LAST year will long be reviled as the year a once-in-a-century pandemic cut a swathe across the world, taking millions of lives and afflicting over 100 million people. Even those not directly infected with the coronavirus have had their lives turned upside down by the economic effects of a pandemic that is estimated to have sliced an incredible 3.5 trillion dollars from the global economy in one year. Just as COVID-19 now is known to have both immediate and long term physical effects on those infected, so it is likely that the social and economic effects of the pandemic will linger as well, long after vaccination programs have run their course.
Yet while the world has responded to, and focused on, the COVID-19 pandemic, a number of other landmark medical events have occurred with little fanfare. Indeed, these other events may well mark the beginning of a new frontier in public health, and they have the potential to further increase both inequality and inequity globally. Importantly, they will need community engagement and oversight at a time when all of us have been exhausted and overwhelmed by the pandemic.
The first event was the award of the 2020 Nobel Prize in Chemistry for the discovery of the gene editing technology known as CRISPR-Cas9. CRISPR is an abbreviation for “clusters of regularly interspaced short palindromic repeats” and the Cas9 is an enzyme that is able to cut DNA at precise locations, like a pair of molecular scissors. This surprisingly inexpensive and simple technique for gene editing was developed by Professors Emmanuelle Charpentier of the Max Planck Institute in Berlin and Jennifer Doudna of Berkeley, who shared the Nobel Prize. Many other eminent scientists have also played key roles in the development of CRISPR technology, which is now almost ubiquitous in genomics research laboratories.
CRISPR is a molecular defence system, found naturally in bacteria, that plays an immune role, cutting up foreign DNA from viruses that infect the bacteria. Scientists have harnessed the technology and can program the CRISPR-Cas9 “molecular scissors” to excise precise sections of a cell’s DNA. Since DNA has robust mechanisms to “heal” damage, it can be left to heal naturally (through a process known as non-homologous end-joining) or directed to repair, by simply introducing a short strand of “normal” DNA as a template, the missing section can be replaced with a desired stretch of genetic material (homology-directed repair).
The other remarkable event was that, for the first time globally, recruiting began for the population-level genetic screening study known as Mackenzie’s Mission. This study is a large-scale pilot study of the processes required to offer couples pre-conception screening for serious and potentially lethal childhood illnesses caused by autosomal recessive and X-linked conditions such as spinal muscular atrophy. These conditions are important not only because of the direct health effects they have on a child, but because of the severe economic effects and disruption that families face when a child is affected.
It has been estimated that, as a group of inherited mutations combined, these recessive and X-linked conditions have a similar incidence to that of trisomy 21. The lifetime cost-of-care of such conditions can exceed $1.5 million dollars and newly released drugs can cost in excess of $2 million for a single dose, meaning that the economic case for screening at a population level is very persuasive.
Using information about our genetic constitution to provide prognostic information about our present and future health is termed “genomics”. World-leading population-level genetic studies such as Mackenzie’s Mission portend a future in which our individual genetic inheritance can be laid bare and used to guide multiple aspects of our lives, not only our health.
Many of us will have heard of the concept of “personalised medicine”, in which information about our DNA and its billions of intricate base pairs is brought to bear so as to allow precision not only in predicting our risk of disease or disability, but in employing the most effective ways to mitigate those risks or tailor treatment when disease occurs.
One might assume that, when it comes to our DNA and its effect on health and disease, doctors would be leading the way. You would be wrong. In many respects, doctors are playing catch-up, and this has been a major concern to professional bodies such as the Australian Medical Association (AMA) and medical indemnity providers such as Avant Mutual, both of whom have recently released detailed documents that, in part, detail the risks now evident with acceleration of genomic knowledge in human medicine.
The AMA document, for example, details multiple important issues for the profession to consider: here are some examples. Just how much genetic information should be obtained for children before they are old enough to consent to such testing themselves? Do you have the right to have your genetic information destroyed? Can somebody be compelled to take a genetic test? What happens when there are unexpected genetic or genomic findings on a test, unrelated to the original reason for the test? What if genetic testing identifies an abnormality in one member of a family and the abnormality is likely to be present in the DNA of another family member who has not consented to having any testing? How can we guard against genetic discrimination?
The list of issues goes on and on. Yet medical indemnifiers also have concerns about the consequences of not offering genetic testing, reflecting concern within and without the medical profession about the appropriate role of ordering and interpreting tests in an environment where some of the information involved is imperfect and, indeed, difficult to interpret.
It is well recognised globally that developments in genomic technology continue to create complex ethical, legal and social implications (ELSI). Most of the major funding agencies have provided a dedicated funding stream to facilitate ELSI research for the past 30 years. For instance, the Australian Genomics Health Futures Mission announced its first round of ELSI stream funding in 2020, including funding for projects on genetic discrimination, return of raw sequence data and Australian community responses to genome editing (led by one of the authors). This type of research requires expertise in social sciences and law as well as genomics. But it is also vital to involve those most directly involved in the delivery of genomic technologies.
As things stand, many doctors – not only in Australia but globally – feel a sense of disengagement with the rapidly advancing technologies and utilities of genomics. The majority of doctors in clinical practice today trained before the advent of current genomic technologies, presenting challenges in developing confidence in applying genomics towards routine patient care. Zebrowski and colleagues, after undertaking interviews with clinicians, described “a culture of physician reluctance to participate in genomic focused clinical studies due to unfamiliarity with genomic testing or ambiguity in the interpretation and application of its results”. This sense of disengagement by doctors with genomics has been repeatedly described across multiple medical disciplines. As last year’s Avant discussion paper points out:
“The potential for genomic medicine is great [yet] the challenges it presents are also significant. As increasing numbers of doctors find their practice intersecting with genomic medicine, the level of concern we are hearing from doctors is growing. Genomic medicine is increasingly a part of mainstream medical practice and doctors are being asked to keep up with the science, often without the benefit of recent training in the field. They may be in the position of having to explain particularly complex questions of risk and uncertainty to patients. These are inherently difficult to understand and weigh up.”
Adding to this complex clinical environment is the fact that genomic testing now is offered direct to the consumer. Direct-to-consumer (DTC) genomics is big business, with predictions that the market capitalisation of DTC companies will reach $50 billion by 2025. While DTC genomics testing is an expanding and profitable enterprise many doctors find themselves being asked to deal with the results of such testing without having provided the all-important pre-test counselling.
Although DNA sequencing has reduced in cost dramatically it still imposes a financial burden on the individual. This is particularly so if disease-associated mutations or variants are discovered: the costs associated with follow-up of these results can be considerable. There is robust evidence from Australia, published in 2020 by one of us (SR), confirming that pre-conception genetic screening is largely the province of the wealthy at this point. This leaves society with the issue that people with the least resources to allow them to care for an affected child have the least capacity to afford pre-pregnancy testing. This is an inequity that has the potential for generational effects and that can further entrench socio-economic inequality.
A population-level program to screen for genetic conditions causing disease and disability such as Mackenzie’s Mission is a major initiative. What options are available to prospective parents if they are found to carry such mutations? The practical options are limited. It is possible to try for pregnancy and, once this occurs, undergo invasive testing with a view to ending the pregnancy if an affected fetus is detected. Another option is to use donated eggs or sperm, or perhaps not to become pregnant at all.
For most couples, though, the use of in vitro fertilisation (IVF) will be the next step to consider. IVF treatment has become so mainstream that, now, one child in 10 born to a woman over the age of 35 years is an IVF baby. Importantly, data from the University of New South Wales Australian and New Zealand Assisted Reproduction Database (ANZARD) show that, as of 2018, 13% of all IVF cycles in which an embryo was created or thawed involved genetic testing of the embryo before transfer. By any definition, this represents a “mainstreaming” of genetic analysis as a routine part of assisted reproduction.
Aside from the prospect of population-level genetic screening for future parents, and the routine use of genetic analysis of embryos before pregnancy, it is possible to take a DNA test at your local pharmacy. Incredibly, more than 26 million Americans have had their DNA stored and analysed purely out of curiosity regarding their “ancestry”. For many of us, having a genetic or genomic test now has become as routine as having a blood pressure check – and there is no involvement of a doctor whatsoever. At least until a potential problem is found.
As birth rates fall in developed countries around the world, the pressures for “perfection” in our children may well increase. Anyone who doubts that parental expectations regarding their children’s genetic phenotypes affect reproductive decision making need only consider the fact that, globally, more than 100 million girls are “missing” due to prenatal sex selection and newborn mortality or neglect. As genomic studies identify DNA patterns associated with intelligence, longevity, obesity, even factors associated with “success” such as tall stature, might prospective parents with the financial means wish for their offspring to be specifically gene-edited with such traits? Would there be enterprises prepared to provide such services for profit?
The scientific expertise, equipment, and reagent kits required for gene editing – in particular, for the editing of human embryos – are freely available and inexpensive. Indeed, CRISPR-Cas9 kits are available for merely a few hundred dollars by mail order. The ready availability and low cost of these genetic technologies has even prompted antiterrorism authorities to warn about the possibility of groups genetically engineering bioterrorism threats and listing CRISPR-Cas9 as a potential terrorist weapon.
