It won’t be that simple of course. There are a whole range of technological hurdles to overcome, not least the fact that one of the four Yamanaka factors, c-Myc, is known to promote cancer. But in the few years since that key publication in Cell, substantial progress has been made in improving the technology so that it is moving ever closer to the clinic. It’s possible to make human iPS cells pretty much as easily as mouse ones and you don’t always need to use c-Myc[13]. There are ways of creating the cells that take away some of the other worrying safety problems as well. For example, the first methods for creating iPS cells used animal products in the cell culture stages. This is always a worry, because of fears about transmitting weird animal diseases into the human population. But researchers have now found synthetic replacements for these animal products[14]. The whole field of iPS production is getting better all the time. But we’re not over the line yet.
One of the problems commercially is that we don’t yet know what the regulatory authorities will demand by way of safety and supporting data before they let iPS cells be used in humans. Currently, licensing iPS cells for therapeutic use would involve two different areas of medical regulation. This is because we would be giving a patient cells (cell therapy) which had been genetically modified (gene therapy). Regulators are wary particularly because so many of the gene therapy trials that were launched with such enthusiasm in the 1980s and 1990s either had little benefit for the patient or sometimes even terrible and unforeseen consequences, including induction of lethal cancers[15]. The number of potentially costly regulatory hurdles iPS cells will have to get over before they can be given to patients is huge. We might think no investor would put any money into something so potentially risky. Yet invest they do, and that’s because if researchers can get this technology right the return on the investment could be huge.
Here’s just one calculation. At a conservative estimate, it costs about $500 per month in the United States to supply insulin and blood sugar monitoring equipment for a diabetic. That’s $6,000 a year, so if a patient lives with diabetes for 40 years that’s $240,000 over their lifetime. Then add in the costs of all the treatments that even well-managed diabetic patients will need for the complications they are likely to suffer because of their illness. It’s fairly easy to see how each patient’s diabetes-related lifetime healthcare costs could be at least a million dollars. And there are at least a million type 1 diabetics in the US alone. This means that at the very least, the US economy spends over a billion dollars every four years, just in treating type 1 diabetes. So even if iPS cells cost a lot to get into the clinic, they have the potential to make an enormous return on investment if they work out cheaper than the lifetime cost of current therapies.
That’s just for diabetes. There are a whole host of other diseases for which iPS cells could provide an answer. Just a few examples include patients with blood clotting disorders, such as haemophilias; Parkinson’s disease; osteo-arthritis and blindness caused by macular degeneration. As science and technology get better at creating artificial structures that can be implanted into our bodies, iPS cells will be used for replacing damaged blood vessels in heart disease, and regenerating tissues destroyed by cancer or its treatment.
The US Department of Defense is providing funding into iPS cells. The military always needs plenty of blood in any combat situation so that it can treat wounded personnel. Red blood cells aren’t like most cells in our bodies. They have no nucleus, which means they can’t divide to form new cells. This makes red blood cells a relatively safe type of iPS cell to start using clinically, as they won’t stay in the body for more than a few weeks. We also don’t reject these cells in the same way that we would a donor kidney, for example, because there are differences in the ways our immune systems recognise these cells. Different people can have compatible red blood cells – it’s the famous ABO blood type system, plus some added complications. It’s been calculated that we could take just 40 donors of specific blood types, and create a bank of iPS cells from those people that would supply all our needs[16]. Because iPS cells can keep on dividing to create more iPS cells when grown under the right conditions, we could create a never-ending bank of cells. There are well-established methods for taking immature blood stem cells and growing them under specific stimuli so that they will differentiate to form (ultimately) red blood cells. Essentially, it should be possible to create a huge bank of different types of red blood cells, so that we can always have matching blood for patients, be these from the battlefield or a traffic accident.
The generation of iPS cells has been one of those rare events in biology that have not just changed a field, but have almost reinvented it. Shinya Yamanaka is considered by most to be a dead cert to share a Nobel Prize with John Gurdon in the near future, and it would be difficult to over-estimate the technological impact of the work. But even though the achievement is extraordinary, nature already does so much more, so much faster.
When a sperm and an egg fuse, the two nuclei are reprogrammed by the cytoplasm of the egg. The sperm nucleus, in particular, very quickly loses most of the molecular memory of what it was and becomes an almost blank canvas. It’s this reprogramming phenomenon that was exploited by John Gurdon, and by Ian Wilmut and Keith Campbell, when they inserted adult nuclei into the cytoplasm of eggs and created new clones.
When an egg and sperm fuse, the reprogramming process is incredibly efficient and is all over within 36 hours. When Shinya Yamanaka first created iPS cells only a miniscule number, a fraction far less than 1 per cent of the cells in the best experiment, were reprogrammed. It literally took weeks for the first reprogrammed iPS cells to grow. A lot of progress has been made in improving the percentage efficiency and speed of reprogramming adult cells into iPS cells, but it still doesn’t come within spitting range of what happens during normal fertilisation. Why not?
The answer is epigenetics. Differentiated cells are epigenetically modified in specific ways, at a molecular level. This is why skin fibroblasts will normally always remain as skin fibroblasts and not turn into cardiomyocytes, for example. When differentiated cells are reprogrammed to become pluripotent cells – whether by somatic cell nuclear transfer or by the use of the four Yamanaka factors – the differentiation-specific epigenetic signature must be removed so that the nucleus becomes more like that of a newly fertilised zygote.
The cytoplasm of an egg is incredibly efficient at reversing the epigenetic memory on our genes, acting as a giant molecular eraser. This is what it does very rapidly when the egg and sperm nuclei fuse to form a zygote. Artificial reprogramming to create iPS cells is more like watching a six-year-old doing their homework – they are forever rubbing out the wrong bit whilst leaving in the mis-spelt words, and then tearing a hole in the page because they rub too vigorously. Although we are starting to get a handle on some of the processes involved, we are a long way from recreating in the lab what happens naturally.
Until now we have been talking about epigenetics at the phenomenon scale. The time has come to move into the molecules that underlie all the remarkable events we’ve talked about so far, and many more besides.