cells at the CSIR, was the first biologist in South Africa to record video footage of cardiomyocytes, or heart muscle cells, generated from adult skin cells.
Scholefield was recently recruited to join Mhlanga’s lab as a postdoctoral fellow, and started with the experimental protocol at the end of October. By early December, the team had generated iPS cell lines, each line indicating a single genetic background. “It was remarkable and completely took my breath away,” says Scholefield, describing the moment she saw evidence of the first cardiomyocytes.
She had been searching for other stem cells, which have a very distinct flat disc- like structure. The cell colony she found, however, was folded up and three-dimen- sional – and then it started beating. “It was apparent as soon as I saw it. You know you’ve done it right when you can see the beating,” she says, explaining that rhythmically beating cells is one of the characteristics of making a heart cell lineage.
Still, Scholefield was incredulous, and called in lab partners to verify what she was seeing. The team was able to keep the iPS cells going for two to three weeks – which she says is a significant amount of time – before the surrounding cells started dying.
The CSIR’s breakthrough is especially significant because it provides an alternative to the ever-controversial issue of embryonic stem cell derivation, the process whereby stem cells – cells present at the earliest stage of life – are generated using discarded in vitro fertilisation (IVF) fertilised eggs.
“We have to be aware, as scientists, that there are a number of people who are uncomfortable with that kind of work,” says Scholefield. “This technology, however, circumvents these issues altogether.”
The argument with embryonic stem cell derivation is whether or not IVF embryos constitute human life. However, iPS cell technology uses adult skin cells and not embryonic cells to create stem cells. “This bypasses the ethical conundrum and creates an advantage out of traditional stem cell technology,” she says, adding that most people are not likely to take offence with the 2 mm × 2 mm-wide skin sample used in the new process.
Another significant advantage of the new technology is that the iPS cells generated will have the exact genetics of the individual who provides the sample. This opens up new medical possibilities for biomedical stem cell technology, including the ability to grow new tissue, which, in application, can restore sight by replacing defective tissue in the eye or restore the heart by transplanting new heart muscle cells into people with heart disease.
Similarly, people with anaemia can be given healthy new blood cells and harnessing new brain cells can treat those with Parkinson’s disease. “It’s theoretical at the moment,” says Scholefield, “but not improbable, and that’s what makes the research so exciting.”
Scientists will also be able to generate what they call ‘disease in a dish’ models, which is the process of growing stem cells from sick patients into diseased tissue. “The power of this is really remarkable,” says Scholefield. “Now we can compare healthy heart cells with unhealthy heart cells in a Petri dish, without invasive surgery, because the cells contain the exact genetics of the person they came from.”
This is especially important to the CSIR’s Gene Expression and Biophysics lab, which is working towards applying this knowledge in an African context.
“Cutting-edge medical research is not useful to Africans if knowledge is being created and applied only in the developed world,” says Mhlanga. “Given the high disease burden on Africa, our aim is to become creators of knowledge, as well as innovators and expert practitioners of the newest and best technologies.”
His laboratory is particularly interested in host-pathogen interaction – how a pathogen gets into an individual and what makes that individual more, or less, susceptible to a particular disease. The group aims to research diseases prevalent in Africa and is, therefore, interested in South African individuals who have the genetics they want to research.
Scholefield recently submitted a comprehensive ethics report to the CSIR Research Ethics Committee. Once approved, the team will be allowed to sample skin cells from South African individuals to further research the treatment of typically African diseases like HIV, tuberculosis and malaria.
“The Research Ethics Committee has a mandate to look through the research protocol to ensure that the science is sound and that we’re not exploiting people in any way,” she says, adding that the team hopes to have ethical approval within the month so they can start recruiting patient samples.
The Future of Stem Cell Technology
While iPS cells are being used primarily for ‘disease in a dish’ models globally, there is significant interest in using the technology for regenerative medicine and cell replacement therapy. Because the patient and the transplanted cells contain the same genetics, they should bypass any immune rejection normally associated with traditional regen- erative medicine, explains Scholefield.
“There are already a number of these models in rats and mice with heart, brain and blood disorders like sickle cell anaemia,” she adds. “Scientists have been able to take skin cells, restore the genetic mutation, make bloods cells and put them back into the mouse.”
However, while there are a number of experts interested in that particular body of work, the likelihood that they will start clinical trials in the short term is slim. “It’s a long-term goal and there are a number of hurdles that have to be overcome,” says Scholefield, explaining that stem cells are essentially artificial, as the process of making them involves scientists modifying the cells.
“They wouldn’t occur naturally in the body, so we have to coax them into becoming stem cells. By doing this artificially, many doctors are not comfortable putting them back into a patient.” Scholefield does predict, however, that some clinical trials will be undertaken in the next 10 to 15 years.
Creating iPS cells requires a combination of technical skills and proficiency across many biological and molecular disciplines, and while many researchers are skilled in those techniques, finding one person who has acquired all the required skills takes time. Scholefield is one such person, having spent three years at Oxford University on a prestigious Oxford Nuffield Medical Fellowship, working with international experts to perfect the technique of creating iPS cells.
“It is a farely rare skill,” she admits, “but because the technology is so new, it’s a good thing that South Africa is not far behind. Having had no stem cell experience, we [at the CSIR] are so pleased that we could transfer the technology here so quickly. Essentially, it means we know what we’re doing.”
The cost of iPS cell generation is also significant – about R10 000 to generate one cell line. Nevertheless, Scholefield stresses that the tool created from this technology is worth every cent and that the cost will eventually decrease.
“Once you’ve generated one line, it grows indefinitely, which is another incredible advantage about stem cells,” she says, adding that, while skin cells will only last for a few divisions, once you divide them into stem cells those will continue to subdivide. “So you will have made an almost infinite amount of stem cells and you won’t have to go back and do it again.”
An Important Milestone
Doctors Kazutoshi Takahashi and Shinya Yamanaka, of Kyoto University, Japan, were the first to establish iPS cell generation from mice cells, in 2006, and human cells, in 2007. The protocol is now being practised all over the world in elite universities such as Harvard, the University of California, in San Diego, the University of Massachusetts, the University of Wisconsin and Oxford University.
“This is why we were so pleased to establish the protocol in South Africa so quickly,” says Scholefield, adding that, while there is a significant amount of existing data on this technology, this breakthrough by the CSIR is the most recent stem cell work to date.
Emerging Research Areas
The Department of Science and Technology (DST) Emerging Research Area (ERA) initiative and the CSIR have jointly funded the development of the CSIR Synthetic Biology ERA. The Gene Expression & Biophysics Group, headed by Mhlanga, is one of three research groups located within the Synthetic Biology ERA.
The collaboration was initiated in 2007, when the DST identified three emerging research areas, namely nanototechnology, synthetic biology and robotics to create new scientific research and development capabilities with the goal of attaining international recognition within five years.
The DST recruited internationally recognised scientific experts to lead each of the three initiatives, approaching Mhlanga to head up the Synthetic Biology ERA. In June 2008, Mhlanga’s research group relocated from the Institut Pasteur, in Paris, France, where they were pre- viously based.
The DST has since been supporting the Synthetic Biology ERA, contributing R7-million a year to develop South Africa’s capabilities in synthetic biology. Each ERA also receives about R15-million a year from the CSIR, through Parliamentary grants, to steer the advancement of crosscutting research areas.
The CSIR ERAs continue to work closely with the DST, helping to formulate national policies in their individual fields.