Mitochondrial donation law reform

Recently, a new Bill on mitochondrial donation, the Mitochondrial Donation Law Reform (Maeve’s Law) Bill 2021, was tabled in the federal Parliament. Although a vote was scheduled for last June, circumstances conspired against the parliamentary agenda, and it has been held over until later in the year.

The Bill proposes to introduce mitochondrial donation — and to legalise the intervention, which would be unlawful under current law — into the Australian health system. One of the reasons the Bill was needed is that, under current law, an act that alters a human genome is unlawful in Australia and will result in a penalty of 15 years imprisonment — one of the strictest penalties for genome alteration in the world.

That penalty is set out in section 15 of the Prohibition of Human Cloning for Reproduction Act 2002 (Cth) (the ‘PHCR Act’). That provision has remained unchanged since 2002, despite huge advancements in science, including the invention and discovery of several completely new forms of editing and altering human genomes. One such advancement was the discovery of a way of editing the human genome with great precision; this was the CRISPR Cas-9 (and related) techniques, and the discoverers won joint Nobel prizes for chemistry in 2020 for their achievements.

How Mitochondrial Donation Works

Mitochondrial donation involves taking healthy mitochondria from the egg of a donor and transferring that healthy mitochondria into the egg of a mother who has defective or diseased mitochondria. Replacing the defective mitochondria in the mother’s egg with healthy mitochondria from another woman’s healthy egg means that the child who will issue from the mother will not have mitochondrial disease or any other disease associated with defective mitochondria (such as Leigh syndrome). Where the procedure is not undertaken, a child born of a mother with defective mitochondria is virtually guaranteed to inherit mitochondrial disease or a related condition. Most of these conditions are not well treatable, and certainly not curable. After all, imagine if every cell (or most cells) in your body had a defect! The health implications of any mitochondrial defect are serious indeed.

Figure 1: Here is a diagram of mitochondrial donation.

This figure is taken from this article, pulished in Harvard University’s Science in the News website (CC BY 4.0). The figure is by Rebecca Clements.

As may be seen in figure 1, mitochondrial donation involes a few steps. First, a medical practitioner will remove the nuclear DNA from the donor egg, leaving an ’empty egg’ (an egg sans nucleus) containing healthy mitochondria (purple). Second, the medical practitioner will then remove the defective mitochondrial DNA from the birth mother’s nuclear DNA (teal). This creates a healthy nucleus with all of the defective mitochondrial material removed. Then, the altered nuclear DNA from the mother is transferred into the empty donor egg that is free of any defective mitochondria. The result is a newly engineered egg comprising the donor’s mitochondrial DNA and the mother’s nuclear DNA. This new egg is then fertilised by the father’s sperm outside of the body (ex vivo) and, once fertilised, implanted into the mother’s womb.

Once this transfer, fertilisation, and implantation process has taken place, the mother will possess a new egg. As noted, this will be an engineered egg — a product of the mother, the father, and the donor. Inside that egg, an embryo will develop that will now possess (1) nuclear DNA from the mother, (2) nuclear DNA from the father, as well as (3) the donated mitochondrial DNA from the donor’s egg. The defective mitochondrial DNA has been removed and in its place we have only healthy mitochondrial DNA.

The reason this is possible is because, fascinatingly, mitochondria have their own chromosomes and their own DNA. This DNA is separate from the DNA that we find in the nucleus of cells (the nuclear DNA). As such, it is possible to swap out the mitochondrial DNA in an egg without disturbing the nuclear DNA.

Since the nuclear DNA is the trait-giving DNA (that is, the DNA of primary genetic inheritance, imparting such things as eye colour, height, bone density, etc.), the child’s primary genetic inheritance will remain undisturbed by the addition of the donated mitochondrial DNA from the donor. In fact, the mitochondrial DNA is just that: DNA that relates only to the mitochondria in the cells. The anatomy of a cell is visible in figure 2, below. As we can see, the nuclear DNA and mitochondrial DNA are separated and rarely interdigitate. But while the mitochondrial genome is separate from the nuclear genome, its volume is much lower. The mitochondrial genome is built of 16,569 DNA base pairs, while the nuclear genome is made up of some 3.3 billion DNA base pairs.

Figure 2. The image above shows where mitochondria and nuclear DNA are distinct; it also shows the number of genes contained in the cell nucleus compared to the number of genes in the mitochondria, which sits outside the cell nucleus.

This figure is taken from this article, pulished in Harvard University’s Science in the News website (CC BY 4.0). The figure is by Rebecca Clements.

Hang on — what are mitochondria?

Mitochondria are known as the ‘energy powerhouses’ of our cells. They are membrane-bound organelles within our cells that generate enough energy to facilitate cellular activity. Mitochondria also contain their own chromosomes. They are essential in converting the energy we receive from exogenous sources (such as food and sunlight) into energy that the cell can use in the tissues or organs. Mitochondria create energy by storing it chemically in the form of adenosine triphosphate (ATP).

