Molecular life extension

By Cynthia Forlini and Ainsley Newson

This article was originally published in Australasian Science and is reproduced with permission. It can be cited as Forlini, C and Newson, A (2018) Molecular life extension. Australasian Science; Vol. 39, Iss. 6, (Nov/Dec 2018): 49. Retrieved from: https://www.australasianscience.com.au/article/issue-novdec-2018/molecular-life-extension.html

Older person shaking a sinlge pill out of an open medicine bottleIt is a universal certainty that we will all die one day. And we have a near universal goal for our deaths to come painlessly, after a long and full life.

Of course illness, disease and accident can cut life short. For many of us, however, our deaths will come as a result of growing old and our bodies gradually failing us.

But should we accept this biological status quo as the basis of our lives? Or is ageing something to rail against and try to defeat?

We already engage in plenty of strategies that claim to slow the outward signs of ageing of our bodies. We also eat well and exercise to protect our hearts and our bones. We continue to read and think to protect our minds. But now, a growing number of geneticists and molecular biologists are seeking a cure for the ageing process itself.

Researchers in Australia and internationally are investigating a number of compounds that might extend life by intervening in key genetic and metabolic pathways. The goal is to live a longer life free of the decline we typically associate with ageing – lower energy, susceptibility to illness, frailty.

While this is no doubt cutting edge science, it raises some big questions that haven’t yet been debated in much depth. Alongside the question of whether we can treat ageing (as we do for many individual diseases), is the question of whether we should.

Promising results from studies using anti-ageing compounds in animal models are appearing in high-ranking journals. Some scientists are even taking these compounds themselves, or giving them to their family members and pets. Products from commercial offshoots of this research are already being marketed, often as health supplements (as these tend to be regulated like food products), but they have yet to go through rigorous independent trials.

Could this research be proceeding too fast? Research translation can be slow and expensive, but it generates the evidence that regulators need to decide whether something should be made accessible to populations. In an era of heightened commercialisation, laissez faire regulatory regimes and ‘need it yesterday’ consumerism, we risk not stopping to look at what the end points might be; and how we feel about them.

The scientists doing this research draw careful lines around being mortal and being immortal; between being human and transcending humanity.

But maintaining these bright lines in research and beyond needs an important conversation about responsibility for the oversight and outcomes of research. Whether this research should be taking place and under which limitations, if any, are critical questions.

There are broader questions about molecular life extension, too. Some have to do with collective responsibilities to share limited global resources. For example, the impact of an ever-increasing population on the environment and food supply would be massive. It would also redefine our common understanding of health, illness and the goals of medicine. In this light, would it be fair to prioritise anti-ageing interventions when many don’t have access to basic healthcare requirements? These are all issues that require a wider community conversation.

From a community perspective, the idea of living and ageing well remains a matter of debate. Some initial research with members of the public suggests that people are not uniformly in favour of life extension, as might be expected. At the very least, quality of life is favoured over quantity. Even if quality could be assured, what would constitute an ethical notion of a reasonable length of life?

Other questions have to do with individual responsibilities. Living longer could influence whether, when, and how individuals should choose to reproduce. The potential for pharmaceutical interventions to slow ageing could have an impact on the lifestyle choices that people make to maintain their health. Would it be acceptable if pharmaceuticals could replace the need for eating well and exercising? Are such activities inherent to a notion of a life lived authentically and well?

Such questions are not unique to this research. They are also arising in the context of gene editing, another technology poised to radically change health. But we don’t yet have any clear answers there either.

The role and expectations around ageing in our society are profound. This process shapes our life courses, relationships and expectations. Moving from a position where ageing is inevitable (and, usually, accepted) to it being seen as something to ‘cure’ would cause a drastic shift in the collective and individual responsibilities that our societies are built upon. We are left to consider whether ageing is part of our humility, or less than it?

 

Dr Cynthia Forlini is a Research Fellow in neuroethics at Sydney Health Ethics, University of Sydney. She was awarded an Australia Research Council Discovery Early Career Research Award (2015-17) for her work on cognitive ageing.