This is far from wild speculation – concerns were raised in the early phase of the COVID-19 pandemic that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was actually a biological weapon that had escaped containment. In treating this almost believable hypothesis as anything but a fringe conspiracy theory, scientific efforts were made to reassure the public that the virus had natural origins.
There now are multiple competing forces at work in the human genomic space. In the first instance, research, advancing at a dizzying pace, is revealing new insights into how our DNA affects our health and wellbeing. The technologies that drive our ability to manipulate the human genome – and to understand the downstream and potentially unanticipated effects of such manipulation – are progressing rapidly.
Secondly, a clearer understanding of the economics of genomic medicine is beginning to emerge. As one example, new developments are the use of CRISPR to genetically engineer skin cells in the lifelong and disabling condition epidermolysis bullosa have been described. Epidermolysis bullosa has been estimated to cost as much as $80 000 a year in direct medical costs and indirect opportunity costs, totally exclusive of the personal impacts of having the condition. From a strictly economic perspective – irrespective of the ethics or regulatory aspects inherent or even the human cost of suffering the disease – a financial case could be made for germline gene editing if proven safe. There is little time for reflection on the ELSI, and meanwhile the law “limps behind”.
The world was shocked by the announcement that embryos leading to a twin pregnancy in China had undergone gene editing, prompting international action and the establishment of two international committees to examine the issues: the World Health Organization Expert Committee on Genome Editing and the International Commission on the Clinical Use of Human Germline Genome Editing. Yet, globally, regulation of gene editing is patchy and in many parts of the world there is little formal legislation enforcing standards in the clinical use of these technologies, particularly for heritable alterations. Australia is one notable exception, particularly when it comes to heritable alterations, which are prohibited by legislation. With economic devastation in the wake of the COVID-19 pandemic, it is not difficult to imagine highly profitable “pop-up” gene editing clinics emerging in countries where regulation has a light touch: there are already well established systems and pathways for “reproductive medical tourism”.
For all of these reasons it is absolutely critical that the Australian society in general and the medical profession in particular engage with genomic medicine as a matter of urgency. The Australian Government has committed half a billion dollars to the Genomics Health Futures Mission, signalling a strong commitment to integrating these technologies and, as mentioned previously, to understanding the ELSI.
There are commercial pressures to bypass the medical profession in having testing and, potentially, fortunes to be made in offering treatment. The economic advantages of preventing chronic disease, not in utero but actually “pre utero”, may well begin to look attractive as Australians have fewer and fewer children and the economic effects of chronic disease continue to mount.
It is possible to have a comprehensive, community-based but profession-led, discussion about potentially controversial reproductive issues: this was beautifully demonstrated by the National Medical Health and Research Council, in 2020, with its consultation regarding mitochondrial donation. Yet mitochondrial diseases ultimately are uncommon, and there are many other conditions and traits that might be amenable to in vitro gene editing.
The need for community consultation is well recognised globally, and is recognised as being particularly acute by international bodies charged with examining this field (here and here). One of the authors is involved in an ambitious project involving the creation of the world’s first global citizens’ assembly aimed at addressing some of these questions using deliberative democracy methodologies.
Providing safe, ethical, and equitable access to these technologies – in a way acceptable to the broad community – will challenge all of us. Allowing a society of “genetic haves” and “genetic have nots” should be utterly unacceptable to all of us too. Yet avoiding the situation where Australians with the financial means simply seek these treatments overseas, in poorly regulated health environments, must underpin out efforts.
As genomic research advances apace, society must expect that the legal and ethical framework guiding the way tests are performed and treatments are undertaken – especially those with the potential to reshape the genetic inheritance of the next generation – both respects our individual choices yet protects us from harm: from becoming an unequal community of “genetic haves” and “genetic have nots”. These are fundamental questions about our health and our wellbeing. Without engagement from the medical profession – the group in a unique position to understand the health needs of each of us as individuals – we run the risk of forces beyond our control changing our genetic inheritance forever.
Steve Robson is Professor of Obstetrics and Gynaecology at the Australian National University, and immediate past-president of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. He is a member of the Federal Council of the Australian Medical Association. Steve is a member of the Ethics Committee of the Office of the Gene Technology Regulator.
Dianne Nicol is a Professor of Law and Director of the Centre for Law and Genetics at the University of Tasmania. She is chair of the National Health and Medical Research Council (NHMRC) Embryo Research Licensing Committee. The views expressed here are her own and should not be attributed to the NHMRC or the Australian Government. Her research on genome editing is supported by Australian Research Council grants DP180101262 and LP190101198 and Genomics Health Futures Mission grant 76648.
The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.