In most discussions of medicine's future, stem cells are almost synonymous with the once science-fictional idea of replacing the body's lost or diseased organs. Need a new heart? A fresh liver? Unworn joints, unscarred skin, or maybe even a replacement retina? Let stem cells' ability to transmute themselves into more specialized types of tissues come to your rescue.
That's the promise, at least. For now, the reality is less gratifying. Despite some very encouraging early clinical trials, such as ones involving treatments for the retina of the eye, the road to testing and approval for most therapies that involve implanting stem cells is going to be long and hard because of safety concerns (and the sheer difficulty of making the cells do what we want reliably).
Yet stem cells can also do other jobs. An underappreciated part of their impact on medicine will come from their quickly emerging usefulness to the pharmaceutical industry in the discovery and development of new drugs. For the biotech sector, these pharmaceutical revenues might be faster to emerge than those from regenerative medicine.
In a recently released report, the business information publisher Visiongain estimated that global revenues for stem cell technologies would reach $7.4 billion by 2014 and could exceed $100 billion in the 2020s. A large share of the revenues now and into the foreseeable future will involve what are now well-established treatments: transplants of bone marrow, peripheral blood and umbilical cord blood that contain stem cells. In 10 years, however, a third of the revenue could come from drug development-related opportunities.
Improving on animal studies
In May, Prochymal, a stem cell drug manufactured by Osiris Therapeutics, became the first in the world to be granted marketing approval when Canada authorized its use for the treatment of acute graft-vs.-host disease. The administered stem cells may exert their therapeutic effect by secreting factors that support the body's own tissues rather than replacing any cells the body has lost. The drug is also under evaluation as a therapy for Crohn's disease, for protecting the insulin-making cells in people with type 1 diabetes, and for repairing tissue damage from heart attacks and pulmonary disease.
Such a direct use of stem cells as a drug might become the exception rather than the rule for pharmaceutical applications, however. The cells have tremendous potential for improving the current ways of testing the effectiveness and toxicity of potential drug compounds.
Highly promising drugs at late stages of development can be checked out on humans in clinical trials. But economics and ethics make that approach impossible for the early stages of drug development that involve huge numbers of possibly dangerous molecules. For that early screening, compounds need to be tested on other animals or on cultured cells.
But experiments on nonhuman animals and their tissues are notoriously problematic, even if they have historically been the best available option. Animals' physiologies don't always respond to drug compounds exactly as the human body would. Moreover, not all human diseases have good animal analogues.
Meanwhile, cultured human cells pose their own problems. The cell lines available represent only a fraction of the tissues and disease states of interest to drug makers. Cells that can survive in vitro have a variety of abnormalities that distinguish them from body cells, which casts uncertainty on the screening results. And isolated cells in a dish miss can't capture the complexity of how systems of tissues will react in the body.
All those problems contribute to an expensive, ongoing hurdle in pharma research: that companies routinely spend hundreds of millions of dollars on developing possible drugs only to see more than 90 percent of them fail in clinical testing or later.
Stem cell advantages
In principle, stem cells could reduce pharma's woes by providing a consistent supply of normal human cells for basic research, compound screening, and predictive toxicology (that is, the identification of unwanted side effects). Active interest in doing so was low for years, however, because of the practical difficulties. Then two discoveries changed that picture dramatically.
The first was the realization by Shinya Yamanaka of Kyoto University and his colleagues in 2006 that by inserting the right combination of genetic elements into normal adult body cells with viruses, they could reprogram the cells to transform into a more embryonic, stemlike state. These induced pluripotent stem cells (iPSCs) could differentiate into all different tissues types, just as embryonic stem cells can. The ability to create iPSCs on demand from specific patients immediately circumvented many of the ethical, legal, and practical difficulties of obtaining embryonic stem cells. [Update: The day after this story first posted, Yamanaka was awarded the prestigious Millennium Technology Prize.]