Dr Ainsley Newson is Associate Professor of Bioethics and Deputy Director of Sydney Health Ethics at the University of Sydney

Photo by rawpixel on Unsplash

Is Cognitive Enhancement a Problem in Australia?

By Cynthia Forlini

This article was originally published in Australasian Science and is reproduced with permission. It can be cited as Forlini, C (2018) Is Cognitive Enhancement a Problem in Australia? Australasian Science; Vol. 39, Iss. 5, (Sep/Oct 2018): 49. Retrieved from: https://www.australasianscience.com.au/article/issue-sepoct-2018/cognitive-enhancement-problem-australia.html [paywalled]

Graphical representation of a head containing cogs alongside a broken capsule releasing more cogsJust because the non-medical use of cognitive stimulants isn’t common, it doesn’t mean it isn’t a problem.

“Cognitive enhancement” is a catch-all term for the improvement of cognitive function: attention, alertness and memory. It has caught our attention because it is thought to be the main motive for the non-medical use of prescription stimulants like methylphenidate (Ritalin) and modafinil by university students.

People who take these stimulants believe they help gain an edge in competitive environments despite weak scientific evidence to support their so-called enhancement effects in healthy individuals. Over the past decade, international studies have contributed to our understanding about who takes stimulants, when and why. One question lingers: is it a problem?

These stimulants are scheduled as “drugs of addiction” that are illegal to possess without a prescription. A doctor would not prescribe their use to otherwise healthy individuals. Peers, colleagues and family members with prescriptions for stimulants are the major sources of tablets diverted for non-medical use. Others buy them online.

Exact global figures for the prevalence of the non-medical use of prescription cognitive stimulants remain elusive. Studies vary in the measures and methods they report, which makes them hard to compare. In students, results from the USA suggest usage rates ranging from 5% to 35%. In Australia, studies have reported a narrower range: between 6.3% and 10.9% of students used a stimulant for enhancement in their lifetime (6.6% in New Zealand).

In the general population, data from 2012 suggest that around 2.4% of Australians have used a stimulant non-medically. These rates are generally considered low, especially compared with the use of more readily available substances such as high energy drinks, caffeine and alcohol. Just because the non-medical use of stimulants isn’t common, it doesn’t mean it isn’t a problem.

Looking for evidence of harm or adverse effects in those taking stimulants non-medically might provide a better answer. Using prescription stimulants is generally associated with disturbances in sleep, appetite, cardiac rhythm and mental health, but few of these effects have been officially reported as a result of non-medical use.

Little evidence of the harm students may be experiencing doesn’t mean there is none. The problematic aspects of the practice could be elsewhere, or people may not be reporting side-effects because they fear legal consequences.

Investigating the motives behind non-medical stimulant use for cognitive enhancement is also stirring up concerns for the overall health of students. Common motives for use include improving concentration, focus, wakefulness, better marks and some recreational uses.

Some researchers are suggesting that students use stimulants to compensate for sleep deprivation or cope with stress associated with a variety of competing demands (e.g. studies, sports, paid work and social activities). Others have proposed that the non-medical use of stimulants is a mode of self-medication for symptoms of depression caused by disinterest and lack of motivation. We don’t yet know why students turn to stimulants to manage these issues instead of seeking medical attention or using non-pharmacological approaches such as sleep, diet and exercise.

The ethical issues in the non-medical use of stimulants for enhancement are complex. Acceptability of their use among students is generally quite low. Part of the reason might be due to the parallels with doping in sports (e.g. inappropriate possession of a substance and gaining an unfair advantage over peers). However, cognitive enhancement appears to be socially embedded, suggesting that other factors might be trumping individual morals. Many of the risk factors for use have socio-economic underpinnings, such as university location, gender, low or average academic performance, fraternity membership and a history of drug use.

Peer groups are potentially coercive environments. On the one hand, an individual who will not take a stimulant might feel disadvantaged in a group where it is common. On the other hand, the perception that stimulant use is common among one’s friends might make it seem more acceptable.

Whether and on what basis we deem the non-medical use of stimulants a problem in Australia, or not, remains an open question. There is plenty of evidence available to inform this decision, but a conclusion will automatically raise another question: who will be responsible for addressing risk factors or governing the non-medical use of stimulants in competitive environments?

