Did a fun project for a book blog called Shepherd. In which I got to talk about my 5 favourite books
https://shepherd.com/best-books/novels-and-nonfiction-books-about-infections-and-p
Did a fun project for a book blog called Shepherd. In which I got to talk about my 5 favourite books
https://shepherd.com/best-books/novels-and-nonfiction-books-about-infections-and-p
We are on the brink of something remarkable. The virus that I have been working on for 21 years (and that others have been studying for considerably longer) is about to have not one, but three vaccines. The virus is Respiratory Syncytial Virus (RSV), which is a cause of severe disease at both ends of life – putting both babies and the elderly into hospital. However, as we saw with COVID, getting a vaccine for a respiratory virus is not the end of the journey, merely the end of the beginning.
One of the major challenges with viruses is their tendency
to mutate to escape the protective immune response from vaccines. This may be
particularly problematic for another of the approaches being rolled out to
prevent RSV – an antibody called Nirsevimab. Antibodies are proteins made by
the immune system, they are able to bind other proteins with incredible
specificity. In the case of viruses, the antibodies bind the surface proteins
that viruses use to enter human cells. Nirsevimab targets an RSV protein called
F (for Fusion) and has proved highly effective at reducing infection and severe
disease.
The worry is that because Nirsevimab and the vaccines all
target this RSV F protein, the virus might mutate to escape from being seen by
the immune system. It is therefore important to keep a close eye on the virus
to see if it is changing. This is where our latest paper Robust and
sensitive amplicon-based whole-genome sequencing assay of respiratory syncytial
virus subtype A and B comes in. Working with UKHSA (UK Health Security
Agency), the government agency tasked with protecting the nation’s health, a
new and improved method of sequencing RSV was developed. This is faster,
cheaper and more reliable than the old method. The team sequenced over 1,000
different RSV isolates covering a 4 year period 2019-23. Importantly the
approach is now in place ready for the rollout of the vaccines and antibodies,
giving health authorities a fighting chance of keeping on top of this important
cause of childhood disease.
Despite SARS-CoV-2 taking the limelight for the last 4 years, Influenza virus continues to be a significant threat to human health. It poses a number of threats to our health and wellbeing. These fall into three categories: seasonal, pandemic and zoonoses.
1.
Seasonal influenza. Lockdown type
interventions (sometimes called NPI or non-pharmaceutical interventions) were
highly effective at reducing the spread of not just SAR-CoV-2 (the virus that
caused COVID) but other respiratory viruses too. The number of influenza virus
infections went right down during 2020 and 2021. So much so that in fact one of
the strains of influenza has disappeared. However, you can’t keep a good (bad)
virus down and in the following winter (2022) flu had bounced back up to its
usual levels causing illness, hospitalisation and death. Influenza virus is at
its most serious at different times of the year depending upon where you live,
but flu loves the winter – if you are in the southern hemisphere this means it
peaks around June/ July, if you are in the Northern Hemisphere December is peak
flu. These viruses change slowly over time, which is why there is a need for
annual boosters.
2.
Pandemic influenza. There is a grinding
low level of influenza disease year on year which causes a catalogue of low to
middle grade misery. However, every so often (about once every 20 years) a
completely new strain of influenza virus emerges infecting everyone. Not
dissimilar to COVID a flu pandemic would cause immense disruption and death.
3.
Zoonotic influenza. We think of influenza
as something that people get, but really it is an animal disease, particularly
birds. The natural host of influenza is ducks, they spread it to chickens who
spread it to pigs and people and the cycle continues. At the moment there is an
unpleasant bird variant of influenza that has even made it to the icy shores of
Antarctica causing penguins distress.
Vaccination takes the edge off some of these problems, and
it is definitely worth getting vaccinated to protect yourself against the
worst/ most severe disease. But the vaccines could be improved – giving you
broader protection for longer. The huge breakthroughs with the RNA vaccines for
COVID showed that other, newer platforms enable rapid responses to viral
infections.
