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http://www.newscientist.com/channel/health/mg19826591.700-genetically-modified-humans-here-and-more-coming-soon.html
Genetically modified humans: Here and more coming soon
04 June 2008
From New Scientist Print Edition. Subscribe and get 4 free issues.
Nick Lane
CHILDREN with three parents might sound like monstrous chimeras, but they are among us already. In the late 1990s, an American team
created the first genetically engineered humans by adding part of the egg of one woman to the egg of another, to treat infertility.
When the US Food and Drug Administration got wind of the technique it was promptly banned, though related methods have been used in
other countries.
Now a research team in the UK is experimenting with creating three-parent embryos. This time, the goal is to prevent children
inheriting a rare group of serious diseases caused by faulty mitochondria, the powerhouses in our cells. Mitochondrial diseases
affect at least 1 in 8000 people, probably more, and there are no treatments.
Mitochondria are always inherited from the mother, so for women in whom they are faulty, replacing the mitochondria in their eggs
with healthy ones from a donor would help ensure their children are healthy. What makes the idea controversial is that mitochondria
contain DNA of their own, meaning babies created this way will have genes from a "second mother".
Supporters of this approach point out that mitochondria contain a mere 37 of the 20,000 or so human genes. Changing them is akin to
changing a battery, they argue. Yet it is becoming increasingly clear that the influence of mitochondrial genes extends far further:
different variants can affect our energy, athleticism, health, ageing, fertility, perhaps even our intelligence, all of which help
make us who we are as individuals.
The prospect of trying to prevent mitochondrial diseases by creating babies with two mothers raises a host of issues. On the one
hand, if the Food and Drug Administration felt that three-parent embryos were unsafe, what's changed? On the other hand, if this
approach really is safe, wouldn't it make sense to equip our children to live longer, healthier and more active lives by giving them
the best possible mitochondria? The answers to these questions offer insights into some of the most intriguing aspects of sex,
health, disease and longevity - and even into the origin of species.
Mixed up
Male mitochondria are an evolutionary dead end. While there are 100 or so in the tail of every sperm, powering its motility, they
are destroyed when the winning sperm gets inside the egg, which is stocked with 100,000 or more mitochondria of its own. As a
result, mitochondrial DNA almost always passes from egg to egg, mother to daughter.
This is the deepest distinction between the sexes. Forget the Y chromosome, which is a genetic johnny-come-lately, restricted to
mammals: reptiles, insects and plants all have different systems of sex determination. Even many simple algae and fungi have two
sexes, but the only thing their sexes have in common with ours is the passage of mitochondria down the "maternal" line.
How this came about is still hotly debated. The leading hypothesis, proposed in 1992, is that if mitochondria from the father and
mother had to compete with each other for survival, "selfish" mitochondria would evolve to the detriment of the entire organism: the
mitochondria that are best at proliferating are not necessarily best at providing a cell with the right amount of energy. Whatever
the reason, all the mitochondria in our cells are normally identical.
In the 1990s, however, the fertility technique pioneered by Jacques Cohen at the Institute for Reproductive Medicine and Science of
St Barnabas in Livingston, New Jersey, resulted in children with cells containing a mixture of mitochondria from different
individuals - something that almost never happens naturally. The technique, known as ooplasmic transfer, involves transferring tiny
extracts of healthy donor eggs into the eggs of infertile women, with the vague aim of "pepping them up" a little. It boiled down to
injecting a bit of good egg into a bad egg, and hoping for the best. Surprisingly, it seemed to help, although no controlled trials
were done to show this for sure.
Unanticipated consequences
The group suspected it was transferring mitochondria, but didn't anticipate the consequences. Despite injecting less than 5 per cent
of the egg-cell volume, when blood cells were taken from two of the 30 babies born this way, about a third of the mitochondria were
found to come from the donor egg.
While there is no evidence that these children will suffer from diseases as a result of their cells having a mixture of mitochondria
from two different women, there is no guarantee that they won't, either. This is why most researchers think the FDA was right to ban
ooplasmic transfer until its effects are understood. However, Jonathan Van Blerkom, a developmental biologist at the University of
Colorado in Boulder, who sat on that FDA committee, sees the work now taking place in the UK in a different light. The approach
holds enormous promise, he says, and it would be "criminal" to ban it.
The research is led by Patrick Chinnery and Douglas Turnbull of Newcastle University in the UK, who see people with some of the most
dreadful congenital diseases known. Leigh syndrome, for instance, occasionally affects adults but usually strikes children under 2
years old. Sufferers have difficulty moving, swallowing and breathing. The symptoms come and go but inevitably worsen, leading to
mental impairment, seizures and death within months or years. Leber's hereditary optic neuropathy causes blindness, usually in young
men. Another syndrome, called MELAS, can involve anything from digestive problems and mild deafness to diabetes, seizures and
stroke-like episodes.
"In mice it is possible to prevent the transmission of often disabling and sometimes fatal disease," Turnbull says. "The only focus
of our laboratory is to try and determine if this is a valid treatment for our patients." Chinnery and Turnbull are experimenting
with a method originally proposed in the 1980s by the guru of mitochondriacs, Doug Wallace, who is now at the University of
California, Irvine. The trick, he suggested, is not to transplant any mitochondria, just the cell nucleus - the repository of the
main genome.
Peculiar inheritance
Soon after an egg with faulty mitochondria is fertilised, its nucleus is taken out and injected into a donor egg cell whose nucleus
has been removed. The outcome is an embryo with nuclear genes from the prospective parents and mitochondrial DNA from the second
mother. In principle, all the mutant mitochondria should be left behind; in practice, however, a few may stick to the transplanted
nucleus. Even though their numbers start off small, as the embryo grows the proportion of mutant mitochondria could be ramped up in
some cells, as happened after ooplasmic transfers.
Typically the proportion of mutant mitochondria per cell has to exceed a certain threshold before problems begin. This means people
with the same mitochondrial mutation can have quite different symptoms, or none at all, depending on the fraction of mutant
mitochondria in cells in different parts of their bodies. Chinnery and Turnbull are now investigating whether the transfer of a
handful of mutant mitochondria along with the nucleus could result in some cells having a dangerously high proportion of mutant
mitochondria. The early results suggest not, but they are in the middle of more systematic studies and don't want to speak too soon.
Even if children conceived by this means are healthy and stay that way, Van Blerkom points out that a disease might reappear
generations later. The problem is the random segregation of mitochondria into developing egg cells, and their subsequent
multiplication from as few as 10 to the 100,000 in a mature egg cell. If even a handful of faulty mitochondria get into the
germline, they could be amplified to a level high enough to cause a recurrence of disease in descendants of the female line.
Dangerous mutations
This might seem to be a serious argument against three-parent embryos, until you consider the alternative. At the moment, women who
discover that their mitochondria bear dangerous mutations face a terrible dilemma when it comes to having children. The peculiar
nature of mitochondrial diseases means that even when all a woman's mitochondria are mutant, a child could be anything from
perfectly healthy to suffering from a far more severe form of the disease than the mother. In some cases doctors can give more
precise odds, but often they can't.
“Would-be mothers face a terrible dilemma, as their children could be anything from healthy to suffering from severe
disease”Prenatal testing, or IVF with pre-implantation genetic diagnosis (PGD), are not much help either. Such screening methods can
detect some common mitochondrial mutations but cannot reliably reveal what percentage of mitochondria in cells bear these mutations.
Neither method can help women whose mitochondria are all mutant. The bottom line is that the creation of two-mother embryos could
provide would-be parents with by far the best chance of having healthy children - and healthy grandchildren and great-grandchildren.
So let's suppose that all the outstanding issues are solved in the next few years, and that the creation of two-mother babies to
prevent mitochondrial diseases becomes routine in the next few decades. Will this be the first step on a slippery slope towards
creating designer babies?
Designer babies
The idea is not beyond the pale, as we are learning that the role of mitochondrial DNA goes deeper than anyone thought. Perhaps the
biggest surprise over the past decade is that mitochondria are responsible not merely for energy production in cells, but also for
orchestrating programmed cell death. The state of mitochondria is the decisive factor determining whether cells live or die, with
obvious implications for health and disease, from cancer to degenerative diseases such as Alzheimer's.
The most striking example comes from Japan. Here, there is a common variant in mitochondrial DNA, a change in a single DNA "letter".
A decade ago Masashi Tanaka, now at the Tokyo Metropolitan Institute of Gerontology, and his colleagues reported that this tiny
change almost halved the risk of being hospitalised for any age-related disease at all, while doubling the chance of living to 100.
Most Japanese centenarians have the variant, but unfortunately for the rest of us it's very rare outside Japan.
Since the late 1990s, other variants in mitochondrial DNA have turned out to be implicated in all kinds of traits. Several are
linked with longevity, albeit less robustly than the Japanese type. Another common variation is associated with diabetes, while
others increase the risk of neuro-degenerative conditions such as Parkinson's disease. Male fertility depends partly on sperm
motility, which is also influenced by mitochondrial variants. Even IQ, Tanaka has found, is linked to mitochondrial variations, at
least in Japan, though the differences are small.
So could we boost intelligence and lifespan, and prevent many diseases by creating "designer" three-parent embryos? The answer is
probably not, at least in the foreseeable future. There are two main reasons. The first, Tanaka notes, is that old biological
chestnut, trade-off: nothing comes without a cost. In Japan, the mitochondrial group with the highest IQ is most likely to get heart
disease, for example.
Tradeoffs
Wallace, meanwhile, thinks that our mitochondria evolve to match our climate by regulating internal heat generation. Mitochondria
may produce less heat in the tropics, but at the cost of leaking more free radicals, which predisposes individuals to diseases like
diabetes. Conversely, people adapted to northern climates generate more heat internally and are less likely to get diabetes, but at
the cost of more male infertility. So you choose a trait and pay the penalty. Would you opt for a mitochondrial variant that boosted
your child's athleticism, for example, if you knew it would lead to poor health later in life?
Then there is an even more fundamental problem. Of the 1500 or so mitochondrial proteins, just 13 are encoded by mitochondrial genes
and produced locally. The rest are encoded in nuclear DNA, made elsewhere in the cell and exported to mitochondria. These two sets
of proteins, encoded by different genomes, have to work together intimately, yet mitochondrial DNA mutates around 20 times as fast
as nuclear DNA. If such mutations mean the two genomes don't function well together, then an individual is more likely to suffer
from a range of diseases. At worst, the embryo could die.
Ronald Burton, a marine biologist at the Scripps Institution of Oceanography in San Diego, California, has even suggested that such
incompatibilities might be behind the origin of species, or at least some of them. He works with tiny marine copepods, shrimp-like
crustaceans that live along the Pacific coast close to Scripps. Their populations don't interbreed much, and so steadily accumulate
differences in their mitochondrial DNA. When Burton and his colleagues experimented with interbreeding between local populations,
they discovered that mitochondrial incompatibilities undermined the health of offspring. The animals lacked energy, developed
slowly, were less fertile and were also more likely to die early. It is only a matter of time before these incompatibilities reach a
level that rules out successful interbreeding altogether - the very definition of a species. What's more, because mitochondrial
genes evolve so quickly, they might even play the dominant role in natural speciation.
Wallace and others have found that these evolutionary patterns apply not only to crustaceans, but also to mammals - and notably to
primates. Our genes show all the cardinal signs of selection for compatibility with mitochondria (Gene, vol 378, p 11), and
mitochondrial incompatibilities might play a huge role in human health and happiness.
Inhumane
For example, around 40 per cent of all pregnancies end in early miscarriage for unknown reasons. Many could be caused by
mitochondrial incompatibilities. Not only that, but Tanaka suspects the high incidence of diabetes among Californian Hispanics is
related to incompatibilities between mitochondrial and nuclear genes due to the mixing of long-separated populations. If he's right,
there could be many other examples.
The issue of compatibility means there is an inherent danger in any attempts to boost health, longevity, fertility, athleticism or
IQ by transplanting mitochondria: putting the wrong mitochondria and nucleus together could harm children rather than improving
them. Leaving aside the ethics, the risks appear to outweigh the benefits.
For those who risk passing on mutant mitochondria, however, the odds are very different. The Newcastle team plans to minimise
incompatibilities by picking donors with a broadly similar mitochondrial genome, or haplotype. The risk cannot be completely
eliminated, but it is far lower than that of inheriting a mitochondrial disease. "It's inhumane not to treat such conditions if we
can," says Van Blerkom. "There's no other reason to go into medicine at all."
Nick Lane is an honorary reader at University College London and author of Power, Sex, Suicide: Mitochondria and the meaning of life
(Oxford University Press, 2005)
From issue 2659 of New Scientist magazine, 04 June 2008, page 38-41
Mitochondria - the basics
Each of our cells contains anything from one to thousands of mitochondria
Mitochondria "burn" food to produce the fuel that powers cellular processes
Their size and shape varies from cell to cell
Each contains up to 10 copies of a piece of circular DNA encoding 13 proteins
These proteins are produced within the mitochondria
The vast majority of the 1500 or so mitochondrial proteins are encoded in nuclear DNA and exported to mitochondria |
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