New Scientist: GM Humans Coming Soon.

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Genetically modified humans: Here and more coming soon

 

 

04 June 2008

by

Nick Lane

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http://www.newscientist.com/article/mg19826591.700-genetically-modified-humans-here-and-more-coming-soon.html?full=trueCHILDREN

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."

 

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

 

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)

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