Clones, identity and the future
She was ‘a miracle baby’ conceived after a long wait and several failed attempts. People said it could never be done. Her adoptive parents were becoming frustrated. Cells had been taken from breast tissue donated by a healthy relative. These cells were in a resting state and DNA from one of the cells was extracted and put into a scooped-out egg cell without a nucleus (i.e. with no DNA). The DNA and the new egg lining were fused together by a short burst of electricity to form a single cell that started to divide within a few days. This group of cells was then transplanted into a surrogate mother. She was happy to nourish the adopted fetus until she had a normal delivery several months later and then handed her back. To general joy, the baby was born, and appeared to be normal and healthy in every way.
When she was older she managed to produce several normal children naturally. However, when she was in her early forties she started to develop pain and problems when running. This spread to pain even just walking, and she was diagnosed as having premature osteoarthritis. She deteriorated rapidly and also developed progressive lung problems and trouble breathing, despite never smoking. Lab tests showed she had shortened telomeres on her chromosomes (the markers of biological age we have mentioned before), suggesting that she was ageing twice as fast as her contemporaries. Sadly she died soon afterwards, and although she personally never spoke to the press, being such a celebrity she was deeply mourned around the world.
This birth was no ordinary IVF treatment. Rather than taking the egg and sperm from two individuals, the baby was created from a single genome of one individual – and the baby was Dolly the sheep. She was named by her creators Ian Wilmut and Keith Campbell after Dolly Parton, in tribute to the mammary source of her DNA. She died prematurely in 2003 aged only half the normal lifespan – the first successfully cloned mammal. This was the first time a differentiated adult cell (somatic cell) had been reprogrammed backwards to become a simple universal cell that could develop into every cell the body needed. It was a great breakthrough that earned Wilmut and Campbell a Nobel Prize. As so often in science, someone had in fact got there first, but without the same worldwide recognition. John Gurdon, a modest Cambridge scientist, had done much the same thing 40 years before when he cloned a tadpole from a mature frog cell and showed that reprogramming cells back to their original state was possible.1
Despite the excitement of the scientific world, Dolly’s early death raised a number of questions about reproductive cloning. The first was how difficult it was. Dolly was the only success in 277 attempts and was incredibly costly, making this a poor method for a commonplace procedure. The second problem was the small but consistent ageing defects in Dolly that were also picked up in other animals that have been cloned since. The DNA of Dolly and her genetic mother were identical, so any differences had to be epigenetic. Something about the process of artificially creating the egg may have bypassed some of the normal processes of clearing the epigenetic signals that occur when a sperm and egg fuse.
Since 2004 attempts to clone pets by companies like Genetic Saving and Clone have produced a few cats. Little Nicky was the first created for a bereaved Texan lady for $50,000, and BioArts International Inc successfully cloned Missy the dog. But most commercial programmes have now stopped, because of the high failure rate, early deaths and complaints by customers that often their beloved animals don’t look or act exactly the same. As an example, the very first cat to be cloned was called ‘cc’ (for carbon copy) in 2002, after 87 failed attempts. She was a cute brown and white tabby cat, but unfortunately looked nothing like the genetic original, which was a tricoloured calico (tortoiseshell). The reason for this was that the colour banding on the fur hairs is caused by imprinting of one copy of the X chromosome, which is naturally random. This means that because of epigenetic differences even clones – despite sharing the same DNA sequence – are not going to have the same colouring. She apparently also had quite a different personality to Rainbow the original, and it’s highly likely that there were myriad other differences under the surface.
A Korean team (RNL Bio) who have cloned several wolves and dogs have been more successful, and after cloning five copies of an original pet ‘Booger’ for a grateful US customer are now offering the service for a mere $150,000 a puppy. In China they recently cloned five piglets from a 150 kg castrated hog (named ‘Strong-willed pig’) that became a porcine national hero after surviving an earthquake, buried in rubble for 36 days. But if you’re not that rich and you are interested in cloning your pet – you can’t just dig up Fido from the garden – you need to be well prepared in advance and use fresh or cryo-preserved cells. The good news is that for only $6,000 you can have your favourite cat or small dog cryo-preserved. Goldfish are much cheaper.
The dawn of reproductive cloning in humans was announced to the world in 2005 by the South Korean scientist Woo-suk Hwang. After successfully working on dogs, he published a study showing that he had created embryonic stem cells from skin cells that could grow into a potential human fetus. He became a national hero. Sadly he got into trouble, first for taking eggs from the ovaries of his female research staff, and then accused of fraudulent research. He (like others before him) initially claimed his work had been sabotaged, but he was exposed and the scientific papers retracted.
