Friday, 17 December 2010

Stem cell therapies, visual disorders and dangerous clinical practice

Yesterday I blogged about the story of Izabelle Evans, a girl who received a stem cell transplant to treat septo-optic dysplasia. Following comments on that piece by Prof. Stephen Moss, Prof. David Colquhoun and Suirauqa, I've done a little more digging around the use of stem cells for treating visual and other disorders - here I try to separate the maverick from the marvellous.
As I've mentioned before on this blog, my research centres around inherited visual disorders - I'm interested in the mechanisms that lead from genetic mutations to disease, and in developing gene therapy treatments. I am fortunate enough to work in one of the very best research groups in one of the very best institutions in vision research in the world - fortunate because I can see first hand (if not always produce myself!) scientific research of the highest order.

Much of that research hints at the enormous potential that stem cells hold for the treatment for an assortment of disorders - not least those affecting the nervous system - by replacing cells lost due to disease.

Genuine stem cells originate from the inner cell mass of the early blastocyst-stage embryo - that is to say, they are the small group of cells which can give rise to all the different cell types of the body, from stomach and lung cells (derived from the endoderm), to muscle, skin and blood cells (which derive from the mesoderm) and neurones in the brain and eye (originating in the ectoderm). For a more detailed description of stem cells and their properties, I'd recommend the National Institutes of Health resource for stem cell research, brought to you by the folks behind the scientific publications gateway PubMed.

Aside from these 'true' stem cells, many adult tissues contain cells that are partly developed into 'progenitor cells;' these are often referred to as adult stem cells, and can give rise to most if not all cell types of that particular tissue.

A key development in the last few years has been the creation of induced pluripotent stem (iPS) cells - adult cells, usually take from skin, that are reprogrammed in a dish to behave like actual embryonic stem cells that can give rise to any cells type in the body, even whole organisms in the case of mice.

Stem cells display key behaviours that make them of real interest as potential treatments; they can divide indefinitely (at least on paper), giving a potentially endless source of cells from very few original cells; depending on the environment they are placed in, they can differentiate into any cell type you require; and because they mature in the same way as normal human tissue, when transplanted the differentiated mature cells that arise from can form connections with host tissue and restore function to a diseased tissue. At least, this is what the latest peer-reviewed, scientific literature intimates.

So picture a disease such as Parkinson's, where dopamine-secreting cells in the brain's subsantia nigra degenerate; or muscular dystrophy; or any of the myriad inherited retinal degenerations, where mutations in hundreds of different genes lead to the death of the light-sensitive cells of the retina. These are all diseases where cells die for various reasons, and potentially could be replaced either by stem cell transplantation - in the hope that the undifferentiated cells mature by virtue of finding themselves surrounded by mature brain/muscle/eye cells - or by coaxing stem cells to develop into the mature cells in a dish and transplanting those. And my list of diseases is hardly comprehensive - common conditions such as stroke, heart disease and diabetes could all benefit from stem cell-derived technology.

Little wonder then that there is a great drive towards developing stem cell-based therapies. And real progress is being made, at what is a remarkable rate in terms of medical research. Just taking my own field of eye research as an example, it is now possible to take fibroblasts (a general-purpose cell type) from the skin of a mouse, reprogramme it into an iPS cell in a dish by expressing a few key genes, add in a cocktail of factors known to encourage development into many of the cell types found in the eye (see this excellent review from a current and a former colleague for details), and isolate cells from the resultant mix that look remarkably like mature photoreceptors. On the other hand, progenitor cells from a newborn mouse retina can be transplanted into a degenerating recipient retina and restore - to some extent - sensitivity to light - it's nothing like a complete cure as yet, but proof-of-concept studies show that cleverly manipulating both the donor cell and the recipient retina can allow thousands of these stem cells to integrate and form connections with host cells. Combining the two techniques - generating induced pluripotent stem cells and developing them in a dish to resemble adult retinal stem cells for effective transplantation - remains the elusive goal.

Thousands of such studies show that stem cells of all flavours have great potential as treatment - but they also show how difficult they are to work with, how little we understand of how they work, and the dangers they represent.

Which is why careful, rigorous, scientifically robust studies are needed before stem cells are widely applied to patients in the clinic. There are hundreds of official clinical trials using stem cells underway, for many diseases - partly the number is inflated due to a loose definition of stem cells - and these vital studies will provide answers to many important questions over safety and efficacy. Without systematic trials of this nature we really can't say with any confidence that stem cell therapy is safe for humans, let alone effective.

This is what makes the behaviour of certain clinics and doctors, seemingly more so in China than anywhere else, disturbing. As I wrote about yesterday, a Chinese clinic is offering spinal injections of stem cells from the umbilical cord as a treatment for a host of diseases. Commenting on that piece, Prof. Moss said he found nothing on PubMed suggesting the clinic has a publication track record to speak of. Looking for more details, I found this website which is an astonishing mixture of anecdote, patient testimonials and extraordinary claims - and not one mention of a properly conducted, peer-reviewed and published study.

To quote the great Carl Sagan, "extraordinary claims require extraordinary evidence" - and I see lots of the former and virtually none of the latter.

The blogger Suirauqa (whose own latest blog post links to another scientific study  linked to a story on NPR which cast a somewhat skeptical eye on the claims of efficacy for Chinese stem cell treatment in the case of Laylah Teague. The story is still on the credulous side for my liking, but at least discusses the possibility that any treatment effect may be placebo-driven (patients tend to receive massages and other 'alternative' or palliative care alongside their stem cells), and/or short-lived - as well as the spectre of dangerous side-effects.

I despair at this sort of thing - along with the enormous potential as therapies, stem cells carry with them unknown dangers which could easily be fatal. Medicine is not perfect and even the safest looking treatments can turn out to be fatal - let's hope that the irresponsible, cavalier by-passing of the scientific method and lack of respect for due process on display at these clinics doesn't harm the patients desperate enough to pay massive sums demanded.


Stephen Moss said...

More very useful insight. The point about the placebo effect is a good one. One tends to think of placebo effects in the context of conventional pharmacological therapies, but in cell-based therapies the placebo effect may be enhanced by genuine physiological responses. For example, it was shown years ago (by colleagues at the Institute of Ophthlamology and elsewhere) that subretinal grafting of retinal pigment epithelial (RPE) cells can slow photoreceptor degeneration (and blindness) in the RCS rat.

The assumption was always that the grafted healthy cells replaced the diseased RPE cells. However, it was then shown that the same protective effect could be achieved using almost any cell type, and even just the sham surgical procedure elicited a favourable response (albeit shorter-lived).

What all this means is that, as is pointed out in this great blog, any 'desirable' effects of the stem cell treatment may have had nothing to do with the type of cells used, and that just the surgery might have been quite effective on its own.

SUIRAUQA said...

Agree with Prof. Moss; very well-written post describing the promises and perils of stem cell therapies. In addition to what you have already mentioned, another point needs to be emphasized, I think:

Adult stem cell (iPS cells), which are differentiated adult cells artificially endowed with pluripotency in vitro, are fraught with their own unique issues. First, the retrovirus-mediated insertion of four transcription factors required for the iPS generation always poses the risk of cancerous mutations. Secondly, the iPS cells grow at a reduced rate compared to embryonic stem cells, and are more prone to early senescence. Here is a link to an old news report on this issue; particularly, read Prof Segal's comment - quite illuminating.