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Growing in a bare room full of incubators, microscopes and monitors is one of the great hopes of medicine. Melanie Generali opens the cabinet, which is kept at a temperature of 37 degrees, pulls out a clear culture dish and places it under the microscope. The screen shows cells growing in the wells of the dish, the fine tissue forming a transparent layer and pulsating regularly. What the astonished viewer is seeing is heart muscle cells, still young but already beating, cultivated from a donor’s blood cells. They’re ready for further examination by the institute’s researchers. One day, cells of the same type will replace the heart tissue of heart attack patients.
We are in the stem cell room of the Institute for Regenerative Medicine (IREM) at UZH, high above Wagistrasse in Schlieren, just outside Zurich. This is where Generali and her team operate the iPSC Core Facility, a service center that produces stem cells based on revolutionary technology developed by Japanese researcher Shinya Yamanaka. The 62-year-old physician from Kyoto University was awarded the Nobel Prize in 2012 for the invention of induced pluripotent stem cells. In 2006, by adding four genetic factors, he succeeded in reprogramming skin cells into a primordial state that resembles embryonic cells, what experts refer to as induced pluripotent stem cells, or iPSCs. In further steps, these can be differentiated back into different cell types such as heart muscle or nerve cells. What the Japanese scientist managed to do still fills Simon Hoerstrup, a physician who is professor of regenerative medicine at UZH and director of the IREM, with enthusiasm: “Yamanaka solved two fundamental problems in one fell swoop.” On the one hand, he resolved the ethical dilemma of the origin of embryonic stem cells, which were previously only available at the price of destroyed human embryos. Yamanaka’s induced stem cell method eliminated this issue. It also solved the problem of tissue compatibility. While conventional embryonic stem cells are usually rejected by the patient’s immune system during transplantation, induced stem cells are tailormade for each recipient from their own tissue and are usually tolerated by them.
You might expect that 20 years after the discovery of the procedure and 12 years after the Nobel Prize, induced pluripotent stem cells would be part of everyday clinical practice. But this isn’t the case. While more and more clinical studies focusing on eye, brain and heart diseases are being launched abroad after initial trials, routine clinical applications are still a long way off.
The farthest advanced is a study involving Parkinson’s patients by Jun Takahashi of Kyoto University. The neurosurgeon and director of the Center for iPS Cell Research and Application (CiRA) has transplanted induced nerve cells directly into the brain of the first patients. The cells are intended to replace diseased nerve cells that no longer produce dopamine and are seen as triggering the disease. The results of the study aren’t yet known. When asked about the long development time, Simon Hoerstrup says, “In biology, processes often turn out to be more complicated than initially thought.” Melanie Generali believes that the initial hype may have been exaggerated, but stresses that iPSC cells are still a beacon of hope.
One reason for the delays lies in the four Yamanaka factors, which have turned out to be complex and a mixed blessing. These factors are the genetic blueprints for four regulatory enzymes with the cryptic abbreviations Oct4, Sox2, c-Myc and Klf4. One of their functions is to switch on dormant genes, returning the differentiated cells to a quasi-embryonic state. However, they can also activate dormant cancer genes in the genome or stimulate the cells to divide uncontrollably.
Since Yamanaka’s discovery, methods have therefore been sought to prevent or minimize these undesirable effects. One possibility is to activate the factors only temporarily and outside the cell nucleus instead of integrating them into the genome in the nucleus. This is possible thanks to a carrier virus called Sendai, a method that is also used at the IREM. Another problem lies in the cells’ state of development. Hoerstrup describes it as follows: the induced stem cell of an older patient is not a fountain of youth by or of itself, as despite reprogramming, it retains the patient’s original cell machinery.
Nevertheless, Hoerstrup is convinced that these biological processes can also be brought under control. He says that researchers are gaining a better understanding of the underlying processes and are able to gauge the risks more accurately. “I’m in no doubt that in the future we’ll be able to produce clinically safe induced stem cells.” But the issues raised mean that testing and quality control of the cells has to be a top priority. This applies in particular to their use in clinical trials involving humans. Unlike in countries such as Japan or Germany, these are not an imminent prospect in Switzerland. Another issue is the costs. All steps in the process for producing induced stem cells are still reliant on laborious manual work and therefore give rise to costs that can run into hundreds of thousands of francs per cell sample.
I’m in no doubt that in the future we’ll be able to produce clinically safe induced stem cells.
Researchers at the IREM are working on replacing heart and nerve tissue. Weakened hearts are among the most common chronic conditions. If someone suffers a mild heart attack as the result of a circulatory disorder in the coronary arteries, most of the affected muscle tissue dies. Unlike other tissue such as the liver, this does not regenerate; instead, it becomes scarred. This leads to a permanent restriction of function and in the worst case to death. This is an area where reprogrammed heart muscle cells could come into play in the future, applied to the patient via a catheter, for example. The goal would be for the patient’s own stem cells to replace the tissue around the scar and permanently improve the weak heart. “I’m confident that we’ll be able to carry out the first clinical trials involving humans in the next few years,” says Hoerstrup.
In addition to the work on heart muscle cells, preliminary work with blood vessel cells and heart valve tissue is also under way at the IREM. Another important field relates to the replacement of nerve tissue. Hoerstrup sees great potential for neurodegenerative diseases such as Parkinson’s or dementia. Elsewhere, researchers are also focusing on the replacement of retinal tissue in the eye – the sensory organ that, incidentally, was the first subject of clinical trials in humans: in 2014, Japanese researchers injected induced stem cells into the eyes of an 80-year-old patient suffering from retinal degeneration, saying that this slowed the progression of the condition.
Induced pluripotent stem cells can also be grown into millimeter-sized organoids, which can be used to study disease processes and test new active agents.
Hoerstrup and Generali point out that tissue and organ replacement dominates the public perception of this field of research. What people forget is that induced stem cells also have huge potential in less spectacular areas such as optimizing medical therapies and developing new active agents. Induced stem cells can be used, for example, to individually adapt and optimize the effectiveness of a therapy, for example to treat cancer. The stem cells can also be grown into millimeter-sized organoids, which can be used to study disease processes and test new active agents. “Induced stem cells open up a wide range of applications in the field of personalized medicine,” says Simon Hoerstrup, predicting that this field will gain enormously in importance in the near future.
This article is taken from the UZH Magazin Nr. 2/2024