Four decades after the first preparation of embryonic stem cells, early hopes for regenerative medicine have failed to convert to real world applications. While rogue clinics try to cash in on unproven treatments, the real cures are still in medical trials and new avenues like the use of animals as intermediate hosts are still being explored. Michael Gross reports.

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The initial success of cultivating embryonic stem cells, published in 1981 for mouse and then in 1998 for human cells, inspired naïve hopes of regenerative medicine. With the right sort of guidance, these cells could be brought to develop into replacement tissues and organs in the patient. However, fundamental problems including the risk of cancer formation and tissue rejection, along with the ethical objections against the use of human embryos for research have slowed down progress.

Instead, stem cell research advanced in different, often unexpected directions. The dogma of the one-way street from embryonic stem cells to fully differentiated somatic cells fell with the cloning of Dolly the sheep in 1996. Somatic cells can be de-differentiated by implantation into an enucleated egg cell, in cloning, or by switching on a specific combination of regulatory genes.

The resulting induced pluripotent stem (iPS) cells are a way of bypassing the ethical concerns, and they can be produced from a patient’s own cells, which provides better immune compatibility. Still, the cancer worries remain — and they were highlighted by the fact that, in the first recipe for generating iPS cells, one of the four factors needed was a known oncogene.

As yet, the interface of stem cell development and carcinogenesis still needs to be elucidated more comprehensively before one can be entirely certain that stem cells implanted into patients aren’t going to become cancerous. This problem hasn’t stopped some rogue clinics from offering miracle cures based on stem cells.

False promises Anybody typing ‘stem cells’ into a search engine will be flooded with offers of therapies for everything from skin ageing and sport injuries to multiple sclerosis and Parkinson’s disease. These offerings often come from dubious clinics, many of which are based in the US and operating on the edge of legality. They use the language of real stem cell research, but they don’t tell you that whatever they are offering is at best an unproven, experimental treatment. Reaching out: Stem cells cultivated in the lab may one day lead to revolutionary treatments in regenerative medicine. The image shows human neural stem cells growing in culture. (Image: Yirui Sun (CC BY 4.0).) Part of the problem is that stem cells can’t be filled into bottles or pressed into pills and offered as a ready-made and thoroughly tested medication for a given ailment. This has already scared the pharmaceutical industry away from the field, as companies find it more difficult to protect their revenue given the complexities of cell therapies. It also means that the US regulatory authority for medicines, the FDA, does not normally get involved with stem cell treatments. If clinics remove cells from a patient and reinject them elsewhere, that doesn’t count as a product requiring FDA approval. Instead, it is seen as akin to a blood transfusion. To the uninitiated consumer, the advertised therapies appear to be fulfilling the promises of miracle cures that were made since the late 20th century. As decades have passed since the first reports of stem cell lines, it would be entirely plausible to expect that cures have by now been developed. In reality though, proven treatments are very few, and only a handful of others are now in clinical trials.

What really works Almost human: Pigs are similar to humans in many ways to the extent that growing human organs in a pig host is a realistic avenue currently under investigation, although many challenges remain. (Image: Kenneth Schipper Vera.) Proven stem cell therapies do exist — the most widely used is haematopoietic stem cell transplantation, more widely known as a bone marrow transplant. Developed in the 1950s to 1970s, this method is now routinely used against life-threatening cancers like multiple myeloma and leukaemia. More recently, its use has been expanded to autoimmune diseases such as multiple sclerosis. In some cases, haematopoietic stem cells for treatments can also be extracted from umbilical cord or peripheral blood. If the cells are not derived from the patient to be treated, the compatibility between cell donor and recipient is a major concern that often limits the use of the technique. A rare example of a new and genuine stem cell treatment already available for a specific group of patients in the EU is Alofisel, a preparation based on adipose-derived stem cells, which under the name of Cx601 were successful in a phase 3 clinical trial (Lancet (2016) 388, 1281–1290). In March 2018, the European Medicines Agency (EMA) approved its use for the treatment of complex perianal fistulas (abnormal narrow tunnels forming between the gut and the skin) in Crohn’s disease that have proven intractable with at least one conventional treatment. Alofisel was developed by the spin-out company TiGenix based in Leuven, Belgium, which has since been bought up by the Japanese pharmaceutics company Takeda. Preliminary clinical tests have been successful for dry age-dependent macular degeneration (AMD), a common cause of blindness in older patients. AMD has been a prime target for stem cell therapies, as the eye is easy to access, well understood, and shielded from the immune system. In 2011, Steven Schwartz at the Jules Stein Eye Institute, Los Angeles, USA, and colleagues reported a preliminary clinical trial that involved the injection of retinal pigment epithelial (RPE) cells differentiated in vitro from human embryonic stem cells. The researchers treated one eye in each of nine patients with AMD and in nine others with Stargardt disease, an inherited juvenile form of macular degeneration. Follow-up observations published in 2015 suggested that the treatment was generally well tolerated and did not lead to any cancer or rejection problems (Lancet (2015) 385, 509–516). The only adverse issues observed were linked to the surgery and the immune repression. Visible regeneration of the retina was observed in 13 of the 18 eyes treated. Vision clearly improved in ten of the eyes treated, deteriorated in one, and stayed the same or improved only slightly in the others. An alternative approach is to incubate the cells in the lab and grow a patch of the epithelium on a biodegradable scaffold, which can then be surgically implanted into the eye. This way, it may be more of a technical challenge to get the cells into the eye, but it also means the surgeon has more control over where the cells are and whether they are still developing to form the tissue that is needed. Two phase 2 clinical trials using the patch approach were launched in 2019. The group of Mark Humayun at the University of Southern California at Los Angeles, USA, uses embryonic stem cells to grow the RPE cells on the patch. Meanwhile, the team of Kapil Bharti at the National Eye Institute at Bethesda, USA, uses induced pluripotent cells derived from CD34+ blood cells obtained from the AMD patients to be treated. This team has recently published the results of the animal experiments on which the clinical trials are based (Sci. Transl. Med. (2019) 11, eaat5580). After the eye, the brain is the next big challenge for the stem cell treatments. The group of Anne Rosser at the University of Cardiff, UK, for instance, works on developing neurons from stem cells to treat Huntington’s disease. Thus far, however, the research is not yet ready to be applied to human patients.