No Case for Embryonic Stem Cells Research

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16 Dec 2004 19:50:36 -0000

 

No Case for Embryonic Stem Cells Research

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ISIS Press Release 16/12/04

 

No Case for Embryonic Stem Cells Research

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Technical and financial hurdles add to ethical and safety

concerns over embryonic stems cells while adult stem cells

are achieving remarkable clinic successes. Dr. Mae-Wan Ho

reports

 

References for this article are posted on ISIS members'

website http://www.i-sis.org.uk/full/NCFESCFull.php. Details

here http://www.i-sis.org.uk/membership.php

 

First human embryonic stem cell bank in the UK

 

The first human embryonic stem (hES) cell bank was

officially opened in the UK in May 2004 [1], with Health

Minister Lord Warner saying, " This potentially revolutionary

research could benefit thousands of patients. " The centre

contains just two stem cell lines developed by research

teams at King's College London and the Centre for Life in

Newcastle. The House of Lords recommended approving human

embryonic stem cell research in 2002, the justification for

which was to provide cells for replacing tissues in patients

with organ failures.

 

ISIS had already pointed out at the time that research on

hES cells was ethically unjustifiable, especially given that

adult stem cells, easily obtainable from the patients

themselves (see Box 1), appeared just as developmentally

flexible as ES cells, and showed much greater promise in the

clinic without either the ethical concerns or the risks of

cancer from hES cells [2-6].

 

Research and clinical findings since have borne out all our

objections to ES cells, as well as the promises of adult

stem cells. There is simply no case for supporting research

in hES cells any longer.

 

 

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Box 1 What are

stem cells?

 

Stem cells are special cells that can divide indefinitely

and give rise to differentiated cells. There are two main

kinds of stem cells: embryonic stem cells isolated from the

`inner cell mass' of an early embryo, which are pluripotent,

in that they can develop into all cell types of the embryo;

and adult stem cells, found in adults, the best known of

which, until recently, are certain cells from the bone

marrow that can develop into all types of blood cells.

However, within the past decade, many more stem cells have

been found, not just in the bone marrow, but also in the

brain, the skin, the muscle, the gut, the liver, and other

tissues of the adult; and at least some of these stem cells

seem to have as wide a developmental potential as embryonic

stem cells.

 

Bone marrow cells, in particular, were found to give rise to

many cells besides those in the blood: in the skin, lung

epithelium, kidney epithelium liver parenchyma, pancreas,

skeletal muscle, heart muscle, endothelium, nerve cells in

the cortex and cerebellum. They have moved rapidly from lab

to clinic, especially in repairing damage to the heart after

a heart attack (see " Patient's own stem cells mend heart " ,

this series http://www.i-sis.org.uk/POSCMH.php). Another

source of easily obtainable stem cells is umbilical cord

cells, which have been routinely isolated from the umbilical

cord of the newborn for transplant therapy, and has made

headlines in successfully treating a woman paralysed for 19

years (see " Cord blood stem cells mend spinal injury " , this

series http://www.i-sis.org.uk/CBSCMSI.php).

 

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Turning eggs and embryos into commodities

 

There are two ways of creating hES cells depending on the

source of human embryos, which are destroyed in the process.

The first is from surplus fertilized eggs in fertility

clinics donated by the parents undergoing in vitro

fertilization (IVF) treatments. The second, much more

controversial, is embryos created by somatic cell nuclear

transplant (SCNT), which gave rise to Dolly the cloned

sheep. This involves transferring the nucleus of a cell of

an adult (such as the patient requiring transplant) to an

unfertilised egg that has had its nucleus removed, which is

then stimulated to develop into an embryo. In both cases,

the egg is allowed to develop into a hollow ball with `inner

cell mass', the future embryo, which is harvested and

destroyed to create hES cell lines.

 

The stated advantage of SCNT is that it avoids immune

rejection in the transplant patient by using the

individual's own genetic material to produce the embryo. It

is also euphemistically referred to as `therapeutic' human

cloning, to distinguish it from reproductive human cloning,

in which the embryo obtained by SCNT would be allowed to

develop further into a live birth, as Dolly was.

 

`Therapeutic' cloning gives genetically and epigenetically

defective ES cells

 

Reproductive cloning is now almost universally rejected,

mainly because the success rate is extremely low - it took

277 nuclear transfers to enucleated eggs to create a single

Dolly –and even when successful, cloned animals, Dolly

included, invariably suffer many genetic abnormalities and

incomplete epigenetic reprogramming (the heritable erasure

and re-marking of genes that's crucial to normal

development). Currently, the efficiency of nuclear transfer

cloning across all species is between 0–10%, i.e., 0–10 live

births after transfer of 100 cloned embryos [7]. Of about 10

000 genes analysed in mouse clones approximately 400 showed

abnormal expression patterns, especially in placentas [8].

