The Oxford Scientist: Frontiers Of Science (#8)

The Hard Problem p9 ISSUE 8

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When Science Fails p13

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Citizen Scientists p20 MICHAELMAS 2020

Oxford University’s independent, student-produced science magazine.

Frontiers of Science

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EDITORIAL

Let’s All Be Scientists

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elcome to the MT20 issue of The Oxford Scientist. This magazine was put together in difficult circumstances.

Especial thanks are therefore owed to our brilliant team, our writers, illustrators, and our readers, who have kept the spirit of science communication alive in spite of being locked down in their homes and college rooms.

To provide some light relief from the seriousness of the pandemic, we decided to use cartoons to complement many of this issue’s articles. The illustrator Ralf Zeigermann drew these in the approximate likeness of Venki Ramakrishnan, the current President of the Royal Society and Nobel Laureate famous for discovering the structure of the ribosome. We hope you enjoy this feature of our Frontiers of Science issue!

It’s high time to not focus on doom and gloom more than necessary. Let’s instead have a look at a possible silver lining of these times: the pandemic has brought science in public focus as it has perhaps never been before. Interviews with epidemiologists made headline-news (page 19), as did heated debates on how to best ‘follow the science’. We witnessed successes and setbacks in vaccine development and learned how in-

tegral uncertainties and careful conclusions are to the scientific progress (page 13). And perhaps for the first time did many of us observe the drama of translating science into real-life politics – even though this is an age-old problem (page 16).

Next to highlighting science itself, this pandemic has shown that science communication is a cornerstone in our fight against future pandemics, at the base of which lies our own willingness to grasp the discoveries that are waiting out there (page 14). In that spirit, this issue includes some of our finest science picks ranging from stories about brain alteration far ahead of Elon Musk’s Neuralink device (page 10), over the unlikely connection between Zack Efron and ageing research (page 26), up to the surprising role of citizen scientists in current research (page 20) – and many more.

Let’s keep in mind that we can all be scientists, in how we explore the world, in how view twitter feeds and news channels, in how we voice our opinion and in how we read magazines such as this one. And so we hope you’ll follow ‘Venki’ on his journeys in this issue as he explores the Frontiers Of Science.

Linus and Angus

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CONTENTS

OxSci Editors-in-Chief Angus Barrett Linus Milinski Website Editor Bianca Pasca News Editor Nicola Sharp Comment Editor Louis Minion Creative Director Dominika Syska Business Team Daniel Farley Betty Lung Broadcast Director Kunal Patel Schools’ Coordinators Natasah Harper Maria Violaris Sub-Editors Alice Gowland Alice Scharmeli Ashley Wong Ava Chan Cara Press Gideon Bernstein Hamza Rana Jia Jhing Sia Malhar Khushu Maribel Schonewolff Nandini Guzman Natasha Harper Nicole Borgers Paris Jaggers Sea Yun Joung Vanessa Wynter Contributing Artists Ralf Zeigermann Dominika Syska Emma Braine Holly Anderson Isabel Caffyn Michelle Mendieta Mean Pippa Newberry

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News Alice Scharmeli, Jess Sellar, Nid Ling

Maths and Morality Truth and ethics in a post-God world

Aditya Ghosh and Sea Yun Pius Joung 6

8 The Drug Dilemma

Which pharmaceuticals are worth developing?

Charlotte Green 9 Too Hard A Problem?

Solving the mystery of consciousness

Gideon Bernstein

10 Brain Augmentation

A better version of Elon Musk’s Neuralink?

Atreyi Chakrabarty 13

When Science Fails Is failure science’s biggest achievment?

Sian Wilcox

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16

Schools Competition Winner Professor Kevin Harrington’s Immunotherapy Goes Viral Lucy Addis Ozone A story of human responsibility and international collaboration.

Sophie Littlewood

18 When Science Meets Politics

Of fake news, experts and why we need science

Emma Hedley 19

Creative Competition Winner The Waterfront A poem by Annie Sland

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The Frontier In Your Living Room The hidden potential of citizen science Jake Burton

22 Robots In Our Blood

The future of nanotechnology in medicine

Dhruval Soni 24

Biology Meets Physics Theoretical biophysics, phase separation in cells and the origin of life Tasmin Sarkany

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Is Growing Old Getting Old? Why we age and how we might combat it Maribel Schonewolff

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COVID-19: Researchers Perspective What it’s like to work at the forefront of a global pandemic response Darlan da Silva Candido

28 Apollo’s Reckoning

Is there an ultimate destination for science?

Angus Barrett

OSPL Chairman Christopher Sinnott Managing Director Hung-Jen Wu Company Secretary Annabel Bainbridge Finance Director Maggie Wang Legal Director Annie Fan

Brain Augmentation, p10

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NEWS Oxford Vaccine Makes Progress

The UK has a lot riding on the AstraZeneca/Oxford COVID-19 vaccine.

100 million doses have been secured by the government compared to just 5 million of the current frontrunner by Moderna.

The vaccine is based on a viral vector designed in 2012 by the Jenner Institute. It can be readily modified, meaning the Oxford team were able to rapidly insert a SARS-CoV-2 gene into their pre-existing construct rather than having to design a completely new vaccine de novo. This propelled them to the forefront of vaccine development.

In late August, results from phase I/II trials were published in The Lancet showing that the vaccine was well tolerated and induced strong immune responses. However, these could not determine whether the vaccine was protective; such efficacy data can only be obtained from phase III trials. In these, significantly more people are vaccinated, and researchers compare Covid-19 rates in vaccine and placebo groups.

Currently, 30,000 patients have been enrolled for such a trial in the UK, US, Brazil, and South Africa. Sir John Bell, Regius Professor of Medicine at Oxford, said that interim results could be expected within weeks, and that ‘everything was looking good’.

This comes at the same time as reports of high efficacy (>90%) in vaccines by Moderna and Pfizer/BioNTech, leading to suggestions by Sir John that life may be normal again by spring. However, it is likely that seasonal coronavirus vaccines will be needed as although the virus does not mutate very quickly, the immunity it generates is short-lasting.

All in all, things are looking up. Results from Oxford’s phase III trials are eagerly awaited and are likely to be encouraging - a home-grown vaccine may be just around the corner.

Alice Scharmeli

Inaugral Varsity Sci

Penrose Wins Nobel Prize

The 2020 Nobel Prize in Physics has been awarded jointly to Roger Penrose, Oxford’s Emeritus Rouse Ball Professor of Mathematics, along with Reinhard Genzel and Andrea Ghez for their breakthrough work on blackholes.

Penrose was the first to prove that blackholes are a direct consequence of Einstein’s theory of relativity, something which Einstein himself believed was impossible. Since this discovery in 1965 our knowledge of blackholes has further improved, allowing Genzel and Ghez most recently to discover that an invisible, heavy object governs the orbits of stars at the centre of our galaxy. The only explanation is a supermassive black hole.

Penrose described winning the prize as ‘a huge honour’ and explains how important it is to appreciate blackholes and how they break the laws of nature. He believes this is only the beginning of discoveries such as this and that our knowledge ‘could increase in unexpected ways in the future.’ He continues to strive for new discoveries, at the age of 89, by applying quantum theory to biology.

Jess Sellar

This term saw the inaugural Oxbridge Varsity Sci Symposium, a fiveday online event that brought together the best in scientific research from Oxford and Cambridge.

In a huge collaborative effort, the event was hosted by Oxford and Cambridge Biological Societies, together with partners from across the sciences, including the Chemical, Nanotechnology, Genetics, Clinical Research, Biotech, Physics, Synthetic Biology, Quantum Information, Pharmacological and Biomedical Societies from both universities. Students and early-stage researchers each presented their work in a 20-min talk followed by a brief Q & A session. The eclectic range of subjects covered ranged from the environmental impact of our Google searches to the mammalian gut-brain axis to how green algae might transform agriculture.

A spokesperson for the event organisers said, “In this difficult time, we believe that it is more important than ever for us to collaborate more closely as Oxbridge science societies, and to bring the exciting research work conducted at the two universities and affiliated institutes closer to student communities and the wider world.” OxSci reporters attended the event, and you can now read a diverse set of reports summarising the talks at www.oxsci.org.

Natural History Museum turns 160!

Oxford’s Museum of Natural History was the original scienctific hub of the University and is a unique fusion of science and art. To celebrate 160 years since its opening, the Museum has released Temple of Science - a series of illustrated podcasts, viewable on Youtube, about its spectatcular architecture, nature-inspired decoration and rich history. Definitely worth a watch!

