Hybrids: separating hope from the hype

Recent weeks have seen a furore erupt over controversial laws that would allow the creation of human-animal embryos for research, with much talk of the sacredness of human life and the danger of scientists playing God.
Human-animal embryos have caused controversy in recent weeks

But there are some, both professors and priests, who are using the facts in ways that are at best selective and at worst misleading. More importantly, even though proponents say there is a moral imperative to do hybrid embryo research to find cures, some scientists are sceptical that it is worth diverting money from more promising research.

Last week the news emerged that Newcastle University had created the first European hybrids, a blend of cow and human. The coverage made much of how the embryos could yield highly flexible parent cells, or stem cells, that could be used in a dizzying array of treatments, from diabetes to heart disease.

This is precisely the kind of science that the Embryology Bill is designed to address, and that has caused such bitter argument. Opponents of the Bill try to convince the public that embryos are "people" whose "body parts" will be raided by monstrous researchers to make "Frankenstein creations" (in fact these "people" are microscopic balls of cells).

Yet some scientists have also been manipulating the media when it comes to the most divisive part of proposed legislation, to allow "admixed human embryos". They have underplayed concerns by their peers that this work is speculative by downplaying the role of animal DNA.

In the Bill, these embryos could result from a human egg and animal sperm, or blends of cells from animal and human embryos (chimaeras). The Newcastle team made another version, a "cybrid".

This is created by inserting human DNA, in the form of a broken human cell, into an empty animal egg, in the same cloning method used to make Dolly the sheep.

This work will be high on the agenda of the first national stem cell research conference being held in Edinburgh this week. There is a need for more science in the public debate because the animal DNA does a special job in these embryos, one which diminishes their direct relevance to cures.

The cells in our bodies contain two kinds of DNA. Most research concerns nuclear DNA, so named because it resides in a compartment in the heart of cells called the nucleus. This DNA comes from our parents, and provides the recipe for the proteins that make and run the body.

Variations in this genetic message have been linked to the inheritance of individual characteristics, and also to hereditary diseases and risk of illnesses.

The animal DNA in the cybrids would be of the second kind, which resides in lozenge-like structures outside the nucleus called mitochondria. These are power packs that we inherit from our mothers.

Scientists say that cybrids of human and animal are "99.9 per cent human", in order to comfort those who think (wrongly) that an embryo would end up with horns or hooves. But this figure misleads the vast majority of people, who know little about human biology.

There probably is about 0.1 per cent animal DNA by weight when there are 500 cells in the embryo. But in the initial embryo, there are 100,000 copies of the mitochondrial DNA, around half animal DNA by weight.

This proportion declines because only the nuclear DNA replicates at first. In addition, some human mitochondria could come along for the ride with the human nuclear DNA and persist as the cells grow, perhaps even take over.

The 99.9 per cent figure probably refers to the fact that there are 37 instructions (genes) in mitochondrial DNA, compared with 29,000 in nuclear, which means 0.1 per cent animal instructions. But this is hardly reassuring.

Decades of work has shown that even one genetic spelling mistake in the three billion letters of the nuclear code can be fatal - just 0.0000001 per cent. And mitochondria are important: faults in them are responsible for around 50 metabolic disorders that affect one in every 6,500 people.

This includes fatal liver failure, stroke-like episodes, blindness, mental retardation, muscle weakness, diabetes and deafness.

Some claim that using animal mitochondrial DNA in cybrids would be like changing a battery in a computer, leaving the "hard disk" - the nuclear DNA - unaffected. But Dr Marc Vermulst of the University of Washington in Seattle, who has linked changes in mitochondria to premature ageing, says: "In flies, if you mix the mitochondrial DNA of one strain with the nuclear DNA of another strain, the mitochondria of the mixed strain work less efficiently than they normally would.

By evolving together, mitochondria and nuclei have become very finely tuned to each other. I am not sure how well human and cow DNA would communicate with each other. That would be very important."

Although a pioneering study in China suggested rabbit and human could be successfully blended, using animal mitochondria in human cells could sometimes be like trying to put AA batteries into an AAA compartment.

For animal and human DNA to work in harmony is "a big ask," says Prof Neil Scolding, a Catholic stem cell researcher at Bristol University. Prof Jun-Ichi Hayashi, of University of Tsukuba, who in the latest issue of Science shows that mitochondrial mutations can encourage tumours to spread, has also - unsuccessfully - tried to make mouse nuclear DNA work with rat mitochondria.

"It is clear that human embryos with animal mitochondrial DNA may develop in the initial stage," he says, "but [they] could not survive any further."

Prof Scolding points out that, thanks to pioneering work in Japan, there is now an egg and embryo-free alternative source of stem cells, albeit one that might present other ethical issues (such as the ability of men to make eggs).

"That has led scientists all over the place (including Sir Ian Wilmut, the creator of Dolly) to embrace this technology. Which makes it all the more inexplicable why a small minority of UK stem cell scientists wants to pursue the extraordinarily complex and frankly speculative hybrid approach."

For many scientists, such as British stem cell pioneer and Nobel prizewinner Sir Martin Evans, resolving such issues provides a clear scientific rationale for using cybrids to find out more about the basic role of mitochondria in development and in disease.

There is, for example, research at Newcastle to transplant healthy human mitochondria to treat serious metabolic diseases that could benefit from that. However, the hard sell has been about the medical use of cybrid stem cells - not by using the cells themselves in human bodies, but to test drugs and study disease.

When even human stem cells are poorly understood, it will take a lot of slogging to show whether cybrid stem cells will behave properly. Here, even Sir Martin feels the immediate potential has been hyped and claims about cures "overheated".

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