 

Yet, defective embryos are routinely used to produce ES

cells, and positively recommended by some researchers [9],

who stated, " Perhaps genetically deficient cells may be

entirely suitable for somatic cell replacement. " That is a

large assumption, fortunately, not shared by other

researchers [10]: " We suggest that the wide range and high

incidence of epigenetic defects in nuclear transfer embryos

will preclude safe use of this approach [in creating hES

cells] until the procedure is dramatically improved. "

 

But if epigenetic reprogramming error is inherent to the

somatic nuclear transfer procedure, as pointed out by some

researchers [8], then it is a blind alley as far as tissue

replacement is concerned, even if the ethical concerns are

set aside. Yet, China, Singapore, UK and USA have already

legalized therapeutic human cloning (seeBox 2 [11]), and

Korean scientists reported the first hES cell line created

using this procedure in February 2004.

 

 

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BOX 2 please see

http://www.i-sis.org.uk/NCFESC.php for a correctly formatted

box 2

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The first hES cell line created by somatic cell nuclear

transfer

 

The research team in South Korea Seoul National University

made headlines in creating the first hES cell line by SCNT

[12]. The hES cell line proliferated for more than 70

passages, maintaining normal chromosomes and is genetically

identical to the somatic nucleus donor.

 

Actually, the nuclear donor and recipient were one and the

same – healthy women who provided both the cumulus cells

surrounding the developing oocyte (immature egg cell) and

the fresh unfertilised eggs. The nuclei from the cumulus

cells were transplanted to the egg of the same individual. A

quarter of the SCNT eggs reached the blastocyst stage (at

which the inner cell mass is harvested to create hES cells).

From a total of 30 blastocysts, 20 inner cell mass were

harvested, but only one ES cell line was obtained.

 

The research, led by Dr. Woo Suk Hwang, was soon mired in

controversy [13]. The team had recruited 16 women prepared

to have hormone injections to make them super-ovulate,

providing the 242 eggs that produced the single hES cell

line.

 

Citizen' rights activists and bioethicists complained of the

lack of transparency surrounding the recruitment of the egg

donors, and raised questions over how rigorously Hwang and

his colleagues followed the ethical guidelines laid down for

their research. One PhD student, a co-author and another

member of the lab were reported to have said they donated

eggs, but later denied it, blaming poor English for the

misunderstanding. The Korean Bioethics Association has

called for an enquiry concerning the recruitment of donors

and funding sources [14].

 

Even if one sets aside the ethical concerns of using human

embryos and eggs as instruments and commodities, evidence

has accumulated on the risks and problems of using hES cells

that are insurmountable.

 

Risks and problems of using hES cells insurmountable

 

Fatal teratomas

 

There is significant risk of fatal teratoma formations when

ES cells are used in transplant [15], that has been

highlighted for many years; and is a major deterrent to

progression to clinical trials. This alone has persuaded

Germany and Norway to prohibit research on fertilized eggs

[11]. The legislation regarding embryonic stem cell research

in Norway was recently changed to specifically ban both the

derivation and use (including import) of embryonic stem cell

lines.

 

Cross-transfer of animal viruses and other disease agents

 

All existing lines have been cultured on feeder layers of

mouse cells, and are hence unsuitable for transplant,

because it risks transferring mouse viruses and other

disease agents to human patients and creating an epidemic.

 

When President Bush gave the green light for research on

human embryonic stem cells in 2001, he said federal funds

could only be used for research on stem cell lines created

before 9 August 2001, and more than 60 were listed. But in

fact only 17 are currently available for distribution, and

only because the US NIH (National Institutes of Health) Stem

Cell Registry was created to document existing cell lines

and their availability, and to carry out initial tests to

assess of the quality of the lines.

 

Researchers have created their own hES cell lines since.

Douglas Melton's group in Harvard created 17 new lines, but

like all existing hES lines, are still grown on mouse feeder

cells, so their usefulness in clinical applications will be

limited [16]. There have been attempts to develop

alternative feeder or feeder-free culture systems, but these

were not optimal for deriving and growing clinical grade hES

cells, as they all use animal products of one kind or

another, and carry the risk of cross-transfer of animal

viruses and other disease causing agents [17].