Nid Ling

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MATHS AND MORALITY Aditya Ghosh and Sea-Yun Pius Joung explore an unlikely source for ethical guidance.

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n Ethics, a central problem is what Nietzsche coined as the death of God. ‘God is dead. God remains dead. And we have killed him’. Unlike the triumphalist tone that New Atheists have framed this in, the original formulation was one of fear and angst. It was as though the one source of truth, God, had ceased to exist.

The problem is, ‘In a post-God, secular age, what should a consistent ethical system look like?’. It seems impossible to guarantee a natural set of rules from which to hang our system of ethics without an absolute starting point like God. It is not readily apparent from reason alone, why we should value human rights to begin with.

All M.C. Escher6 works © 2020 The M.C. Escher Company - the Netherlands. All rights reserved. Used by permission. www.mcescher.com

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Could Mathematics help?

Mathematics may not be everyone’s cup of tea but all of us have mathematical intuitions. We understand what “three” means and what straight lines or parallel lines are. Before the 19th century, mathematics was developed mostly from intuitive understandings like these.

As early as 300 BCE, the Greek mathematician Euclid laid down the foundations of geometry. He provided five “axioms”, which were common notions of space, from which all geometry could be derived. Axioms were considered self-evident statements that seemed too intuitive to be questioned. Try and see if the following axioms make sense: 1. A straight line segment may be drawn from any given point to any other.

2. A straight line may be extended to any finite length.

3. A circle may be described with any given point as its centre and any distance as its radius.

4. All right angles are congruent.

5. Given a line and a point not on it, at most one line parallel to the given line can be drawn through the point.

Geometry, as formulated by Euclid, was held in very high regard among mathematicians. To them, it represented an ideal form of the physical universe. Later, other mathematical concepts like Calculus emerged from it.

The use of axioms suffered a blow in the 19th century when Russian Mathematician, Nikolai Lobachevsky ditched Euclid’s Fifth Axiom and developed “Hyperbolic Geometry”, an equally sound alternative to Euclidean Geometry. As Richard Wells writes, ‘The “disaster” to mathematics was the loss of its long-held conviction that mathematical truths were certain and that through them mankind could know the world solely by the raw power of logic and reason’.

A new school of thought emerged among mathematicians called Formalism: that any mathematical system comprises its own set of “axioms” or rules which have no intrinsic truth value just like rules in chess or ludo. As Alan Weir put it, ‘Mathematics is not a body of propositions representing an abstract sector of reality’. Any statement that can be derived by reasoning with axioms is called a theorem.

This was a paradigm shift in the philosophy of maths. The question had become not one of “intuitive absolute truths” but of “truths in context”. Much like the popular belief in morality, absolute truths, which once underpinned Mathematics have been questioned to the point that the relevant question has become whether the Mathematics is useful in a given context, rather than whether it is “true”.

In the 20th century, Einstein’s General Theory of Relativity proved that space is not Euclidean, contrary to our intuitions.

Although we no longer have the comfort or the certainty of absolute truths, the systems we create allow us much more freedom to explore the physical and mathematical world.

The problem of choice Let’s look at an even more controversial example, the Axiom of Choice. What it essentially says is: suppose you have an infinite number of cricket teams, you can make a new team by choosing one player from each of the original teams, thus you have the power to make an infinite number of choices. It is so innate that it forms the key component of many mathematical proofs.

Assuming the Axiom of Choice, however, leads to paradoxes such as the Banach-Tarski paradox which says that it is possible to cut up a ball into a finite number of pieces and reassemble them into two copies of the original. This paradox would have been enough to put off those relying on intuition to establish mathematical axioms. Even the concept of √2 was dubbed “irrational” by Greeks be-

gears that seem to run modern, popular morality is the right to liberty balanced by the axiom of reciprocity. But these gears run at their own pace and if we press the analogy too far, they may break. This is perhaps why we emphasise tolerance over moral consistency - because if we press the axioms too hard, we start noticing the cracks in our ethical gears.

In mathematics, the Axiom of Choice gives some “contradictions”, but we keep it regardless, as it forms the bedrock of many essential results. One can put this poetically and say we should value choice in a society despite the apparent paradoxes that might arise from it. One such commonly-cited example is the “Paradox of Tolerance”—that tolerant societies must be intolerant to intolerance. Similarly, a free society must restrain absolute freedom to prevent basic liberties from degeneration.

The key to a sound system, whether Ethical or Mathematical, is to minimise, rather than eliminate contradictions.

Back to Ethics: What have we learnt?

In Ethics, although it may seem we arestraying too far from familiar notions of morality and order into primeval chaos, there is no need for alarm. Mathematicians have opted for more rigorous treatment of mathematics, but they haven’t diminished the role of intuition. They are guided by it yet resort to Formalism to make arguments more concrete.

In our secular age, there might be lessons from Mathematics, and perhaps it is time for Ethics to become more rigorous in our everyday lives—to use reason to minimise contradictions. But rather than dis-

The vessels that once carried “ethical axioms” have now been shown imaginary for the secular world. cause it had an infinite sequence of digits after the decimal, without any pattern.

After the transition to Formalism, mathematicians like David Hilbert wanted to axiomatize all of mathematics: to find the perfect axioms to explain everything.

However, by 1931, Kurt Gödel showed that an axiomatic formal system cannot prove its own completeness or consistency via his Incompleteness Theorem.

Similarly, the vessels that once carried “ethical axioms” have now been shown imaginary for the secular world. The two

missing intuition, we should acknowledge the heritage of traditional morality, and rather than base our intuition on reason, base our reason on intuition. We have to venture into the dark chaotic world of relative truths but keep the flickering lamp of intuition for context. For millennia, we confided in absolute truth, but as the world changeth, so must the Truth.

Aditya Ghosh and Sea-Yun Pius Joung are both Undergraduates at Oriel College, studying Mathematics and Theology and Religion respectively.

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THE DRUG DILEMMA Charlotte Green asks which pharmaceuticals are worth developing.

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hen people learn that I study biochemistry, a common joke is whether I’ll find a cure for cancer.

As I enter my final year, my mum still thinks it should be my goal. I sometimes wonder why it’s a cure for cancer she wants, rather than dementia, malaria, or a new drug for treating heart disease. This made me question whether my family’s focus on curing cancer was shared by the pharmaceutical industry.

The World Health Organisation (WHO) uses a disability-adjusted life year (DALY) value to quantify the burdens of different diseases. One DALY is defined as one lost year of “healthy” life, so a sum of DALYs across a population is a way of measuring the gap between current health status and an ideal world where the population lives to an old age free of disease or disability. A simple way of viewing the DALY calculation is the sum of years lost to death and disability for those living with the health condition or its consequences.

The latest WHO dataset on DALYs was published in 2018 and is based on 2016 data. I hoped looking at the UK data would give me some insight into the burden of disease on the population.

Cancer has the highest DALY value of any

developed countries, with the number of publications, using “big pharma” research as a further sub-category. Their analysis showed that there is a research bias towards diseases that have a greater burden in Western countries. Malignant neoplasms (cancers) are one of the most well-researched areas, and yet have relatively low worldwide DALY values. Infectious and parasitic diseases, on the other hand, which include HIV and malaria, have higher DALYs worldwide compared to Western countries yet remain underrepresented in research. This isn’t just a pattern in the literature either: in 2018

There is a research bias towards diseases that have a greater burden in Western countries. group. Neurological conditions, on the other hand, have half that. Perhaps my family’s encouragement is well-directed.

Nevertheless, given my focus on UK data, the burden of disease worldwide is unsurprisingly very different.

Nature Index analysed the latest WHO data to compare worldwide DALY values, and those of a large group of

over 25% of the novel drugs approved by the FDA were cancer treatments.

There are other possible reasons why the pharmaceutical industry may choose diseases with a smaller worldwide burden. The outcome for those diagnosed with cancer has certainly improved over the years but survival is not guaranteed: some cancers have little or no known

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treatments. In contrast, most forms of heart disease are now more treatable. I also think we’re more concerned about researching diseases that might personally affect us. Dementia, which disproportionately impacts older people, is not as well researched as cancer (which can affect us at any stage of life) despite being almost as common as the latter. Meanwhile, Europe was declared malaria-free in 2016, and thus appears as even less of a health threat to those in developed countries. It is concordantly less researched.

