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.

The Goldwater rule prevents psychiatrists diagnosing Trump from afar but some say there’s too much at stake

This article was originally published on The Conversation, here. I have altered the styling slightly.

In the late nineteenth century, Sigmund Freud’s colleague Wilhelm Fleiss successfully diagnosed an illness in one of Freud’s relatives, without even having met them. Freud was so impressed by Fleiss’s “diagnostic acumen” that he went on to advocate the method in certain circumstances. Freud would write that diagnosing someone without personally examining them was acceptable where the features of certain disorders, such as paranoid schizophrenia (then known as dementia paranoides), made the interview process counterproductive. Here, Freud noted that “a written report or a printed case history can take the place of personal acquaintance with the patient.”

Now, a controversial debate about the ethics of diagnosis at a distance or long-distance diagnosis has arisen in the US. It has come about as commentators have proposed that President Donald Trump suffers from narcissistic personality disorder (NPD) and attention deficit hyperactivity disorder (ADHD), among other conditions. Health professionals have weighed in as well. Psychotherapist and former assistant professor of psychiatry John D. Gartner has been particularly vehement in his assessment of the President. Gartner asserts that Trump suffers from malignant narcissism, a specific manifestation of NPD.

According to the DSM-5—the authoritative psychiatric manual—this condition is characterised by various “traits of antagonism”, including “manipulativeness, deceitfulness, [and] callousness.” Notably, the DSM-5 names the condition only once throughout its hundreds of pages; and some academic psychiatrists say the disorder is understudied and its features largely unsettled, with no treatment yet established.

Despite this, Gartner is convinced that the president’s conduct fulfils the criteria of malignant narcissism—even without having interviewed him:

We’ve seen enough public behaviour by Donald Trump now that we can make this diagnosis indisputably.

Recently, the American Psychoanalytic Association (APsaA) issued a memo to its more than 3,500 members, advising they were “free to comment about political figures as individuals”, and that the APsaA did not regard “political commentary by its individual members an ethical matter.”

By contrast, the American Psychiatric Association (APA) has long maintained a strict ethical stance on the open discussion of public figures’ mental states. Enshrined in the so-called Goldwater rule, the APA’s prescription cautions psychiatrists against diagnosis at a distance. As former APA President Herbert Sacks put it, psychiatrists should avoid engaging in “psychobabble,” especially when it comes to politicians. He said that, when “reported by the media,” such diagnostic speculation only “undermines psychiatry as a science.” Although the Goldwater rule is not enshrined in Australian law, a code of ethics provides guidance to Australian psychiatrists about their conduct in the media.

What is the Goldwater Rule?

The Goldwater rule is named after an incident involving Republican presidential nominee Barry Goldwater. Having been defeated in the 1964 US election, Goldwater sued the editor of the shortlived political magazine Fact for defamation. Just one month before the election, Fact’s front page had printed a controversial declaration:

1,189 psychiatrists say Goldwater is psychologically unfit to be president!

Fact had conducted a broad but clinically invalid survey, providing questionnaires to more than 12,000 psychiatrists whose details the magazine had obtained from the American Medical Association’s membership list. Of the 2,417 responses it received, some 1,189 psychiatrists asserted Goldwater was unfit for office.

In the feature article, Fact purported to quote many of the psychiatrists it had surveyed, and used their words to suggest that Goldwater was a “megalomaniac, paranoid, and grossly psychotic”, and even suffering from “schizophrenia.” In the trial that followed, Goldwater was awarded some US$75,000 in punitive damages—enough to ensure that Fact never published another issue. The ruling raised disturbing questions for the APA, threatening not only the reputation of the psychiatric profession, but the future livelihoods of practitioners. In slightly different circumstances, a psychiatrist might face similar civil action, whether “for invasion of privacy or defamation of character.”

In 1973, some four years after the trial, the Goldwater rule was first published in the APA’s professional ethical code. In the most recent 2013 edition, the rule reads as follows:

On occasion psychiatrists are asked for an opinion about an individual who is in the light of public attention or who has disclosed information about himself/herself through public media. In such circumstances, a psychiatrist may share with the public his or her expertise about psychiatric issues in general.

However, it is unethical for a psychiatrist to offer a professional opinion unless he or she has conducted an examination and has been granted proper authorization for such a statement.

The Rule in Dispute

Many academic psychiatrists disagree with the rule. Some have suggested that breaking the Goldwater rule is ethical when it’s necessary to diagnose “mass murderers” from afar, or when “the importance of the diagnosis of an individual … rise[s] to the level of a national threat.” Others have criticised the rule more generally, calling it “an excessive organisational response” to “an inflammatory and embarrassing moment for American psychiatry.” And one psychiatrist has recently described the prescription as “American society’s gag rule.” In February this year, the New York Times published a letter signed by some 33 psychiatrists who blamed the rule for silencing them at this “critical time”. They wrote that “too much [was] at stake to be silent any longer”, and that Donald Trump’s “emotional instability” had made him “incapable of serving safely as president.”

The tension between the APA and its members, and between the APA and the APsaA, partly reflects the history of the two disciplines. Since the 1940s, psychiatry has increasingly focused on medical interventions, while tending to neglect the “in-depth talk therapies” which, despite their general decline, remain central to the psychoanalytic method.

But the situation is still more complicated than this. After all, the methods of psychiatrists and psychoanalysts often overlap. In many practices, for instance, psychiatrists employ intuitive reasoning in the diagnostic process. For some diagnosticians, the so-called “Praecox-Gefühl” or “praecox feeling” remains at the “clinical core” of diagnosing schizophrenia, despite the method’s varied reliability. First described in the 1940s, the praecox feeling is a complex, emotionally charged intuitive sense that a psychiatrist sometimes gets when detecting the subtle symptoms of an emergent psychosis.

What now for the Goldwater rule?

That psychoanalysts may wish to distinguish themselves from psychiatrists on the Goldwater rule, and vice versa, is unsurprising. In countless ways—more than can be named here—psychoanalysts and psychiatrists adopt different views of their roles in the diagnostic process. This is the result of their different training backgrounds, histories, and professional cultures.

Less expected, however, is the growing feeling among psychoanalysts and psychiatrists alike, that today, more than ever, the Goldwater rule should be set aside. While neither group may wish to admit it, the Trump era may have brought psychiatrists and psychoanalysts closer together—at least on this point.