Interview on genome-editing and xenotransplantation

I was pleased to be invited to reflect on the future of xenotransplantation and human genome editing recently in an interview on ABC’s The World with Beverley O’Connor. The interview was broadcast following news of the unfortunate passing of Richard “Rick” Slayman — the first human to have received a genome-edited pig kidney. Mr Slayman passed less than two months following the xenotransplantation, although the General Massachusetts Hospital has stated that there is no indication that the transplant was the cause of death.

As I note in the interview, it is likely that the pig from which the kidney was sourced was a cloned pig. While this has not been confirmed (to my knowledge) by eGenesis, there are reports that the firm uses cloned pigs.

Moreover, the protocol by which pigs are prepared for this process is confirmed in the academic literature as involving somatic cell nuclear transfer (SCNT). SCNT is a kind of cloning that makes use of cultured fibroblasts — skin cells that excrete proteins like collagen — that are transferred into the enucleated nucleus of endogenous oocytes (eggs) . Willard Eyestone and colleagues describes the process in this way:

A major step forward in the generation of pigs as organ donors was the advent of somatic cell nuclear transfer (SCNT). In the pig, cultured fibroblasts were used as nuclear donors to replace the endogenous nuclei of porcine oocytes. Upon fusion with an enucleated oocyte, fibroblast nuclei were reprogrammed to totipotency by factors in oocyte cytoplasm. The newly reconstructed oocyte then developed into a new individual with the genetic constitution of the donor nucleus. SCNT technology opened the door for genetic modification of cultured somatic cells, which could be used to generate pigs bearing those modifications.

https://link.springer.com/chapter/10.1007/978-3-030-49127-7_6

In essence, pig oocytes or eggs are enucleated — their nucleuses removed — and then they are fused with the somatic (adult) nuclei of the fibroblast cells. The fused or engineered egg undergoes ‘reprogramming’ as a result of this process. This means that the genes within the engineered egg cells are expressed differently once the fusion occurs; indeed, the so-called ‘fate’ of the cell is ‘switched.’ This means that ‘potency’ (or differentiation pathway) of the egg cell is changed. By ‘differentiation pathway,’ I mean the cells’ ability to differentiate into other cell types.

Cell biologists speak of several different cell potencies. Stem cells can express different degrees of potency, and may be classified as totipotent, pluripotent, multipotent, oligopotent, and unipotent cells:

  • totipotent stem cells can differentiate into all adult somatic cell types, as well as tissues of the placental and fetal membranes; eg, the zygote (until the 16-cell stage)
  • pluripotent stem cells are capable of differentiation into all adult somatic cells in all three germ layers: the endoderm, mesoderm and ectoderm. They have two defining features: the ability to form teratomas when injected in immune-deficient mice and the ability to form chimera or contribute to the germline of a mouse if injected into the blastocyst. An example is an embryonic stem cell or a somatic cell reprogrammed into the pluripotent state using somatic cell nuclear transfer (SCNT).
  • multipotent stem cells are capable of differentiating into multiple but limited cell types, usually within one germ layer: eg, hematopoietic stem cells can differentiate into lymphoid, myeloid, erythroid and megakaryocyte precursors; mesenchymal stem cells, which are often used for attempt to regenerate tissue and other cells, can differentiate into osteogenic, chondrogenic, and adipogenic cells.

As the pig oocytes undergo reprogramming through the fusion process, they become pluripotent cells. This means they can give rise to another new form of life (eg, a pig may be ‘cloned’ from this engineered donor cell). This is how the pig was likely to have been created in respect of this process; and the pig kidney would have been harvested from the pig that was made through this process.

I suspect the 69 gene edits that were made to the pig, which included pig gene knockouts, human gene knock-ins, and pig endogenous retrovirus (PERV) gene knockouts, was done at the pre-fertilisation stage — that is, that were applied to the engineered pig oocyte.

In any event, it will be important to understand how well these treatments last, especially given that they will continue to be offered. A second recipient of a xenotransplanted pig kidney, a woman from New Jersey, was given her xenotransplanted organ at the New York University Langone Health around 24 April 2023. The organ, however, also included the pig’s thymus glad, according to reports.

Around the same time as the organ xenotransplant, the NYU surgical team also transplanted a mechanical heart pump into this patient. It is noted in reports that the patient was given these treatments under an FDA emergency authorisation; that would mean that it was likely authorised by an Investigational New Drug licence under pt 312 of Title 21 of the Code of Federal Regulations.