It’s unlikely that public opinion is the sole factor determining the direction of biomedical research, although it probably holds significance. A more important factor could be the cost and potential success of these trials. Since 2003, there has not been a single successful new treatment for Alzheimer’s disease, the most common form of dementia. In recent years, numerous attempts at drug development have resulted in consistent failure at clinical trials, meaning efforts to produce a cure for Alzheimer’s have come at significant expense. In fact, a 2018 article estimated an average cost of around $5.7 billion, considering how many drugs have been approved versus how much has been spent in development for both successful and unsuccessful drugs. This is compared to $0.8 billion for a cancer drug. This lack of success, and high price of development, may mean the pharmaceutical industry is hesitant to prioritise diseases where progress seems unlikely.

With so much invested in developing new drugs, it is interesting to question how the pharmaceutical industry is choosing their targets. Should public opinion, prevalence, or likely success determine the focus of research? Perhaps it should be a combination of factors. It’s a decision I don’t envy: there’s limited funding, but so much research still to do.

Charlotte Green is an Undergraduate in Biochemistry at Trinity College

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TOO HARD A PROBLEM? Gideon Bernstein wonders if we will ever understand consciousness.

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escartes famously proclaimed that his consciousness was the only thing he could be sure of.

Yet despite the monumental advances of modern psychology, an explanation of how consciousness arises still eludes us. But will it eventually fall to the incoming tide of knowledge, as so many other ‘mysteries’ before it?

The hard problem Perhaps the best modern formulation of the problem of consciousness was created by the philosopher David Chalmers in 1995. He distinguishes between the ‘easy problems’ of consciousness and the ‘hard problem’. The easy problems are concerned with understanding phenomena related to consciousness such as the ability to focus, or to report mental states.

It seems clear that as we discover more in the fields of neuroscience, we will be able to develop and test theories, which explain how these phenomena work. This is contrasted with the ‘hard problem’, the question of why any neurological process should be accompanied by experience. We could fully explain the functioning of the brain: how it processes information, produces dreams, remembers, etc… and still ask ‘why does this give rise to experience?’ It’s certainly a good question. And luckily for us, modern scientists may have begun to make some progress.

Peering into the brain There are some who maintain that as we solve the easy problems, the hard problem will simply fade away, just as the seemingly intractable problem of how living beings are constructed from non-living matter disappeared a mere century ago.

One of the current methods, which seems most promising from this angle is the search for what have been termed the ‘neural correlates of consciousness’. The logic is that if we could determine which neural processes always and only occur when someone is conscious, we would

discover the basis of consciousness in the brain, enabling us to solve a huge number of the easy problems in one fell swoop. If the above argument is accepted, this could also mean real progress on the hard problem.

It is, of course, deeply unsatisfying to resolve the issue by appealing to some as yet inconceivable future knowledge. It may also be a fundamentally flawed approach. All of modern science is geared towards producing explanations of how certain functions are performed, in terms of simpler concepts. For example, in order to explain how a muscle works, we only need to explain the biochemical mechanism in muscle cells causing them to contract. However, the crux of the hard problem is that this kind of explanation does not seem likely to work with consciousness. It seems possible to fully explain the functioning of the brain and still not have solved the hard problem.

ting from consciousness to brains, potentially opening up a whole new avenue of inquiry into the hard problem.

Tononi began by trying to identify the features of consciousness that are present in all cases. From these features he identified the properties that a physical system would need in order to produce them.

Then, through a lot of complex maths, he’s come up with what he claims is a quantitative measure of consciousness – integrated information (Φ).

There are many potential problems with Tononi’s theory. Most importantly, he doesn’t even claim to have explained why Φ should give rise to consciousness.

Despite this, he has perhaps demonstrated that Φ is necessary for consciousness, which means that this theory could be a useful step towards solving what has been termed the ‘pretty hard problem’ of being able to determine whether a brain is conscious.

Working it out backwards

Should we just give up?

The fact that we can’t seem to get from brains to consciousness led neuroscientist Giulio Tononi to try the opposite – get-

Some people, like Chalmers, opt for a philosophical resolution to the hard problem. Chalmers thinks that consciousness should be recognised as fundamental, in the same way that gravity and mass are.

This removes the need to search for an explanation, because something that is fundamental can simply be taken axiomatically as a ‘brute fact’ – which can lead to the interesting conclusion that non-living things could be conscious.

Ultimately, Chalmers and most others working on the hard problem admit that it’s still an open question; for all our theorising, we haven’t achieved much. However, what is crystal clear is that even if we can’t solve the hard problem, we will surely expand the wealth of human knowledge into unchartered territory in the attempt, and for me that seems like justification enough to keep going.

Gideon Bernstein is an Undergraduate in Biology at St John’s College.

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Artwork by Isabel Caffyn

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BRAIN AUGMENTATION Atreyi Chakrabarty in conversation with your brain.

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n 2006, the first paralysis patient could control a computer cursor using just her thoughts and a brain-computer interface. In 2012, two more paralysis patients were able to control an independent robotic arm to grab a drink from a water bottle. Reading the brain’s electrical signals was an impressive feat, but no computer could yet directly influence the brain. Today, as we still grapple with understanding the 1.4kg gelatinous mass inside our heads, Professor Newton Howard of Oxford may have cracked its code.

Howard, an ex-lieutenant of the American security services, was compelled to understand the language of the brain when he suffered a traumatic brain injury. Through his interdisciplinary research and collaborations in mathematics, natural language processing, and computational neuroscience, Howard proposed a theoretical framework drawing from mathematics, called the Fundamental Code Unit (FCU), as a way of deciphering the brain’s activity. Using this code, he and his team are now developing a device to be able to modify activity in dysfunctional regions of the brain.

‘Think of [the FCU] as Morse code – with Morse code, you are able to express a compelling amount of information using a very basic code’, Howard explains. The FCU uses what is known in mathematics as unary code, such that for example

110 represents the number 3, and 11110 represents the number 5 and so on. Similarly, in Howard’s FCU, when a single neuron generates electrical pulses, the number of pulses, their duration, the intervals between them all result in a unary code, for example 11110. The unary code is transferred to another neuron, whose activity is then directed spatially. So for this instance a neuron receives this signal and says, “okay your job is done, I’m going to neuron number 5 next to you” and so forth.

‘We essentially will be able to read from a specific neuronal circuit and manipulate specific neurons that are dysfunctioning and allow them to be re-coded to carry out their job’, says Howard.

The final version of Howard’s implant chip, referred to as the KIWI (Kinetic Intelligent Wireless Implant), is designed to be a tiny 1.2 by 2.2 millimetres, roughly the size of a grain of rice. It will have an astounding 1 million channels, made of materials such as carbon nanotubes, enabling them to connect to surrounding neurons very precisely and operate at a higher resolution than current implants.

Compared to Elon Musk’s Neuralink device, which is the size of a coin, has 1024 hair-like channels, and connects to large populations of neurons all at once, the KIWI device has 1000 times greater precision in communicating with specific neurons in a circuit.

The KIWI chip would be especially

useful for individuals with neural deficits such as Parkinson’s Disease patients, whose deficits occur due to a degeneration of neurons that produce the neurotransmitter dopamine, which gives rise to the characteristic motor deficits such as tremors and progressive loss of cognition.

The lack of dopamine means that surviving non-dopaminergic neurons cannot be modulated and become over-active. ‘[The KIWI chip] is directed to be placed in the areas where neurons are not working’, Howard explains. ‘It reads the activity… understands what this information means in relation to the FCU, and reconstructs [these] “modulation recipes” in the form of very small micro-volt currents’. These currents would stimulate the remaining healthy dopamine neurons to increase the levels of dopamine; ‘like a train junction…[it] bypasses the damaged neurons to relay information to the healthy ones’.

This strategy is based on the principles of deep brain stimulation, which involves using electrodes to activate dysfunctional brain regions in the hope that some of the functioning neurons take over control.

But what about Parkinson’s patients who don’t have dopamine releasing neurons left? Howard stated that ‘the KIWI chip has 3 therapeutic modalities. One is neuromodulation by electrical stimulation. The second is carrying on-board viral vectors for DNA modification. And the third is modulation by light [optoge-

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netics]’, introducing the truly novel feature of his device. Optogenetics involves using a viral vector, with the replicating properties of a virus but not its pathogenic properties, to introduce DNA coding for a protein type called an opsin into neurons. These opsins are channels controlled by light, which can influence electrical currents in neurons, allowing the modulation of neuronal activity using light without the need for dopamine.