In our study Optimizing
a linear ‘Doggybone’ DNA vaccine for influenza virus through the incorporation
of DNA targeting sequences and neuraminidase antigen, we worked with a
company called Touchlight Genetics who have a process for making DNA without
all the bother of cells. Their Doggybone DNA (so called because of its shape)
can be rapidly produced and in large amounts. This makes it a strong contender
for future vaccine programs, especially against pandemic viruses. However, the Doggybone
DNA vaccine platform needs a bit more work to be effective as a human vaccine,
which is where our joint project came in.
We looked at two aspects to improve responses. The first was
quite technical and involved tweaking the DNA sequence to allow more of it to
get to the place it was needed (the nucleus). The second was looking at targeting
a different part of the virus. Influenza makes two proteins on its surface, one
that it uses to get into cells (Haemagglutinin or HA) and another that it uses
to get out of them (Neuraminidase or NA). One thing to remember about the HA
protein is that in spite of publishing papers about it for the last 15 years, I
still cannot spell it – putting in too many or too few G’s, T’s or N’s. Most
influenza vaccine research targets the HA protein, the idea being if you stop
the virus before it ever gets into cells you can stop it in its tracks.
However, targeting the NA protein has some advantages – it changes less than
HA, so possibly you can increase the breadth of responses. This is helpful
because the broader the anti-influenza response, the more protection you have
when the virus changes its coat. We explored using the Doggybone DNA to make a
vaccine that targeted influenza NA and showed that it could indeed protect
against infection and disease.
Overall this work demonstrated that it is possible to further
improve a DNA vaccine. By taking this marginal gains type of approach, it may
be possible to develop influenza vaccines that cover all strains for all people.
In which I got to say Shit in Times Higher Education (first published there 2023)
The editor has allowed me 800 words to give you the secret
to academic happiness, but I can sum it up in eight: stop giving a shit about
every little thing. To be honest, it doesn’t even need the “about every little
thing”. But I should probably expand a bit, and not least because I get paid by
the word.
In case my head of department is reading this and I sound
overly nihilistic, I need to provide some clarification. I am not saying “don’t
try” and I am not saying you don’t have to work hard – whether we like it or
not, academia isn’t a nine-to-five job. What I really mean is stop stressing about
the things you cannot control – which, to be honest, is most things. I also
mean loosen your attachment to the standard metrics of academic success – “high
impact” papers, measures of esteem, fellowships of exclusive organisations. Most
of these things have little or no relevance outside the ivory tower – as a fun
way to test this, explain to a non-academic friend how you paid
£8,490 for the privilege of someone else posting your research data online.
A more grown up way to put it is to have some perspective,
but that way I don’t get to say shit in Times Higher Education.
An important point in the N.G.A.S. philosophy is that it applies
predominantly to the higher levels of Maslow’s hierarchy of needs – those of self-esteem
and self-actualisation. No amount of not giving a shit is going to help if you
are underpaid, overworked and worrying where your next contract is coming from.
If you are in this position, you have my utmost sympathy. But if you have
survived that stage and are still feeling unfulfilled and miserable then read
on.
Much of the current system equates academic happiness with
academic success. But this can lead to chasing of endpoints for the sake of
accolade rather than enjoyment of the thing itself. The goal should be a
well-written paper that, through the effort of yourself and your team, pieces
together a story addressing a research question that was important to you. The
goal should not be getting it past a specific editor, who has a particular target
audience in mind. One of the healthier developments in recent years has been
the uptake of the Declaration on Research Assessment (DORA) and the move to recognise papers for their
own merit, not just for where they are published.
Likewise with funding, write the best grant you possibly
can, enjoy the process of thinking up new ideas, but accept that it may not be
what the funders are looking for at that time and you might need to repackage
for somewhere else.
And there are so many things that matter more than papers
and grants. Strip away the stuff that is valued collectively by “the system”
and focus on the stuff that matters to you. Be that teaching an enjoyable
course with engaged students; widening participation in your field; answering a
research question or finding the perfect bon mot for your writing. Academia
sans merde gives you amazing opportunities to set your own path.
A corollary is to do things outside the academy that give
you joy. If all you have in your life is your work, it is much easier for it to
overwhelm you when things don’t go according to plan.