Salient details about this pig kidney from the media release include the following points:

  • The genome-edited pig kidney was sourced from biotech firm United Therapeutics Corporation
  • It was an investigational xenokidney that ‘matched’ the donee (presumably this is something like a HLA match?)
  • Although chronic kidney failure ordinarily rules out patients from receiving a mechanical heart pump, the potential for this patient to live without a need for kidney dialysis (provided the xenotransplant succeeds) meant that the heart pump could be given to this patient
  • The pig kidney was engineered to “knock out” the gene responsible for producing the sugar known as alpha-gal
  • NYU Langone studies (although it is not clear what kinds of studies — presumably non-human primate studies?) demonstrated that removing alpha-gal was sufficient to prevent an antibody reaction that causes hyperacute rejection
  • The donor pig’s thymus gland, which is said to “educate” the immune system, was included: it was surgically placed under the covering of the kidney to reduce the likelihood of rejection
  • The xenokidney and the thymus tissue combined are called a UThymoKidney
  • The gene edits, pig breeding, and production of the investigational UThymoKidney used in this procedure were performed by United Therapeutics Corporation. No other unapproved devices or medications were used in the procedure.

In the media: VAD in Victoria; the thalidomide assistance scheme; sexual misconduct reforms in health care

This post is just a brief discussion of three media contributions I have made in the last few months.

Interview on SIX News about Victorian VAD laws

I was interviewed in December last year for the Six News Australia program Between Parkes Place and Capital Hill about a judgment of November 2023, delivered by Abraham J as a single judge of the Federal Court of Australia. The judgment concerned the validity and operation of certain provisions of the Victorian euthanasia law — the Voluntary Assisted Dying Act 2017 (Vic) (VAD Act).

That decision of Abraham J, in the case of Carr v Attorney-General (Cth) [2023] FCA 1500 (30 November 2023), found that certain sections of the VAD Act (s 57(a); and ss 19(1)(d)–(e) and 28(1)(d)–(e)) were inoperative because they authorised a form of assisting suicide that was inconsistent with sections of the Commonwealth Criminal Code Act 1995 (Cth) — namely, ss 474.29A and 474.29B. Those criminal provisions, which were inserted into the Code in 2005 by the Howard government in the context of an earlier stage of the euthanasia debate, made aiding and abetting suicide by a carriage service a criminal offence. See, eg, section 474.29A(1) below (noting that the many subsections that follow sub (1) are omitted here):

It was unsurprising, I guess, in view of the legislative history of the Code provisions that, on a purposive analysis, Abraham J would find that the criminal Code was intended to criminalise the very thing authorised by the Victorian VAD Act.

The implications for the applicant doctor in this case, and for the operation of the VAD Act in Victoria, were considerable. That’s no surprise, however, as this was really a test case to determine a question of law: namely, whether a doctor discussing assisted dying with a patient over the phone would be prosecutable under the Cth criminal law. In other words, the doctor-applicant here saw his and his peers’ exposure to criminal liability as a possibility and was proved correct in going to the FCA to ensure that he would (or would not) be so exposed if he were to discuss suicide with any of his relevant patients under the Victorian law.

The interview is about 30 minutes’ long, and I thank the presenters for their detailed discussion. Oh — and one last note. I was alerted just yesterday that Kate Chaney MP has moved a Bill — which is here — that would amend the Criminal Code so as to make the Victorian law operative again.

Comments on the thalidomide inquiry and the federal government’s response

Also in December, my brief comments appeared in a short news story on thalidomide, which was published in the wake of a report published by the Senate Community Affairs References Committee about thalidomide, titled Support for Australia’s thalidomide survivors, and following the apology in Parliament by the Prime Minister to those who survived thalidomide and their families for the trauma and harms caused them in the 1960s.

There is a lot to say about the Australian thalidomide episode; however, what is unusual about the Senate Report is its discussion of and request for legal advice received by Australian MPs regarding the question of the Commonwealth’s liability or ‘obligations’ after it permitted thalidomide to be supplied in the Australian therapeutic goods market. Ultimately, the Report recommended that the legal advice be published to the public. However, that recommendation was not accepted by the government; it was merely noted, with no reasons or any response.

As the Senate report states (footnotes removed):

2.87. Early in the inquiry the committee was advised that the former Minister for Health, the Hon. Sussan Ley MP, commissioned advice from Maddocks Lawyers about Australia’s obligations to its thalidomide survivors.

2.88. On 19 June 2018, the Senate agreed that a copy of the document should be provided to the Senate by 20 June 2018. On 16 August 2018, Senator the Hon. Bridget McKenzie, representing the Minister for Health in the Senate, made a public interest immunity claim over the document. Senator McKenzie’s public interest immunity claim was based on the fact that the document was legal advice to government:

It has been the long-standing practice of successive Australian Governments to not disclose privileged legal advice, including advice that canvasses possible constitutional issues.