Unfortunately, there are numerous ethical and societal barriers to deploying this technology into mainstream medicine, particularly as viral vectors have not been widely accepted for use in human brains (though they are safe for use in animal and non-human primate models).

Nevertheless, Howard says that ‘we are engaged in a discussion with the FDA (Food

& Drug Administration) and waiting to hear what the outcome is’, and he seems cautiously optimistic that a version of the KIWI could see its way into clinics soon, ‘within the next year’ he says. Howard thinks that this technology is ‘something

that needs to be adapted into the fabric of our society’, emphasising that ‘my goal is to see that things like neurodegeneration are not destroying personal life and personal dignity’.

While the science of decoding the brain is still in its infancy, Howard may have found one language that it uses, perhaps one of many still to be discovered.

This language can be used to communicate with the brain to prevent debilitating conditions and significantly improve quality of life even in our twilight years.

Technologies such as the KIWI chip are groundbreaking for science and medicine, the next step is for them to push the frontiers of society.

Atreyi Chakrabarty is studying for a PhD in Neuroscience at St Cross College.

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WHEN SCIENCE FAILS Sian Wilcox on failure: science’s greatest achievement

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hen most people think of science, they recall news articles detailing logical and coherent stories that reach a satisfying conclusion. Each neatly packaged piece of research is then further condensed into an eye-catching title that showcases the main finding. Nevertheless, this presentation of science does not recognise the many years of research preceding the report, not to mention the countless failed experiments. Simply put, failure is fundamental to the scientific process; it is the backbone upon which great science is built.

With the recent events of the pandemic, many are witnessing the scientific process unfold before them in real time for the first time.

The countless U-turns and the reality of the time it takes to produce anything tangible can be disheartening, but this isn’t an isolated example, it’s just science in progress.

For example, astronomer and Assistant Professor Erika Hamden, from the University of Arizona recently spoke about the numerous setbacks her team faced over a 10+ year period working on a single project. During the talk, Hamden summarises the pursuit of science in a single sentence, ‘The reality of my job is that I fail almost all the time and still keep going’. This sentiment is echoed in the CV of failures, written by Johannes Haushofer, an Assistant Professor of Psychology at Princeton. Haushofer states, ‘Most of what I try fails, but these failures are often invisible, while the successes are visible’.

Open discussions about failure are vital for normalising the reality of science.

Resilience and perseverance in the face of challenges can result in astounding discoveries. For example, the first image of a black hole, which was released last year, was only made possible through the dedication of over 200 scientists over the course of two years. In the pharmaceutical industry, where discovery can remain elusive for much longer, it takes a drug 12 years on average to make it to market.

Moreover, 90% of drug candidates fail during the development process. Despite this, failed drugs are still important as they can form the basis of a new medica-

tion or be repurposed with great success.

For example, thalidomide was originally developed as a morning sickness medication but was pulled from the market due to it causing developmental defects in unborn children. Now however, thalidomide is used to treat certain cancers and has been shown to increase overall survival rates. In addition, failures and mistakes may lead to their own discovery. A classic example is the discovery of the first antibiotic, Penicillin, which revolutionised the treatment of bacterial infections.

Despite the prevalence and importance of failure as part of the scientific process, failure is still a taboo topic. This may be

due to our perception that science is exact and meant to provide answers. We tend to overlook the inherent value of failure as we assume that we have simply done something wrong. Moreover, there is little incentive to openly discuss failures due to the competitive environment in research and the publication bias towards positive results. For example, a study that reports a novel protein interaction will be more likely to be published over a drug that did not produce any effects when screened.

However, it is important that these negative results are also reported as it prevents similar studies being conducted and can inform future drug structures.

Ignoring failure can have a number of consequences: scientists may leave research due to feelings of inadequacy; multiple groups may run the same doomed experiment in tandem; and researchers are unable to make informed hypotheses due to glaring gaps in the available information.

The combination of these factors hinders innovation and progression, thus limiting the ability to push the boundaries of scientific knowledge.

Failure is an inevitable and necessary part of advancing science and this reality needs to be embraced. There has been progress in recognising the value in failure, but more work and discussion is needed. Only by knowing both the successes and failures can we be at the frontier of science. This is nicely summarised

by Maryam Zaringhalam in Scientific American: ‘Without failure, we lack a complete picture of science’.

Sian Wilcox is studying for a PhD in Neurophysiology at Balliol College.

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Portrait of Kevin Harrington by Holly Anderson

Professor Kevin Harrington’s Immunotherapy Goes Viral Lucy Addis is the winner of this term’s Schools’ Writing Competition.

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evolutionary. It’s a word that’s seldom used to describe cancer treatments, but that’s about to change. Immunotherapy is a “game-changing” new treatment that uses viruses to directly kill cancerous cells and make it much easier for the immune system to spot these, preventing deadly relapses in cancer patients. At its forefront is Professor Kevin Harrington, of The In-

stitute of Cancer Research, London; one of the world’s leading immunotherapy scientists, he studies the use of oncolytic virotherapies, in combination with existing radiotherapy and chemotherapy treatments, to selectively target cancer cells.

Imagine you are a white blood cell, floating around your body waiting to pounce on whatever poor viruses have wandered in there. Being a white blood

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cell, you are excellent at recognising and killing viruses like these, but, unfortunately for your body, not so great at spotting cancer cells, which seem to be playing an endless game of hide and seek. But what if we take one of those viruses and put it inside the cancer cell? Well, then you as a white blood cell can easily sniff out and destroy that tumour. Simultaneously, the viruses inside the cancer cells for once make themselves useful by replicating and bursting the cell from within. So next time that annoying cold sore pops up from nowhere, just remember that the same virus which created it also can be used to target and kill cancer cells.

Now you’ll never look at a cold sore in the same way again…

But why should we bother with Harrington’s pioneering immunotherapy when we already have other cancer treatments like chemotherapy? Well, here’s where immunotherapy gets even more T-rrific (excuse the lymphocyte pun). The major drawback with chemotherapy is how it destroys not only cancerous cells, but healthy ones too, leading to serious side effects in cancer patients. Immunotherapy, however, selectively targets the cancer cells, leaving healthy cells untouched, and, crucially for the patient, dramatically reduces side effects.

Harrington first conducted clinical trials of viral immunotherapy in 2016, on patients with advanced head and neck cancers. The immunotherapy drug which he developed for the trial, nivolumab, was the first ever treatment to extend life expectancy in a phase 3 clinical trial for patients with advanced head and neck cancer after chemotherapy had failed.

Even better, 13% of patients receiving nivolumab experienced serious side effects compared to 35% on chemotherapy.

The following year, Harrington co-lead research into using immunotherapy to prevent cancer relapse. With chemotherapy, leftover cancer cells will lie dormant for long periods before a chemical signal, TNF-alpha, promotes aggressive growth of the cancer cells once again. However, in a major breakthrough for immunotherapy, researchers discovered that these resistant cancer cells had high levels of a molecule called PD-1 on their surface that causes T-cells to ignore them. Therefore, by making PD-1 the target for immunotherapy inhibitor drugs, it’s much easier for the

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body’s immune system to spring back into action and destroy the revengeful cancer cells. The devastating news of being told your cancer has come back could soon be a thing of the past.

Building on the promising nivolumab and PD-1 results, a new immunotherapy drug, pembrolizumab, astonishingly increased life expectancy of advanced head and neck cancer patients by more than 3 years; the side effects were just as astonishingly low: only 17% were reported in

immunotherapy patients compared to chemotherapy’s 69%. More recently, Harrington proved that he had found a way to “eradicate tumours” of deadly sarcoma by infecting them with a modified version of the vaccina virus, found in smallpox vaccines. A similar virus, T-VEC is now hoped to be rolled out across the UK in the near future.

It seems extraordinary that in a year when one virus is wreaking havoc across the globe, others are being used by Pro-

fessor Harrington as a revolutionary new cancer treatment with the potential to dramatically improve both the life expectancies and qualities of cancer patients.

As with all new treatments, cost is an initial issue, but Professor Harrington plans to change that with new research and evaluation methods. His lateral thinking and bravery to lead the scientific world into unchartered territory to me is inspirational. In the future, prepare to see immunotherapy go, quite literally, viral.

