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.

November–December 2023 updates: AABHL presentation; thalidomide apology; unlawful welfare convictions

Just a quick blog post to note a few news items

  • In late November, I presented the following presentation remotely at the Australasian Association of Bioethics and Heath Law (AABHL) on ‘risk-based regulation.’ My abstract was as follows:

What risk? A critical analysis of risk-based regulation of therapeutic goods, from stem cell medicine to osseointegration devices

Therapeutic goods (medicines, biologicals and devices) are regulated both in Australia and globally via ‘risk-based regulation’ (RBR). Recently, the OECD has described RBR as rules that are ‘science-based, targeted, effective and efficient,’ invoking the paradigmatic ‘risk-benefit analysis.’ But, as this paper contends, this description is misleading. In essence, RBR is neither health-focused nor harm-minimising but about ‘less-is-more’ governance. As with other neoliberal creations, RBR’s aim has been to prioritise private sector remediation (eg, civil litigation) and self-regulation over centralised governmental control. While the impact of RBR in the financial sector has been studied in detail, scarce legal scholarship has examined the state’s devolution of responsibility and control over therapeutic goods law to private individuals and organisations, such as hospitals or private practitioners.

As this paper will illustrate, while therapeutic goods legislation does control risk and experimentation (‘innovation’), it does so only for high-risk therapies: ie, those ‘worth’ regulating. Two examples are on point: the practice of stem-cell medicine and the use of osseointegration devices. In pursuit of efficiency, RBR eschews ‘overregulation’ and avoids duplication of oversight and enforcement. In concert with the Australian Civil Liability Acts, RBR has arguably achieved its implicit goal of ‘deresponsibilisation.’ However, a regulatory vacuum for unregulated or unapproved experimentation, creating confusion among practitioners and leaving regulators open to accusations of arbitrary decision-making. While better ‘upfront’ guidance for practitioners may assist, I contend that better-publicised reasons by regulators will enhance standard-setting.

A video recording of the presentation is below:

  • On 7 December, I was quoted in the Guardian in a story written by Paul Karp about two people remain in jail for welfare fraud offences based on defective and unlawful evidence. That defectiveness and unlawfulness has been recognised by the Ombudsman and the welfare agencies, and even, seemingly, the Cth Director of Public Prosecutions. I make the point that more should be done to facilitate the review of these cases. The CDPP have disclosure obligations, but it appears to me that the nature of the disclosures may be narrow (notifying of a potential problem) or broad (giving detail as to the nature of the evidentiary issues). The story is here.

Chimeric monkey sheds light on what can be done with embryonic stem cells

I was quoted in this article today regarding a newly published study in Cell that demonstrates, in the author’s words, that ‘mammalian pluripotent stem cells possess preimplantation embryonic cell-like (naive) pluripotency.’ As the summary notes, this discovery about embryonic stem cells can now be said to have been demonstrated experimentally through the generation of a chimeric animal — a monkey whose embryonic development has been ‘complemented’ by homologous embryonic stem cells derived from another ‘donated’ line of cells. The monkey, in short, has developed from a blastocyst that is a compound of two embryonic stem cell lines.

Unsurprisingly, news stories have been focusing on one of the eye-grabbing aspects of this experiment: that the monkey in question has fluorescent green fingers and eyes. Unfortunately, the monkey died after only 10 days — which is still the longest period of time for which such a chimeric organism has lived before.

The reason that the monkey has these features is because the researchers used green fluorescent protein (GFP) to ‘label’ the embryonic stem cells (ESCs) that were incorporated into the host embryo at the blastocyst stage. And so what one is looking at when one sees the monkey with green fingers and eyes (visible even to the naked eye) is visual evidence that the embryonic stem cells have survived the process of being ‘complemented’ into the blastocyst of the host monkey and have spread throughout its body. In other words, the cells have been incorporated into the monkey’s cellular DNA; the monkey has both its ‘natural’ DNA and a ‘foreign’ line of DNA. Indeed, as the images indicate, there is a proliferation of these complemented ESCs throughout the monkey’s organs, including plenty in the brain and ileum (small intestine).

As the ‘Highlights’ section of the article points out, when these embryonic stem cells (ESCs) in the body of the monkey were ‘characterised’ (assessed), it was revealed that they remained in a so-called pluripotent state. In other words, the ESCs seem to have been able to differentiate into the different kinds of cellular categories: glial (brain) cells, heart cells (myocytes), lung cells (epithelial cells), and so on. Indeed, they continue to be in this pluripotent state, even as they maintain a ‘functional’ presence in the monkey’s body.

The news.com.au story quotes me as follows:

Sydney University lecturer in health law Dr Christopher Rudge told new.com.au the medical experiment had been on the cards for a long time.

“This is another step along the journey,” he said.

