[tt] NS: Genetically modified humans: Here and more coming soon

Tue Jul 1 00:48:58 UTC 2008

Genetically modified humans: Here and more coming soon
http://www.newscientist.com/article.ns?id=mg19826591.700&print=true
8.6.4
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.

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

Related Articles

Correct address may fix faulty genes
http://www.newscientist.com/article.ns?id=mg19526174.000
18 August 2007
Turning back the years
http://www.newscientist.com/article.ns?id=mg18925341.500
14 January 2006
IVF creates fetuses with three parents
http://www.newscientist.com/article.ns?id=mg18024171.400
18 October 2003
The Force
http://www.newscientist.com/article.ns?id=mg16522274.400
26 February 2000

Weblinks

Mitochondrial Research Group, Newcastle University
http://www.ncl.ac.uk/nnp/research/mrg/
Mitochondrial DNA disorders: Is there a way to prevent them?
http://www.hfea.gov.uk/docs/2005-10-17_R0153_Extended_Summary_for_HFEA_Website__2_.pdf
The Children's Mitochondrial Disease Network
http://www.emdn-mitonet.co.uk/

E-mail me if you have problems getting the referenced articles.