On 6 November 1998, the world woke to news of an astonishing discovery. James Thomson and his colleagues at the University of Wisconsin-Madison had generated stem cells from human embryos. Unlike other types of stem cells, these were ‘pluripotent’ – meaning they had the potential to generate any type of body tissue if given the right signals.
For many this news, and the accompanying claims that embryonic stem (ES) cells could revolutionise medicine, appeared to come out of the blue. However, for those of us already working in the stem cell space it was the vital next step in exploring the potential of stem cell science.
Back in 1998, I was a keen PhD student, part of the stem cell research effort at Monash University. I was trying to create pluripotent stem cells from the skin cells of a mouse. The idea was to first clone a mouse embryo from its skin cell and harvest the ES cells. In the lab next door, Ben Reubinoff had been working with Alan Trounson and Martin Pera for several years to see if they could make embryonic stem cells from donated human embryos – effectively in parallel to their colleagues in Wisconsin.
There was a lot of excitement about how we might one day be able to use these cells to make ‘replacement’ body tissues – effectively ‘on demand’– and alleviate suffering for many patients. Although we all recognised this was going to take an enormous amount of effort – and time – to deliver.
Outside the lab if I mentioned that I worked in stem cell research, I was met with overwhelming curiosity. But people also wondered why we couldn’t just use adult stem cells which are found in some of our organs. Many people I spoke to already knew somebody who had been helped by a stem cell transplant using bone marrow or cord blood. Why did we need to use human embryos and ES cells at all?
The reason was, and still is, that adult stem cells are not able to generate any type of tissue because they are not ‘pluripotent’. Bone marrow stem cells, for instance, can regenerate an immune system but they cannot regenerate the pancreas or brain tissue. The only source of pluripotent cells was surplus human embryos – originally created in an IVF clinic and then donated to research.
In 2007, Japanese scientists made a landmark discovery that side-stepped the need to use embryos. They were able to manipulate ordinary human skin cells to make them pluripotent (a much more elegant and effective approach than my attempts with mice skin cells during my PhD). Dubbed induced pluripotent stem cells or iPSC, these cells share the same desirable features as ES cells. They can be grown in the lab and coaxed to form specific types of body cells.
But both sources of pluripotent stem cells also carry the risk that they could form a tumour if we don’t fully direct their developmental fate. Any clinical application must meticulously weed out the stem cells as part of the laboratory recipe used to make the replacement cells. For me, the crucial challenge is how to harness the potential of stem cells to develop safe and effective treatments.
These days, as the head of the outreach and policy program for Stem Cells Australia, a nationwide consortium of Australian stem cell scientists, I spend a lot of my time talking to the public. To some extent I’ve become a ‘race caller’ – frequently asked to predict what new treatments are likely to come galloping down the track. Sometimes I’m asked to offer an opinion on stem cell ‘treatments’ that are not on the track at all. Promoted as a sure thing and available now for a price, these interventions lack credible evidence that they work or are even safe. Providers are effectively peddling hope and should be viewed with caution.
Fortunately, we do have providers committed to responsibly advancing the field with lots of bona fide contenders in clinical trials. So with my binoculars firmly in place, here is my reading of what’s coming down the track.
Leading the charge towards the clinic is a possible treatment for the most common cause of age-related vision loss: macular degeneration. In Australia about one in seven people over the age of 50 have some evidence of this disease. In this condition, damage to the cells at the back of the eye – the macula – affects central vision and the ability to read, drive and recognise faces. The actual ‘seeing’ cells in the macula are intact but sight is lost because a tiny underlying patch of darkly pigmented cells are damaged. Known as retinal pigmented epithelial cells or RPE cells, they act like a pit stop team, feeding and clearing away waste for the highly active cells of the retina.
Because the number of RPE cells needed is very small and pluripotent stem cells readily develop into this exact tissue (you can easily spot a patch of darkly pigmented cells in the dish), macular degeneration has long been a favourite. Clinical trials are now underway in the United States, United Kingdom and Japan to determine whether replacing faulty RPE cells with those made in the lab from either human embryonic stem cells or induced pluripotent stem cells could help.
At this early stage, safety is a key concern. The surgical technique to deliver the cells carries the risk of detaching the retina and causing further vision loss. In May 2018, the London Project to Cure Blindness announced that two patients with macular degeneration – specifically what’s called the ‘wet’ form due to extensive blood vessel growth under the retina – had improved their vision with no significant side-effects after participating in a clinical trial.
Another early entrant in the race to the clinic is type 1 diabetes. It’s a disease caused by friendly fire: the immune system seeks and destroys the beta cells of the pancreas. These remarkable cells can both sense rising blood sugar levels and release the exact amount of insulin needed to lower glucose levels to normal. When these cells are destroyed, which often occurs in childhood, the person is no longer able to control their blood sugar levels.
More than 120,000 Australians manage the disease with regular injections of insulin. But they can’t regulate their blood sugar levels as precisely as beta cells do. And there are consequences: high blood sugar levels can damage the blood vessels in the heart, eyes and kidneys, while low levels can be fatal. Some patients have been lucky enough to receive a whole pancreas transplant or tissues containing beta cells from cadavers. But there are two problems. First, transplant donors are in short supply. Second, the donated tissue will likely suffer the fate of the original: attack by the immune system.
Enter pluripotent stem cells. Supply is no longer a problem. After two decades of trying, scientists are now able to make large quantities of fully functional beta cells in the lab. And as far as keeping the immune system at bay, several start-up companies have come up with the ‘tea-bag’ approach. They encase the beta cells in a porous capsule. Like tea leaves, the beta cells are netted in but soluble factors easily move in and out across the net, including insulin and blood-borne glucose as well as other nutrients. Crucially, the net also stops marauding immune cells from getting to the beta cells.
Courtesy: Cosmos, The Science of Everything.