Q&A: Mitochondrial Donation

About 1 in 200 children in the UK carry a mitochondrial DNA mutation, while around 1 in 6500
children is thought to develop serious mitochondrial disease. The Wellcome Trust Centre for
Mitochondrial Research are developing a technique known as mitochondrial donation, which can
prevent mitochondrial DNA disease from being passed on from mother to child.

For the technique to be used in patients, the Government must pass new regulations. The draft
regulations were published in March and anyone can comment on these until 21 May 2014.
Following the consultation, the regulations will be considered by Parliament and there will be a
debate and vote on whether to bring the regulations in. If the regulations are approved by
Parliament, the intention is that they may be in place by the end of 2014, allowing mitochondrial
donation to be used to help patients have healthy children once the science is ready.

What is mitochondrial DNA disease?

1. What are mitochondria?

Mitochondria are small structures found in our cells which

generate the energy required to allow our bodies to function (see
Figure 1)1. They sit outside the nucleus, which houses most of the
cells DNA. Mitochondria also have their own DNA, which makes up
only 0.1% of the total cell DNA and does not affect the features
that make each person unique, such as appearance and
personality.

2. What causes mitochondrial DNA disease?

When mitochondrial DNA contains genetic defects, the

mitochondria do not work properly, so do not produce enough
energy. This results in mitochondrial DNA disease.

Mitochondrial DNA disease is a genetic disease. There are many different genetic defects that can
cause mitochondrial DNA disease and therefore symptoms and severity can vary considerably between
mitochondrial DNA disease sufferers.

3. What are the symptoms of mitochondrial DNA disease?

Symptoms vary depending on which organs are affected. They can include loss of control over
movement, muscle weakness and pain. It can result in heart disease, disorders of the stomach and
intestines and disorders of the brain. The severity of mitochondrial DNA disease varies from mild to
extremely debilitating, and it can result in childhood death.

4. Can mitochondrial DNA disease be treated/ cured?

1
Figure 1: Diagram of human cell cutaway to show content. N0027743, Miles Kelly Art Library, Wellcome
Images. wellcomeimages.org
There is no cure for mitochondrial DNA disease at present. Current treatments aim to decrease the
effect of the symptoms but do not change the course of the disease.

5. How is it passed on?

Mitochondrial DNA defects leading to mitochondrial DNA disease are often passed down from mother
to child. Women who inherit faulty mitochondrial DNA can develop symptoms or be carriers of the
condition without experiencing symptoms, and in both cases they are able to pass the defects on to
their children.

What can be done to prevent it?

6. What is mitochondrial donation?

Faulty mitochondrial DNA from a mothers egg can be replaced with healthy mitochondrial DNA from a
donor egg. This prevents mitochondrial DNA defects from being inherited, so the child that develops
from the egg will not get mitochondrial DNA disease.

7. What techniques are used in mitochondrial donation?

Two techniques can be used for mitochondrial donation:

- Maternal Spindle Transfer

Maternal Spindle Transfer involves removing the nuclear DNA (which contains 99.9% of the total cell
DNA) from the donor egg, leaving the part of the cell containing the healthy mitochondria. The
nuclear DNA from the mothers egg is then inserted into this cell. The healthy egg is fertilised and is
then implanted into the mothers uterus in the same way IVF is carried out already.

- Pronuclear transfer
Pronuclear Transfer is similar to Maternal Spindle Transfer but involves fertilising the mothers egg first
and then transferring the nuclear DNA to the fertilised donor egg containing healthy mitochondria,
from which the original nuclear DNA has been removed. The healthy fertilised egg is then implanted
into the mothers uterus in the same way as in Maternal Spindle Transfer.

8. How safe are the techniques?

Maternal Spindle Transfer has been successfully performed in monkeys, leading to the birth of
healthy offspring. Pronuclear Transfer has been performed in mice and is successful in preventing
mitochondrial DNA disease in mice that carry a genetic defect in their mitochondrial DNA. There is
no evidence to suggest that a mitochondrial donation pregnancy would be unsafe for the mother or
child.

Maternal Spindle Transfer has been used on human eggs and Pronuclear Transfer on human zygotes
(fertilised eggs), in both cases leading to the successful development of a bundle of cells (blastocyst).
This suggests that they would develop as normal if implanted in the uterus.

It is impossible to say that any new technique would have zero risk. However, scientific reviews of
the current research by an Expert Panel in April 2011 and March 2013 found that there was no
evidence to suggest that the techniques were unsafe for clinical use and both techniques had the
potential to be used in patients with mitochondrial disease. The Department of Health has also
asked the HFEA to reconvene the Expert Panel to review the latest evidence of safety and efficacy
and will consider their advice alongside the responses to the consultation.

There is a well-recognised significant risk of children continuing to be born who will die in infancy if
these techniques are not used to ensure that the children are free from mitochondrial disease.

Before these techniques can be used the HFEA will have to be satisfied that the balance of risk lies
with allowing doctors to offer this treatment option.

9. Why does the law need to be changed?

The law does not currently allow an egg or an embryo which has had its mitochondrial DNA altered to
be used in treatment in humans. In 2008 when this law was updated Parliament did, however, foresee
that techniques such as those described above were being developed to prevent mitochondrial DNA
disease. It therefore provided the Parliament of the day the power to pass regulations to enable
techniques which prevent serious mitochondrial disease to be used for patients in the clinic. The
Government proposes to give Parliament the opportunity to exercise its power under the existing law
to debate and pass new regulations. This would then allow a very few specialist doctors to apply to the
Human Fertilisation and Embryology Authority for a licence to do this work. The HFEA will continue to
review the evidence from research to ensure that there are still no indications that the methods may
be unsafe and a license would only be granted by the Authority after they are satisfied that any risk of
their use is low.

What are the principles behind the new regulations?

10. What are the ethical arguments in favour of the techniques being allowed?

Although mitochondrial DNA disease affects a small number of individuals, it has extremely disabling
and often devastating effects on families. Mitochondrial donation will enable mothers to choose to
have children who are genetically related to them but free from mitochondrial disease, preventing the
transmission of a fatal disease in much the same way as organ donation. Doing nothing in the face of
this suffering would be unethical if a safe and effective way of preventing it is available. Throughout
2012 the HFEA conducted extensive public debates and engagement events concerning the ethical
issues that surround the two mitochondrial replacement techniques and in March 2013 they published
a report demonstrating broad public support for the use of these techniques, providing that their use
would be carefully controlled. Similarly in June 2012 the Nuffield council on Bioethics held a discussion
and lively debate at Westminster palace on the two novel techniques, which again revealed broad
public support for the use of mitochondrial replacement techniques within the UK, within a robust
regulatory framework. Such broad public support suggests it would be unethical if the techniques were
not made available if they are classified as sufficiently safe and effective.

11. Should we be creating three-parent babies?

Scientists estimate that our DNA is made up of 20,000-30,000 genes. Using this new technique,
almost all of the childs genes will come from its parents; the mitochondrial donor will only
contribute 37, which enable the mitochondria to produce energy. The donor mitochondrial DNA
will not affect the childs appearance, personality or any other features that make a person unique
it will simply allow the mitochondria to function normally and the child to be free of
mitochondrial DNA disease. Furthermore, the Nuffield Council on Bioethics conducted an ethical
review which concluded that, by the societal norms, [mitochondrial] DNA does not confer genetic
identity. As a result, there is no reason why the techniques should affect the childs sense of
identity. The term three-parent children is misleading. These children will only have two
biological parents, with the donated mitochondria falling under the same category as organ
donation.

12. Could allowing mitochondrial donation be the start of a slippery slope towards allowing
other techniques, such as nuclear genetic modification, which could be used to create
designer babies?

Mitochondria are separate structures from the nucleus (see Figure 1) and the regulations will only
allow the techniques to be used on mitochondrial DNA, not on nuclear DNA. The ban on altering
nuclear DNA will remain in place, and there is no intention of changing this. Mitochondrial donation
is totally different to altering nuclear DNA and allowing mitochondrial donation will not allow
genetic modification in the nucleus, nor give us the capability of doing this. Any change in the law
in this area would need an entirely separate change in primary legislation requiring a new Act of
Parliament.

13. Mitochondrial donation involves germline modification (changes to sperm or egg cells),
which enables DNA modifications to be passed on to children. Should we be changing future
generations in this way?

These techniques replace the mitochondria, and involve reconstruction (where nuclear DNA is
moved from one cell to another) but do not involve any modification of the DNA sequence itself.
New combinations of mitochondrial DNA and nuclear DNA occur in nature every time an egg is
fertilised. Mitochondrial donation will have the hugely beneficial effect of future generations being
born without mitochondrial DNA disease but will not alter other physical or character traits. It is
not and cannot be used for eugenics (state directed alteration of physical traits).
How will the regulations work in practice?
14. How will doctors be licensed to offer the techniques?

Once Parliament has passed regulations allowing mitochondrial donation, doctors will still need to
obtain approval from the Human Fertilisation and Embryology Authority (HFEA) in order to use the
techniques, which will only be granted when the Authority is satisfied that the use of the
techniques is safe and low risk. The HFEA will carefully assess each application to use the
techniques, so doctors will need to get specific approval and it will only be provided at specialist
clinics.

15. What legal status will the mitochondria donor have?

Although women donating mitochondria would also be egg donors, only the mitochondria-
containing part of their eggs would be used for the procedure. The HFEA report and
recommendations to the Government after a large public consultation in 2013 advised that
mitochondrial donors should have a similar status to that of tissue (organ) donors and that the
children born after mitochondrial donation should not have a right to access identifying information
about the donor.

What happens next?

The Department of Health have published draft regulations to allow licensing of new IVF
technologies for mitochondrial replacement and a public consultation is currently running until 21st
May 2014. This provides a chance for patients and the public to have their say on the regulations
governing the new techniques. Following the consultation, the regulations will be put to a free vote
in Parliament.

If the regulations are approved by Parliament, the Governments intention is to bring them into
force by the end of 2014. Never before has a new medical technology been subjected to such
thorough examination before it has been approved. Approval of the regulations will allow more
reproductive choice for parents at risk of having a child with mitochondrial DNA disease, giving them
the possibility of having a healthy child free from a fatal disease.

Links to further background information

Wellcome Trust Policy Spotlight on Mitochondrial Disease

Video from the Human Fertilisation and Embryology Authority: Mitochondrial Replacement -Some
facts.

HFEA advice to Government on the ethics and science of mitochondria replacement

Nuffield Council on Bioethics report Novel techniques for the prevention of mitochondrial DNA
disorders: an ethical review

Mitochondria: Nuts and bolts What are mitochondria?

Healing Broken Batteries A short film about mitochondrial disease and the new techniques being
developed at Newcastle University.