Recent writing: ‘SBVs’ and ‘GMOs’

The most recent two issues of the Journal of Law and Medicine carry articles authored or co-authored by me. The first is lead-authored by Mike O’Connor (with me and Cameron Stewart) and is titled ‘Sexual Boundary Violations by Doctors – Context, Regulatory Consequences and Preventive Strategies’ (see PMID 38761390). In that paper, we discuss the difficulties associated with regulating health practitioners who commit what we call SBVs; indeed, particular difficulties beset regulators in Australia, where AHPRA and the health professional boards (as well as the co-regulatory Councils in New South Wales, and the Health Ombudsman in Queensland) have been unable to stem the tide of increasing notifications of boundary crossing from patients. We also briefly engage with the proposed reforms (see here) being considered by Australian health ministers — reforms designed to discourage SBVs across health practice. Our conclusion is that more data are needed, and that more must be done to educate and train practitioners at the earliest stages of training: eg, medical school.

The second article is sole-authored and titled ‘Challenging Pandemic Law: From Vaccine Mandates to Judicial Review of Vaccine Approvals’ (see PMID 38963244). This article represents my attempt to clarify aspects of the polycentric (multi-centered) regulation of therapeutic goods, gene technology and health practice in Australia. It is particularly concerned to clarify the interaction of the Gene Technology Act 2000 (Cth) (GT Act) and the Therapeutic Goods Act 1989 (Cth) in light of claims that the so-called mRNA vaccines for SARS-CoV-2 (eg, Pfizer and Moderna) should have been subject to the licensing regime set out in the GT Act.

Following the Federal Court of Australia’s holding in Fidge v Pfizer Australia Pty Ltd & Anor [2024] FCA 161 (Rofe J), the article underscores the purposive approach courts are required to take in interpreting co-operative and interacting statutory regimes; indeed, as Rofe J observed in Fidge (at [66]), the GT Act (Cth) was intended to regulate ‘GM products (non-live or non-viable products) [only] where they are not regulated by an existing regulatory scheme.’

The article also undertakes a serious analysis of the law of standing as it relates to proceedings brought by self-identifying ‘aggrieved’ parties in respect of therapeutic goods and gene technology law. Notably, the article was written and published before the recent US Supreme Court decision on expanded access to the abortion drug mifepristone: Food And Drug Administration et al v. Alliance For Hippocratic Medicine et al 602 US 367 (2024). However, that US apex decision only reinforces the impediments faced by medical practitioners and special interest groups involving doctors when it comes to seeking court orders or relief relating to administrative decisions by drug regulators. No doubt FDA v Alliance will inspire a great many debates in relation to standing and challenging regulatory decision-making. Of course, the apparent demise of Chevron in the US may have other interesting impacts on these matters too.

‘Challenging Pandemic Law’ is also the first scholarly article I’m aware of that discusses the first ‘partially successful’ COVID-19 mandate litigation: Johnston & Ors v Carroll (Commissioner of the Queensland Police Service) & Anor [2024] QSC 2. No doubt many other articles will analyse this case.

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.

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.

A small injection of strictness: The TGA’s clampdown on cosmetic injectables advertising

Last month, the Therapeutic Goods Administration (TGA) announced it had updated its guidance on advertising cosmetic injectables. I have written about the subject, and have been interviewed about these policy reforms, here, here, here, and here. But I was again recently interviewed on ABC Drive Canberra about the new changes. That short but lively conversation, embedded below, inspired this post.

In essence, the updates make it abundantly clear that all direct or indirect advertising of prescription-only medicines is prohibited in Australia. Although unwieldy, direct-to-consumer advertising of prescription medicine is often denoted by the acronym DTCA-PM. In essence, because many dermal filler or nerve-killing cosmetic injectable products, such as Botox, are prescription-only medicines, they cannot be advertised legally in Australia (without specific and exceptional approval).

Read the full blog post on Sydney Health Law blog >

CRISPR’d pig kidneys for xenotransplantation

Last week, the biotech firm eGenesis supplied a donor kidney sourced from a genome-edited pig to a surgical team at Massachusetts General Hospital (MGH) in the US. The donated kidney was transplanted into a patient with end-stage renal disease whose existing kidney transplant (‘allotransplanted’ from a human) was wearing out. The FDA had granted an expanded access authorisation for the procedure and, as of today’s date, the patient is reported to be doing well.

It is not clear to me from any of the materials online how exactly the pig was edited, other than that it was broadly subject to CRISPR/Cas9 editing of three kinds. First, there was so-called knock out editing of the glycan antigens (which lead to hyperacute rejection); second, there was knock in editing of seven human transgenes, which are thought to help with ‘acceptance’ (or which mitigate immunogenic rejection); and, finally, there was editing directed towards inactivating the genes known to cause porcine endogenous retroviruses (PERVs).

In total, eGenesis and MGH report that sixty-nine (69) discrete gene edits were made. That appears to be a record for a xenotransplantation, because the previous two pig-derived heart xenotransplants from 2022 and 2023 in the US are reported to have only been subject to about 10 edits.

I am assuming that the edits were made to the germline cells of a pig embryo fertilised in the laboratory, as opposed to being made on primordial germ cells or embryonic stem cells, but I am not able to find any specific protocols for this firm’s method. I suspect that somatic cell nuclear transfer (SCNT; ie, cloning) was not used, even though SCNT is technically legal in the US. In any event, I wrote a piece for the Conversation on some of the issues arising in relation to this recent news item here.

A Generational Miscalculation: Unpicking Centrelink’s Unlawful Income Apportionment

Today on Welfare Law in Australia, Darren O’ Donovan analyses an internal document released under the Freedom of Information Act 1982 (Cth) just a few days ago. That document reveals the inner working of Services Australia as it continues in its efforts to remediate a multi-decade calculation blunder likely affecting more than 100,000 people. What is more, the calculation blunder was also unlawful — well, at least according to the Commonwealth Ombudsman.

The post comes only a day after Charlesworth J of the Federal Court of Australia found, in Patrick v Attorney-General (Cth) [2024] FCA 268, that governments will no longer be able to deny information requests that are determined at a date after the relevant Minister’s term has expired because (among other things) a document will be viewed as an ‘official document’ as it exists as such at the time of the request rather than at the time of the determination [8].