Different tissue and organ cells have varying numbers of mitochondria. A mature red blood cells or erythrocyte may have no mitochondria; by contrast, liver cells (hepatocytes) can have more than 2,000 mitochondria in a single cell. Mitochondria even exist in collagen-producing cells like fibroblasts (see figure 3, below).

Figure 3. Fluorescent microscopy image of the mitochondria (red) and cell nucleus (blue) of two mouse embryo fibroblast cells.

Image taken by the Institute of Molecular Medicine I, University of Düsseldorf (CC BY 4.0) and obtained here via this Wikimedia Commons page.

What does the Maeve’s Law Bill do?

Among other things, the Maeve’s Law Bill amends section 15 of the PHCR Act to carve out an exception for mitochondrial donation, essentially decriminalising the procedure. Recall that altering the human genome is unlawful, and that mitochondrial donation would have to be deemed an unlawful alteration of the human genome under the existing law. This is because, when a mitochondrial donation intervention takes place, the medical practitioner will be altering the human genome by transferring the DNA contained in the mitochondria into a new egg that will ultimately be implanted into a mother. Precisely how and when the alteration occurs (for instance, is it unlawful to alter the genome ex vivo?) is probably not worth considering. The provision seems broad enough to capture almost any kind of alteration, at least potentially. So, without the amendment in the Bill to make an exception for mitochondrial donation (and the Bill proposes to makes a huge number of amendments across three separate Acts), a practitioner who administers the treatment would be liable for up to 15 years imprisonment.

The question I have is as follows: Is the Maeve’s Law Bill a sign of things to come? Could we see further carve outs for CRISPR-style interventions in the near future? While interesting to contemplate, I do not think we shall see any such change. The reason is that we are still too far away from wielding CRISPR (or other genome editing techniques) in ways that would be safe and effective. Somatic cell genome editing, however: that may be a different matter. But I digress. Somatic cell editing is a different case altogether.

Federalism and Mitochondrial Donation

Despite many good aspects, the Maeve’s Law Bill does have some issues. Some of those relate to the ways in which the treatment is to be made available across the state and federal levels of government. As always in health, the dualism of our federal republic — and the indelible separation of the state and federal tiers on matters of health — threaten to complicate the roll out of any medical treatment.

On my analysis, it is quite possible that certain states, for whatever reason (perhaps ethical ones), may in the future enshrine a law prohibiting mitochondrial donation in that state, despite a Commonwealth laws that permits the intervention (Maeve’s Law). In such an instance, the current Bill is powerless to overcome that issue. Of course, it is arguable that federalism would require that to be just so, since the Commonwealth lacks a power to legislate on health. However, I wonder whether a National Cabinet memorandum of understanding could not be reached, and whether the states and territories could not refer their powers to legislate on this narrow area of health law to the Commonwealth under s 51 (xxxvii) of the Constitution.

Submission to Senate Inquiry

I and my colleague Professor Ainsley Newson set out some of our perceptions of the Bill in our submission to the Legislation Committee of the Senate Standing Committee on Community Affairs. Our submission is available here; it is submission number 49.

New substack blog: Welfare Law in Australia

I’ve begun a substack blog titled Welfare Law in Australia. The purpose of the blog is to write and compile a bunch of informal notes about welfare law in Australia, primarily in the Administrative Appeals Tribunals, as I develop my interest in this field. Please visit the substack at https://welfare.substack.com/

Although my primary interest remains in medical law, my experience in administrative law, through reviews of administrative decisions in relation to medical and other health practitioners, means that this work, dealing with the Administrative Appeals Act 1975 (Cth), is still familiar and relevant.

A Remedy for False Cures?

Australia’s Therapeutic Goods Administration has been more vigilant in policing advertisements for unproven COVID-19 ‘treatments’. But have some slipped through the cracks?

This article was first published on Pursuit. Read the original article. It is co-authored with Professor Megan Munsie.

Beware false COVID-19 cures.

The COVID-19 pandemic has seen the emergence of multiple dangers. The obvious public health danger is the novel coronavirus strain and the disease itself.

But a secondary threat has emerged for health consumers.

Since March, several unregistered ‘treatments’ for COVID-19 have been advertised to the public. Most are untested and unproven.

A controversial example was the Biocharger NG, a “hybrid subtle energy revitalization platform”. That product was unlawfully promoted as a COVID-19 remedy by former celebrity chef Pete Evans. Evans’ company was issued infringement notices totalling $A25,200.

Although no clear cases of liability have arisen in Australia, it’s not difficult to imagine these advertisements causing harm. In a period already witness to anxious consumer behaviour, a spell of pharmaceutical panic-buying might just be too predictable.

