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Introducing the CPM ‘vlog’ series

Last week, we launched a new flash interview “vlog” series. In this blog post, our Junior Research Fellow Dr Katherine Wood discusses the aims of these interviews and some of the key insights she took away from making the videos.

In this series, I have interviewed a range of different people involved in personalised medicine in one way or another, discussing their careers and their views on precision medicine now and in the future. These interviews will be released on a weekly basis so keep an eye on the CPM website and our Twitter feed (@CPMOxford) to ensure you don’t miss them! 

I have interviewed people from Professor Andrew Wilkie, a consultant in clinical genetics; to Dr Patrick Short, the CEO of Sano Genetics; and Professor Nina Hallowell, a professor of social and ethical aspects of genomics, to name but a few of our excellent speakers. The interviews covered many aspects of personalised medicine, from routine genetic testing in the clinic, the differences between academia and industry, the ethical implications of precision medicine, the role of bioinformaticians within the framework of large-scale genomics, and personalised therapies and pharmacogenetics.

One of the key themes which stood out to me was the difference in view between clinicians and academic researchers on the utility of genomic testing. Both Professor Andrew Wilkie and Dr Ed Blair raised the point that, from the perspective of a doctor, medicine has always been personalised and one would expect that whenever one sees a clinician, the care and treatment should be tailored towards the individual. While both highlighted the utility of targeted genetic testing for specific cases, there was scepticism about the role of widespread genomic screening in the clinic. On the other hand, both Dr Alex Geary and Dr Jamie Ellingford (bioinformaticians) hailed the exciting implications for research of being able to access and analyse vast quantities of DNA sequencing data. One key area many interviewees highlighted as a potential challenge going forward was the ability to process all the data we are collecting; is there really any point having so much information if we can’t analyse it all? Another interesting point raised by both Professor Andrew Wilkie and Professor Nina Hallowell was whether we should be investing so much into the genomics revolution at the expense of other factors which contribute to ill health (such as poor living conditions) or which we can test for simply and cheaply in the clinic (e.g. blood pressure). Overall, perhaps the take home message is that personalised medicine has many things to offer but it will not be the solution to everything!

On a different track, both Professor William Newman and Dr Andrew Douglas discussed the amazing potential of utilising “omic” data to tailor treatments to an individual. Professor Newman told us about the PALOH (Pharmacogenetics to Avoid Loss of Hearing) trial, a rapid point-of-care genetic test for newborn infants to prevent antibiotic-related hearing loss, while Dr Douglas’ discussion on antisense oligonucleotide therapies and the incredible successes there have been in the field so far left no doubt over the potential impact that tailored treatments can have on the patients’ lives. Finally, a particularly interesting chat with Dr Patrick Short from Sano Genetics highlighted the role that industry can and will play as we go forward with the personalised medicine revolution, and the fluidity between academia and industry these days. His careers advice for PhD students and postdocs is certainly worth a listen!

I really hope that you enjoy watching the videos and these snippets of insight into personalised medicine from many different perspectives! I certainly learned a lot making them.

Watch the Flash Interview Series here.

In conversation with Dame Mary Archer – CPM Podcast: Meet the Advisory Board Episode 2

The centre of personalised medicine podcast is hosted by Jiyoon Lee, president of the Oxford personalized medicine society and Dr Anika Knuppel, JRF at CPM.

In the second podcast episode as part of our meet the advisory board series, we had the honour to talk to Dame Mary Archer, who started her career as a chemist with a focus on sustainable energy production and solar energy conversion, and taught and researched at Oxford and Cambridge. When Dame Mary Archer left academia, she held a number of appointments, among them chairing Cambridge University Hospitals National Health Service (NHS) Foundation Trust and is currently chairing the Science Museum group. In 2012 she was appointed Dame Commander of the British Empire for her services to the NHS.

In our conversation with Dame Mary Archer we talked about her most notable career move and her views on the NHS and the future of the NHS. How having a grounding in science can be a perk in other industries, although “less usefully, it makes you obsess about details” making decision making hard at times. We discussed the role of science museums and why she now has considerable knowledge about railways. Furthermore, as a St Anne’s alumni, Dame Mary Archer could tell us about the changes in the university experience since leaving St Anne’s in 1966.

