Stem Cells: Controversy at the Frontiers of Science

Dedication

This book is dedicated to my father Leon Szer

to whom I trace the beginnings of my fascination

with science

CONTENTS

Cover

Dedication

Prologue

Introduction: The stem cell equation

1 Ethics

2 Background to the science

3 Australia’s battle for stem cells

4 How Australia entered the stem cell race

5 Selling the science

6 Putting stem cells to work

7 Parkinson’s disease

8 Diabetes

9 Mending a broken heart

10 Kidney growers – impossible dreamers?

11 Repairing the spinal cord

Epilogue

Endnotes

Searchable Terms

Acknowledgements

Praise

Copyright

PROLOGUE

As truth is said to be the first casualty of war, so science has been the first casualty of the stem cell debates. As the battles raged white-hot, dreadful distortions of the science occurred in the media, in public speeches and in parliaments. Partly it was because the science was so complex, but largely it was intentional distortion by lobby groups determined to quash stem cell research.

It was not just the specifics of stem cell science that were distorted but also the fundamental nature of the scientific endeavour. Science cannot give definitive answers. Science is about exploration. When a new continent is discovered there is tremendous excitement and potential but there is no certainty as to what the nature of the new discoveries will be. The discovery of human embryonic stem cells is the new territory for science. There can be no certainty as to what rewards it will bring, or when, but what is quite certain is that cutting off major routes of exploration will cripple the endeavour.

As one of the journalists covering Australia’s stem cell debate for international science journals and occasionally the local media, I felt compelled to straighten out the science that had become so distorted.

I was also dismayed that the public was missing out on the real story about the extraordinary era into which we have just entered. Twenty years ago, I was a research scientist at the University of California in San Francisco. It was a heady time. We were identifying the genetic instructions that a fruit fly uses to fashion a body out of a formless egg. A profound revelation soon emerged. The fruit fly instructions were universal — all animals used the same basic set of genetic tools to fashion their bodies and organs. At the time, it was astonishing enough to be part of the generation that demystified one of the great wonders of biology. Today, I see researchers putting that universal tool kit to work on human embryonic stem cells to engineer new body tissues. I never imagined this knowledge would be used in such a literal way for the progress of medicine.

The researchers are excited; they sniff the heady winds of a new frontier. Some are drawn by the irresistible lure of knowledge: stem cells offer the chance to unravel the mysteries of human development. Others are the physician – scientists who daily switch from patients and stethoscopes to lab coats and white rats. For them, stem cell science is a shining doorway to new treatments and new hope.

But this science is not simple. It is like some message from an alien civilisation, written in an arcane language. The media, society’s go-betweens, have difficulty delivering the translation, syntax and all. They guess, and they cream off the simplest translations that seem to make sense. The goal of this book is to render a more faithful translation, one that better reflects the message and culture of stem cell science. One of the best ways to learn about an alien culture is to read its stories. This book tells the stories.

INTRODUCTION

The stem cell equation

A global hurricane

In the first years of the new millennium the debate over human embryonic stem cells took hold of the world like an advancing hurricane, tearing through country after country. It was a hurricane unleashed by the clash of powerful forces: on one hand, the eternal human drive to progress; on the other, fear of the moral consequences of unleashing science.

Human embryonic stem cells represent an epochal technological breakthrough, as revolutionary to medicine as the metal age was to industry. These cells are the raw, malleable material from which human tissues might be fashioned. Once scientists learn to master the feat, humans — like lizards and salamanders — will be able to regenerate damaged brains, hearts, pancreases, kidneys, lungs, livers and so forth. But making embryonic stems cells requires the destruction of human test-tube embryos and therein lay the source of the virulent opposition to entering this new era of ‘regenerative’ medicine.

Human test-tube embryos have been controversial since the late 1970s when researchers first started fertilising human eggs in the test tube for couples who could not conceive any other way — a procedure known as in vitro fertilisation (IVF), literally fertilisation in glass. Human life had never been conceived in a test tube before and it raised new ethical dilemmas. Were these embryos human beings? What rights did they have?

These metaphysical considerations became a pressing issue because of the way the test-tube embryos were treated during the course of IVF. The problem was that Nature had set a very high fault rate for the human embryo: only one out of five was viable. Most people are quite unconcerned by the fact that four out of five naturally conceived embryos are defective and flush away with a woman’s menstrual period. But these poor odds created a moral dilemma for the practitioners of IVF. In order to give a woman a decent chance at conceiving a baby, they had to fertilise many of her eggs in order to pick out the few viable embryos. And that meant there would always be leftovers. Mostly these were the non-viable embryos but occasionally viable embryos also ended up in the surplus bin. Though it was arguably immoral to create human life only to throw it away, it was arguably more immoral to implant defective embryos into a woman. Most IVF clinics around the world decided that producing multiple embryos, selecting a few viable ones and discarding the rest was the more moral thing to do. As a result the IVF success rate climbed from the 1980s average of 2–3 per cent to today’s 20–30 per cent per attempt.¹ Better than nature! (Italy recently bucked the trend and decided that it is more moral to give all embryos a chance at life, mandating that Italian doctors implant abnormal embryos into women.²)

However, when scientists learned how to make human embryonic stem cells and asked to be allowed to use leftover embryos for this purpose, the long-dormant controversy over the status of human test-tube embryos awoke with a vengeance.