 

Dr Cynthia Forlini is a Research Fellow in neuroethics at Sydney Health Ethics, University of Sydney. She was awarded an Australia Research Council Discovery Early Career Research Award (2015-17) for her work on cognitive ageing.

Image Credit: Sangoiri/Adobe

It’s not (just) about the money

By Miriam WiersmaIan Kerridge and Wendy Lipworth

This post originally appeared in August 2018 edition of the Research Ethics Monthly and is reproduced with permission. It can be cited as Wiersma, M., Kerridge, I. and Lipworth, W. (22  August 2018) It’s not (just) about the money. Research Ethics Monthly. Retrieved from: https://ahrecs.com/research-integrity/its-not-just-about-the-money

Let’s imagine for a moment that you are a mid-career university researcher with growing expertise in a particular field. A pharmaceutical company contacts you and says that it would like to recognise the important work you are doing in this area, and has asked you to choose among the following forms of recognition:

Black and white image of a laboratory hallway, glass doors in the distance

Credit: Bill Dickinson

  1. $10,000 towards a research project related to one of the company’s drugs.
  2. Being chosen as a Keynote Speaker to present at a prestigious conference, with no honorarium.
  3. Being invited to join an international advisory board.

What would you choose? Would you choose the money? Or is there something appealing about the acknowledgement of your expertise in Option B, or impressive status associated with Option C?

Perhaps simply contemplating these questions makes you feel uncomfortable. After all, as medical researchers, questioning what motivates our behaviour or actions beyond the pursuit of scientific knowledge is not exactly pleasant. We like to think that we act in a way that is free from bias – and that while other researchers may have conflicts of interest, we certainly do not. Or not at least conflicts of interest that matter. Which begs the question – what types of things create conflicts of interest (COI)? Is it only when money enters the equation, or are there other forces at play?

It would appear, from the emphasis placed on financial COIs by medical journals, conference organisers and professional societies, that only money matters (Komesaroff et al. (2012)JAMA (2017). The COI disclosure forms that we dutifully complete tend to focus on financial COI and are comparatively vague when it comes to the declaration of non-financial COI (if indeed such declaration is required at all). Similarly, the disclosure statements made by speakers at conferences tend to take the form of ‘Dr X received $$$ from Company Y, $$ from Company Z’ and on the list goes.

But we believe that this exclusive emphasis on money overlooks many other non-financial interests that can create significant COI. These may stem from personal or religious beliefs – for example, Christian views about the moral status of the embryo held by legislators and scientists undoubtedly played a major role in the securing the prohibition of public funding of embryonic stem cell research.

Non-financial COI may also arise from a researcher’s desire for status or respect. As the case study illustrates, pharmaceutical companies may utilise both financial and non-financial incentives to encourage industry collaboration and promote industry agendas.

Personal circumstances and relationships also have the potential to give rise to non-financial COI – for example, if a member of a drug regulatory agency had a close relative who could benefit from the subsidisation of a drug under consideration this would constitute an obvious non-financial COI. Interests such as these have long been recognised in other contexts, including in the public sector (Australian Public Service Commission (2017)OECD (2003)). The OECD Managing conflicts of interest in the public service guidelines state that any ‘forward looking’ policy should describe non-financial sources of COI – including non-financial personal interests and relationships (OECD). The Australian Public Service Commission also specifies that social relationships and personal interests should be declared by employees.

We argue that to overlook non-financial COIs is problematic for several reasons (Wiersma et al. (2018a)Wiersma et al. (2018b). Most importantly, disregarding non-financial COI ignores the fact that serious harm may arise from such conflicts. We need look no further than the notorious Tuskegee scandal (Toy (2017) or Guatemalan ‘research’ (Subramanian (2017) to see that the drive to satisfy scientific curiosity can not only cloud researchers’ judgement, but can also cause significant harm to (unwilling or unknowing) participants.

