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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.

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Emotions and Device-Oriented Psychiatry in the Early Twentieth Century

In July, 1907, the Swiss psychiatrist Carl Gustav Jung and American neurologist Frederick Peterson published the results of their investigations into the galvanometer and the pneumograph in BRAIN, the journal of neurology. The pair had subjected various people to these instruments—people they had identified as “normal” and “insane”—in an attempt to record and quantify certain “emotional” and “psychical changes” in their moods “in connection with sensory and psychical stimuli.” At this time, only a few years into the twentieth century, these scientists—and many others like them—were eager to develop a systematic means of measuring emotion. They sought to demystify and provide a scientific explanation for the enigmatic interface between the body’s nervous system (both the peripheral and central nervous systems) and the presentation of varied human emotions. To this end, instruments such as the galvanometer and pneumograph, then understood as effective “measurer[s] of the emotional tone,” promised to illuminate the physical meanings, mechanisms and perhaps even causes of what they called the “emotional complexes.”

Among the most extreme of the “emotional complexes” was the category of dementia praecox. This was a condition whose “chief characteristic” was, as George H. Kirby noted, “a particular disturbance of the emotions.” Kirby was the first American to develop a classification of psychoses, and his system was later adopted by the American Psychiatry Association in something of a precursor the Diagnostic Statistical Manual of Mental Disorders, the authoritative diagnostic manual used by psychiatrists today. But Kirby was not the first twentieth-century psychiatrist to undertake a modern classification of the psychoses. That honour belonged to Eugen Bleuler, the Swiss psychiatrist under whose supervision Jung and Peterson had conducted their work on the galvanometer and the pneumograph. In fact, Jung and Peterson undertook their research in Bleuler’s laboratory, within the huge University Clinic for Psychiatry at Zurich known as Burghölzli (fig. 1), a building that was idyllically depicted in 1917 by swiss painter Max Gubler (fig. 2), who would tragically later move and die there. In Burghölzli, Jung and Peterson also used Bleuler’s apparatuses—his galvanometer and the pneumograph—to produce their study of the relations between the nerves and emotions. Jung had been awarded his PhD in 1902 based on Bleuler’s reports, and the tense relationship between the two men has been a subject of some scholarly interest.

Figure 1. The Burghölzli psychiatric clinic in Switzerland (1880s). Image: Public Domain.

Figure 2. Max Gluber, Winterlandschaft Burghölzli [Winter Lanscape at Burghölzli] (1917). Courtesy of the Eduard, Ernst and Max Gubler Foundation.
In 1911, only four years after the publication of Jung and Peterson’s investigation, Bleuler would coin the term schizophrenia, proposing that it should replace “dementia praecox.” That older term had been coined by the French physician or “alienist” Phillippe Pinel in the early nineteenth century, and popularised by the influential German psychiatrist Emil Kraeplin in his 1896 textbook Psychiatrie. In Bleuler’s 1911 monograph, titled Dementia Praecox or the Group of Schizophrenias, the Swiss psychiatrist would argue that the earlier term was misleading for practitioners, conveying as it did two deceptive associations. The term, he said, suggested that schizophrenia had something to do with the disease of dementia, as well as with the concept of “precocity,” when in fact it had nothing to do with either. Moreover, Bleuler argued that it was impossible to express the phrase “dementia praecox” as an adjective, which made writing about the disorder nearly impossible.

Despite the fact that Jung and Peterson worked in Bleuler’s laboratory, the way in which these scientists described mental disorders differed markedly, at least in one respect. Strikingly, Bleuler’s paradigmatic psychiatric work of 1911, translated into English from the original German in 1950, almost entirely omits the word “emotion” or “emotional complex.” By contrast, Jung and Peterson’s study of 1907 uses the term “emotion” or “emotional” some 108 times (in a study of roughly 18,000 words). Of course, this is not to say that emotions are altogether excluded from Bleuler’s understanding of schizophrenia. On the contrary, emotions lie at the heart of his symptomatological description of the disorder. At one point in his monograph, Bleuler writes that “many schizophrenic symptoms originate from emotionally charged complexes” and that the “symptomatology is determined by the emotionally charged complex which, in turn, is often dependent on the Anlage [predisposition].” As such, the omission of the word emotion and the general concept of emotionality in Bleuler’s text is puzzling. Of course, it might be explained by the fact that there is no easy German equivalent to the word, and that the text would presumably employ the word “gefühl” (meaning feeling) or “affekt” (meaning affect) to denote the same concept.

Indeed, as psychiatry developed in the following decades, the concept of “feeling” and specifically of the “praecox gefühl”—the praecox feeling—would become one of the most important in the diagnosis of the psychoses. First named by the Dutch psychiatrist H. C. Rümke in the 1940s, the praecox feeling described the way in which the diagnostician would, in some circumstances, need to rely on intuitive reasoning—on their highly attuned and sensitive emotional senses, refined as they were by clinical experience—to reach a diagnosis of schizophrenia. It would be necessary to use this method when a patient was, for reasons related to their pathology, “fundamentally inaccessible,” such as when, because the basic structure of their “being-in-the-world” had altered, the practitioner could identify something about them that was hard to describe in words but “definitely incomprehensible.”

Perhaps one of the reasons that Bleuler’s work so rarely refers to emotions and emotional states, whereas Jung and Peterson’s study describes “emotions” so often, is due to the divergent aims of and influences on their authors. Despite presenting itself as a work of psychiatry, Bleuler’s study inherits much from psychoanalysis and Freud, routinely referring to such Freudian concepts as symbolisation, resistance, and the Oedipus complex, among others. Jung and Peterson’s study, by contrast, focuses almost entirely on the quantification of emotions by means of their instruments; it is less a study in taxonomy than an attempt to break away from those symbolic concepts that Freud had introduced only six years earlier. Using instruments and devices, Jung and Peterson seek to bring these disorders of the mind out of the realm of the “invisible” and into the clear light of day. This, as Jeffrey Lieberman notes, was precisely what distinguished the work of neurologists from psychiatrists: “Physicians who specialized in disorders with an observable neural stamp became known as neurologists,” he writes, whereas “those who dealt with the invisible disorders of the mind became known as psychiatrists.”

Historians and philosophers of science have identified the rise of a “device paradigm” in psychiatry from the mid-twentieth century and onward. They point to the invention of electroconvulsive therapy (ECT), the emergence of repetitive transcranial magnetic stimulation (rTMS) and, from the mid-1950s, the use of psychopharmacological drugs, as evidence of this newly device-oriented science of the mind. However, Jung and Peterson’s investigations—together with some similar, though more controversial, experiments with x-rays in chiropractic medicine—illustrate an earlier turn towards devices. In fact, not only was the shift toward devices well underway in the first decade of the twentieth century, but devices were, at this time, central to the study of emotion. Before psychiatrists such as Bleuler and Kirby established psychiatry’s classification systems, subsuming “emotional complexes” into their systematic taxonomies, measuring human emotions by means of physical tests had been a central object of neurological enquiry.

Figure 3. The most recent version of the E-Meter (courtesy Scientology.org).

Ironically, Jung and Peterson’s methods would be revived in the 1950s, when, after attending a lecture delivered by L. Ron Hubbard, an American inventor named Volney Mathison patented a new device that he described as a “bio-electronic instrument which registers human dynamic emotion in a more accurate and sensitive manner than has been possible with any previous device of comparable simplicity.” Hubbard quickly embraced the device, which is now known as the E-meter (fig. 3, above), and a modified version of this same galvanometer today forms part of the Church of Scientology’s official practices, used to “audit” the emotional complexes of the Church’s adherents.