The administrative body responsible for controlling drug advertising in Australia is the Therapeutic Goods Administration (TGA). The TGA wields considerable regulatory power to ensure no individual or company promotes unproven therapeutic goods to the public.

In recent months, the TGA has used its powers rather vigilantly. But unlike the newly-crafted emergency orders declared in our states and territories, the TGA’s swift and strict response comes from pre-existing levers.

The TGA’s Regulatory Clout

The TGA’s ability to act against “restricted” and “prohibited” advertisements emanates from legal amendments made as long ago as 2003.

But more recent changes have enhanced the TGA’s powers.

Following a major review, the TGA became the sole complaints handling body for drug advertising nationally in 2018. Further amendments that year gave the TGA a more punitive offence regime.

In many ways, COVID-19 has been the first real test of this greater regulatory clout.

Communication over Complication

But the TGA is a complicated organisation with complicated rules.

After years of incremental tinkering, the therapeutic goods legislation is diffuse and intricate. If this legal complexity alienates consumers at the best of times, it must bewilder during a global pandemic.

The administration’s principal regulatory powers come from the Therapeutic Goods Act 1989 (Cth). But several subordinate materials, including the Therapeutic Goods Regulations 1990 (Cth), the Therapeutic Goods Advertising Code (no 2) 2018 (Cth) (or, ‘the Code’ for short) and dozens of guidance documents, supplement this primary law.

The pandemic has required the TGA to improve its communications to cut through this complexity. Now more than ever, up-to-date guidance has been crucial to reach stakeholders and consumers.

To that end, the regulator has issued several important warnings on its main website and in its specialised ‘advertising hub’.

As COVID-19 was just emerging, the TGA announced that any therapeutic goods advertisement referring to the ‘novel coronavirus’, whether explicit or implied, would be a “restricted representation”.

Although the warning did not explain the mechanics of the legislation, identifying and controlling “restricted representations” is central to the TGA’s advertising controls.

So, What Exactly is a ‘Restricted Represntation’?

The primary law defines a “restricted representation” as a representation about therapeutic goods referring to a disease, condition, ailment or defect that the Code classifies as “serious”.

Back in 2005, the Code listed a range of “serious” diseases, stopping advertisers from promoting related treatments without permission. But today, the Code provides more flexible criteria.

A ‘serious’ disease may be one that, for instance, requires practitioner-led diagnosis, testing or screening.

COVID-19 was quickly identified as a serious disease, and advertising referring to it was said to be a restricted representation. But what kinds of penalties can be imposed?

Enforcing restricted Representations

In 2018, the TGA introduced a new offence regime for unlawful advertising.

Publishing an advertisement likely to result in harm was now an aggravated criminal offence, punishable by a jail term of up to five years and a fine of up to $A888,000 (or both). Civil penalties for non-compliant advertising could incur fines of more than $A1.1 million for individuals or $A11.1 million for body corporates.

Given the quantum of these maximum penalties, it’s arguable that the actually-issued infringements have been minor.

In June, a Sydney-based chemical company was fined $A63,000 for unlawfully advertising a medicine known as RibaMin. On its website, the ingestible tablet was described as a “low-cost effective treatment for the devastating COVID-19 virus (and possibly other related viruses or mutations)“.

It was the lone ‘pharmaceutical’ amid a host of maintenance chemicals, including concrete polishing and graffiti control products.

Earlier in June, a Cairns-based technology company was fined $A50,4000 for advertising a large tank said to produce a purified form of molecular hydrogen as a treatment for COVID-19.

In addition to these novel products, a Melbourne-based company was fined $A12,600 for unlawfully advertising a seemingly more conventional product – a COVID-19 test kit. But as the advertisement referred to COVID-19 without TGA permission, it was a restricted representation.

Evaluating the TGA’s Response

Though the pandemic has tested all levels of Australia’s healthcare system, it has been a special test for the TGA.

From all appearances, the TGA has been more vigilant than ever in policing non-compliant advertising during the COVID-19 pandemic. However, it’s possible some non-compliant advertising has slipped through the cracks.

In early April, the US Federal Drugs Administration (FDA) wrote to a Perth-based company promoting herbal remedies to animals, including COVID-19 treatments.

The FDA warned the company that it had violated US law by making its products available for purchase by US citizens.

But it seems no infringements were issued to the company by the TGA, possibly due to a regulatory exception that excludes homeopathic practitioners from the regulatory regime, or because the goods were not advertised for human use.

Moreover, the TGA has been criticised for not imposing more stringent penalties during the COVID-19 period.

As one critic noted, the fine imposed on Pete Evans’ company for advertising the “energy revitalization platform” is less than the cost of just two of those unapproved devices.

Time will inevitably reveal whether the TGA has responded adequately to the unlawful advertising of unapproved products during COVID-19. What’s clear, however, is that the TGA has never been better equipped to control false cures than now.