Embryonic stem cell breakthrough

It all began in November 1998 when three research teams announced they had learnt how to make human embryonic stem cells. It was a tour de force. Researchers had managed the feat in mice seventeen years earlier but the human equivalent had remained out of reach. Two groups had already published their work: James Thomson’s from the University of Wisconsin, and John Gearhart’s from Johns Hopkins University in Baltimore. The third — Alan Trounson’s group at Monash University in Melbourne, collaborating with researchers at the University of Singapore — had not yet published their research.³

Two sources

The human embryonic stem cells had been made from two distinct sources. Trounson and Thomson had made them from surplus test-tube embryos obtained from IVF clinics. They allowed the embryos, usually balls of about two to four cells, to multiply for five days till they formed a hollow sphere of about 100 cells known as the blastocyst. Buried in the centre of the sphere was a tiny clump of cells known as the inner cell mass. If the embryo continued to develop, the inner cell mass would give rise to all the different tissues that make up a human being. Like students entering high school, the cells would gradually become committed to particular specialities: brain, heart, gut, skin and so on. The researchers dissected out the inner cell mass from the embryo and coaxed it to grow in a culture dish. In the dish most of the cells would start to specialise but occasionally the researcher would find a rare cell that did not. Instead of entering a particular speciality stream, such a cell prolonged its moment of youth indefinitely, while continuing to multiply. Such cells were unlike any others known to science — they were both immortal (they grew without ceasing) and pluripotent (they had the potential to produce any type of tissue).* They were human embryonic stem cells.

Two ways to make human embryonic stem cells

John Gearhart’s human embryonic stem cells were derived from a different source — aborted embryos between five and nine weeks of gestation. At this stage, the embryo contains a store of germ cells that will later give rise to sperm or eggs. Sperm and eggs are pluripotent cells — that is, they can (when they eventually get together) generate every type of body tissue. Germ cells too have the potential to make any type of tissue. Gearhart painstakingly dissected out the germ cells from these older embryos, and cultivated them. He too was able to trap rare, immortal, pluripotent stem cells.

Though both types of embryos served as a starting point to derive human embryonic stem cells, most researchers focused their attention on the cells from test-tube embryos. One reason was that these cells appeared to be easier to grow in the culture dish.** Another was that the moral equation was perhaps a little simpler when it came to using surplus test-tube embryos.

Surplus test-tube embryos — morally less problematic?

Five- to nine-week-old aborted embryos are clearly nascent human beings. But the status of test-tube embryos is far more debatable. Not one of their cells is a brain or heart cell — indeed, most of the cells go on to become cells that are not part of the embryo, such as the placenta and amniotic sac. The embryo can also still split to form two or more individuals. And society already accepts without a second thought the tremendous attrition that occurs at this stage. In a normal pregnancy, less than 20 per cent of such embryos are viable. Women who use intra-uterine devices or the mini-pill flush out such embryos every month with their menstrual flow. And in IVF clinics, embryos at this stage are thrown away in their thousands every year.

But anyone who thought that solving the moral equation for test-tube embryos would be simple made a grave miscalculation. In the minds of many, once a human egg had been fertilised, that was human life. For some, the derivation of stem cells from these embryos was tantamount to dismembering a human being. Swirling into action at the very moment human embryonic stem cells appeared on the scene was a vigorous opposition to the use of surplus test-tube embryos for that purpose. And so the human embryonic stem cell debate began.

The stem cell equation

The core of the debate boiled down to a simple equation. On one side were the potential benefits to medicine from allowing embryos to be used to make human embryonic stem cells. On the other, the moral cost of using embryos for this purpose — regardless of the fact that such embryos were normally thrown away. Weighing the moral cost required resurrecting that old chestnut: were test-tube embryos human beings?

But the equation was confounded by two more variables — two more breakthroughs from the brave new world of science. The first of these was cloning.

Cloning

In 1997, the world learnt about the birth of Dolly, the sheep that proved what many had thought impossible: it was possible to clone a mammal, perhaps even a human.* Many people were alarmed that the world was now on a dangerous slippery slope that would lead to human cloning, and they assumed that human embryonic stem cell research was part of that same slippery slope.