SCHOOLS’ COMPETITION This term, school students from across the UK in Years 11-13 submitted an essay on the theme, ‘An inspirational scientist, alive now, whose work is helping us to advance into the future’. The winning student, selected by our panel of judges, was Lucy Addis, a Year 12 student at the Royal School Armagh, who chose to write about the research of Professor Kevin Harrington at The Institute of Cancer Research, London. Professor Harrington said, “The essay is fantastic - a great mixture of science and excellent, humorous prose. I congratulate Lucy on her wonderful explanation of the exciting field of immunotherapy.”

JUDGES Dr Kerstin Timm is a Career Development Fellow at the Department of Pharmacology. Her work focuses on early detection and cardioprotection in chemotherapy-induced cardiotoxicity. She is also a Stipendiary Lecturer in Medicine at Somerville College and holds the position of Isobel Laing Career Development Fellow in Medical Sciences at Oriel College. Kerstin is passionate about disseminating research to the wider public and enjoys taking part in outreach events.

Ben Jaderberg is a 3rd year DPhil student in Oxford Physics and is developing quantum algorithms and applications for the first generation of quantum computers. He has industry experience with software and has worked with the quantum computing team at IBM. He enjoys public outreach and has recently developed quantum coding workshops for University and High School students with Oxford Quantum Information Society.

Naomi Mburu is a 3rd year DPhil student in Engineering science and Rhodes Scholar whose research seeks to explore the use of liquid metal surfaces in nuclear fusion reactors to improve reactor performance. She has served on the executive board for two national organisations aimed to increase participation of people of colour in engineering, teaches a course on nuclear fusion at secondary schools in Oxford, and is currently working on a series of podcasts for the Oxford Scientist.

To enter next term’s competition, visit www.oxsci.org/schools/

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OZONE Sophie Littlewood on what the ozone hole tells us about human responsibility, manufactured doubt and international collaboration.

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n May 1985, three scientists from the British Antarctic Survey published a shock discovery: the ozone layer had a hole in it. The hole – or, more accurately, the area over Antarctica where ozone concentration is abnormally low – posed a serious health risk. The ozone layer protects Earth from the Sun’s harmful UVB ultraviolet rays, which can cause skin cancer and eye damage, and any reduction in ozone concentration has direct consequences for human health.

The culprits? A group of seemingly harmless chemicals known as chlorofluorocarbons (CFCs), which were being used in hairspray, aerosol cans, air conditioning units and refrigerators. By 1987, the Montreal Protocol on Substances that Deplete the Ozone Layer had been written and signed by 43 nations, pledging to phase out CFCs and restore the ozone layer.

The Montreal Protocol is often hailed as one of the most successful examples of international cooperation. But there’s a large part of the story that’s missing: atmospheric scientists suspected that the ozone layer was under attack more than ten years before the ozone hole was discovered.

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n 1970, British scientist James Lovelock built a homemade device to detect CFCs in an urban haze of pollution that had descended over his holiday home in Ireland. But even when the haze cleared, and the air was coming from over the Atlantic – without passing over an urban area for thousands of miles – CFCs were still detectable. Lovelock even took his instrument on a voyage from England to Antarctica, and to his surprise, CFCs could be found wherever he travelled. It seemed that CFCs weren’t being broken down in the Earth’s lower atmosphere. In

fact, almost all of the CFCs manufactured since their invention in 1930 were still in the atmosphere.

A few years later, atmospheric chemists Sherwood Rowland and Mario Molina made a hypothesis: that these stable CFCs might eventually float into the Earth’s upper atmosphere, known as the stratosphere, where solar radiation would break down the molecules and release highly reactive chlorine atoms. These chlorine atoms could, in turn, catalyse the destruction of ozone at a devastating rate. A single chlorine atom could destroy 100,000 ozone molecules.

From there, the evidence mounted.

Chlorine monoxide, a product from which the only known source is the destruction of ozone by chlorine, was detected in the stratosphere in 1976. A year later, the governments of the U.S., Canada, Norway and Sweden moved to phase out CFCs from aerosols. But there, the momentum stopped. It would be another ten years before the Montreal Protocol was signed, and CFCs would begin to be phased out from all products, not just aerosols. If the evidence existed, then what caused the delay?

The answer lies in a public relations ‘playbook’ that was written by the tobacco industry to sow doubt over the link between smoking and cancer and would now allow the CFC industry to question the link between CFCs and ozone depletion. At the time, the industry generated $8 billion and employed 200,000 people.

The Chair of the Board of DuPont, the inventor and largest producer of CFCs, was quoted as saying that Rowland and Molina’s hypothesis was “a science fiction tale...a load of rubbish...utter nonsense.”

In 1980, DuPont initiated the formation of the Alliance for Responsible CFC Policy, joining the ranks of other trade groups

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such as the Aerosol Education Bureau, the Council on Atmospheric Sciences and the Western Aerosol Information Bureau. All worked to defend their products to the government and the public, donating research grants to ‘white coats’ – scientists who were sympathetic to their cause or whose findings might be spun into a defence of CFCs – and emphasising that the science was too uncertain to justify action. Even as late as 1987, DuPont testified before the U.S. Congress that “we believe that there is no immediate crisis that demands unilateral regulation.”

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hese same tactics – of manufacturing doubt in science for commercial gain – had been played out by the tobacco industry and would since be used again and again, from global warming to vaccines to acid rain. Meanwhile, carbon emissions continue to rise amid a pandemic dubbed a “hoax” by senior politicians across the globe. In the words of Carl Bergstrom, professor of biology at the University of Washington: “It never occurred to us that if a pandemic actually broke out, there would be political lines drawn over whether it even existed.”

As for the Montreal Protocol? It was the first United Nations treaty to be signed by all 197 member nations, and the ozone hole is on track to heal completely by 2080. Jonathan Shanklin was one of the scientists who discovered the ozone hole in 1985. “It has been really astonishing to me that that little discovery has unified the world’s countries to really produce a measurable effect,” he said to the Verge in 2016. “And I only wish that they could unify in the same way over the many issues that affect the climate today.”

Sophie Littlewood is an Undergraduate in Chemistry at Magdalen College.

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Artwork by Dominika Syska

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When Science Meets Politics

Emma Hedley on fake news, experts and why we all need to learn about science.

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n the past few years we have heard time and time and again that people are tired of being told what to do by experts. To quote Michael Gove, ‘I think the people in this country have had enough of experts’. This is ironic in many regards as we rely on experts to advise us on many things in our daily lives, from doctors on our health, to mechanics for advice on car repairs. However, when scientists at the frontiers of their field inform

decisions in public policy this is often met with suspicion. This narrative is also very different from that surrounding the global COVID-19 pandemic, particularly in the early stages, where politicians claim they are being guided by the science and offer this as reason to trust their decision-making.

The complex nature of the pandemic means that the scientific expertise that must be drawn upon encompasses the physical and life sciences, as well as so-

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cial and behavioural science. However, this discussion is not limited in scope to the pandemic.

There is a wider, more fundamental discussion to be had about how we translate scientific knowledge into public policy. In a democracy this requires general public support, which itself depends on public understanding of the science to build trust into presented scientific evidence.

If for example an alien visited

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earth from another planet and you told them that flour, yeast and water combine to make bread they probably either wouldn’t believe you or would think you are some kind of wizard unless you describe to them the process and some fundamental concepts, such as what an oven is. In essence, if people don’t understand how science works, they have no reason to trust that the outcomes are legitimate.

To be scientifically literate means that you can understand reports around scientific concepts, and make use of this understanding for personal decision-making, and that you know the impact of science on your daily life. It also means that you have the ability to critically analyse claims and decide what may and may not be a reliable source of information. However, there is very little education until the second half of a science degree on how the scientific process, peer review, and journals actually operate. There is even less education on the role that scientific evidence plays in informing public policy. Improving scientific literacy is a job for everyone in science if we want to demystify the scientific process. In doing this we also make science feel like a more welcoming and inclusive community. When people can feel that they are a part of that community they are more likely to trust it.

The typical example of public distrust is the fall in vaccination rates arising from since disproven evidence that the MMR vaccine causes autism.

This issue threatens to raise its head

The Waterfront I’ll find her there Find her where the pier becomes the air And falls away, deep and deep.

I’ll find where the waters swirl and sleep.

At the joining of our hands I’ll feel her where the waves confront the sands And the sun begins to bleach her swirling hair But, oh, where the pier becomes the air — Where old men came to chase the western sky, Where young men such as I Now come to chase a girl.

