Regulating Human Genome Editing in Australia: Overdue Legislative Review

The ethical concerns of human germline editing (on sperm, eggs, early embryos)

A grave worry is germline editing performed on humans. The germ cells become the egg or sperm of a developing organism and transmit its heritable characteristics, i.e., the genes in germ cells are passed on to future generations. Many of the ethical debates related to genome editing center around human germline editing. For many, the clinical use of germline editing is an ethical line that cannot be crossed.

All other cells are called somatic cells. If the insertion is performed on specialized or differentiated body tissues, e.g., liver cells, muscle cells, or blood cells, it is known as somatic cell gene modification and the changes do not go beyond the individual whose DNA is modified and are not passed on to their offspring. Gene alterations in humans are referred to as gene therapy. Somatic gene editing does not raise severe ethical issues; as long there is informed consent provided by the adult patient. Hence, there is an ethical distinction between somatic cell editing and germline cell editing.

If the couple has a gene that may predispose their children to inherit a particular condition, genetic manipulation would appear desirable, even morally imperative, to avoid the undesired outcome. The earlier during embryonic development the targeted gene(s) are modified, the less likely is the person to be affected by the unwanted gene. While the objective of such a modification is to change the genetic constitution of the individual, changes made to an early embryo would also affect the offspring of the future human. The aim is to eliminate the gene pool of harmful genes, e.g., to cleanse cystic fibrosis from the germline and thus save the pain, suffering, and expenses it causes, which can also avoid the need for recurrent somatic gene modifications.

When a gene involved in a specific condition is recognized, it appears to be appropriate to change or replace the gene(s). However, biological traits may be influenced by interactions among multiple genes, and the activity of genes is impacted by some processes that occur both within the organism as well as in its surroundings. ¹⁷ Presently, experts are unable to speculate the effect that a gene modification will have on the traits of a human. ¹⁸

As the connection between genes and diseases is still not adequately understood, we cannot be assured that by changing genes associated with traits we wish to avoid, we will not alter qualities we would like to keep. Genes that are linked with diseases which will cause complications in one setting may be beneficial in others. ¹⁹ Changing disease risk by replacing genetic variants with others is fraught with challenges, and editing out one disease may even increase the risk of others. ²⁰ For instance, a variant in the gene SLC39A8 reduces a person's chance of developing Parkinson's disease but increases their risk of developing schizophrenia. ²¹ In Dr. He's experiment, inactivating the CCR5 is not benign; it has been reported to increase significantly the risk of various complications and even fatalities from other infections, e.g., influenza and West Nile virus. ²²

Introducing genetic modifications to future generations could have permanent and detrimental effects on the human species. ²³ The mutations cannot be removed from the gene pool unless the people with edited DNA agree not to have offspring.

Obtaining informed consent from an embryo or their descendants is impossible. While parents make the decisions in these situations, it is doubtful whether there is genuine informed consent when the risks are not known. Also, it is not possible to be accountable to humans in future generations who may be harmed or stigmatized by wrongful or unsuccessful germline modifications of their ancestors.

Moreover, couples who are concerned about transmitting severe genetic diseases to their offspring currently already have other safer and more-established alternatives, e.g., preimplantation genetic testing (PGT), prenatal testing, and gamete donors.

An important distinction needs to be made between germline editing conducted purely for research purposes and for reproductive purposes. The former concerns a pure primary study by researchers whereas the latter is a clinical application which achieves pregnancy. While germline editing for reproductive purposes raises serious ethical issues, conducting germline editing purely for research purposes is arguably ethical and justifiable (in fact, a moral imperative) provided it is performed under very stringent conditions. Accordingly, this research activity should be legalized subject to strict requirements. However, first, as a society, we need to fully explore and debate this matter in Australia, and a comprehensive review of the law will enable these discussions before making the recommendation on whether to amend the current law.

The ethical concerns of non-medical enhancements and the creation of designer babies

Another concern is the possible creation of “designer babies” not even related to a medical condition. Germline modification would enable couples to enhance specific characteristics of their offspring. CRISPR could be used to edit the human genome to select for athleticism or intelligence. Genes could be altered to remove unwanted traits or insert desirable ones. Germline changes could design people to look more attractive, run faster, and be better mathematicians. Religious groups might find this objectionable as this is tampering with nature.

This is the slippery slope argument: if we allow germline editing even for only pure research purposes, it will start us down a path towards using it for nontherapeutic and enhancement purposes in the future. In egalitarian Australia, this issue is particularly pertinent.

The impact of treating humans as biologically perfectible artifacts would be negative. People who fall short of some ideal would be seen as damaged goods, while the standards for the genetic desirable will be those of the economical and politically dominant sections of society. This will only accentuate stigmatization, prejudices, and discrimination in a society where biases are already occurring. Parents could be under pressure to enhance their offspring. Children with edited DNA might be affected psychologically.

However, it can be argued that one person's medical treatment is another person's enhancement. ²⁴ Inserting genes that increase muscle growth is therapeutic in people who have muscular dystrophy but not in healthy individuals training for competitions (e.g., the Olympic games). It is a challenge to differentiate between remedial action and enhancement. Public forums are necessary to further explore these arguments before deciding on how to regulate this.

The ethical concerns of social inequities

This argument is especially relevant in egalitarian societies such as Australia. Genetic enhancements may only be available to specific sections of society which could accentuate social inequities. While the wealthy can afford to use it to enhance their offspring, the rest cannot. There are already existing disparities in access to health care and other interventions. If taken to the extreme, germline editing could create classes of people defined by the quality of the engineered genome.

International summits on human genome editing

To date, there have been two major global conferences on human genome editing. In the first International Summit on Human Gene Editing, held in December 2015, the organizers stated that basic and preclinical research, as well as the clinical use of somatic cells, are permitted provided they are subject to the existing regulatory framework. However, deploying clinical application of germline editing is irresponsible until its impacts are entirely understood. The summit statement provided that “it would be irresponsible to proceed with any clinical use … unless and until (i) the relevant safety and efficacy issues have been resolved … and (ii) there is a broad societal consensus about the appropriateness of the proposed application.” ²⁵ Dr. He's recent experiment suggests that this summit statement was not adequate.

At the recent Second International Summit on Human Genome Editing in Hong Kong (November 2018), ²⁶ its organizing committee issued a statement recommending how human genetic engineering ought to be regulated. While it acknowledges that research is progressing in both somatic and germline genome editing, an essential point in the statement is that the clinical use of germline editing is irresponsible at present. This message is an iteration of the first conference statement. Given the ethical concerns associated with editing the human genome, the cautious approach was recommended in the summit. The committee recommended that researchers should not use CRISPR in clinical application to alter the human germline at present and it stressed that society needs to debate about the ethical considerations.

The summit committee stated that currently, heritable genome editing, whether gametes (sperm and eggs) or embryos, poses risks that are still difficult to assess. In embryos, if changes are performed in only some cells, the unedited cells may even perpetuate a disease. Also, if researchers are permitted to edit a human germline, future generations might not be able to opt out. There could be severe risks affecting not only the embryo but also their descendants.

The organizing committee did not rule out germline entirely in future. This is provided that the risks are sufficiently addressed and stringent conditions are imposed. The requirements include independent oversight, a compelling necessity, an absence of alternatives, long term follow-up, and attention to societal effects.

The committee called for public forums to debate and consider policies for improving equitable access. In addition to the call for a continued global discussion to promote open dialogue, the summit committee also recommended attention to societal effects. They acknowledged that acceptability may differ among nations, leading to a variety of regulations. This leaves some room for countries to adopt different pathways informed by their respective cultures and values. Despite the overall cautious approach recommended by the organizing committees in both summits, the word “moratorium” was not used and some scientists, e.g., Dr. Paul Knoepler, a cell biologist of the University of California, were disappointed. ²⁷

Call for international moratorium on clinical application of human germline editing

Following the controversial announcement by Dr. He, 18 prominent stem cell scientists and ethicists from seven countries have recently called for an international moratorium (temporary ban) on the clinical application of human germline editing. The objective of the moratorium is to provide more time to have discussions to set up a global framework. This call for a moratorium was supported by the U.S. National Institutes of Health (NIH). ²⁸

The call does not favor a permanent ban on germline editing, as they consider that approach to be too rigid. The experts think such bans are appropriate for certain other technologies such as nuclear, chemical, and biological weapons, but not for germline editing. ²⁹

The call allows each nation to maintain its right to reach its own decision on how to set up their regulatory framework. The proposed moratorium would be of five years' duration. After that, clinical applications of germline editing could be allowed by the respective countries on condition they comply with some requirements. They include public notice of two years of their intent to conduct the clinical application and also engage in a global discussion, a careful assessment and well-informed decision that the clinical use is justifiable, and finally, a broad societal consensus within the country. The experts suggested that a coordinating unit could be formed under the World Health Organization (WHO). This unit should then set up an international panel, comprising two subgroups, one to oversee technical/scientific issues and the other on ethical/societal matters. As an international panel, they would provide objective information.

However, not all scientists support this call for a moratorium. ³⁰ Among them are prominent experts such as Jennifer Doudna (University of California, Berkeley), David Baltimore (California Institute of Technology), George Daley (Harvard Medical School), and George Church (Harvard biologist). The scientific community itself is divided on the issue of whether to impose an international moratorium on human germline editing. Doudna was concerned that the moratorium was of indefinite length. ³¹ But a moratorium is a temporary measure with, in this case, a proposed duration of five years. The dissenters question the wisdom, practicality, and benefits of a moratorium, such as how it would be enforced or whether it provides a clear pathway to the responsible use of the technology. ³²

I respectfully disagree with these contentions of the dissenters. The call for a moratorium on clinical applications in human germline editing has set out clear, specific, and detailed steps. I support this call as this would be a clear and transparent path in the right direction. The call stressed that this activity should be considered only in circumstances where there are compelling reasons and the bar should be set high. While this moratorium approach will undoubtedly slow down the progress of the technology, these restrictions would ensure openness and due respect given to differing viewpoints on a critical issue that affects the human species.