As technologies, cloning and the making of stem cells really have nothing to do with each other. To clone Mr Smith (still a theoretical proposition), a genetic technician would have to isolate one of his skin cells and pluck out the dark round nucleus — the ‘hard drive’ that programs the function of his skin cell. The technician would then ‘reboot’ the nucleus by popping it into a donated human egg, whose own nucleus had been removed. Now something remarkable would happen. The nucleus that once ran the program for skin would now return to its original operating state of ‘totipotency’, where it is able to make a whole new embryo, and that is what it would do. It would start directing the same processes that take place in any fertilised egg, developing ultimately into a baby that is a carbon copy of Mr Smith.

On the other hand, to make embryonic stem cells, the technician starts with a test – tube embryo, grows it to the blastocyst stage, removes the inner cell mass and patiently cultivates the cells till an odd immortal stem cell appears. The technologies are totally different: one could clone humans without ever making human embryonic stem cells, or make human embryonic stem cells without ever cloning.

There were a few notoriety-seeking scientists who kicked up a tremendous stir by announcing their intention to clone humans. These included Italian fertility specialist Severino Antinori, American reproductive physiology professor Panos Zavos, and Clonaid, the company associated with the wacky Canadian-based cult, the Raelians. In 2002, all three claimed either to have already cloned a human baby or that there were heavily pregnant women carrying cloned foetuses. As of August 2004, no evidence for these babies has surfaced and the Raelians have all but admitted it to be a hoax.⁴

Apart from these fringe dwellers, scientists had little interest in cloning humans. Even if it were possible to guarantee the production of a healthy baby clone, the quagmire of ethical and legal issues would be bad enough. But animal experiments showed that clones were often born abnormal and for every live animal, hundreds of foetuses spontaneously aborted. Clearly, any attempt to clone a human being with such a high likelihood of abnormality was immoral.

It was the combination of the technologies for cloning and making human embryonic stem cells that created a compelling new possibility — therapeutic cloning. Embryonic stem cells, for all their potential, suffer from a major drawback. Imagine that, in a few years, researchers are able to fashion embryonic stem cells into the pancreatic tissue that is lost in a child with diabetes. The child would be spared the dire complications of diabetes, but would require lifelong treatment with drugs to stop their immune system from rejecting the foreign graft. But what if the graft was not foreign but had exactly the same genetic make-up as the child? That could be achieved by combining the technologies for cloning with those for making embryonic stem cells. A nucleus taken from one of the child’s skin cells would be introduced into an egg, perhaps an egg donated by the child’s mother. That egg would be allowed to grow into a blastocyst, at which point inner mass cells would be harvested, and cultivated to generate embryonic stem cells. These ‘customised’ stem cells could be used to produce a tissue graft that was a perfect genetic match for the child.

Reproductive vs therapeutic cloning

Therapeutic cloning offered legitimacy to the notion of cloning. At the very least, it put the whole issue of cloning on the table as a topic for serious discussion. But some people began to fear that if society were convinced to soften its views to allow therapeutic cloning then worse would surely follow. Human eggs (needed for cloning) would become a commercial commodity leading to the exploitation of poor women who might be tempted to sell their eggs. And if society countenanced therapeutic cloning today, then surely it was only a matter of time till reproductive cloning became acceptable and then the cloning of people to harvest their body parts, and then … clone armies. It was the old slippery slope argument.*

Adult stem cell revolution

The second confounding variable came from another scientific breakthrough: the adult stem cell revolution. Adult stem cells were traditionally thought to have an extremely restricted repertoire but new research suggested they might have the same capabilities as embryonic stem cells, a finding almost as astounding as the cloning of Dolly the sheep. The upshot of this breakthrough was that some pundits proclaimed that research on embryonic stem cells would now be unnecessary.

Adult stem cells are poorly named. They exist not just in adults of all ages, but also in foetuses and children; in fact, they exist anywhere that organs do. They replenish the cell population of a particular organ in much the same way that a queen bee replenishes the population of her hive. Bone marrow and skin are well known for their stem cells, which do a prodigiously good job of regenerating these tissues. In recent years it has emerged that even the poorly regenerative brain has a stem cell, perhaps a ‘B’ grade stem cell, since it doesn’t do a very good job of it. (You can donate some of your bone marrow knowing the tissue will regenerate. You wouldn’t want to try the same thing with your brain.)