I’ll find her here Find her at the falling of the pier Where the waters sleep and swirl.

Annie Sland is the winner of this term’s Creative Competition on the theme ‘Boundary’.

tists and in the government must play hand in hand or take up of the vaccine will be low.

Inevitably there is also a degree of uncertainty in science that must be conveyed by researchers and accepted by the public. Science doesn’t hold all the answers and all that scientists can do is pursue knowledge and leave the judgement of the best course of action

If people don’t understand how science works, they have no reason to trust that the outcomes are legitimate. again. There has already been a wave of fake news stories and conspiracy theories surrounding vaccines under development for COVID-19. Some of these stories come simply from a lack of understanding of vaccines and others come from a mistrust of the government. Here the public trust in scien-

to politicians. Some science is particularly politicised, such as research informing on climate change, as it highlights a threat that requires organisation on the scale of national governments in order to tackle it. Scientists have to make individual decisions whether to be political and advocate

for change or simply to do the research and present the facts. If scientists are seen as too political, they can come across as biased. Yet if the results argue for one particular course of action the backing of renowned scientists can add credibility.

Without people understanding why decisions are made, and why they should make certain choices, science will continue to plough on pursuing knowledge without the informed support of the general public. This makes the ambition of many scientists aiming to change the world for the better harder to achieve. As Neil deGrasse Tyson once said, ‘The good thing about science is that it’s true whether you believe it or not’. To believe the outcome is one thing but to trust the process is a different thing altogether.

Emma Hedley is studying for a PhD in Materials Science at St Catherine’s College.

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THE FRONTIER IN YOUR

LIVING ROOM Jake Burton on the unlikely benefits of citizen science.

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our Scientists Need You Citizen science, where members of the public contribute to collecting and analysing data to further scientific research, has a long history. One project, the Christmas Bird Count, has been taking place across North America every year since 1900.

And though ecological surveys may be the bread and butter of citizen science, they are by no means the only way to get involved.

Today you no longer need to traipse around muddy fields on a cold December day to leave your mark on the world of science. Instead you can while away the hours solving puzzles that help determine the structures of proteins. Or cast your eye over images of distant stars, identifying the ‘debris disks’ where planets form.

The choice is yours.

Whatever you choose, citizen science projects like these have one thing in com-

mon (besides, of course, involving the public) – they generate vast quantities of data. But one of the concerns about citizen science is just how good all these data really are.

Houston, We Have A Problem Scientists obsess over eliminating error from their work. That is, the discrepancy between the observations scientists make, and the truth reflected in nature.

Though error often arises by chance, it can also be introduced systematically. It is this systematic error that poses a problem for citizen-led science.

You see, people are only human, and they make mistakes. For instance, when conducting a survey to identify the animals living nearby, we’re somewhat unlikely to register yet another rabbit. But you’d certainly be telling everyone if you saw something as elusive as a badger! It turns out this can skew the results some-

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what. Indeed, several bird population surveys have found that the abundance of birds over time is entirely dependent on who is doing the observing. Not, as hoped, the actual abundance of birds.

But it would be silly to ban the public from science for not being quite so detail-oriented as the professional scientist.

Since citizen science has other benefits.

In fact, one of the areas where citizen science has excelled is when it focuses on local issues.

The city of Antwerp, Belgium, has been using citizen scientists to track air quality across the city by encouraging people to mount sensors for nitrogen dioxide (an indicator of traffic pollution) to their homes. As well as providing a trove of data on how the urban environment affects the dispersal of pollutants, the project has also landed air quality squarely on the agenda of local elections.

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Artwork by Michelle Mendieta Mean

This shows a key benefit of citizen science: it can answer questions with important societal consequences. So although you might not be ecstatic about contributing to some obscure scientific paper, you could certainly get excited about making the place you live more, well, liveable.

even begin to imagine, though we can certainly try.

Don Your Cowboy Hats The ‘DIYBio’ (or ‘Do it yourself biology’) movement, home to such crazy ideas as “Could I light my street in an eco-friendly way using glow-in-the-dark plants?” pro-

You no longer need to traipse around muddy fields on a cold December day to leave your mark on the world of science.

Of course, citizen science doesn’t have to be quite so serious. One citizen-led project tracked repeated dog mess offenders by matching the DNA from tennis balls to the aforementioned dog mess. Ideas like this show that rather than having to be led by ‘professional’ scientists, people can concoct exciting uses for science all by themselves. Some of which we can’t

vides one example of how citizen science might look in the future.

Many traditional biology techniques can now be done, on the cheap, at home.

Gel electrophoresis, a technique for separating DNA samples by size, requires nothing more than a bit of DIY and some ingredients from your nearest Tesco.

Coupled with DIY PCR, a technique for

amplifying interesting bits of DNA, you can suddenly do things like assessing the origin of your food or identifying those mysterious insect eggs in your garden.

Previously, citizen science has revolved around collecting data for others, but the introduction of DIY tools and equipment like those above will completely alter the way citizen science is done. The future of citizen science is one where participants devise their own questions, develop their own methods, and produce their own analysis. So that ultimately, everyone can contribute a little to making the world a better place. In this future, the limit is not what equipment you have, but rather your imagination.

So, put on your cowboy hats (and your lab coats) because the Frontier is coming to you!

Jake Burton is studying for a PhD in Immunology at Linacre College.

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he past decades have seen robots become smaller and smaller, until in March last year this development moved past a long-standing frontier - robots became microscopic and thus viable for entry into the human body. Every field of medicine from oncology to paediatrics will be influenced when robotics becomes integrated with healthcare. May this be a technology to revolutionize medicine?

How could nanobots act on our body?

One potential benefit of the medical nanobots is to reduce the severity of strokes,

which cause 32,000 deaths annually in the UK alone. Robots in our blood could navigate to an accumulated blood clot in the brain and ‘burrow’ through the clot, secreting enzymes to break apart the blockage and restore blood flow. Further, a recent study found that nanorobots injected into mice can starve tumours of their blood supply and hence fight off cancer. Here robots contain sheets of DNA wrapped around tumour-destroying enzymes, that bind with a protein only found in tumours. This technique has great potential because it targets cancerous cells without harming healthy tissue, avoiding the unpleasant or dangerous

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side effects associated with most cancer drugs currently available.

No one knows yet exactly how consumer nanobots will appear but they might end up looking similar to bacteria that are of the same size. For example, a study published in 2017 looked at how navigation through the bloodstream could be achieved through rotating projections similar to bacterial flagellae. This would allow for highly targeted delivery of medical payloads in a minimally invasive procedure. Other techniques currently being explored include coating the robots with proteins and guiding them magnetically to an injury site, and even integrating

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ROBOTS IN OUR BLOOD Dhruval Soni discusses the future of nanotechnology in medicine.

micro-motors powered by gas bubbles rising from reactions in the stomach. The latter techniques brought about the first nanorobot-powered drug delivery into the body.

Magic bullet or Pandora’s Box? Obviously, many people might be opposed to the use of an unfamiliar concept such as medical nanobots. A specific reason for concern may be the uncertain long-term effect on human health, which research has yet to address.

For example, some robots already tested in the animal model use artificial magnetic fields to fight cancerous tumours,

which may disrupt the electrical activity of the heart. Yet, a more general problem might be the size these robots: materials that are not normally harmful could become toxic on the nano scale and end up posing a significant health risk. Nanobots might pass to the foetus in pregnant women or cause lung inflammation when they are absorbed by lung cells and induce local effects. To date, the procedure for removing nanobots from the body has barely been investigated. Robots decaying on their own inside the body is only one of many issues that needs refinement.

The public must be made aware of the potential risks of new technology before it

is adopted by the consumer market, and long-term studies are needed to examine the safety of nanomedicine products.

We know that participants often underestimate the risk factors of taking part in research studies, so the testing of the technology itself must be strictly regulated. The world of possibility opened up by nanotechnology can all too easily become a pandora’s box. It might never have been more crucial for the scientific community to be aware of technological developments. Medicine continues to change at breakneck speed, and with the emergence of nanorobots, the stage is set for a transformation.

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BIOLOGY MEETS PHYSICS Tasmin Sarkany on how interdisciplinary scientific research might lead to major insights and discoveries about disease and the origin of life.

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t can often seem that biology, chemistry and physics are growing further apart, but some of the current major scientific frontiers defy this. Lying on the boundary of theoretical physics and cell biology is the fascinating study of liquid-liquid phase separation in cells. Although the name may sound obscure, this research promises amazing applications in areas ranging from the study of Alzheimer’s and Parkinson’s disease, to insights into the origin of life.

It all started with the problem of how biochemical reactions in cells are spatially organised – how does a cell make sure that the chemicals needed for a reaction all congregate in the right place for it to occur? This is easy to explain when reac-

out that the explanation can be found using theoretical physics.

Although scientific history is full of examples of physics being applied to biology (optical microscopes and X-ray diffraction techniques are applications well established in biological research), the research into phase separation in cells is exciting because looking at biological systems from a theoretical physics standpoint is still very new.

Research into phase separation A leading research group that is looking into this is the ‘Mesoscopic Physics of Life’ group at the Max Planck Institute for Complex Systems, run by Dr Christoph Weber. The group investigates the theo-

Looking at biological systems from a theoretical physics standpoint is still very new. tions occur in compartments (organelles) bound by membranes, which means that chemicals are confined to where they need to be. But it is more puzzling when we consider the many “non-membrane bound” organelles in cells. Here it turns

retical physics of ‘liquid-liquid phase separated droplets’ inside cells. Liquid-liquid phase separation refers to two liquids of different compositions, which are separated in space due to a repulsive interaction between their molecules. Weber and col-

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leagues use the fact that, ultimately, this relates to a very general principle in physics: systems will tend to a state in which the energy of the system is at a minimum.

In thermal physics this means that two liquids can separate into a droplet and a surrounding liquid. The important point here is that there is no membrane, or solid boundary, separating these two liquids.

In 2009, Clifford Brangwynne (Princeton) showed that structures called ‘P granules’ in the nematode Caenorhabditis elegans actually displayed liquid behaviours.

This meant that the physics of liquid-liquid phase separation could be applied to these ‘granules’ and other similar structures observed in cells.

There are many important outcomes that arise as a result of these droplets being liquid-liquid phase separated: since the droplet is liquid, there is fast diffusion within, meaning that chemicals in the droplet will be well mixed. Thus chemical reactions can occur in these droplets, and it may even be favourable to do so if the droplet has a chemical composition with a higher concentration of reactants (or proteins) than the surrounding liquid.

Applications to Alzheimer’s disease?

A thorough understanding of this has the

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Artwork by Emma Braine

potential to revolutionise multiple areas of biology. For medical science, the study of cellular compartments with high concentrations of proteins holds particular relevance for diseases such as Alzheimer’s and Parkinson’s disease. These diseases are characterised by solid or crystalline formations occurring in the cell. It has been suggested that these occur due to the formation of a liquid droplet going wrong and instead forming a solid. Therefore, gaining insights into the theoretical physics of phase transitions could tell us more about why these diseases occur.

New views on the origin of life?

Another implication of research into phase separation inside cells may be new discoveries about the origin of life. On early Earth, the atmosphere, land, and sea contained a huge variety of chemicals, including many based around carbon.

These chemicals were used to synthesise biological molecules (amino acids), which are the building blocks of proteins. One major research question on the origin of life is how this dilute mixture of amino acids became concentrated enough to allow for the chemical reactions that ultimately lead to the occurrence of life. Since phase separation can spatially organise reactants to concentrate them, this research may provide answers into how life could have originated on Earth.

Recently, physical research into the dynamics of droplets has also led to discoveries on how the droplet shape can change under different conditions depending on the chemical reactions happening inside the droplet and other conditions such as pressure and temperature. A study in 2016, using the theory of these droplets, showed that they are able to divide under certain conditions. The computer mod-

elling simulations of this process showed shapes very similar to those in cell division, so it has been postulated that the physics of these droplets may even be used as a model for protocells (cell-like objects before the cell as we know it had evolved).

This would be a huge advancement in the study of the origin of life, stemming from the combination of theoretical physics and biology!

Using theoretical physics to study liquid-liquid phase separation in cells is a fascinating example of how interdisciplinary scientific research can lead to major insights and discoveries. This might just be the start of a new era of interdisciplinary studies as major frontiers in science – for when we collaborate with those in different fields, we never know what we can find.

Tasmin Sarkany is an Undergraduate in Physics at Lincoln College.

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IS GROWING OLD GETTING OLD? Maribel Schonewolff on why we age and how we might combat senescence in the future.

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hen I asked my friends to brainstorm about ageing their first responses were “white hair, wrinkles, no teeth”, “calm and wise grandparents”, “no sex”. These associations are quite common and show that aging is mostly referred to as something negative – at least by younger generations: a decline in activity, health and fun. With society growing older and older in many countries, both the anti-aging industry and biomedical sciences are continuously challenged to come up with ways to stall one of the greatest mysteries and most natural frontiers of life: the aging process.

The mystery of aging has two components. How is my life going to change as I get older? And, when will I die? We can attempt to answer the latter using a nation’s average life expectancy. For example, a child, born in the UK in 2020 will live for 81 years on average. The oldest woman to ever have lived was probably the French Jeanne Louise Calment, who allegedly died in 1997 at the age of 122, which is close to the suggested maximum human lifespan. So, what is the highly sought-after secret to a long life?

It’s commonly accepted that both lifestyle and genes heavily influence our lifespan. The existence of so-called blue zones in Italy, Japan or Costa Rica with extraordinarily high numbers of centenarians (people who are a hundred years old or more) who share dietary habits or rare genetic mutations supports this hypothesis. It does not come as a surprise that Disney Star Zac Efron left Hollywood to ex-

plore these magical places and unravel the secret of a long and healthy life far away from Botox and protein shakes in his Netflix travel and lifestyle documentary.

But let’s check the facts: what do we really know about aging on a scientific level?

For a molecular biologist, aging is the decline of organismal integrity and cellular function over time. “But that’s another quite negative and complicated definition that makes me want to join Zac in eating pasta and drinking litres of goat milk” you might think. The central question of aging science is to understand how and why we age. Because it is a relatively new discipline, aging research follows an efficient bottom-up approach, aiming to understand basic biological principles in healthy organisms and use this knowledge to explain dysfunction in age-related diseases. It is commonly accepted that important maintenance mechanisms in our bodies break over the course of a lifetime.

The loss of cellular repair mechanisms leads to an accumulation of more and more damage until the body has reached its limit and dies.

The nine most prominent age-related defects were grouped in a paradigm-defining 2013 article by Lopez-Otin titled “The Hallmarks of Aging”. They include mechanisms responsible for growth control and nutrient perception, regulation of energy metabolism, immune system and

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microbiome influence, DNA replication and protein homeostasis. Aging researchers use model organisms like fruit flies to investigate the impact of random or targeted manipulations of their genome sequence. Through such manipulations, small point mutations help identifying genes that play a role in maintaining crucial functions, like preventing uncontrolled growth of oncogenic (pre-cancer) cells. Such findings from basic organisms can be translated to more complicated animals like humans, if genetic programs and molecules are conserved throughout evolution.

Current efforts vary from administering vitamin supplements to the round worm C. elegans, a model for improving protein quality control mechanisms, to studying the naked mole rat, which never gets cancer. Researchers from the Max-Planck-Institute for Biology of Aging in Germany showed the life expectancy of fish increased when their old microbiome was removed with antibiotics and their gut was recolonized with bacteria extracted from the excrements of younger fish.

Now it is up to you if you will “store a bag of your young poop and keep it for later” as the lead scientist in this study, Dario Valenzano, jokes about in a TV interview. It remains to be understood what exactly the essence of a long and healthy life might be, but it is clearly fascinating to explore the frontiers of life(span) where nature performs its miracles with molecular precision.

Maribel Schonewolff is studying for a PhD in Biochemistry at Wolfson College.

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A RESEARCHER’S PERSPECTIVE Darlan da Silva Candido on what it’s like to work at the frontier of COVID-19 research.

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hen the first cases of Covid-19 were reported early this year, I had no idea how much this would change the world, my life and my career. Just over six months into the amazing experience of working on the scientific and public health response in Brazil, I thought it was time to look back and share my journey.

As a genomic epidemiologist, my research focuses on understanding and reconstructing virus outbreaks. I like to think that in my field we work as outbreak detectives: we sequence the genomes of viruses and use the genomic information from different samples to find out when, where and how an outbreak starts and spreads. Previously, my work had no direct relationship with respiratory viruses or pneumonia. I had mainly focused on viruses transmitted by mosquitoes such as dengue, Zika, chikungunya and yellow fever.