“The advancement here is that scientists have never been able to show such a prolific survival / proliferation of donated (or ‘complemented’) embryonic cells through a single organism.

“You’ve got more of these donated or secondary cells throughout the organism in a mammal.”

But he cautioned whether it would lead to anything substantive.

“Regenerative medicine has been hyped since the late 1990s,” he said. “Unfortunately it has not borne fruit.”

See https://www.news.com.au/technology/science/stunning-monkey-born-with-glowing-eyes-and-fingers/news-story/27d84700628476da1579968e76cbda5d

Obviously this scientific study demonstrates that certain new techniques can be adopted to expand the capacity of scientists to create chimeras. Scientists have long had the capacity to infuse mouse and rat blastocysts with pluripotent stem cells to generate live chimeric animals that feature this high proliferation of homologous cells. What is new here is that this capacity now extends to non-human primates — a species of animal much closer, in evolutionary terms, to humans.

It is arguably another step along the way in discovering how stem cells, including pluripotent embryonic stem cells, can be used as technologies of biological inquiry (for diagnosis, and to study developmental mechanisms) and, ultimately, to biological treatments. Of course, there is still so much more to learn.

Whether an experiment of this nature would be approved in Australia is an interesting question. If nothing else, this finding indicates that discoveries in stem cell medicine are continuing apace. Of course, given that this involved the effective fusing of two monkey embryos (or embryonic cell lines), the more serious bioethical questions regarding human-monkey chimeras, which have been posed before, do not arise in this instance.

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:

Updates on welfare law

I have been writing on welfare law over on my substack blog Welfare Law in Australia. One recent post and video deals with the question of ‘unlawfulness’ as it arises in respect of the former section 1073B of the Social Security Act 1989 (Cth). The way that that section was applied by the welfare departments between 2003 and 2020 was, as the Ombudsman has confirmed, unlawful. But what does unlawful mean here?

As I suggest, it essentially means that the departments acted in a way that was not expressly authorised by the legislation. But, perhaps more faultily than this, the departments misinterpreted or misconstrued their powers under the section; and, accordingly, they acted without power on an assumption that they did have power. As I note (perhaps somewhat agonisingly), this is a little like playing football with ‘boots on your hands’ — essentially doing something that is within the rules (‘kicking the ball’) but completely misunderstanding what the rules mean (ie, the rules require players to kick the ball with their feet; not simply ‘with boots on one’s limbs’). For mine, the lesson to arise from this (the Ombudsman’s statement, after all, is titled ‘Lessons in Lawfulness’) is that reading legislation carefully is absolutely indispensable. The more sophisticated version of that lesson is that:

  • internal calculators or automation tools in government departments need to be crafted in accordance with legislation to the letter;
  • the calculator in this case, the Earnings Apportionment Tool (within the Adex Debt Statement) should never have been permitted to create apportionments that went beyond the statutory limit of one ‘instalment period’; and
  • cross-disciplinary legal practitioners must be identified and employed, or alternatively trained — those who have skills in statutory interpretation as well as computer and software design — in order to avoid internal tools being run and applied that perform operations that are contrary to law.

The issue that arose in relation to the legal construction of the provision was simple enough — at least in hindsight. The provision provided as follows:

1073B Daily attribution of employment income

(1) If:

(a) a person is receiving a social security pension or a social security benefit; and

(b) the person’s rate of payment of the pension or benefit is worked out with regard to the income test module of a rate calculator in this Chapter; and

(d) the person earns, derives or receives, or is taken, either by virtue of the operation of section 1073A or any other provision of this Act, to earn, derive or receive, employment income during the whole or a part of a particular instalment period of the person;

the person is taken to earn, derive or receive, on each day in that instalment period, an amount of employment income worked out by dividing the total amount of the employment income referred to in paragraph (d) by the number of days in the period.

As I have noted in my analysis in this video, it was perfectly lawful for the agencies to apportion income, as the provision provides, by ‘dividing the total amount of the employment income… by the number of days in the [instalment] period.’ However, it was not lawful for the agencies to divide the ‘total amount of the employment income … by [a greater number] of days [than exist] in the [instalment] period,’ which is what they did. It’s all there in the last sentence of the provision.

The word ‘period’ as it is used in the last clause of the provision appears to have taken on an expanded meaning on the agencies’ construction so that it could apply to the entire payslip period; however, as is clear on a plain language reading of the provision, the term ‘period’ can only refer back to the word ‘instalment period’ that appears earlier in the provision. Otherwise it has no fixed meaning, which is clearly unbearable.