About the same time as Dr Hwang was being exposed as a fraud, a Japanese group led by a young Shinya Yamanaka had made a real breakthrough after years of genuine research. He managed to shock adult skin cells back into their primitive multipurpose (pluripotent) state as stem cells using a cocktail of four natural chemical factors.2 In other words, he turned back the clock on fully developed cells so that they ‘regressed back’ into an earlier state. Although these are not quite the same as embryonic stem cells and can’t create a whole human being, they are amazingly useful in medicine and can in theory produce and so replace most other cells in the body, such as neuronal, pancreas and heart cells.3 The key chemical factors used to shock the adult cells to regress are under tight epigenetic control, showing how the two processes are closely linked.4 We have started looking at stem cells from identical twins and have already found differences in how they grow and respond.
But what about the common procedure of producing test-tube babies, also known as in vitro fertilisation (meaning combining the sperm and egg outside the body in a glass or plastic tube)? Could epigenetics be a complicating factor in that process which occurs outside the normal process of the cell? The first IVF baby was created by Nobel Prize winner Robert Edwards in 1978, and IVF is now commonplace, with millions born every year. However, there are downsides that may emerge with time. Studies show that rates of certain birth defects seen in the first year (like cleft lip, heart defects and club foot) are approximately double those expected in normal pregnancies.5 A certain number of rare diseases, which include Beckwith–Wiedemann syndrome, are up to six times more common – diseases caused by imprinting (the turning off epigenetically of one copy of a gene or large chromosomal section).
So although most children born to IVF are healthy, clearly some epigenetic problems do occur which could cause disease problems later in life.6 The issue is complicated by the fact that 20 per cent of infertile males have imprinting defects in certain key genes. These same sub-fertile males are likely to use IVF anyway to have kids, and so may pass on these epigenetic defects directly to their children. This is in addition to any effect of the artificial process on the genes.7 No IVF kids have yet lived for more than thirty years – the time for which the treatment has been available – so we don’t know yet whether they will in the future develop any age-related diseases associated with abnormal imprinting or epigenetics. It is however clearly a worrying possibility.
The other group that has flourished and grown thanks to IVF is twins. It is estimated in Western countries that over 25 per cent of newborn twins are due to IVF – many of them it seems these days to Hollywood celebs. The usual reason is implanting several fertilised eggs as a back-up in case one fails, so they are usually non-identical twins. Some studies have shown that IVF twins tend to be born slightly smaller and earlier than natural twins and have more medical problems soon after birth.8 A recent Chinese study in 59 IVF twin pairs has shown greater variability of epigenetic signals than expected.9 We are currently exploring rare identical twins born by IVF with a Melbourne team to see if they have more early epigenetic differences as they develop.10 As we discussed previously, chemicals in plastics could interfere subtly with our genes. Some studies suggest that multipotent embryonic stem cells stored in plastic plates have more epigenetic changes than natural ones. This could explain why eggs or sperm stored in plastic could have minor epigenetic memories that stay with them during their development.
While IVF babies have been with us for 30 years, and problems are mainly theoretical, producing human clones safely is still a long way off, both scientifically and legally. But what would it be like to be a human clone? Much of our perception comes from our cinema screens. Science fiction films such as The Island, Multiplicity, The Surrogates, Sleeper and The Stepford Wives generally depict either doppelgangers with a shared mind and identity or robotic automatons. I asked some 13- and 14-year-olds about human cloning – they had just heard Professor Wilmut at the Royal Institute Christmas lecture talking about Dolly the sheep. They were unanimously opposed to the idea.11 The irony was that I was asking identical twins who were all clones themselves. Other more rigorous population surveys of students show similar patterns, with many wanting to ban the creation of a theoretical belated twin born years later.12 My view is that our sense of identity is so strong, we have such a powerful sense of ‘I’, that you would probably never ‘feel like a clone’. Identical twins are probably more similar to each other than any artificial clone could ever be, sharing the same time and space with each other, yet they feel completely different.
When with my colleague Barbara Prainsack, who works in the developing field of the politics of bioscience, we asked the views of several thousand identical twins by questionnaire, 45 per cent said that reproductive cloning should never be allowed for any reason, even for medical purposes.13 When Barbara probed more deeply in one-to-one interviews,14 she found that what most upset the twins was the idea that whoever was overseeing or planning the cloning – ‘the cloner’ – had an ulterior motive, which would upset the clone. Whereas the identical twins were created by ‘chance’, and so had no ‘cloner’ to blame. Another fear they had was that because of their physical similarity the clone pair would be mistaken for having the same personality and therefore a lack of individuality. This mirrors a common complaint of twins: they hate being referred to collectively as ‘the twins’, as often happens in families and social groups. So can the experiences of twins inform us all about our own feelings of self?