 

Genetic instability

 

There are reports of high differentiation rates of hES cells

(which destroy their stem cell status) and genomic

instability after prolonged culture [18]. For example, some

hES cell lines display a certain level of aneuploidy (gain

or loss of chromosomes) including the gain of chromosome

17q, chromosome 12 [19], trisomy 20 (three copies of

chromosome 20) or abnormal X chromosome.

 

Epigenetic errors

 

There are also frequent epigenetic errors in hES cells.

These include differences in the expression of SSEA-4, in

telomere length, the down-regulation of collagen, STAT4, a

lectin and two genes involved in TGFb signalling, which have

been described in different hES cell lines derived in the

same laboratory and cultured under feeder-free conditions

[18, 20].

 

Genetic and epigenetic heterogeneity among hES lines

 

Existing hES cells lines are by no means all characterized.

But those that are show considerable heterogeneity even in

the same laboratory.

 

Three different hES cell lines in the same laboratory

expressed 52% of genes examined in common, but the

expression of 48% of the genes was limited to just one or

two of the cell lines [21]. In addition, not all hES cell

lines maintain their pluripotency under the same culture

conditions, their potential for large-scale culture and

growth under feeder-free protocols, or their ability to form

teratomas after injection into SCID (severe combined immune

deficiency) mice. Moreover, their capacity to differentiate

spontaneously into different cell types under in vitro

conditions is variable [22].

 

The reviewers stated [17], " To our knowledge there is no

study which describes the epigenetic status and stability of

different hES cell lines or even one hES cell line after

long-term culture. " And later, " ..it is of concern that

application of genetically and epigenetically unstable hES

cells in transplantation therapies could be detrimental. "

 

The problem is deeper. Such variability among hES cell lines

could mean that knowledge of one cell line would not apply

to another line; and worse, if they are unstable in culture,

then there can be no possibility for quality control.

 

No applications in the foreseeable future

 

Other commentators stated [11], " Due to the number and

severity of the technological challenges remaining to be

solved before the initiation of large scale clinical trials,

embryonic stem cells are not likely to be a part of routine

clinical practice in the foreseeable future. "

 

High costs unjustifiable

 

The technical difficulties in derivation and culture of hES

cells could be expected to involve high costs, especially

when these cell lines and procedures can attract patents. It

is difficult, therefore, to justify allocation of such large

amount of public funds in supporting hES cells research and

in maintaining hES cell banks, that could be much better

deployed elsewhere; as, for example, in supporting research

and development of adult stem cells (including cord blood

cells).

 

Exacerbating health inequalities

 

Another objection to hES cells research is that it will be a

very costly procedure, even if it succeeds, and will

exacerbate the global inequalities in access to healthcare

[11]. Populations in developing countries have more urgent

diseases to fight, and they will be that much more

disadvantaged if large portions of the available funds are

diverted towards developing hES cell technology by the hype

and misinformation surrounding it.

 

 

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Box 3

Advantages of adult stem cells

 

 

Long clinical experience in use and

handling of bone marrow cells and cord blood cells

 

Neither cells nor procedures attract patents

 

Developmentally as flexible as ES cells

 

Numerous promising results in repairing tissues and organs

including brain and spinal cord

 

Easy to obtain Can be harvested from patients requiring

treatment thereby avoiding immune rejection

 

Easy to use Can be used directly without expansion

 

Can be expanded in culture if necessary

 

Genome stability maintained in culture Growth and

differentiation controllable Low risk of cancer and

uncontrollable growth

 

Low risk of cross-infection with animal viruses and other

disease agents

 

Many successful clinical treatments reported

(heart-repair documented in randomized trial)

 

Repair damaged organs and tissues in situ, without major

surgical intervention

 

Minimize intervention, side effects and risks

 

Minimize costs and hence potentially widely available to all

 

No ethical concerns over their use

 

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Why we should support adult stem cell research instead

 

We have stressed the advantages of adult stem cells [6] as

opposed to ES cells two years ago (see Box 3 for an updated

longer list). Adult stem cells, in particular, bone marrow

cells and cord cells, already have well-established clinical

histories; and cannot be patented. They have shown great

promise and potential in treating a variety of diseases (see

Box 1), including more recently, brain and spinal cord

repair in animal models [23]. Adult stem cells can be

harvested directly from the patients requiring transplant,

and used without culture or after only brief periods of

culture, thereby avoid immune rejection and all other

technical problems and risks arising from prolonged cell

culture. Adult stem cells appear to have all the

developmental potential of ES cells - even though the

precise mechanisms are debated - without the risks of

cancer. On account of the ease of harvesting, handling and

use, and the lack of patents, costs are minimal, and hence

the treatments developed are likely to be widely available

to all. Finally, there is little or no moral objection to

using them.

 

 

 

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