Finally, we spoke about personalised medicine and how the discovery of DNA has shaped our expectations of medical science and health. Dame Mary Archer’s career and personal health experience has given her a unique insight into the role of personalised medicine in patient decision making. She notes “Personalised medicine is here to stay, it is a force for good, increasingly powerful and should be a part of the clinicians and patients armoury in all appropriate cases to weigh that information and evidence and the balance what is the best way forward for that individual patient.”

Listen here for the full interview.

Dr Stanley Ho Memorial Lecture – Professor Jennifer Doudna

On the 2nd March 2021, the Centre for Personalised medicine was honoured to host Professor Jennifer Doudna to deliver the annual Dr Stanley Ho memorial lecture. Professor Doudna is an outstanding biochemical scientist who was the recipient of the 2020 Nobel Prize in Chemistry in conjunction with Professor Emmanuelle Charpentier, for their discovery and development of CRISPR-Cas9 gene editing technology.

CRISPR has revolutionised our ability to edit the sequence of DNA, which has important applications for understanding genetics and huge promise for treating human genetic disease. In this fascinating and engaging talk, Professor Doudna introduced how CRISPR-Cas9 was discovered and harnessed, from its origin within a bacterial immune system to its translation to human medical research (along with many, many other fields).

CRISPR stands for ‘clusters of regularly interspaced short palindromic repeats’. In simpler terms, this means a CRISPR sequence is made of repeating sequences of nucleotides (the building blocks of DNA). These repeats are separated by ‘spacers’. Unlike the repeated blocks, these spacers are variable. In bacteria, the original home of CRISPR, these variable regions are made up of DNA sequences taken from a virus the bacteria has encountered before.

If the bacterium is attacked again by this virus, this CRISPR DNA is transcribed, and RNA is transcribed from the CRISPR region. The produced crRNA (CRISPR RNA) then guides a ‘cutting enzyme’, Cas9, to the foreign virus’ DNA, damaging it, and preventing the virus from causing harm. It’s a basic immune system, and one which is very effective.

One of the overwhelming advantages of CRISPR-Cas9 editing compared to other technologies is how easily specificity of the system (i.e. which specific DNA base it is targeted to) can be changed; simply by changing the provided guide RNA in the CRISPR system, the Cas9 enzyme’s target site can be easily switched. This high level of site specificity combined with the efficacy of CRISPR-Cas9 gene editing gives CRISPR technology a clear advantage compared to previous gene editing technologies.

However, being a novel technology, CRISPR is not without current limitation. Currently, while cleavage can occur with high specificity, there is no known biological agent capable of carrying out specific DNA single nucleotide substitutions which would be desirable to treat human diseases driven by single DNA base changes. Professor Doudna discussed exciting on-going work to investigate adaptation of mechanisms known to exist to edit RNA in bacteria.

Despite limitations, some very promising clinical translation has already taken place. For example, the New England Journal of Medicine [1] reported the findings from two patients with ß-thalassemia and sickle cell anaemia who both have been successfully treated through a CRISPR-Cas9 edited bone marrow transplant. However, further clinical use is hampered by significant limitations on cell-specific targeting. Currently, all CRISPR-Cas9 editing for human use must take place outside of the body, which can be invasive and result in significant side-effects when the cells are returned to the patient. Professor Doudna discussed some of the innovative approaches being taken in pre-clinical research to potentially target specific tissue systems within the body, including the extra challenge of targeting the central nervous system for potential treatment of neurodegenerative disease.

There is also the issue of cost of treatment. CRISPR-Cas9 therapy is not cheap, and treatment in the NEJM published trials costs around a million dollars a patient. There is naturally then, a financial as well as a scientific barrier to more widespread clinical implementation, and Professor Doudna discussed how part of her current work at the Innovative Genomics Institute (ICG) at the University of California, Berkeley and the University of California, San Francisco, is to increase both accessibility and affordability of CRISPR-Cas9 therapy.

Jennifer Doudna delivering lecture

It is fitting in the ongoing pandemic that Professor Doudna also discussed how the high sequence specificity of CRISPR is being developed for use in COVID-19 diagnostic testing, allowing for a much more rapid testing than PCR alternatives. The fluorescence emitted by a ‘positive’ test could potentially even be detected using a smartphone camera, according to research published in Cell using a CRISPR-Cas13a system (one of many alternative Cas enzymes being studied) [2]. As the pandemic continues, this has huge potential for the future of commonplace and convenient SARS-CoV2 testing.

Professor Doudna rounded off the talk with a Q&A session, with audience questions including those on risk of immunogenicity of human harnessing of a bacterial system, Professor Doudna’s own opinions on the biggest barriers to therapeutic implementation, and discussion of some of the ethical concerns of human gene editing, to name a few.

We would like to extend a huge thank you to Professor Doudna for a fantastic and engaging talk and discussion. We hope everyone who was able to attend the webinar at this heavily subscribed event is excited (if you weren’t already!) about the potential CRISPR technology holds for the future. The talk is available on the CPM YouTube channel and is a fascinating watch which we highly recommend checking out!

Written by Holly Eggington, Secretary of the Oxford University Personalised Medicine Society (OUPM) and DPhil student at St Anne’s College

1.        Frangoul, H. et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N. Engl. J. Med. (2021). doi:10.1056/nejmoa2031054

2.        Fozouni, P. et al. Amplification-free detection of SARS-CoV-2 with CRISPR-Cas13a and mobile phone microscopy. Cell (2021). doi:10.1016/j.cell.2020.12.001

In conversation with Dr Magdalena Skipper – CPM Podcast: Meet the Advisory Board Episode 1

The centre of personalised medicine podcast is hosted by Jiyoon Lee, president of the Oxford personalized medicine society and Dr Anika Knuppel, JRF at CPM.

In the first podcast episode as part of our meet the advisory board series, we had the honour to talk to Dr Magdalena Skipper, geneticist and editor and chief of the journal Nature.

She has over 18 years of experience in science publishing and has made history as nature’s first female editing chief and first editor-in-chief from a life sciences background.

In our conversation with Magdalena we spoke about women in Science, the work as an editor and new possibilities for scientific publishing, reproducibility as well as personalised medicine research, a topic described by Magdalena as “close to my heart”. Importantly, she highlighted the role of diversity in this personalised medicine “as wonderful as it has been and as much progress as we have made – the field has by and large focused on a subset of the global population. There has been great predominance of research on individuals of European descent […] but this is a tremendous opportunity to collect the data but also engage those communities in the research that’s being done […]”.

You can listen here.

Debating data: a mini citizens’ jury during a perfect storm

Post written by Professor Nina Hallowell and used with permission.

Professor Nina Hallowell is a member of the Wellcome Centre for Ethics and Humanities in the Nuffield Department of Population Health at the University of Oxford, and a member of the Steering Committee for the Centre for Personalised Medicine at St Anne’s College Oxford. In this guest blog post, she writes about what she learned from holding a citizens’ jury to understand how people feel about the way different kinds of health data are used. 

Given the speed at which research on data-intensive technologies is advancing, it is important to regularly gauge people’sviews on the use of healthcare data. As a group of researchers who either use healthcare data in our research or are interested in publics’ views about this issue* we decided to run a citizens’ jury in early 2020.  

Our aim was to gain some understanding of what members of the public think about the use of different types of healthcare data (MRI images, digital images of pathology slides and genomic data, i.e. DNA sequences) in research. Specifically, we were interested in people’s views on the benefits and challenges of sharing these different data types, and the acceptability of sharing healthcare data with commercial companies. We also wanted to trial the citizens’ jury method of public deliberation. 

Citizens’ juries

Citizens’ juries involve members of the public who come together to hear expert evidence about a topic of interest, deliberate the issue, (hopefully) reach a consensus and deliver their verdict.  

So over the last couple of months of 2019 we advertised in local media for jurors to participate in the ‘Debating Data Citizens’ Jury’ in early 2020.  

Data access on trial

On February 15th 2020, with the COVID-19 pandemic reaching the UK and storm Desmond making landfall overnight, twenty people braved the elements to attend our citizens’ jury in Oxford Town Hall. The jury members heard evidence about data collection, data analysis and data access from a series of expert witnesses in the fields of digital pathologyMRI imaginggenomics research and bioethics. The jury was given the opportunity to cross examine the witnesses, and then broke off into smaller groups to discuss a number of questions, including:  

Finally, each group was asked to reach a verdict on data use in research by answering the following question: How should the different data types be used, who should they be used by and why?  

The verdicts 

The jurors returned a series of statements about data use and commercial involvement in research:  

In addition to finding out what the jurors thought about researchers using healthcare data we asked them to reflect on participating in this event. Most were very positive, and said they had learnt a lot about the use of different types of data in research and appreciated the fact that we were interested in hearing their views. One participant said they: “learned much more about underlying science” and “felt better able to take an informed view.”  

Not all were so happy though. Another participant said that they felt the information they received was biased in favour of the use of data for research (although we did instruct witnesses to be as neutral as possible). This juror also felt there was not enough focus upon wider discussions about the use of personal data by the state and the politics of the NHS.   

Going forward 

This was the first citizens’ jury the team had organised, so Debating Data was a learning exercise for us too. At the end of the day we were relieved it appeared to go so smoothly. We were grateful that so many people had attended, given the weather. We were also pleased to hear a number of participants say they felt the day had given them a good opportunity to air their views.  

We noted a number of improvements for implementation in future events, including: more targeted recruitment to get a more representative sample of jurors, allowing more time for the witnesses to give evidence, and for jurors to cross-examine, deliberate and reach their verdicts.  

What will we do next? As you may have spotted, one of the jury’s conclusions was that people should give consent for the use of data in research. There are many ways to give permission for the use of data, including: opt-in, opt-out, broad or narrow consent and dynamic consent, to name but a few.  As it stands, the National Data Opt-Out allows people to opt-out of having their confidential patient data being used in healthcare research and for planning services. But if people do not opt-out does this really mean they consent to their data being used?  This sounds like an important question for a citizens’ jury, and we have plans to explore this in the future.  

Members of the Wellcome Centre for Ethics and Humanities and the Centre for Personalized Medicine developed the event and members of two of the AI Centres of Excelllence – NPIC and NCIMI – helped us to run the event on the day.

Revisiting 2021 Annual Lecture by Dr Adam Rutherford

On Friday 26th March 2021, the CPM welcomed geneticist, best-selling author, and broadcaster Dr Adam Rutherford to give our annual lecture, titled Race, Genomes & Data: The Bias Built into Science. If you missed this outstanding talk, you can still catch it on YouTube here.

In this blog, we revisit Adam’s lecture and discuss some of the key concepts.

Dr Rutherford introduced three fundamental topics for his talk: (1) data is not neutral, (2) science is always political, and (3) scientists lack the language necessary to approach some of these issues.

Human genetics is the study of similarities and differences between individuals, but differences are often not solely, or at all, driven by genetics. Consider, for example, differences in experiences of the COVID-19 pandemic. In many Western countries, the risk of death from COVID-19 was substantially higher for those from minority groups. 

For example, one of the first large-scale studies of risk factors associated with COVID-19 death that was undertaken in the first phase of the pandemic in 2020 found that, after adjustment for other factors, Black and South Asian people in England were almost 1.5 times more likely to die from COVID-19 than people of white ancestry  (hazard rate 1.48 (95% confidence interval: 1.29 – 1.69) and 1.45 (95% confidence interval:1.32 – 1.58) respectively) [1].

Most observers appreciate that these differential experiences of the pandemic are not likely to be driven by genetic differences alone and that socioeconomic factors play an important role. Indeed ethnicity is a social construct that is associated with countless factors that amplify, influence, mediate, or confound associations between health exposures and health outcomes. For example, there was a clear occupation-related gradient in death from COVID-19; London bus drivers, regardless of their ethnicity, experienced higher death rates from COVID-19 than did residents of London more generally [2].

What is much less widely appreciated is how challenging scientists find formulating and applying an appropriate vocabulary to understand differences associated with ethnicity. Dr Rutherford argued that race and ethnicity are both socially constructed concepts that exist because society enacts them. He noted that race, genetic population, ethnicity, geographic population and ancestry are often used interchangeably in everyday language. Despite this, there are no precise or widely accepted definitions or even conventions to express these concepts in science or medicine [3].

“There are no generally agreed norms of race language in science or medicine”

Differences in pigmentation associated with skin colour are often a tangible source of difference between people, and are a conventional basis on which “race” might be assigned to a particular person. However, there is little to no correlation between skin colour and the similarities and differences between people and wider populations. Moreover, genetic variants that influence skin pigmentation emerged hundreds of thousands of years before homo sapiens itself emerged as a distinct species. There is more genetic variation related to pigmentation within Africa than outside it. Racial groups, as traditionally conceived, do not correspond to inherited, biological sources of variation.

It remains the case, however, that experiences of COVID-19, social status, occupational achievement, and health outcomes differ in many societies by conventional classifications of ancestral background (even if misunderstood and misapplied). This clustering of resources and socioeconomic advantages reflects wider historical, political and economic processes.  

Dr Rutherford also emphasised the role of science, in particular the scientific study of genetics, in developing notions of “race” . Carl Linneaus, the Swedish botanist and father of modern taxonomy, was the first naturalist to classify humans in the animal kingdom. In 1735, the first edition of his Systema naturae included “man” in the class of Quadrupeds and the order Anthropomorpha, later changed to Mammals and Primate respectively.  Man was classified into four types according to geography: 

In the tenth edition of Systema naturae, Linneaus further characterised these four principal types of man in five categories: skin colour, physical traits, behaviour, manner of clothing, and form of government.

Not coincidentally (Linneaus was born in Sweden and spent most of his life there), the traits assigned to Europeans painted a more flattering picture of appearance and behaviour than those assigned to others. Europeans were wise and inventive, Asiatics haughty and greedy, and Africanus sluggish and neglectful. Indeed, the widely used and apparently neutral term ‘Caucasian’ was originally used (by Blumenbach) to characterise Europeans as beautiful (and by implication, more beautiful than other races).   

Linneaus’ classification was arguably the origin of scientific racism, the expression of which did not escape some of the most eminent names in the history of biology and of genetics specifically. Thomas Huxley, Darwin’s “bulldog” and passionate defender of evolution and natural selection, attempted a classification of humanity in which he identified some ten or eleven “races” referencing skin colour and geographic distribution.

Huxley’s classification included distinctions of race based on skin colour within the continent of Africa, a very distant echo of which was felt in the extremely violent genocidal conflict in Rwanda between the Tutsi and Hutu groups in the 1990s. This distinction between these groups stemmed from the 1930s, when the Belgian colonial government classified the local population into three ethnic groups (majority Hutu, minority Tutsi and the small Twa group). The classification, as one might imagine, lacked any meaningful basis, notwithstanding the subsequent entrenching of inter-group differences by the mythologizing propaganda of colonial and proselytising Christian influences. Over one million people are estimated to have died in this conflict.

Darwin himself was reserved about contemporary efforts to identify what may be described as race. Noting in the Descent of Man (1871) “the greatest possible diversity” of whether there was a single race or many, he concluded “…that it is hardly possible to discover clear distinctive characters between them”. Darwin’s sober opinion was not to be last word in this field.

“If you teach or work in human genetics, the ocean from which human variation is drawn, you have little choice but to speak of race and the history of eugenics”

Many methods still used in genetics and indeed science more generally were motivated by an interest in eugenics. The legacy of some of these individuals has been both productive and pernicious. To this day, many buildings, statues and scientific achievement awards are named after these individuals. Dr Rutherford’s view is that “we should be able to have complex and nuanced views about people”.

Another key point that Dr Rutherford discussed is how “data is never neutral”. Every stage of experimental design, data collection, and data analysis are conceived by individuals who themselves are influenced by both implicit and explicit biases. Some of these biases may be structural biases in the way in which we do science that may have existed for centuries.

“Data is never neutral because it is curated, designed and harvested by humans”

Dr Rutherford’s talk began by noting the changing context surrounding genetics and debate on race. One is the wider political environment in which debates around “race” have, in some respects, grown more divisive. This has occurred despite (or perhaps in part because of) the tremendous growth of genetics as a scientific discipline. Efforts to reduce and redress the historical imbalances in society as well as in the practice of genetics were subsequently discussed in the CPM’s “Facing Disparities in Healthcare” online conference, which confirmed both the need for urgent attention to these issues, but also their complex and multi-faceted political nature.

References:

[1] https://www.nature.com/articles/s41586-020-2521-4

[2] https://www.instituteofhealthequity.org/resources-reports/london-bus-drivers-review/london-bus-driver-review-phase-2-report.pdf

[3] https://arxiv.org/ftp/arxiv/papers/2106/2106.10041.pdf

Welcome to the CPM blog

Welcome to the very first post from the new Centre for Personalised Medicine (CPM) blog.

In this post we will introduce you to the CPM, and give you a sneak-peak into the posts we have planned for the near future. We hope you are as excited about these as we are!

So what is the CPM?

The CPM is a partnership between the Wellcome Centre for Human Genetics (WHG) and St Anne’s College, at the University of Oxford. It is a forum for communication and engagement that brings together students, academics, clinicians, and the public, to explore the benefits and challenges of Personalised Medicine. We are a group of academics and scientists who are passionate about different areas of personalised medicine – you can find out more about individual members of our team here. We also work closely with the student run Oxford Personalised Medicine Society.

But what is this ‘personalised medicine’ you speak of?

Personalised medicine is a broad field that aims to use what we can measure about individuals to inform healthcare. In particular, how can we effectively analyse the vast amounts of data that are being generated in our world today and use it to more effectively diagnose and treat patients, as well as predict disease risk in the population. For example, we know that some people are more susceptible to certain diseases, or to having specific health issues. When we try to treat these conditions, some individuals respond better to certain drugs and therapies. Understanding the reasons for this variability, whether it be underlying biology, socioeconomic factors, or environmental influences, can help identify the best drug to give to the right patient, and/or highlight strategies to prevent disease in vulnerable communities. As another example, a single genetic change that is unique to an individual can cause a severe childhood developmental disorder. Identifying this genetic change, and understanding how it leads to this disease, can help us design individually tailored treatments for that child. In other cases, using individual-level data on millions of molecular and physical measures may help us improve prevention, diagnosis and treatment for groups of individuals.

Whilst we believe that personalised medicine is hugely powerful when done right, it also raises a lot of challenges. It is both these benefits and challenges that the CPM is here to discuss.

The CPM was first formed in 2013, and since then has hosted a series of talks, seminars, and events on a wide range of aspects relating to personalised medicine. Recordings of many of these talks can be viewed here.

So what can I expect from the CPM blog?

Like most people over the last year, the CPM has had to adjust to a more virtual life. Whilst we are sad not to be able to host events in person right now, this has also allowed us to broadcast events to a much wider audience. We have also started this blog, and are working on a new podcast series, to further embrace bringing our mission to the masses. 

So here is an insight into what content you can expect on this blog:

  1. Posts from us, and from guest writers exploring different aspects of personalised medicine.
  2. A ‘what does personalised medicine mean to me?’ series, where we will direct questions to people and groups working in, or impacted by, personalised medicine.
  3. Introductory posts to accompany our brand new podcast that will be launching very soon.
  4. Posts summarising our events and lecture series, or providing alternative opinions on what our speakers discuss.

We hope you enjoy reading our upcoming blog posts. Please get in touch with any feedback, or with any suggestions or other content you would like to see.

Written by Nicky Whiffin, CPM Junior Research Fellow