Furthermore, ignoring non-financial COI also fails to take into account the fact that financial and non-financial COI are frequently entwined. For example, recognition by the pharmaceutical industry as a ‘Key Opinion Leader’ is not only associated with financial remuneration (for example, speaker’s fees), but also status and prestige.

We have also argued that non-financial COI can be managed using similar strategies to those used to manage financial COI (Wiersma et al. (2018a) There is no reason, for example, that a person on a drug regulatory committee could not disclose that they have a relative with a medical condition that may benefit from the drug under consideration and recuse themselves from voting in relation to that particular drug.

Of course, given the highly personal nature of some non-financial interests, it is important that declaration should only be required when evidence indicates that these may lead to a non-financial COI. Here we can draw from the Australian Public Service Commission guidelines which state that a personal interest does not lead to a conflict of interest unless there is ‘real or sensible’ (not merely theoretical) possibility of conflict. It is also crucial that declarations are handled with discretion.

None of this is to disregard the difficulties in determining what precisely constitutes a conflict of interest in medicine and how these should be managed. Medical researchers and practitioners have long grappled with these questions, and heated debate as to what should or should not be considered a ‘COI’ and what types of COI should be managed continues to this day (Bero 2017, Wiersma et al. (2018b).

However, we believe that acknowledging the importance of non-financial COI may be the starting point for a more sophisticated approach to managing both financial and non-financial COI in health and biomedicine. Perhaps most importantly, by acknowledging that we are all conflicted in certain ways, and that having a COI is not necessarily ‘bad,’ we may be able to take some of the ‘sting’ out of the label. And this may, in turn, encourage open discussion and disclosure of both financial and non-financial COI, enhance our understanding of COIs in general, and help us develop and refine a more nuanced approach to all forms of COI.

References

Australian Public Service Commission (2017) Values and code of conduct in practice.Australian Government. Available from: https://www.apsc.gov.au/aps-values-and-code-conduct-practice

Bero, L. (2017) Addressing bias and conflict of interest among biomedical researchers. JAMA: The Journal of the American Medical Association, 317(17): 1723-4.

JAMA: The Journal of the American Medical Association (2017) Conflict of interest theme issue. JAMA: The Journal of the American Medical Association, 317 (17):1707-1812. Available from: https://jamanetwork.com/journals/jama/issue/317/17

Komesaroff, P., Kerridge, I. & Lipworth, W. (2012) Don’t show me the money: the dangers of non-financial conflicts. The Conversation. March 30. Available from: https://theconversation.com/dont-show-me-the-money-the-dangers-of-non-financial-conflicts-5013

OECD (2003) Managing conflict of interest in the public service. OECD guidelines and country experiences. Organisation for Economic Co-operation and Development. Available from: http://www.oecd.org/governance/ethics/48994419.pdf

Subramanian, S. (2017) Worse than Tuskegee. Slate26. Available from: http://www.slate.com/articles/health_and_science/cover_story/2017/02/guatemala_syphilis_experiments_worse_than_tuskegee.html

Toy, S. (2017) 45 years ago, the nation learned about the Tuskegee Syphilis Study. Its repercussions are still felt today. USA Today. Available from: https://www.usatoday.com/story/news/2017/07/25/tuskegee-syphilis-study-its-repercussions-still-felt-today/506507001/

Wiersma, M., Kerridge I. & Lipworth, W. (2018a) Dangers of neglecting non-financial conflicts of interest in health and medicine. Journal of Medical Ethics, 44: 319-322. Available from: https://jme.bmj.com/content/44/5/319

Wiersma, M., Kerridge I. Lipworth, W. & Rodwin, M. (2018b) Should we try and manage non-financial interests? British Medical Journal, 361: k1240. Available from: https://www.bmj.com/content/361/bmj.k1240

Conflicts of interest: All authors had financial support from the National Health & Medical Research Council (NHMRC, grant number APP1059732) for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Miriam Wiersma is a PhD candidate at Sydney Health Ethics, University of Sydney, studying biomedical innovation.

Ian Kerridge is Professor of Bioethics and Medicine at Sydney Health Ethics, University of Sydney, and a Haematologist/Bone Marrow Transplant Physician at Royal North Shore Hospital.

