The Truth About Stem Cell Technology

 [This is an edited version of a talk given at the 40th LIFE National Conference
 at Warwick in October 2010.]

Medicine is a wonderful enterprise when it is Hippocratic-Christian medicine, that is, when its ethics and practices are robust and wholesome.  Nowadays medicine’s ethics tend to be arbitrary and its practices utilitarian.  Even so, modern medicine has managed to bring about at least one laudable feat – our life expectancy has increased dramatically.  In other words, we will live longer.  And therefore we will die of causes different from those of our grandparents – not from acute infectious diseases, like tuberculosis, diphtheria and typhoid, but from chronic degenerative diseases, like dementias, cancers and cardiovascular diseases.  Thus modern medicine has created a new dilemma and acquired a new focus – the new buzzphrase is: regenerative medicine.  And stem cell technology is at its very centre.

Twentieth-century Stem Cell History
t was in the early 1960s that James Till and Ernest McCulloch of Toronto University first demonstrated the existence of adult stem cells, in the bone marrow of mice and described their unique ability for self-renewal, self-replication.  But stem cells are not new – they have been around since human history began.  Think about it.  We all developed from embryonic stem cells.  All human life begins with just that one ovum and one sperm, which when united in fertilisation produce that one-celled zygote.  This rapidly becomes 2, 4, 8, 16, 32 cells, and so on, by the process of cell division.  These early human embryos are composed of stem cells – embryonic stem cells.

After a little while these unspecialized stem cells begin to differentiate into specialized cells, such as myocytes, neurons and osteoblasts to form the embryonic heart, brain and bones, plus the other 200 or so types of cells that constitute the complexities of the human body.  Thus, these stem cells are termed pluripotent, meaning they have the potential to differentiate into numerous cell types.

This is modern biology at its most fascinating.  It is truly awesome.  Three thousand years ago, when King David wrote in Psalm 139:14, that, ‘... I am fearfully and wonderfully made; your works are wonderful ...’ he did not know the half of it!

But it was not until 1998 that James Thomson and his colleagues, at the University of Wisconsin, first isolated stem cells from human embryos.  So human stem cells, both adult and embryonic, are not new.  They have been around, since Adam and Eve (well, to be exact, embryonic stem cells have existed only since Cain).

Nor is the therapeutic use of stem cells particularly new.  Some 50 years ago, Dr E. Donnall Thomas, in a temporary basement laboratory in Seattle was convinced, despite the scepticism of many, that leukaemias and other cancers of the blood could be cured by destroying a patient's diseased bone marrow with near-lethal doses of radiation and chemotherapy and then transplanting healthy marrow from a donor.  At that time, a leukaemia diagnosis was a death sentence because the probability of survival was little more than zero.  Eventually, Thomas demonstrated that infusions of donor bone-marrow stem cells into patients could re-establish their blood cell production.  Thanks to this innovative therapy, tens of thousands of leukaemia patients now lead normal, productive lives.  In recognition of his pioneering work, Thomas received the 1990 Nobel Prize in physiology or medicine.

Twenty-first Century Stem Cell History
But the discovery and early use of stem cells is all so-last-century.
 Now, during the twenty-first century, stem cell technology has become one of the hottest ‘hot button’ areas of medical research.  It has become the sweetheart of regenerative medicine.  It has been heralded as the cure for illnesses ranging from Alzheimer's disease to spinal-cord injuries to severe heart conditions.  If you Google it you get about 12m results, there are world summits discussing it, and it even has its own dedicated journal, Cell Stem Cell.

But the world of stem cell technology is not uncomplicated.  These two sources of stem cells, embryonic and adult, and their use in regenerative medicine have started a bioethical war.  The point is that the production of embryonic stem cells always requires the destruction of the human embryo.  As James Thomson, the man who first isolated embryonic stem cells from human embryos, has so nicely summarized the issue, ‘If human embryonic stem cell research does not make you at least a little bit uncomfortable, you have not thought about it enough.’