I was very disappointed by the Deputy Secretary of DSS, as well as by the Ombudsman, when they appeared recently in the Senate inquiry on poverty in Australia, because both these senior governmental figures bemoaned the ‘complexity’ of the matter, and stressed how difficult it was to explain. I was disappointed because it really need not be described in this way. It can be explained quite tersely and clearly. And if senators who are not legally trained have questions, they can be answered pretty well. What needs to be explained is that the agencies made a very rudimentary reading error. They identified the word ‘period’ in the provision as a word that has no fixed meaning but could potentially expand to any quantum. When one thinks about it, that was a very amateurish mistake. And one imagines, as in the case of robodebt, the mistake was bordering on one that used to be described, in the old actions on the case, as faulty for ‘want of due care.’

I will be aiming to write a more complete analysis later on why this is not an error that is wholly or even at all distinguishable from robodebt, as seems to be the message from all and sundry now, from the Ombudsman himself, through the department heads, through to the relevant ministers (Hons Shorten and Rishworth). But it is an untextured and, ultimately, untrue message. As the appendix to the robodebt Royal Commission clearly illustrates, more than twenty of the earliest robodebts that came before the AAT1 were subject to recalculation orders by AAT members who found them to be ‘unlawful’ precisely because they were calculated impermissibly under s 1073B.

This project to distinguish miscalculated debts under s 1073B from robodebts is something of a legal nonsense. Yes: robodebts involve debt letters that alleged debts based on ATO data. And, yes, the s 1073B problem predates the OIC and other version of the robodebt programs. But, in terms of the legal problems presented by robodebts, these debts were unlawful, in the end, for two reasons: first, they were insufficiently evidenced in terms of their quantum, as the Federal Court observed in its settlement orders. The Court (Davies J) put it this way (at paragraph 9):

there was no material before the decision-maker capable of supporting the conclusion that a debt had arisen pursuant to s 1223(1)(b) of the SS Act.

But the second and very much related reason why robodebts were unlawful is because they were calculated contrary to s 1073B. The fact that this second reason was not explored in the Royal Commission nor articulated in the reasons of Davies J in Amato, and had not been aired publicly before this month, does not make it any less true that robodebts were unlawful because of this problem. To be sure, the smoking gun in this respect is the fact that the Amato submissions made the s 1073B impermissibility argument (emphasis mine):

56.4 Section 1073B provided for averaging of income earned by a person receiving social security payments over an “instalment period”. An “instalment period” could not exceed 14 days. The effect of s 1073B was to produce an average daily rate of income for each day in the instalment period. Section 1073C then provided that “(a) the rate of the person’s employment income on a fortnightly basis for that day may be worked out by multiplying that amount by 14; and (b) the rate of the person’s employment income on a yearly basis for that day may be worked out by multiplying that amount by 364”. Sections 1073B and 1073C do not authorise apportionment of the kind done under the EIC program. They simply provide a mechanism for working out “the rate of the person’s employment income on a yearly basis” where it is relevant, under the SS Act, to calculate the rate on a yearly basis. The relevant period for Austudy payments was a fortnight, not a year. As the relevant explanatory memorandum states, the main purpose of ss 1073B and 1073C was to facilitate the “working credit” rules in the SS Act, the function of which “is basically to allow a person’s ordinary income to be reduced before it is put through [the] income testing process”. The working credit rules provided for the calculation of “the participant‘s rate of employment income on a yearly basis” for the purpose of working out the effect on working credit balances of social security pensioners. The working credit rules did not apply to Austudy recipients.

But, as I say, more on that later.

Another recent post deals with another issue that arose this month regarding historical errors on the part of the welfare agencies. Services Australia’s IT system committed errors that affected almost 50,000 child support payment recipients in an unspecified period prior to and around 2018. While the IT issue is said to have been resolved in 2020 (some two years after the agency had been consulted on the issue by the Ombudsman), only around 35,000 people had by that time had their assessments and entitlements re-assessed and remediated, while another roughly 15,000 recipients’ entitlements were not reassessed or remediated. Instead, they were simply ‘written off’ as inconsequential and unnecessary to address by the welfare delivery department.

This decision was made by the agency despite the fact that it had committed to reassessing all the affected files in 2019 in representations it had made to the Ombudsman. All of this, of course, was occurring during the robodebt settlement and through the Royal Commission. Clearly concerned that this backsliding on a prior commitment could result in unfair outcomes, the Ombudsman this year sought to re-engage with the department to ‘make things right’ — and that, as it happens, is the name of the statement published by the Commonwealth Ombusdman in respect of this matter.

This short statement is not to be confused with a report of the same name published by the Ombudsman with respect to the Department of Education back in 2015. (I suppose, when one is the Ombudsman, titles like Making things Right or Lessons in Lawfulness will probably need to be recycled every few years.) As I argue in the post, it is just another example of the recalcitrance of the agency among several that have emerged since the Robodebt Royal Commission.

If you have not been following my activity on Welfare Law in Australia, please do subscribe. Relatedly, my media appearances in recent times on welfare law are as follows: