Stem cells: sorting out the hope from the hype

This essay was written by Alex P. Gould and François Guillemot and was first published in the 2009 Mill Hill Essays. An updated version was published in the Mill Hill Essays anthology.  

Stem cell research makes it possible to contemplate new and effective treatments and cures for diseases that have afflicted mankind over centuries.

Prime Minister Gordon Brown, The Observer, May 2008

Patients from around the world have fl ocked to a Beijing surgery practice, where Dr. Hongyun Huang implants cells with what he says are amazing healing powers (but) there were no meaningful improvements in any of the patients after the surgery

Boston Globe, June 2006

California’s bio-tech industry has boomed, offering new cures for spinal cord injuries, Alzheimer’s, Parkinson’s and other diseases.

Governor Arnold Schwarzenegger, January 2007

The South Korean cloning scientist who faked his stem cell research has been charged with fraud and embezzlement. Hwang Woo-suk was also charged with using millions of dollars in grants for private purposes, as well as violating laws on bio-ethics.

BBC News, May 2006

In a breakthrough that could have huge implications, scientists have found a way of reprogramming skin cells, making so-called induced pluripotent stem (iPS) cells. (These) could safely be used in patients while avoiding the ethical dilemma of destroying embryos.

The Guardian, March 2009

When listening to the morning news or reading the newspapers, one regularly hears about new medical treatments and often these are about stem cells. It is not just the public and the media that have become enthralled with stem cells: in many countries, governments and pharmaceutical companies are investing large sums of money in the hope of developing new stem cell treatments. In 2004, in perhaps the largest single investment, voters in the State of California approved an eye-watering $3 billion bond for stem cell research over ten years. Some people doubt whether all this stem cell excitement and investment is really justified. It’s particularly hard to judge because genuine stories of stem-cell breakthroughs are often overshadowed by overoptimistic claims of success and, from time to time, even by serious scientific frauds. So will stem cells become the snake oil of the 21st century, used by unscrupulous doctors to extract money from a frightened and desperate public? Or will they become a genuine cure for many currently untreatable diseases?

How do stem cells work?

A healthy adult human body contains many different types of stem cells. They are important for replacing cells that naturally have a limited shelf life, such as those in the blood, skin or intestine. Two special properties of stem cells make them ideally suited for developing new treatments to repair damaged or diseased organs. First, they can be converted, under the right conditions, into blood cells or skin cells or other kinds of human cell. Second, they can make copies of themselves inside the human body and, in some cases, even in a laboratory Petri dish. Stem cells transplanted into a human or animal body often work by directly replacing those cells that have been lost from damaged tissues. Recently, however, it has been found that some stem cells can act by stimulating the patient’s own tissues to regrow. For example, certain stem cells manufacture beneficial molecules that stimulate the patient’s blood vessels to grow at the injured site, thereby helping the repair process. Despite very intense exploration of the medical value of stem cells, in many cases it is not yet known how they really work inside the human body and much research remains to be done in this area.

Stem cell therapy has been a reality for decades

Although stem cell treatments are often portrayed as a distant future prospect, in fact they began in 1968 with the first successful bone marrow transplant (Figure 1). Since then, many thousands of patients with cancer and blood diseases have been treated, and saved, by transplants of bone marrow and, more recently, of umbilical cord blood. These transplants save lives because the donor tissues (bone marrow and cord blood) are sources of stem cells that can regenerate the patient’s own damaged blood and immune cells. Several other types of cell replacement therapies have been attempted, although with less spectacular success. For Parkinson’s disease, a trial therapy involving transplants of brain cells from aborted foetuses has been ongoing for many years but only with limited success. It seems that variability in the donor foetuses and in the methodologies used have made it difficult to quantify the extent of patient recovery. Also, the parts of the brain affected by many neurodegenerative diseases like Parkinson’s can differ from patient to patient, and so are especially difficult to cure with one standardized therapy. Although it is early days, new stem cell treatments are also being attempted for a wide range of ailments affecting other organs – such as treating damaged hearts with bone marrow stem cells or repairing broken skulls with fat stem cells.

Bone marrow transplant
Figure 1.

The stem cells that are currently used for such treatments are obtained directly from human adults or foetuses but this limits their supply and raises ethical concerns. Research that uses adult stem cells to repair cartilage in horses, tendons in rats, eyesight in mice or muscles in dogs, may hit similar ethical problems when it is ready to move into human clinical trials. An alternative route to stem cell therapies uses a different sort of stem cell, called an embryonic stem cell, or ES cell. Unlike adult stem cells, such as the blood stem cells found in bone marrow, ES cells are not a normal part of the foetal or adult body. Instead, they are manufactured in the laboratory from human or animal embryos soon after fertilization, when they are microscopic in size. Unlike many adult stem cells, ES stem cells can be grown in large numbers in the laboratory and also have the potential to generate all of the cell types found in the body. The choice of laboratory conditions that are used to convert ES cells will determine which kinds of adult cells they can make. There have been some notable successes using animal models, such as treating heart failure in sheep using ES cells converted into heart muscle cells, and treating spinal cord injuries in mice using ES cells turned into myelinating cells. The therapeutic use of ES cells in humans is at a very early stage. Earlier last year, Geron Corporation received approval from the US Food and Drug Administration for the first clinical trial of an ES cell-based therapy to treat acute spinal cord injury.