Human embryos, either specifically created in the laboratory, or donated as ‘spares’ from IVF, are cultured for 5 or 6 days, until the blastocyst stage, at about 100 cells, then disrupted to harvest their stem cells.  On the other hand, adult stem cells are simply harvested from bone marrow, umbilical cord blood, milk teeth, amniotic fluid, eyes, brains, and a host of other physiological locations – the list is seemingly endless, and bioethically uncontroversial.

Over the last few years, we have been repeatedly told by scientists, governments, trendsetters, media men and women that embryonic stem cells are where the action is.  Time, energy and colossal sums of money must, they said, support this controversial research.  Then in 2006 came a biological bombshell.  Shinya Yamanaka, at Kyoto University, discovered how to induce ordinary, somatic adult cells (not adult stem cells) to revert to an embryo-like state.  Initially, he cultured mouse skin cells (fibroblasts) and exposed them to just four genes, (namely, Oct4, Sox2, Kfl4 and c-Myc), which coded for specific proteins, known as transcription factors.  These in turn triggered the production of other genes that ‘undifferentiated’ the adult cells.  He called them induced pluripotent stem cells (iPS cells).  Their production seemed like simplicity itself.  Yamanaka said, ‘It's easy. There's no trick, no magic.’

This 'reprogramming', or 'deprogramming', has been likened to winding back the clock of the differentiation process, from adult cells back to their precursors, namely, embryonic-like stem cells.  The biological basis of iPS cells is, to say the least, surprising.  Few had thought it possible.  It has been called the biological equivalent to making water flow uphill. It was thought that traffic went only one-way, from embryo to adult, that this was an irreversible pathway.  We now know differently.

So, the race was on.  Mouse cells could be reprogrammed to iPS cells, could the same happen with human cells?  There were numerous hurdles to overcome.  For instance, mice are not men, and subtle and unknown biochemical and genetic differences were likely to exist.  Yet, in November 2007, that second biological bombshell exploded.  Two research groups, led by Yamanaka in Japan and Thomson in the USA, simultaneously reported the generation of iPS cells derived from human skin fibroblasts.  Thomson declared, ‘We couldn’t believe it would be that easy.’

It is hard to over-emphasise the importance of this direct reprogramming to produce human iPS cells.  In a nutshell, iPS cells are stem cells that can be made from an individual's own cells, without the need for ova, or for cloning, or for the subsequent destruction of an embryo.  And because such cells are ‘patient-specific’, they are genetically matched and therefore not rejected by the patient.

The Bioethical Stem Cell War
This was (and still is) big news.  Indeed, it was sufficiently ground-breaking for some scientists, including Ian Wilmut, the creator of Dolly the cloned sheep, to abandon their embryonic stem cell research and concentrate their future efforts on iPS cell work.  Wilmut has said, ‘This [the use of iPS cells] is the future of stem cell research’ and ‘I have no doubt that in the long term, direct reprogramming will be more productive.’  Others too, see the importance of iPS cells.  James Thomson has stated, ‘Human ES [embryonic stem] cells created this remarkable controversy, and iPS cells, while it's not completely over, are sort of the beginning of the end for that controversy’ and ‘A decade from now, this [adult versus embryonic controversy] will be just a funny historical footnote.’  Sir Martin Evans of the Cardiff School of Biosciences, Nobel laureate and pioneer of stem cell research, also agrees, ‘This [the use of iPS cells] will be the long-term solution.’

So it is fair to say that a growing number of the scientific community, as well as the general public, now consider the use of embryonic stem cells to be both overhyped and quite unnecessary.  Nevertheless, there are still the inevitable gainsayers, such as ex-prime minister, Gordon Brown.  In May 2008, at the height of the debate over the Human Fertilisation and Embryology Bill, he declared that allowing the production of animal hybrids, or so-called human admixed embryos, as a source of embryonic stem cells would be, 'a profound opportunity to save and transform millions of lives.'  This research is, he continued, 'an inherently moral endeavour that can save and improve the lives of thousands and over time millions of people.’  Nobody talks about human admixed embryos now – they simply don’t work.  Another gainsayer is Humphrey Taylor, the head of Harris, the pollsters.  During October 2010, he published a poll pronouncing that, ‘Americans overwhelmingly support embryonic stem cell research, and that backing stretches across a broad range of demographic groups, including Republicans, Catholics and born-again Christians.’  Responses to polls are easily skewed, especially when the questions relate to sombre issues like death, cancers and cures.