The other crucial development was the demonstration by Kevin C. Eggan and others at Harvard University and Columbia University in 2008 that iPSCs developed from the tissues of patients with a genetic neurological disorder (amyotrophic lateral sclerosis, or ALS) could be chemically directed to differentiate into motor neurons. Researchers could therefore create lines of human cells for models of specific diseases as needed. They could study the physiologies of those cells in detail over time and observe how those neurons respond to potential drug compounds.
Stem cells can also improve animal testing. Human iPSCs can be inserted into animals (or animal embryos) to produce chimeras -- creatures with a mix of human and animal tissues. Such chimeras are ideal for testing how a drug might affect human tissues during early development or over a lifetime in the context of a full living body.
Pharma embraces stem cells
After a somewhat slow start, in the past few years, virtually every major pharmaceutical company has at least begun exploring the use of stem cells in drug development. Partnerships have formed between drug makers and biotech companies and laboratories with stem cell expertise: Roche with Massachusetts General Hospital; Pfizer with Novocell; GlaxoSmithKline with the Harvard Stem Cell Institute; AstroZeneca with Cellartis, and so on.
Drug development has become a significant focus of pharma and biotech gatherings. It was a sizable part of the program at the World Stem Cell & Regenerative Medicine Congress in London (May 21 - 23). The second Stem Cells for Drug Developers meeting was held in Boston (March 27-29).
An industry survey conducted by Hanson Wade, the organizer of that Boston meeting, found that more than 70 percent of the responding companies working with stem cells were using them in research rather than for stem cell therapy development; half of those companies were using stem cells only for that purpose. It makes sense that, if they are able to, biotech companies working on stem cell therapies might hedge their bets by trying to diversify into pharmacological research, too, because the latter might be able to bring revenues sooner. (The catch, however, is that stem cell therapy development and drug development work are both demanding, and many companies might not have the resources to tackle both.)
Here are some examples of work in this area:
- Cellular Dynamics sells cardiomyocytes (heart muscle cells) derived from iPSCs for testing, as well as brain cells, endothelial blood vessel cells, and liver cells.
- GE Healthcare in the U.K. sells cardiomyocytes from ES cells. (Disclosure: I have been an editor at large for GE technology websites; I have never had any dealings with GE Healthcare specifically.)
- iPierian is using brain cells derived from its lines of stem cells to develop monoclonal antibodies that might be useful for treating neurodegenerative disorders.
- At the Select Biosciences Stem Cells 2012 Conference held this past February in San Diego, Robert Halliwell of the University of the Pacific reportedly presented his lab's work on in vitro testing of drug toxicity with neurons derived from stem cells, which have electrophysiological behaviors like those of normal neurons.
- At the same meeting, Steven Sheridan of Massachusetts General Hospital reportedly discussed his success in using iPSCs to create neurons that model the neurological genetic defect called fragile X syndrome.
- In April, VistaGen Therapeutics secured a patent for its method of assaying the toxicity of drug compounds in mammalian liver stem cells.
Can they do it?
As Daniel Cressey recently reported in Nature, GE Healthcare has said that blind tests using its stem cell-derived cardiomyocytes picked up on toxicity problems in drugs that were not recognized until after they were approved by the FDA. If so, such results are encouraging about what stem cells might be able to do to make drug development more efficient in the future.
Nevertheless, many unknowns still hamper the endeavor. Overall, the ability of stem cells to catch relevant toxicities and predict clinical results need to be checked out much more thoroughly. The standards of proof for effectiveness and safety that the FDA will require of stem cell-based testing still need to be clarified. The ability to produce and maintain stem cells in the numbers required for testing is a frequent topic of discussion at drug development meetings.
And of course, researchers are still just beginning to learn how to chemically coax stem cells to differentiate reliably into desired types of adult tissue cells. With iPSCs, there are also concerns that the genetic manipulations that induce them to enter a stem state might subtly alter the biochemistry or behavior of any differentiated cells they produce.
For now, at least, those hurdles don't seem to be daunting pharma's interest in stem cells. Somehow, the industry has to find a way to improve the efficiency with which it turns candidate compounds into useful, safe drugs. If stem cells can accomplish other medical miracles, maybe they can do that, too.