2.89 In the interim report the committee requested that a copy of the advice be
made available to the committee to help it to understand the options available
to the Australian Government.

2.90 The Maddocks Lawyers’ advice was not made available to the committee and
the committee was unable to verify or consider the contents of the advice. This
is important as the advice could have provided the committee with a better
understanding of the legal context in which the Australian Government is
being asked to respond to the Thalidomide Group Australia’s requests. The
advice could have also provided the committee with important information
regarding the current options available to the Australian Government for
supporting thalidomide survivors.

2.91 Instead, the only evidence the committee has about the advice comes to it
indirectly. The committee received some evidence that a ministerial adviser
revealed some of the content of that advice to the Director of the Thalidomide
Group Australia, Ms Lisa McManus. According to Ms McManus, the adviser
provided her with the following information about the advice:

– the advice is 23 pages long;
– it provided five possible options;
– one of the options was to ‘do nothing’; and
– it concluded that the Australian Government had no legal obligation, but
that the Australian Government has a ‘moral responsibility’ to assist
thalidomide survivors.

Committee view
2.92. The committee considers that Australian governments have a moral obligation
to Australia’s thalidomide survivors. The committee notes that both the
Australian Government and the state governments failed to monitor drug
safety at a time when other governments around the world did so. Documents
provided to the committee demonstrate that the Australian Government was
aware that more could be done to safeguard public health from dangerous
drugs. The committee notes that the formation of the Therapeutic Goods
Administration was a direct result of the thalidomide disaster and notes
evidence to the inquiry that suggests such a body could have been, and should
have been, established earlier.

Parl Info

Obviously, whether the Maddocks advice might have suggested or explored any cause of action against the Commonwealth for historical negligence is of immense interest to victims (and to a lesser extent legal scholars). It does seem to me that there would not be very high prospects of a case on today’s law. However, if the Maddocks advice included five possible courses of action, one of which was ‘do nothing,’ what were the others? Are any of those options not canvassed by the Senate Committee?

What really strikes me as difficult about this issue is that the Committee was not itself able to review the advice, in circumstances where one might expect that Senators, as sworn officers of the Commonwealth, might be entrusted with such documents. After all, the lawyers who wrote the advice, while also bound by legal professional privilege, are not sworn officer of the Commonwealth. But I digress. It may be left to negligence scholars such as myself to guess and theorise about what liability might, on a given historical account, be affixed to the Commonwealth — if any.

Sexual misconduct reforms to health practitioner law

Proposed reforms to the Health Practitioner Regulation National Law, or National Law, have been circulated for consultation recently. The National Law is an Act separately enacted in most of the different states as part of a national scheme for regulating health practitioners called the National Registration and Accreditation Scheme, or NRAS. Technically, the NRAS is designed as an applied laws scheme, because the template is a Queensland law that then gets ‘applied’ in other jurisdictions. But because not every state applies the Queensland law (NSW enacts the law itself), it’s actually probably best described as a ‘combination scheme.’ In any event, it’s a co-operative scheme between the states and Commonwealth; however, there is no Commonwealth-level legislation.

I wrote about these promising reforms for The Conversation here. In essence, the reforms aim to put a stop to the rising rates of notified sexual misconduct and boundary violations that are emanating from the clinical practices of health practitioners nationwide. However, a few notes I might now add include the following.

First, much credit for the shape and substance of the reforms should be duly extended to Prof Jenni Millbank of UTS, whose several detailed publications on the National Law have really unearthed the difficulties that these reforms attempt to address. For instance, the second proposal, which is about bringing other states’ reinstatement processes up to the same level of strictness as the process in NSW, would probably not have been possible to float unless Millbank had identified and argued about this problem in one of her excellent refereed articles.

Second, the NSW version of the National Law has been stricter from the very beginning (2009), and the reform processes hence have — in my view inevitably — been a slow and somewhat agonising process of watching all the other states catch up to where NSW began.

In my view, this has also really been the consequence of the National Registration and Accreditation Implementation Project (NRAIP) team not really clicking with the NSW participants in its original discussion in 2008. While the NSW advocates were clear and compelling in arguing for the preferability of the existing NSW practitioner law (and on that basis ‘carved out’ parts of the NRAS to retain those preferable laws), the NRAIP team seemed wedded to the template, and may have failed to identify all the real virtues of the stricter NSW system. That was the NSW system which had developed, in short, in response to several scandals — principally, Chelmsford, “Butcher of Bega,” and Dr Sood, and which, in 1983, created the first ‘HCE’ (health complaints entity) — namely, the HCCC — in the world.

Alright — thanks for reading.