Problems and Answers with iPS Cells
Yet none can doubt that this phenomenon of cellular reprogramming is exciting.  If it can be harnessed, these iPS cells are set to remain the hottest ‘hot-button’ topic of regenerative medicine for the foreseeable future.  In conjunction with adult stem cell treatments, we appear to have discovered a daunting therapeutic armoury.  Bioethically, we should rejoice!

However, we are not there yet.  Such proper, reliable adult stem plus iPS cell therapies may still be several years away.  Even so, laboratories worldwide are reporting novel and improved results almost weekly.  But serious hurdles remain.  Work, such as the translation from animal to human models, human clinical trials and safety tests, will have to be completed first.  And one of the key areas that is still far from understood is that of directed differentiation, namely, how do stem cells become, for example, only neurons or only cardiac muscle cells, and then, how can this process be directed efficiently and with precision within the body?  Until these pieces of the biological jigsaw are understood and controlled there will be no widespread cures for our recalcitrant human diseases.

These formidable obstacles have led some researchers to wonder if it would be possible to short-circuit this complex system and simply transform one type of adult cell directly into another type in vivo, that is, within the organism’s body.  Indeed, in October 2008, Qiao Zhou and co-workers at Harvard reported an example of this in vivo reprogramming, using just three transcription factors, to achieve the transformation of adult pancreatic exocrine cells into β-cells in mice.  In other words, they were able to transform non-secreting pancreatic cells into those capable of secreting insulin, without the need for reversion to the undifferentiated pluripotent stem cell stage.  This novel approach, called transdifferentiation, should be of interest to all diabetics.

Two other major problems arise with the Yamanaka-type approach.  First, the required genes are introduced into the somatic adult cells by way of viruses as vectors, the genes ‘hitch a ride’, but the viruses can hang around and maybe cause tumours and cancers.  Second, the genes used, especially c-Myc, are known to be associated with several types of cancers.  Mindful of these problems, in March 2009, a joint Canadian-UK team, led by Andras Nagy at the Mount Sinai Hospital in Toronto and by Keisuke Kaji at the University of Edinburgh, created iPS cells without using such viruses.  They reprogrammed the cells by inserting the four genes as a ‘cassette’, which was removed by an enzyme, transposase, once the transfer process had been completed.

Then in October 2010, Derrick Rossi and his group at Harvard published the details of a technique that is apparently cleaner, safer, faster, and more efficient than these other methods for reprogramming adult cells.  Instead of transforming the cells’ DNA, it uses messenger RNA (a cousin of DNA) to reprogram new cells, which Rossi has called RNA-iPS (RiPS) cells.  The use of mRNA should be safe in treating patients because while it carries genetic instructions, it does not penetrate the DNA of the target cells as do all other current procedures for creating iPS cells.  On hearing of this new development, Robert Lanza, the celebrated stem cell researcher at Advanced Cell Technology of Worcester, Massachusetts, exclaimed, ‘All I can say is 'wow' this is a game changer.  It would solve some of the most important problems in the field.’

The American Bioethical Tangle
The Americans love a good old legal-political imbroglio and stem cell technology has produced a plum instance.  It centres on the so-called Dickey-Wicker Amendment.  Back in 1995, the Clinton administration’s Human Embryo Research Panel recommended some federal funding for embryo research.  But in the same year, Jay Dickey, Representative from Arkansas and Roger Wicker, Representative from Mississippi, sponsored an Amendment to a finance
bill, which was duly passed by the US Congress and signed by President Bill Clinton.  The Amendment effectively prohibited the use of federal government funds to support any research that destroys human embryos, or puts them at serious risk of destruction.

