Re: animal donors with human genes

Hi Stephanie,

Thanks for writing in - i hope i can answer some of your questions, as a geneticist (although not of the white-coat wearing variety anymore), and as someone who is concerned about the ethical and medical implications of cloning. i hope i can convince you that we should be cautious in our use of these important new technologies.

You're right about the potential use of cloned animals as organ donors for humans - its potentially very important. The idea is that by getting, say, a pig with a few human genes to replace those pig genes that cause an immune response in people, we could use say, pig hearts, livers, etc etc. The tecnology to do this is probably not too very far away, and research on this was continuing until a fairly recent moratorium in the UK - I think its still on-going in the US. The difficulty is in getting the right genes in the right place in the pig genome, but this is more a question of hard work and time than many particularly tricky technological breakthroughs, from what i understand. There are reasons to be very cautious however - for example, some recent research has shown that vertebrate retroviruses have switched host between vertebrate species. Retroviruses can lie dormant in the genome of a species for many generations, but a pig retrovirus in a human body could, potentially, be re-activated and cause devestating disease. We just don't really know. There are also many people who doubt if we could ever get a pig organ with the right 'immune profile' to avoid rejection by humans, but i'm not enough of an expert to comment on that.

You say that you don't understand why anyone would think of using cloned animal organs for transplant when we can clone humans. Presumably you suggest using organs from cloned humans instead? I think its important to remember two things.. being able to 'clone humans' isn't the same as being able to clone a particular body part in isolation. Potentially, we could create a human clone through nuclear transfer - the technique used to create Dolly the sheep - but this would be a human life, complete and every bit as much of an individual as identical twins. A young cloned child would grow up with a personality and mind all of its own. It would be ethically wrong - murder, in fact - to create such an individual just as a source of body parts for other humans. You may have got confused with the use of cloned embryonic stem cells, which potentially COULD be used to create an isolated organ with a particular genetic make-up, but we are still a long way away from doing that. Finally, even if we were willing to clone humans for use in this way, which i think no-one is, it would take many attempts to create a single cloned organisms - for dolly, it was 277. We may be willing to use this many animal ova in this way, but i don't think many women will be willing to donate ova with these chances of success.

To answer the second part of your question, you need to understand exactly what we mean by saying some piece of DNA is a gene 'for' some characteristic of an organism. When we say that scientists have identified a gene for cancer, or multiple sclerosis, we don't mean that the particular gene exists to cause cancer, of course - it does some other particular job in the body, perhaps creating an enzyme involved in altering the properties of particular fats, or even just a protein that switched on or off, or reduces the activity, of a different gene. The same gene can increase someone's chance of internal bleeding while descreasing someone's chance of some forms of heart disease, for example - by thinning blood - so genes can have more than one effect on an organism. Similarly, more than one gene will affect most characteristics - scientists have identified many, perhaps even hundreds, of genes that can have an affect on blood pressure. Geneticists call one gene having multiple effects 'pleiotropy', and multiple genes affecting one particular character, so that these gene's effects interact, is called 'epistasis'. Its important to realise that these aren't special cases, but happen in most cases - the easy examples of classroom genetics, like Mendel's wrinkled and smooth peas, and Drosophila eye-color, are the special cases.

So we now know that saying something is a gene 'for' something simply says that having a particular form of that gene - a particular allele - increases the probability of the organisms showing a particular trait. So a gene for cancer might only increase the chance of a person developing cancer by 1% or even less, and even then might only increase the chance against the background of certain other genes. This become obvious with a few examples. A certain form of the haemoglobin gene causes the debilitating disease sickle-cell anaemia in humans. It's a gene for sickle-cell, but what it actually does is build part of the haemoglobin protein which transports oxygen in the blood. However, it only causes sickle-cell when homozygous, so many people carry this gene without the disease. Even when heterozygous, however, the sickle-cell allele increases resistance to malaria, so this allele is for two different phenotypic affects. The complexity of genetic affects is perhaps even better emphasised by another example, which I've stolen from somewhere but can't remember where. There's a gene on the Y chromosome of humans that is a gene for a violent temperament. its called SRY, and is quite a famous gene. Just saying that SrY is associated with violence hides most of the biological detail, however - SRY is the 'master switch' for maleness! More males are violent than females, so SRY is also a gene for violence.

Having gone on about that for a while, I can try and answer your question. If we genetically engineer humans to replace disease causing genes with 'healthy' ones, we will be replacing many, many genes, and in the process, greatly reducing the diversity of the human race. Its all a question of how far we're willing to go. Most people (including me) wouldn't object to gene therapy for severe disability like Cystic Fibrosis or Haemophilia, but some disability campaigners would object to this, saying that it denies the worth of the life of people with these conditions. I don't entirely agree with them, but I hope you understand their point of view, and can sympathise with it: we wouldn't deny that disabled people like Stephen Hawking, the astrophysicist, have made an important contribution to the world, but all disabled people make a contribution to the lives of friends, relatives and local communities. Should we provide gene therapy to reduce the risk of heart disease, stroke and cancer? It might seem ethically obvious that we should, but in the process, we might be 'treating' people who would never have developed any disease, and we could have no-one with rosy cheeks, no-one slightly overweight etc etc. We don't know how many little features of other people we'd be eliminating in even the most targeted gene-line therapy. What if a gene for blue eyes very slightly increased the risk for a particular disease - should we eliminate blue eyes, as an acceptable cost for a healthier population. I should say not. In fact there's a very obvious example i've just thought of - fair coloured skin increases the risk of skin cancer greatly, but no-one suggests 'gene therapy' for all caucasian people. As far as i know.

By the way, no-one knows yet how many genes humans have, until analysis of data from the human genome project is complete. However, some experts have been involved in a sweepstake guessing at what the total will be, and it seems likely that there will be between 40 and 80 thousand genes in total. I guess you're figure of about one-fifth of them being associated with an increased risk of some disease will be about right, though.

On the cloning question, the Roslin institute - where Dolly the sheep was born - has a set of notes about the technology and its implications Ros lin Institute notes on cloning.

I hope i don't sound too anti- the whole gene therapy and cloning technologies. I'm not against these new technologies, and they will certainly eventually come to play an important role in medical treatment for certain conditions. I do hope, however, that i've explained some of the reasons why certain people - from disability campaigners to cautious scientists like myself - recommend we should be very cautious in using these technologies.

Hope this helps, and wasn't too polemical.
Yours,
James