Adult stem cells, like those in bone marrow, were always considered to be utterly dedicated to one organ. Just as a queen bee can make all different types of bees (workers, nurses, soldiers, etc) but never ants or butterflies, so a bone marrow stem cell could make all sorts of bone marrow cells, but never skin or brain cells. Some startling experiments in 1999, however, turned this dogma upside down. On rare occasions, bone marrow cells did appear to end up in the brain and become brain cells. And brain stem cells could, with some manipulation, end up producing bone marrow-like cells.⁵ Certain research showed that the brain and bone marrow stem cells might even be pluripotent — able to make any tissue at all, just like an embryonic stem cell. It was a full-frontal assault on the scientific dogma of the day, and fiercely fought battles continue to this moment.

Adult stem cell revolution

But this research, still bubbling and frothing with contention, also found its way into the stem cell debate to provide the third leg of the argument against the use of human embryonic stem cells. Making human embryonic stem cells was not only morally wrong and likely to pave the way for human cloning, it was also unnecessary. Adult stem cells, like those readily obtained from bone marrow, could be pluripotent too, and provide a source of spare tissue to repair damaged brains or other tissues. Moreover, a person’s own reserves of bone marrow cells would provide the inestimable benefit of a perfect immunological match.

This formulation of the debate was one of the most blatant distortions of stem cell science. The prevailing logic was absurd — that human embryonic stem cell research was unnecessary because adult stem cells could do much the same thing, and moreover had already been tried and tested. In fact adult stem cells have not been tried and tested except in their traditional use as bone marrow transplants. Nobody can say that bone marrow cells are going to be able to provide a person with replacement brain or pancreas tissue. In any event, the matter under discussion was research, not ice-cream manufacturing. When making ice-cream, by all means use tried and tested products. But research is about exploration. Should oil companies confine their exploration to the tried and tested — just stick with Bass Strait perhaps and forget the North West Shelf? As the research team who landed Spirit and Opportunity on Mars will tell you, success in science comes from researchers proceeding across broad and varied paths and sharing their knowledge. In a terrain where there is so much yet unknown, it seems an obvious fallacy to claim that major paths of exploration could be shut down and not diminish the chances of success.

Stem cell legislation travels the globe

By 2001, many countries had already wrestled with the stem cell equation (the medical promise of embryonic stem cells on one hand, versus the moral problems, dangers and alternative potential of adult stem cells) and reached different solutions. At one end of the spectrum the United Kingdom passed the most permissive laws. Licensed researchers would be allowed to use surplus IVF embryos for the generation of human embryonic stem cells. They were also allowed to carry out therapeutic cloning. Germany, on the other hand, made both practices illegal. The United States produced a strange solution. It passed no legislation about the legality of the practices. Rather, as was its tradition on such things, the government controlled the research by controlling the funds. Researchers were forbidden to use federal government funds to derive human embryonic stem cells from embryos, or to attempt human cloning. They were allowed to use a set of human embryonic stem cell lines that already existed at the time President Bush made his ruling. But there were no laws to restrict privately funded researchers. (James Thomson and John Gearhart, for example, had been able to derive human embryonic stem cells in the first place because the private company ‘Geron’ supported them.)

In August 2002, it was finally Australia’s turn to decide how to solve the stem cell equation.

ONE

Ethics

Brave new world?

In 1968, an extraordinary thing happened. For the first time in history a human life was created not in a woman’s womb but in a culture dish. The Cambridge-based physiologist who did the experiment, Robert Edwards, was no crazed Dr Frankenstein. He was dedicated to alleviating an affliction as old as Abraham and Sarah — human infertility.

Two out of every hundred women are infertile for a very simple reason: their fallopian tubes are blocked.¹ These tubes are the conduit through which an egg, released from the ovary each month, travels down to meet sperm racing up from the opposite direction. But if the tubes are blocked, sperm and egg cannot meet. Retrieving the egg, fertilising it outside the womb, and then returning it to the uterus could solve the problem.

Edwards had already perfected the technique in mice and rabbits. But for humans it was to take years of trial and error and a collaboration with Patrick Steptoe — gynaecologist extraordinaire. Steptoe, based at Oldham General Hospital — a backwater in England’s industrial north-west — was nevertheless one of the few people in the world to have mastered the procedure of laparoscopy, a technique that allowed eggs to be ‘harvested’ from a woman’s ovary without major surgery.* In 1971 the collaboration of Edwards and Steptoe bore its first fruit. They announced to the world that eggs, procured from a woman by laparoscope, had been fertilised with her husband’s sperm and grown in the culture dish to the stage where they would be ready to implant in the womb.

Their report generated an avalanche of public response as if a mountain of fear had been building over the years since the publication of Aldous Huxley’s novel Brave New World in 1932. The novel sketched a future dystopia where people were custom-made in test tubes, perfectly suited to their predetermined niche in life. Its lucid warning of the perils of technology gripped generations of readers. After the Edwards and Steptoe announcement, commentaries announcing the beginning of the slippery