Stem cell therapy: a turbulent adolescence

Unfortunately, the successful use of stem cells to treat a small number of diseases and the promise of how to treat many more, has been clouded with controversy. Some of these have been of a genuine scientific nature. There is for example a concern that the remarkable potential of stem cells to increase in number in a dish may turn out to be a liability inside patients, potentially causing tumours. Growing large numbers of ES cells in the laboratory also increases the risk that they will become unstable or infected with pathogens. Scientists are currently trying to solve both problems by improving and standardizing the conditions under which ES cells are cultivated and subsequently converted into the particular cell type that needs to be replaced. What has been more damaging for progress in the stem-cell field is that several of its most loudly trumpeted achievements have turned out to be grossly exaggerated or even faked. For a while, a type of adult stem cell called a multipotent adult progenitor cell was heralded as being safer and less controversial than ES cells. Unfortunately, only one scientist provided evidence that these stem cells could really make many different kinds of tissues and other laboratories have not been able to replicate this result. In another case, patients with spinal cord injuries and neurodegenerative diseases were implanted with brain cells from aborted foetuses at the Beijing surgery Stem cells: sorting out the hope from the hype of Hongyun Huang. Despite treating hundreds of patients, independent medical assessments revealed no meaningful improvements in any of the patients after surgery. The minor ways in which some patients thought they had temporarily improved illustrates the power of the placebo effect, which seems particularly strong when tens of thousands of dollars have been spent on each treatment. Perhaps most infamously, the South Korean scientist Hwang Woo-suk claimed that he had cloned human embryos to develop stem cells for therapeutic purposes. Despite high hopes and a great deal of attention within the scientific community and the general public, this claim turned out to be fraudulent. In some other cases, the media and politicians have contributed to raising false hopes of breakthroughs. However, the press offices of the organisations funding and carrying out stem-cell research and, in some cases, the scientists themselves also need to get their own house in order – ensuring they report new results to the media in a balanced and cautious manner.

Stem cell therapy: a bright future

Many advances in stem cell research challenge traditional views about the very nature of being human and some have generated intense ethical debates. Is it right that human embryos are used to produce ES cells for transplantation therapy, and how should these embryos be obtained? Should human-animal embryo chimeras be generated to increase the supply of human ES cells? Stem cell science, however, is running way ahead of ethical debate. Research progress has been so rapid and unpredictable that many of the key ethical dilemmas are becoming obsolete. A new cloning technique that utilises unfertilized human eggs rather than fertilized embryos to generate ES cells may be less problematic to at least some of those who believe that human rights begin at conception, when the sperm fertilizes the egg. In this procedure, the nucleus of an unfertilized egg, containing the DNA molecules, is replaced with the nucleus of essentially any other cell type in the body, which contains identical DNA molecules. This new cloning approach is, however, fraught with technical difficulties as illustrated by the Hwang debacle, and is therefore unlikely to become widespread. An alternative and more promising strategy, avoiding eggs and embryos altogether, is to make stem cells from small numbers of cells taken from an adult, such as skin cells or white blood cells. Special cocktails of proteins or other chemicals are then used to convert these adult cells into induced pluripotent stem cells (or iPS cells) that are very similar to ES cells and can be grown in large numbers in the laboratory. Since they were first described in 2006, many stem cell scientists have started to work with iPS cells and the methods for generating them are fast improving. For example, the proteins first chosen to generate iPS cells were not suitable for therapeutic use because some of them had the potential side-effect of inducing tumours. They are now being replaced by more benign chemicals. Since iPS cells can be made from the same patient into whom they are later transplanted, there are no rejection or immune suppression problems, which is a clear improvement over traditional organ transplants. iPS cells have now been generated from patients afflicted with all kinds of genetic diseases, from the neurodegenerative Lou Gehrig’s disease to Spinal Muscular Atrophy. These iPS cells can then be used in the laboratory to pre-test the effectiveness of different drugs in correcting the genetic disease, before the best one is then selected for administering to the patient. In principle, genetic defects could also be corrected in iPS cells, using gene therapy, and the repaired cells then transplanted back into the patient (Figure 2). Some evidence that this concept actually works has been provided recently using rodent models for Parkinson’s disease and Fanconi anaemia.

Combined gene and stem cell therapy
Figure 2.

Although very promising, iPS cells are not without their problems. They share with ES cells the virtually unlimited ability to increase in number and, as a result, concerns about tumours remain. As with ES cells, this potential problem is likely to be solved by improving the efficiency of converting iPS cells into the particular type of replacement cell that needs to be transplanted. Although iPS cells can in principle make any kind of cell in the body, at the moment we have only a limited understanding of how to achieve this in a laboratory Petri dish. Despite this, scientists have made good progress in learning how to make the cells that are destroyed in some prevalent diseases. For example it is possible to make insulin-producing cells to replace those lost in type-1 diabetes, or dopamine-producing neurons to replace those lost in Parkinson’s disease. Researchers learned how to generate these cells from iPS cells by first discovering the molecules that are normally present in the embryo and whose job it is to convert stem cells into these cell types. They have then been able to apply these same molecules to ES cells or iPS cells grown in the laboratory. There are however many more such molecules that remain to be discovered before we have enough reliable chemical cocktails to make each one of the replacement cell types that are needed to treat all common human diseases. On balance, at the current time, it seems that there are grounds for cautious optimism and a good chance that iPS cells may turn out to be the stem cells of choice. But which diseases will be the first to yield to new stem cell therapies? It is more straightforward to convert stem cells into a single kind of replacement cell than into the correct mix of different cell types existing in a complex organ. This means that progress may be somewhat more rapid for conditions involving primarily one defective cell type such as heart disease, diabetes and replacing damaged skin, bone, cartilage or teeth. Brain diseases such as Alzheimer’s disease or stroke, where connections between different types of nerve cells must be re-established will be much more of a challenge. Research is moving so fast at the moment that it’s almost impossible to predict which therapies will end up being the most useful in the clinic. Nevertheless, it seems very clear that stem cells are going to have a big impact on healthcare within our lifetimes.

The authors would like to thank Robin-Lovell-Badge and Caroline Vincent for interesting discussions.

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