The current Australian law on human germline editing

Australian scientists may contemplate performing pure research using gene editing in embryos in the future. Fundamental research is necessary to check the safety and accuracy of genome editing, including the need to address critical issues about human biology. Clinical applications can be considered only after concrete research groundwork has been performed. It is stressed that in such research settings, there is no intention to implant the embryo into the body of a woman to achieve pregnancy. Thus, research is essential for several reasons, provided it is not used for reproductive purposes.

Despite being pure research which does not involve implantation, whether this kind of research is considered ethical is nevertheless debatable. Thus, public debates on this issue are essential. Even if the majority's view is in favor of allowing such research, the existing Australian law on this area is lacking clarity and needs to be amended to provide more certainty and confidence to future researchers who may be concerned about breaking the law. Currently, there is no application submitted for licenses to conduct germline editing and the reason could be the ambiguity in the existing law. ³³

Of relevance in this discussion are two statutes: the Prohibition of Human Cloning for Reproduction Act 2002 (Cth) (PHCR Act 2002) and the Research Involving Human Embryos Act 2002 (Cth) (RIHE Act 2002). The PHCR Act 2002 completely prohibits some practices involving embryos and prohibits other methods used to create embryos unless a license is obtained from the National Health and Medical Research Council (NHMRC) licensing committee. The RIHE Act 2002 establishes a strict licensing system for the creation and use of human embryos and prohibits the use of embryos for research without a licence.

Section 15 of the PHCR Act 2002 needs to be amended to provide more clarity to bona fide researchers. It states that a person commits a criminal offense if, firstly, they alter the genome of a human cell in a way that the alteration is heritable by descendants of the human whose cell was changed, and secondly, if in modifying the genome, the person intended the modification to be heritable by descendants of the human whose cell was changed. The penalty for this criminal offencse is imprisonment for 15 years. In other words, this section prohibits a person from altering the genome of a human embryo in such a manner that the change is heritable by its descendants and the person intended this to be so. This section prohibits the use of genome editing in reproduction. If an Australian scientist had done what Dr. He did, he/she would face 15 years in jail.

While Section 15 is clear about the prohibition of the intentional modification of the genome which is heritable by descendants, whether it also prohibits pure research that utilizes genome editing is not clear. In such research settings, the scientist has no intention to initiate a pregnancy, i.e., there is no implantation. The uncertainty in Section 15 is unsettling for future researchers who may fear breaching the law and face possible imprisonment.

In a recent article, the authors explored the ambiguity in Section 15 of PHCR Act 2002. ³⁴ There was a discussion of both narrow and broad interpretations of this section. A narrow interpretation of Section 15 prohibits the activity only in cases where it is conducted for reproductive purposes; however, a wide interpretation of the section prohibits genome editing for both basic research as well as reproductive applications. To ensure more clarity in the law, the authors suggested the inclusion of a new paragraph to Section 15. ³⁵ They recommended that the section be redrafted, so a scientist is permitted to modify the genome of a cell in a heritable way where they are authorized by a license on the following conditions: the embryo will not be implanted into a woman's body and the embryo will be destroyed 14 days after fertilization. This recommendation of the authors indeed provides much more clarity to Section 15 as it enables basic research to be carried out without any fear of breach of law.

Section 15 should be amended to explicitly state that the prohibition does not cover altering the genome in research settings, but rather only for reproductive purposes. Also, Section 15 is currently stated in Part 2 (Prohibited Practices), Division 1 (Practices That Are Completely Prohibited) of the PHCR Act 2002. Accordingly, it will be more appropriate to insert a section with those conditions in Division 2 (Practices That Are Prohibited Unless Authorised by a Licence) of the Act.

Moreover, to provide further expertise in this innovative area, the current licensing committee membership could be increased or a new agency could be formed, e.g., similar to the Recombinant DNA Advisory Committee (RAC) in the U.S.; ³⁶ the exact details needs to be explored in the public forums.

The authors of the article stated that genome-editing research in human embryos is not feasible in Australia. ³⁷ In addition to the use of excess assisted reproductive technology embryos in research, there should also be a provision in the RIHE Act 2002 to allow zygotes to be used in research. This is due to a provision in the RIHE Act 2002, which only permits surplus embryos derived from IVF procedures to be used for research purposes. Much of the genome-editing research in embryos pursued in other nations occurs in zygotes, i.e., embryos at a one-cell stage. ³⁸ The IVF clinics will develop the embryo to the blastocyst stage before it is evaluated for its suitability for implantation in the body of a woman. At this stage, the embryos are of less value in genome-editing research because it is a challenge to ensure that every cell is appropriately edited. For genome-editing research to be feasible, the RIHE Act 2002 would need to be amended to permit the creation of zygotes for research purposes.

Given the rapid development of genome-editing technologies, it is crucial that the Australian laws around them are clear. Even though genome editing for reproduction is prohibited in Australia, if the Australian public is generally in favor of permitting germline-editing basic research, the existing laws need to be reformed as suggested in this section of the article, so they set clear parameters on the legality of this research. The clarity in the law will give confidence to Australian scientists who are considering pursuing research on germline editing shortly.