This Amendment has been attached to the Health and Human Services Appropriations Bill every subsequent year.  But in March 2009, President Obama issued an executive order that removed this restriction against federal funding of embryonic stem cell research.  On 23 August 2010, two adult stem cell researchers, Drs James Sherley and Theresa Deisher, backed by several pro-life groups, challenged Obama’s action.  In the court, Judge Royce C. Lamberth granted an injunction against federally-funded embryonic stem cell research on the grounds that it, ‘clearly violated the Dickey-Wicker Amendment.’

On 28 September 2010, the Obama administration contested that decision and the Court of Appeals temporarily lifted Lamberth’s injunction while the courts determine the Amendment’s legal meaning.  Meanwhile, Sherley and Deisher have been savaged by the media.  They have been accused of stopping the competition to their own adult stem cell research, putting ethics before cures and slowing down life-saving research, etc., etc.  The legal outcome is awaited.

Stem Cell Treatments – Bad and Good
Finally, what is happening in the treatment clinics of the world?
 Despite ever-increasing reports of stem cells being used to treat various disorders, proven stem-cell therapies remain few and far between, though some small-scale trials appear to be ‘successful’.

Moreover, there are quacks and charlatans out there.  One such is Dr Robert Trossel, who ran clinics in Rotterdam and in Wimpole Street, London.  He charged vulnerable multiple sclerosis patients thousands of pounds for 'pointless' and 'unjustifiable' treatments.  He injected patients with stem cells never intended for human use that contained material from bovine brain and spinal cord and thereby exposed his patients to the risk of developing vCJD.  In September 2010, he was struck off by the General Medical Council.  Similar unregulated ‘treatments’ are advertised by unscrupulous doctors around the world, particularly in countries such as China and India.  Beware of fakes and fraudsters!

Moreover, lexical engineering is rife.  For example, a human embryo is frequently described, and thereby devalued, as a ‘fertilized egg’.  Or the blanket statement that, ‘religious people are against stem cell research’ mischievously conflates embryonic and adult stem cell technologies.  Or there is the case of ReNeuron, a British biotechnology company developing stem cell therapies for disabled stroke patients.  Its lead product, the CTX cell line, is advertised by the company as being, ‘derived from non-embryonic human tissue.’  That sounds OK.  In fact, it was derived in 2003 from the cortex region of the brain of an aborted fetus!

Seriously Successful Adult Stem Cell Treatments
Despite the bioethical and lexical minefields, there are examples of well-documented adult stem cell treatments that have been wonderfully successful.  Two cases illustrate this reality.

First, the case of Claudia Castillo, as reported in The Lancet (December 2008) 372:2023-2030.  In 2008, she was the subject of the first full transplant of a human organ, grown from adult stem cells, carried out at the Hospital Clinic of Barcelona.  Claudia Castillo, a 30-year-old mother of two, suffered from a collapsed trachea caused by tuberculosis.  Researchers from Padua, Bristol and Milan, harvested a section of trachea from a donor, stripped off the cells that could cause an immune reaction, leaving a trunk of cartilage, a bio-scaffold.  This section of trachea was then ‘seeded’ with stem cells taken from the bone marrow of Ms Castillo’s hip and a new section of trachea was grown in the laboratory over the next four days.

The new section of trachea was then transplanted into the left main bronchus of the patient.  Because the stem cells were harvested from the patient's own bone marrow it was not necessary to give anti-rejection (immunosuppressive) drugs.  Before the surgery, Ms Castillo struggled to climb a flight of stairs.  After the operation, she began to lead a normal life and has even been known to go out dancing!

Second, an example of a treatment for blindness.  A paper published in the New England Journal of Medicine (July 2010) 363:147-155 by Graziella Pellegrini and colleagues from the University of Modena stands out as a dazzling example of a proper, scientifically-documented advance in adult stem-cell therapies.

The human eyeball is covered by the cornea – a clear cornea is essential for good eyesight.  There is a narrow zone between the cornea and the conjunctiva known as the limbus, which is the source of corneal epithelial stem cells.  The limbus can be destroyed by ocular burns or infection, which can lead to vascularization of the cornea, chronic inflammation, scarring and, ultimately, corneal opacity and loss of sight.  Conventional treatment is a corneal transplant from a genetically non-identical donor.  Not only are suitable donors in short supply, but the treatment is typically short-lived.

Pellegrini’s team has now demonstrated that limbal adult stem cells maintained in culture can serve as a viable alternative source of cells for transplantation to treat burned human corneas.  Limbal stem cells were obtained from the healthy eye of 112 patients who suffered with partial or complete loss of vision due to chemical or thermal burns.  The cells were cultivated and then transplanted onto the patient’s damaged eye.  It seems so simple, so unsophisticated.

After an extensive, up to 10-year monitoring period, these authors reported the permanent reconstruction of a transparent, self-renewing corneal epithelium in 78% of the studied patients leading to restored or improved vision.  This work represents a group of real people who have already had their lives radically changed through adult stem cell treatments.  But note, not all were cured, the numbers treated were relatively small, the treatment remains experimental and it is not suitable for all kinds of blindness.  BUT, even so, all would agree that the results are still pretty impressive!

Compare these adult stem cell clinical treatment cases with those using embryonic stem cells.  According to the current score is 73 versus 0.  And the former include, albeit often with small-scale trials, a range of conditions like cancers, juvenile diabetes, multiple sclerosis, heart damage, Parkinson's, sickle cell anaemia and spinal-cord injuries.  Meanwhile, on 11 October 2010, the world’s first embryonic stem cell trial with human patients began in the USA. Geron, a biotechnology company based in California, started to test its product of embryonic stem cells in patients with sub-acute thoracic spinal-cord injuries.  This phase 1 trail started with just one patient and its aim is to prove the safety and principle of this putative therapy. We shall see.

The Future of Non-Embryonic Stem Cells
So what of the future for non-embryonic (adult and iPS) stem cells?  First, there will be more adult stem cell treatment studies – they need to be more extensive, better controlled, more thoroughly researched and more rigorously reported.  But they will come.  Second, iPS cells will begin to move into the clinical trial arena.  Already they are being used for drug assessments, thereby reducing animal testing and minimising expensive human trials.  These projects will continue.  Third, adult stem cells will be used for tissue/organ production, thus obviating some donor organ transplantation procedures.  Fourth, the use of stem cells derived from human embryos will decline and eventually become obsolete.  But some experimenters will persist in their demand to trash human embryos.  Many loathe the idea that a human embryo can have any moral standing.

But the take-home message is this: stem cell technology, as part of regenerative medicine, is here to stay.  The production of stem cells from human embryos will prove to be both unethical and unnecessary.  Unethical, because it destroys human embryos.  Unnecessary, because stem cells are available from other diverse, alternative and uncontroversial sources namely, adult and iPS cells.  Moreover, the simplicity and elegance (not to mention, the cheapness) of their production, should end all talk and practice of human embryo destruction.

Where Does All This Leave Us?
  We should be amazed – stand back and be staggered that we are so ‘fearfully and wonderfully made.’  All human life is unique and special.

2]  Regenerative medicine is THE next great advance in medical science.  We will all benefit.  It will change both our thinking and our lives.

3]  We have something positive to say – proper science is on our side and in a few years the general population will agree with us too.  Now that is something of a first – we must capitalize on such good news.  Human embryos deserve protection – destroying them is unnecessary and the next step is to convince the world that such destruction is wrong.

4]  We need to launch a bioethical pincer movement.  If human embryos are not to be destroyed and born children are not to be destroyed, then what about the heartland of the in utero, unborn child?

5]  LIFE should seriously be putting its money where its mouth is.  We should be advancing and funding non-embryonic stem cell research.  Perhaps, first with a LIFE research fellow, for about £50k per year.  Then with a LIFE chair, a professor of ethical medical science, at a prestigious university.  Finally, with the establishment of the LIFE Institute of Ethical Medicine, where good medicine will value and cherish all human life.

Are you excited by adult stem cells and especially iPS cell technology and regenerative medicine?  So am I.

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