Updates for September: Cosmetics and COVID-19

This month has been a busy month for my semi-scholarly work. At the start of the month, I wrote a piece for the Conversation about the so-called crackdown on the cosmetics procedures sector announced by AHPRA around 7 September 2023.

Following the publication of that piece, I was lucky to be asked to appear on a long interview for Mamamia’s The Quicky. It was a great talk and I thank host Claire Murphy for the great interview.

Over the last few days, when it was announced that a COVID-19 inquiry would be run by the Commonwealth government, its terms of reference came under scrutiny. Having co-authored and published an article earlier in the year on COVID-19 mandates — an article that I was very proud to have written, especially when it was given plaudits from now Justice of the High Court of Australia Hon Robert Beech-Jones — I was keen to provide my view on the terms of reference.

Several commentators around the country have argued that the terms of reference are unduly restrictive and a cause for complaint. That, in some ways, is understandable. After all, it is essential that critical minds and governments examine how the public health legislation was deployed during the pandemic, especially where profound human rights issues arise from coercive interventions.

However, as I argued ion ABC News Radio on Friday 22 September, the Inquiry expressly will cover questions of governance, including

the role of the Commonwealth Government, responsibilities of state and territory governments, national governance mechanisms (such as National Cabinet, the National Coordination Mechanism and the Australian Health Protection Principal Committee) and advisory bodies supporting responses to COVID-19.

See Inquiry TORs

Given that our Constitution does not confer on the Commonwealth a competency to make laws with respect to public health, however, the terms of reference strike me as sensible and practical.

After all, it is the states, including New South Wales, that hold the power to regulate public health within their polities. Sections of the states’ public health Acts confer different conditional powers on their relevant health ministers; and, in New South Wales, it is section 7 that gives the Minister massive powers to do whatever they consider to be necessary when, on reasonable grounds, they consider that a situation has arisen that is likely to be a risk to public health, and they seek to deal with the risk and its possible consequences. My phrasing, above, is a little garbled, because it seeks to paraphrase the wording of the provision, which is as follows:

7 Power to deal with public health risks generally
(cf 1991 Act, s 5)

(1) This section applies if the Minister considers on reasonable grounds that a situation has arisen that is, or is likely to be, a risk to public health.

(2) In those circumstances, the Minister–

(a) may take such action, and
(b) may by order give such directions,

as the Minister considers necessary to deal with the risk and its possible consequences.

All of the NSW public health orders were made pursuant to section 7, above.

The Victorian Act, by contrast, requires that a ‘pandemic declaration’ be made before the minister’s powers are enlivened. Following the making of any such declaration, the Minister of Health may exercise their powers to make orders under s 165AI of the Public Health and Wellbeing Act 2008 (Vic), which states as follows:

PUBLIC HEALTH AND WELLBEING ACT 2008 – SECT 165AI

Minister may make a pandemic order

(1) The Minister may, at any time on or after the making of a pandemic declaration, make any order (a pandemic order) that the Minister believes is reasonably necessary to protect public health.

As is obvious, these powers are held by state ministers. They are not controlled or controllable by the Commonwealth government, or any Commonwealth minister. Arguably, any influence exerted by a Commonwealth minister over a state minister to exercise their powers in a particular way may give rise to a misuse of the power, inasmuch as the requisite ‘consideration’ (New South Wales) or ‘belief’ (Victoria) of the health minister has to be held by that relevant state minister. Sure, a health minister’s belief or consideration may be reconfigured by additional information from other actors, including their equivalent ministers in other Australian governments. But the legal fact is that the Commonwealth cannot really repeal, remake or otherwise alter or even influence this power; and this is a point that I have found has been missing from the public debate about the scope of the COVID-19 inquiry.

What would be the best outcome of an inquiry into the way the state health ministers exercised their powers? Would the Commonwealth recommend that the state ministers must have approval from the Commonwealth before exercising these powers? Would they be required to consult? This would seem to be completely contrary to the design of the Constitution, which, as Quick and Garran point out time and again, was premised on a fair compromise between the new central government and the colonies: the states would retain independent powers across a range of areas, including, as I think it must be inferred, health. I am not opposed to more centralisation; however, I think it;’s important to understand what we are proposing when we ask for a Commonwealth inquiry into the exercise of state power. And so I was pleased to feed that into the debate via national radio.

My request, alas, remains with ABC Archives for a copy of the recording! (It cannot be replayed like some other programs on ABC listen, etc).

In the meantime, I feel more compelled than ever to revise and rewrite the serious consideration that I developed in 2018 on the division of health power in Australia — an article that, for various reasons, did not make it through peer review at the top journals but which I have been told several times since would make a sorely needed contribution to the literature in this area. The best articles on the topic I have found are two oldies and a newie: