Cellular songs in the key of life

August 29, 2003

Unlocking the process by which the body renews itself will help scientists tackle disease and give us a better understanding of ourselves, says stem-cell pioneer Roger Pedersen, who famously quit the US to pursue his research in the UK.

You may have wondered, as I have, what goes on in musicians'

minds as they perform, bringing notes on paper into life as sound. Do they let the music sweep them away, like us, into reveries of contemplation and emotion? From their outward behaviour, we might conclude that they are mechanically following the composer's instructions, step by step, until the double bar, the period at the end of a musical story. In so wondering, it occurred to me to watch what happens in the background of my own mind while I work as a stem-cell biologist, doing what may appear to the casual observer as compressing living things into words on paper for publication in scientific journals. The results may surprise you, because I found myself thinking not only how stem-cell research would bring us better medicine, but also how it would give us a more complete understanding of who we are as human beings.

The stem cells in our bodies are the source of our specialised tissues, much like the stem of a plant branches into leaves and flowers.

The defining quality of stem cells is that when they multiply, they can generate one specialised descendant and also another stem cell, thereby replacing themselves. This gives stem cells their unique capacity for sustained self-renewal, which is the key to their story. Many, perhaps all, of our tissues and organs appear to have stem cells. Tissues that form our interface with the environment undergo considerable wear and tear and so have to be replaced frequently from their stem cells. For example, there are prolific stem cells in our intestines, skin and blood. If not for this regenerative process, our health would rapidly deteriorate. Diseases of the pancreas (diabetes), brain (Parkinson's) and heart may reflect the slow pace of spontaneous renewal from stem cells. If we consider how our bodies emerge during prenatal development, we can also recognise the necessity for a "stem cell of stem cells". Such a primordial type of cell can be recognised at the earliest stage of human development, when the embryo is a hollow ball of fewer than 100 cells that has not yet attached to the uterus. These "embryonic" stem cells can be grown in the petri dish, where they have the remarkable capacity to specialise into any type of cell in the body.

The ability of stem cells (particularly those of embryonic origin) to generate such a diversity of specialised cells has excited scientists and non-scientists alike. This is because stem cells offer the hope of improved treatments for incurable diseases. Much of the excitement revolves around the possibility of generating specialised cells for transplantation to patients. For this to work, we need to understand how to control stem-cell specialisation in the petri dish. We also need to ensure that stem cells meet strict standards for transplantation, and we have to deal with problems involved in matching transplanted cells to the patient's immune system. The UK's pioneering efforts in establishing a stem-cell bank will aid in accomplishing these tasks. A variation on the theme of stem cell-based transplantation envisages converting patients' own tissue-specific (that is to say, adult) stem cells into other types of tissues for transplantation back to the same person. This approach would circumvent the immune-system matching problem. For success here we need to learn how to reverse or redirect tissue specialisation, an insight that will likely emerge from studies of cell nucleus transfer. A third and elegant path to medical treatments would be to improve the performance of our body's own tissue-specific stem cells without removing them from the body. We have a profound understanding of only one type of our body's tissue-specific stem cells, that of blood. We need to identify the stem cells of other critical organs, such as the pancreas, and to discover how their self-renewal is controlled in the body. It is not yet possible to predict which of these potential areas of stem-cell medicine will reach the clinic first. Therefore, it is necessary to continue to emphasise research in all areas, including embryonic and adult stem cells. I have chosen to focus my research on embryonic stem cells because their ability to make all body tissues convinces me that they can contribute insights to all areas of stem-cell medicine. What I see persuades me that embryonic stem cells are a "Rosetta Stone" - a key for translating the language used by stem cells.

Supposing that we completely understood the language of stem cells, would the impact of research on stem cells all come down to making useful products for repairing the body? As exciting as that prospect is, I think it is only half the story. The role played by stem cells in our bodies makes us realise something else that is profound in its simplicity: our body is not a static entity but a continuous, self-renewing process. The face we see when we look into the mirror each day, on which so much of our self-concept depends, appears stable, but it is constantly changing. Skin cells welling up from deeper stem-cell layers continually replace those on the surface. Similar processes are occurring in our other organs, at varying paces, replacing old cells with new ones. Even our brains, repository of our thoughts and memories, seem capable of a very limited degree of self-renewal. In other words, much more is going on in our bodies than meets the eye. Our body's dynamic mode could be likened to the tectonic process by which the earth slowly renews itself, adding new surface at the oceanic ridges, removing it at subduction zones. Both processes are so subtle as to almost escape notice, taking place continuously at a slow pace, guided by principles of earth sciences or, in our case, genetics.

Understanding the role of genes in bringing our bodies into existence has been occupying developmental biologists for more than a century. Solving this problem will be accelerated by the recent completion of the human genome-sequencing project. Indeed, learning the genetic basis of stem cells' ability to maintain our body's form and function is a major remaining task for developmental biologists in the "post-genomic" era. This problem has a level of complexity that gene sequences do not have because cells, unlike genes, are organised systems. Stem cells and their immediate descendants are capable of integrating information from their environment and deciding on this basis whether to remain a stem cell or to specialise.

This is what enables stem cells to maintain the vitality of tissues and organs. Understanding stem cells will take time, and clinical treatments will emerge only when numerous basic and practical challenges have been solved. However, answers to our questions will likely herald a revolution in treatment of many degenerative diseases. Understanding how stem cells sustain our body's three-dimensional complexity for the duration of our lifetimes can also give us a new perspective on our potential as human beings. Knowing how our body renews itself, we may then be able, like musicians who have mastered their art, to reach out and touch the hand of the composer.

Roger Pedersen is professor of regenerative medicine in the department of surgery and director of the Centre for Stem Cell Biology and Medicine, University of Cambridge.

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