One of the main arguments against human reproductive cloning is the ‘loss of dignity’ compromising the individuality of the clonee. Ian Wilmut, the creator of Dolly the sheep, doubts ‘that a clone would necessarily have the same opportunity for individual development as a child produced by sexual reproduction’.15 National governments were asked by the UN to ban human cloning because it was seen as ‘incompatible with human dignity’. Part of the rationale underlying this claim is the concern that a person who has purposely been created genetically identical with another person is likely to suffer from greater difficulties in developing an individual identity. The UN clearly hadn’t sought twins’ views on the nature of individuality.
Jessica and June were identical twins whose views were quite typical. Jessica said: ‘People still now always look at us as one person. They don’t see us as individual people.’ Said June: ‘People always thought if there’s something wrong with one of us, there’s also something wrong with the other. They think that because we’re identical, everything’s exactly the same. They never look for any differences. Earlier in our lives we were referred to as “the Twins” or “the Twinnies” and hardly ever as individuals. That was always very annoying.’
When we asked non-identical twins about whether they would have liked to be identical, the universal response was No. As fraternal twin Sara explained: ‘Oh God, yeah. Because I believe in your own identity, you know? You’ve got this other person who looks like you. I find this a bit too sickly, you know … They’re dressed the same, they’ve the same mates. No! It doesn’t seem as if they have their own identity! There’s something very unnatural about identical twins.’ Yet, like all the identical twins we spoke to, Jessica and Jane would never swap places with non-identicals.
Alexis and Saffi, having grown up thinking that they were not identical twins (the paediatrician had drawn that conclusion from the existence of two placentas at their birth), found out that they were MZ twins when we tested them. Saffi describes the effect this had on her and her sister: ‘To actually be told that we were actually one egg that split rather than two separate eggs made the bond much stronger, as if we had that bond anyway. Finding out [that we were identical] was the missing piece of the jigsaw. Knowing we are clones doesn’t change the way we feel – we are still different people that share many things in common.’ According to these MZ twins, being identical twins means being made of a different ‘stuff’ than just genes. In general they didn’t believe their behaviour was predetermined.16
The fact that people don’t usually wish to swap places is perhaps part of the general human phenomenon that you value more something you already have, as opposed to what you might have – the so-called endowment effect. While the vast majority of twins are very happy being twins and dismiss genetic determinism, a few twins are not so happy.17 We have several identical twin pairs who attend our research sessions on the understanding that they never meet their co-twin, with whom they are in permanent dispute. Sometimes twin or normal sibling rivalry can be unbearable.
The Han twins Gina and Sunny were born in South Korea, but moved to San Diego as teenagers. They both did well at school, but were very competitive and from when anyone could remember were always fighting. Sunny was the first born by a few minutes and in Korean culture was favoured. Schoolmates and teachers recalled that ‘although both were bright and attractive, Sunny was the more outgoing and popular’. After school they first did waitressing but then separated. Gina became a croupier, which was well paid, but she couldn’t keep up with the gambling habit she had picked up. Sunny was more successful. She enrolled as a student in a university outside LA, wore designer clothes and drove a new BMW. This was all done without any obvious source of income. Some of Sunny’s suspicious wealth came from stolen credit cards, which she was eventually arrested for, but managed to avoid jail. Meanwhile Gina’s debts increased and one day she stole Sunny’s cards and car. A fight ensued and Sunny broke Gina’s nose and pressed charges, so that Gina would have to serve jail time.
Gina, driven by envy and revenge, was not a happy twin, and a few months later she was looking for help in murdering her sister. ‘I want that bitch killed,’ she said. She used her looks and powers of persuasion to find two gullible teenage boys to help her. They bought rope, duct-tape and some guns. While she waited in the car, the boys broke into the house posing as salesmen and tied up Sunny’s flatmate Kim and then Sunny herself, and put them both in the bath with a gun to their heads. Luckily Sunny had rung 911 on her mobile seconds before the boys discovered her, and the police were just round the corner and arrested them both. The next day they tracked down her sister. At the trial Gina contended that she only ever meant to scare Sunny: ‘I loved her, as we are the same blood.’ The jury didn’t believe her, and she is serving 26 years in jail. Her sister Sunny seemed full of remorse – ‘When you think about whose fault it is for Gina’s conviction, it’s probably my fault,’ she told the local paper. However, her guilt had worn off when she happily sold her exclusive story to the media for another $100,000. Gina is due to be released on parole in a few years and it would be interesting to sit in on the family reunion.
Though few twin disagreements are this extreme, the story of Sunny and Gina shows the possible dangers for some personalities of competing continuously with someone others regard as so similar. This rivalry and urge to be different is frequently seen also in non-identical twins and normal siblings who share only half their genes. The fact that identical clones (twins) also often feel they are very different to their clone, and that genes are not that important, perhaps gives us clues to our own views of self and our individuality. To return to the conjoined identical twins in our preface who shared a part of their bodies, they still felt very different and wanted independence even at the risk of death. It would appear we are programmed to think and be that way – so that we can be distinguished more clearly. This is why, as we saw earlier, twins tend to react more differently than expected to the same stimuli, such as parents or schoolteachers.
We have seen lots of examples where nature sets up a part of our non-crucial development to be random and variable, and this variability or plasticity can be counter-intuitively considered hard-wired. It is as if nature and evolution didn’t want us to be too similar to each other – perhaps this is part of the success of the human race – and plays a role in our ability to adapt and survive when thousands of other species have failed.
In the 1978 SF thriller The Boys from Brazil, which starred Gregory Peck, Hitler’s ear is used to clone new versions of himself 25 years after his death. Now that we understand the crucial role of epigenetics, it looks far more likely that if Hitler’s theoretical clone were alive today, and without knowledge of his progenitor, he would be a grumpy retired painter and decorator, not an evil tyrant. Without the trademark bad haircut and small moustache it is unlikely that he would even be recognised, although the facial features and mannerisms would probably be close.
The title of this book is Identically Different. We have seen how genes closely determine our anatomy and looks, and to a large extent most of our unconscious mannerisms, such as the way we laugh or drink a cup of tea. Humans are very sensitive to subtle facial clues and body language to help avoid danger and pick sexual partners. In this way strangers think twins are spookily alike, and often brothers and sisters will appear to a stranger more alike than they or the family perceive. But superficial appearances and mannerisms cloud our views and exaggerate the very real differences in identity and personality. The genes that ensure our flexibility and randomness (plasticity genes) may be protecting us in subtle ways. They ensure greater variation and unpredictability in the characteristics of each generation when exposed to changing environments. This variation is crucial to human survival: without it we might all perish by reacting in the same way to famines, epidemics, gluttony and natural disasters.
When we are young and our quadrillion or so nerve connections are getting established, some neuroscientists believe that each brain network starts to behave semi-autonomously, rather as if each group of brain cells was evolving like a natural animal species – so-called Neural Darwinism.18 This would help explain how even identical brains develop differently as groups and networks of neurones expand by a trial-and-error method. Remember also that memories may actually be formed by reversible epigenetic signals such that an epigenetic change influencing one set of neurones will have knock-on effects on many others, and alter our perception and recall of memories. This autobiographical memory (which in all people contains false memories) is a key part of what we call our personal identity, which is made up of a bundle of neural processes, not of any single brain entity.19 As identical twins have different autobiographical memories, this could explain why even conjoined twins have no problem in separating their identities.
In the classic 1997 SF film Gattaca (the title is made up of the four letters of the genetic code), Vincent, played by Ethan Hawke, says: ‘I belonged to a new underclass, no longer determined by social status or the colour of your skin. No, we now have discrimination down to a science.’ He was conceived and born naturally, which put him at a major disadvantage. His genes, tested routinely at birth, just were not up to scratch. He was correctly predicted to have myopia and a heart defect that would probably kill him at 30.2 years of age. His genes and diseases only allowed him to perform menial tasks. His dream was always to be an astronaut and go to Saturn. He impersonates a genetically perfect alpha male who is paraplegic after a failed suicide bid by using his DNA – and against the odds achieves his dream.
How does the reality stack up? With today’s knowledge, how would Gattaca play out in the future? We know from our twins that the precise genetic predictions in the film, based on structural DNA, are not going to be possible. In the film, most births are artificial, but we now know that this may present insurmountable epigenetic problems, so as a model of a future society, the Gattaca vision may be flawed. However, as in the film, it does seem likely that genetic testing with sequencing will soon be as routinely performed as a blood test is today. It is likely, too, that within ten years gene sequences will be available for the same price as a routine blood screen. The screening test would be performed on the IVF embryo or the pregnant mother’s blood, detecting the DNA in a few floating fetal cells. This test would likely be a combination of DNA sequence and epigenetic changes plus a protein and metabolite analysis. The combination of these checks would give the future paediatrician/geneticist a good idea of any potential medical or genetic problems that could be fixed early.
At birth, a repeat of the protein and epigenetic analyses would be carried out, and then repeated at yearly intervals to check development was normal. This will be performed from collections of blood, nail clippings, hair and the lining of the mouth, to check the different cells and tissues. The Gattaca infant will be checked for skin, oral and fecal bacteria, to make sure that the correct ratio of healthy bacteria are present. Any abnormalities will be corrected with epigenetic smart drugs and vitamin and bacterial supplements. Functional brain scanning in combination with epigenetic assessments and tailored diets will be used to maximise every baby’s potential. Selection of sperm and ovaries that are free of mutations and epigenetic defects will be possible, reducing miscarriages and genetic diseases. The clear difference with the film will be that our understanding of epigenetics and the unpredictable nature of our development will mean that genetics is unlikely to be used to write people off: instead, it might just be possible to use genetics to realise their potential.
Although there is much still to be understood about epigenetics, with what we have learned already we can now rewrite irreversibly at least four key genetic doctrines outlined at the beginning of the book.
The first assumption we have overturned is that our genes are the essence of humans, our blueprint, or the code of life. Because DNA was seen at the centre of all our cells, for a while it was believed to represent the core of life. The gene’s overhyped reputation has been helped by its accepted and infallible use in forensics, as well as through the influence of authors such as Richard Dawkins, who proposed that humans were just robot-like carriers of these self-replicating ‘selfish’ genes.20 We have shown how genes, though still important, have lost their privileged and prominent status, particularly as the distinction between nature and nurture disappears.21
Genes are certainly star players in the body, but they can’t act alone and are one part of a complex team. The cell that hosts them is also a vital member of that team. The cell produces the proteins and enzymes that do the body’s work and maintains all the other key cellular mechanisms, including those that turn the genes on and off – from the longer term epigenetic effects such as methylation to the shorter term fine-tuning effects of small RNAs and gene expression. The cell, its genes and its other components could be compared to the orchestra company, with all of its instruments, roadies, and sales and marketing team. Perhaps, though, we have been searching in vain for an elusive conductor of this orchestra – a genetic soul. We are all super-complex organisms formed by interacting networks of cells, their genes, the systems that modify the genes, their expression and the way they work together. It turns out that the rules that govern the orchestra are far from rigid, and the music it produces is anything but predetermined. Just as you can change your lifestyle and the music you make – you can also change your genes.
The second assumption was that genes and heritable genetic destiny can’t be changed. But we now know that this is the exception and not the rule. Predictable determination occurs only in rare diseases, as when a single gene mutation in Huntington’s disease causes early dementia and death. But even with this disease you can’t predict exactly what will happen in terms of disease severity or timing of symptoms. Epigenetics still plays a role in these most simple genetic disorders, and for example clinical trials are ongoing to modify the Huntington gene using the histone-modifying drug SAHA, used in cancer.
The third assumption is that a single environmental event cannot plant a lifelong memory within your cells. It was believed that any changes were wiped clean every time the cell divided. We now know that this memory can occur by epigenetically influencing your genes, which replicate and produce daughter cells with the same epigenetic messages. The most sensitive and influential times for these epigenetic signals are during development before or soon after birth, but they can occur at any age. As we saw with Romanian orphans and abuse victims, the epigenetic signals persist in your cells long after the event.
The final assumption is that the effects of your parents’ or grandparents’ environments can’t be inherited by you. This is the essence of the ‘inheritance of acquired characteristics’, or ‘soft inheritance’, proposed by Lamarck and accepted as possible by Darwin. Despite the ridicule this received for most of the last 150 years, we now know that it can occur. We have clearly seen the effects of famine and diet changes across three generations, both in humans and in other mammals, and we now have a mechanism to explain it.
The most important lesson that we’ve learnt is that you can change your genes, your destiny and that of your children and grandchildren. It really does matter what you do to your body, and importantly what your grandparents did to theirs many years ago. They may have faced stressful situations like famine or sickness that couldn’t be avoided, but perhaps you might face life choices like quitting smoking, going vegetarian, or changing your bacterial gut flora. These could influence your life and possibly several generations. We don’t know how most of these changes work yet, but if the amazing discoveries from the epigenetic revolution in the last few years are anything to go by, it’s going to be an exciting ride. With this knowledge we should be better equipped to shape our destinies, and yet still remain as we were meant to be: identically different. Vive la différence!