I was at home in northeast Brazil when the news surfaced about a pneumonia outbreak of unknown cause in Wuhan.

At that stage, there were way too many questions and barely any answers. But as weeks went by, it became clear that the novel coronavirus - later named SARSCoV-2—could soon become a global threat. Then, everything changed.

I was in Cambridge in late February when Brazil confirmed its first coronavirus cases, which were the first reported in Latin America. Given our previous work on outbreak response in Brazil, our collaborators at the University of São Paulo made national news by sequencing the samples in a record time of 48 hours. As a result, our team at the Brazil-UK Cen-

tre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE) was pulled into the country’s SARSCoV-2 response. All our projects were abruptly put aside and replaced by daily online meetings with an average of 40 researchers from across the globe.

Meanwhile, case numbers in the UK were increasing and my life in Oxford, just like many of yours, was changing. Whilst the lives and research projects of many friends were slowing down, mine was intensifying. We were all pushed out of our comfort zones through the daily meetings with researchers across diverse fields, ranging from epidemiologists to mathematicians to anthropologists, and the need to quickly answer an overwhelming range of questions. I found myself reading about and running analyses that I had never even heard of before. My responsibilities as a PhD student also changed. I was suddenly managing teams, hosting meetings, and leading research, which eventually was published in major journals. I cannot say I have ever learned so much in such a short period of time.

To reconstruct the introduction and spread of the virus in Brazil, we sequenced and analysed 427 SARS-CoV-2

genomes from samples coming from 18 out of Brazil’s 27 federal states. This was a huge collaborative effort.

There was amazing logistical work sending samples from around the country to three sequencing laboratories in São Paulo and Rio de Janeiro; multiple hours of heavy computational work, manuscript writing, replying to reviewers in a timely manner and making final corrections.

After three months of work resulting from the collaboration of over 100 people, the manuscript was published in Science2. I soon found myself in charge of yet a new responsibility: media coverage and science outreach. The paper quickly made headlines in Brazil and I had to give interviews on multiple media platforms. Even my personal journey from my early life in northeast Brazil to Oxford received public attention.

On the flip side, I was worried about my family back home, feeling the effects of the UK’s long lockdown, and tired from all the rewarding but intense work. Undoubtedly, these sentiments were shared across our team and among everyone else working on the SARS-CoV-2 response.

We realised it was time to slow down and take some time for ourselves.

Looking back now, I can only feel deeply impacted by everything we have seen and experienced this year. Nonetheless, I am extremely grateful for being able to contribute towards the response to the pandemic. More than scientific publications, I will also take new global friendships and valuable knowledge from this extraordinary journey.

Darlan Da Silva Candido is studying for a PhD in Zoology at Merton College.

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APOLLO’S RECKONING Angus Barrett asks whether there is an ultimate destination for science.

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ietzsche thought that existence was found in the tension between two forces: the ordered, rational and conscious Apollonian, and the chaotic, emotional and unconscious Dionysian, both of which he named after the Greek gods who represented these differing concepts. He believed that life was maximised when the two are balanced; when the Dionysian is applied constructively within an Apollonian framework. He was reiterating the ancient idea of the primacy of the universal dipole and the being that was

generated at its interface – which was in turn to be rediscovered by modern neuroscientists in the bi-hemispheric structure of the brain. It turns out that our minds are precisely equipped to address these two opposing parts of experience: the known and the unknown, the self and the other, the predictable and the potential, and so on. While processing of unfamiliar information seems to be dedicated to the right hemisphere, familiarity is more the remit of the left. And if something’s existence is dependent on our knowledge of that thing, this could be described as the

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fundamental process of creation.

Science – our rational inquiry into the workings of the natural world – is a forum for this process. There is what we know and what we don’t, our great consensus and our unsolved mysteries, and then there is the astronomer at his telescope, or the biologist at her microscope, shining a light onto the dark and uncharted territory between the two. But to view science in this way is to ask a question far deeper than any about the inner workings of stars or cells. That is: ‘Is there an ultimate destination for our work?’ Will our rational

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Artwork by Pippa Newberry

inquiry ever uncover every secret of the natural world? Will Apollo, bearing the illuminating torch of science, ever overcome the Dionysian beast once and for all?

Not surprisingly, the jury is still out on this. Many believe that our current framework and narrative correctly describe the universe and that even the so-far impenetrable problems at the bookends of science – the very small and the very big, the origin of life, the fate of the universe – will eventually, perhaps even soon, be understood. The big picture is there, and all we are doing

is filling in the gaps. Others believe that such complete understanding is within our grasp, but that other revolutionary discoveries are still to be made. Some, although acknowledging that an underlying nature exists, think that inherent inadequacies in our resources or cognition mean that it will resist elucidation for ever. And then there are many who doubt whether scientific truth, in an absolute sense, exists at all.

What is absolute truth? Whether we will find it depends on what it is. For the empiricists, what was true could not go beyond conscious obser-

vation – all that is real, all that we can be certain of, is our experience. But the core pre-supposition of science is that there is indeed an objective reality ‘out there’, existing independently of our observation of it, our interaction with it, or our attention to it. The scientific method seeks to transcend the limits of momentary observation and time, to find truth beyond the subjective and beyond the particular. It does this by taking many observations – the more the better – and then abstracting patterns which are common to all of them, a process of wrestling truth from

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its particular context. Interestingly, this is precisely what occurs along the rightleft hemispheric axis of the brain as knowledge is assimilated. Novel information is observed in its context mostly by the right hemisphere, before being abstracted and categorised by the left to be reapplied elsewhere: the unknown becomes the known. But the left hemisphere is also primarily concerned with ‘making things’, with tools, the artificial and the constructed, which may have important implications about the nature of scientific truth. Could it be artificial too?

Science does indeed run into a problem: the natural world from which it attempts to abstract truth inherently resists abstraction. The abstract and the contextual, just like the primary perspectives of the two brain hemispheres, are deeply incompatible. To reduce the abundance of the natural world to absolute truth is like trying to force a square peg into a round hole. Whether the indeterminacy of the quantum world, Gödel’s incompleteness theorems, randomness or the stochasticity

of biological systems, centuries of inquiry have revealed a cosmos with uncertainty, relativity and probability at its core. This uncertainty is not just in human or experimental imperfection, but in the very nature of things. Noth-

breaks, everything is joined anew; eternally the same House of Being is built.’

Progress of any sort, whether scientific or ethical, is simultaneously cyclical and directional, a widening gyre with no destination, an infinite regress of

We should view science not as an answer but as a question, not a product but a process, not a destination but a journey. ing is certain, nothing is completely predictable; there are only tendencies for particular things to occur. What we consider to be scientific truth is no more than an approximation, a useful but ultimately inaccurate construction of the left hemisphere, a ‘best guess’ of sorts, and nothing more.

Nietzsche, too, was sceptical of universal truth: ‘There are no eternal facts, as there are no absolute truths’. Instead, he believed in a process of ‘eternal recurrence’, one in which history repeats itself over and over, where ‘everything dies, everything blossoms again; eternally runs the year of being. Everything

frontiers through which our edifices of truth are to be dismantled and rebuilt from the ashes via the same process of abstraction and transformation. Truth is ultimately relative, provisional, a human construction that comes and goes in cycles.

So, does this mean all of our work is in vain? Personally, I don’t think so.

Nietzsche told us that existence could be found in the tension between the known and the unknown, between the finite and the infinite, and that the preservation of both, along with the process that transforms one into the other, was a pre-requisite for everything: for experience and understanding, for life and death, for meaning itself.

And if our quest for knowledge ended, what would become of us? What would give our existence meaning? Thus, we should view science not as an answer but as a question, not a product but a process, not a destination but a journey. We can be satisfied with partial truth, with provisional and constructed truth, because ‘ultimately, it is the desire, not the desired, that we love’. In other words, not truth, but the pursuit of truth, should be our goal.

Oxford professor Roger Penrose, winner of this year’s Nobel Prize in Physics, put it most plainly and powerfully when he was asked why he thought believing in an ultimate destination for science was a pessimistic outlook.

‘Solving mysteries is a wonderful thing to do,’ he replied. ‘And if they were all solved, somehow, that would be rather boring’.

Angus Barrett is an Undergraduate in Biology at Magdalen College.

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