Associate Professor Wendy Lipworth is a bioethicst and health social scientist at Sydney Health Ethics, University of Sydney.

Image by Bill Dickinson and used under Creative Commons 2.0

 

The Unspoken Limits of Liquid Biopsies

By Ainsley Newson

This article was originally published in Australasian Science and is reproduced with permission. It can be cited as Newson, A (2018) The Unspoken Limits of Liquid Biopsies. Australasian Science, 39(4): 49. Retrieved from: http://www.australasianscience.com.au/article/issue-julyaugust-2018/unspoken-limits-liquid-biopsies.html
Ainsley DNA-test

Photo of a test tube containing bubbles forming a double helix. Credit: Connect World/Amazon

Liquid biopsies promise early detection of cancer, but some of their current limitations risk being overlooked.

Many of the difficulties in efforts to reduce cancer incidence and deaths arise because we don’t yet have reliable ways to effectively identify, pinpoint and treat it in its early stages.

But what if there was a blood test that could pick up a range of early cancers, show where tumours might be and suggest the best treatment? Sounds amazing, doesn’t it?

The exciting thing is that researchers are making some headway in identifying cancer-specific DNA sequences and proteins from blood samples: a so-called “liquid biopsy”.

The technology is based on the knowledge that cancer tumours shed mutated DNA. If an over-abundance of certain DNA sequences is detected in our blood, this suggests there could be a tumour. The hope is that one day there will be a single blood test that could be used to routinely screen anyone in the population.

One study published in Science in January showed promising results, including a false-positive rate (where a healthy person’s sample erroneously suggests cancer) of less than 1%. But because we don’t yet know enough about the required DNA markers, it was better at detecting some cancers (such as ovarian cancer) than others (such as breast cancer). This work is now being extended to a bigger trial.

It’s a lucrative area with a potentially enormous market. There is significant start-up funding being invested, and even more media hype. A US company even took a test to market a couple of years ago, although this was swiftly met with a stern warning letter from the US Food and Drug Administration.

But let’s not get ahead of ourselves. As the authors of another review paper pointed out in March, this test is by no means ready for population-wide roll-out. And even if we get to the point of a fantastic test that correctly identifies and pinpoints tumours within all scientifically important parameters, these may not necessarily be cancers that need to be found. Liquid biopsy could suffer the same problem that befalls many current cancerscreening technologies: while we are getting much better at finding tumours, we are much less good at working out which ones need to be treated and which can be left alone.

Overdiagnosis is said to occur when a test or screen makes a true finding (i.e. not a false-positive) but whatever was identified never needed to be found because it would not have developed further. Conversations about overdiagnosis following cancer screening are not easy. If we hear the word “cancer” our (understandable) reaction is to want it gone immediately.

However, overdiagnosis causes problems because people are given treatments that they don’t need, including treatments that cause harm and cost the health care system money (which in turn impacts access to care down the line). But, it is often hard to tell in advance who needs treatment and who doesn’t.

Overdiagnosis is being talked about by some commentators on liquid biopsy, but it’s notable in its absence from exuberant media releases extolling progress in liquid biopsy research. Some also think it’s their right to demand access to unproven tests or treatments, and see any move to prevent this as medical paternalism or denial of treatment. Yet those responsibly for publicly funded health care are likely to want greater reassurance before committing resources. At the same time, it is terrible when a progressive cancer is missed in a patient when the prognosis would have been better if it was found and treated early.

As a DNA-based technology, and given the significant hype that currently surrounds all things genetic, liquid biopsy may give populations a false sense of security. Its perceived precision may make public conversations about overdiagnosis difficult. We are conditioned to seek information rather than not, we search for our own health information online, and are usually keener to do something rather than “watch and wait”.

How good should a test be before it is introduced to the wider population? Should we discuss not testing? For how long should we measure patient outcomes before rolling a test out to healthy people in a world increasingly less willing to wait? Should we discuss not intervening?

Liquid biopsy won’t give us these answers, but the questions are sure to come around soon.

 

Ainsley Newson is Associate Professor of Bioethics and Deputy Director of Sydney Health Ethics at the University of Sydney.