T

he development of in vitro fertilisation (IVF)

for the treatment of infertility has opened up

new and unexpected methods of alleviating

disease. Creating embryos in a test tube allows

the diagnosis of most known genetic conditions

within days of fertilisation, and new gene editing techniques offer

the prospect of correcting these conditions.

While this brings great hope, it also prompts fears of genetic

manipulation for non-medical reasons, unintended biological

consequences for the child, and even consequences across succes-

sive generations. For example, evidence suggests that the manip-

ulation of gametes and early embryos may cause maladaptive

errors in the programming of normal gene expression, leading

to an increased burden of life-long chronic diseases.

The pace of innovation is breathtaking, yet our knowledge

of the underlying biology may be too immature to allow the

confident prediction of all outcomes. Future research must

focus on these perceived risks, as well as the technical innova-

tions.

Genetic Manipulation of the Embryo

Genetic diagnosis in the pre-implanted embryo is a widely used

technology. The microsurgical biopsy of a small number of cells

from the embryo in the test tube allows most genetic infor-

mation to be retrieved. The diagnosis of common genetic condi-

tions, as well as determining the sex of the embryo, allows

couples to choose whether an embryo carrying a genetic disease

will be transferred back to the uterus. Sex selection is used to

eliminate genetic conditions that only affect males, such as

Duchenne muscular dystrophy and haemophilia. In these cases,

the couple may choose to transfer an affected female embryo but

not its male sibling embryos. In Australia, it is currently not

permitted to choose the sex of the embryo purely for social

reasons, although this is under review by the National Health

and Medical Research Council.

An alternative to the

destruction of embryos

that carry genetic

diseases is now

approaching feasibility.

This involves the use of

gene-editing technology

to replace or repair the defective gene in the oocyte or early

embryo. New tools for gene editing exploit the capacity of

bacteria to recognise and remove invading foreign DNA. The

bacterial molecules that perform this task (e.g. CRISPR/CAS

and TALENs) have been isolated and can be used to perform

sophisticated editing of the human genome. The technique is

highly efficient and has a low error rate compared with earlier

developments in genetic modification. It has been very widely

used in animal models and is now under active discussion in

many international jurisdictions for use in human embryos.

A key issue of concern is that genetic changes to the cells of

the early embryo will inevitably be passed on to every cell in

the body, including the sperm or oocyte (egg). As a result, these

changes will be passed down through future generations.

There are many valid questions about how quality assur-

ance can be performed to ensure that only the desired genetic

changes are induced and that no off-target effects are gener-

ated. There are also inevitable questions about how the tech-

nology can be regulated to ensure that it’s not used for

non-medical purposes that would bring a number of science

fiction scenarios into the real world.

Under current legislation, gene editing of a human embryo

cannot be performed in Australia but its future use in other

jurisdictions will inevitably lead to calls for this to be reviewed.

Treatment of Mitochondrial Diseases

Every cell contains small membrane-bound structures called

mitochondria. These structures convert nutrients into the

14 | JAN/FEB 2016

Brave New

Embryology

CHRIS O’NEILL

New technologies are being developed to improve fertility,

but the effects on the embryo are uncertain.

IIt is chastening

to realise that

after 30 years of

developing these

techniques, only

around 25% of

the embryos

created have

the capacity to

develop to term.