Not giving a shit doesn’t mean not caring about others. Another
advantage of stepping away from externally defined success is that it is likely
to reduce bad behaviour. The zero-sum model of perceived excellence, where only
a select few PIs can win and everyone else loses, promotes toxicity. Focussing
on actual excellence can be done with others, and everyone can win.
Hopefully, I have persuaded you of the case for caring less.
But doing it isn’t as easy as it sounds. Letting go takes commitment. You need
to work at it, especially in the face of the little siren voices that say you
need more success to be happy.
A particular temptation is comparison. Never give in to this one. If there is one sure-fire way to be miserable in academia it is to compare yourself to other academics and their externally broadcast achievements. Bear in mind that those broadcasts are about achievements framed in defined (and quite artificial) terms, not about happiness or fulfilment. You can do better, by focussing on what matters to you and the consequences will be of far greater value.
Originally published in Nature: https://www.nature.com/articles/d41586-023-00528-w
And... the first to openly use AI to write a Nature article
ChatGPT
Which, as
The text here isn’t my
first use of AI for science writing. My first real
use of AI chat bots (beyond asking it to write lyrics to a song called ‘Eggy
Eggy Woof Woof’ for my daughter) was when I got fed up of writing one part of a
grant. I was asked to explain the world-changing ‘impact’ my science would
have, if I was lucky enough to receive funding.
One example where
I have found it extremely useful is writing multiple choice questions. I found
it relatively easy to write the question and the right answer, but coming up
with 3 plausibly wrong answers is tricky. I found that if I prompted ChatGPT with
the following: ‘write a multi choice answer about ‘topic of interest’
with 4 answers, and not using all of the above as an option’ it came up with
good wrong answers. This was incredibly helpful. And as someone suggested on
twitter – if students are going to use ChatGPT to help them write answers, we
might as well use it to set the questions!
As another example, I entered the
prompt ‘Write a diversity statement for a grant application’. The output
starts:
Diversity is a core value at our organization and we are
committed to promoting and maintaining an inclusive and equitable environment
for all individuals.
And continues for 169 words that were generic
to the point of meaningless. Anyone can write this and it requires no evidence
or backing. Instead, it’s better for the form to ask questions that an AI can’t
answer, like: “give examples of how your organisation is promoting diversity
and evidence of the impact these activities have had.” This could be applied to
a whole range of different questions that we are forced to answer.
For now though, while we are forced to
fill in unnecessary boxes on forms, AI offers a way to free up headspace, which
should be a good thing. In a
The question is then how do we use
I have some unrealistically high hopes
of what AI can deliver. I want low-engagement tasks to take up less of my
working day, allowing me to do more of what I need to do to thrive (thinking,
writing, discussing science with colleagues). And then because I don’t have a
Sisyphean to-do list I go home earlier because I have got more of the thinking,
writing, and discussing done in working hours rather than fitting them around
the edges.
Why was the math book
sad?
Because it had too many problems.
In early March 2021, in the middle of the COVID-19 pandemic a surprising-sounding experiment was taking place. Researchers at Imperial College London and Oxford University in partnership with hVIVO were deliberately infecting healthy volunteers with SARS-CoV-2. This was in fact the latest in a long line of controlled human infection studies – where volunteers are deliberately infected with an infectious pathogen under extremely controlled conditions.
Deliberate human infection for health benefit goes back a
long way – the earliest evidence of infection for beneficial use is 10th
Century China, deliberately inoculating healthy people with smallpox to make
them immune to the disease. This practice continued into the 18th
century, when an English Doctor, Thomas Dimsdale deliberately infected
Catherine the Great and her son with a very low dose of smallpox virus to
protect them against disease.
This idea of infecting people deliberately to protect them
from disease led to Edward Jenner’s famous studies inventing the first ever
vaccine. Jenner hypothesized that you didn’t need to use material derived from
smallpox to be protected, you could use material from a related virus, cowpox.
He proved this worked using a human challenge study; he vaccinated James Phipps
(his gardener’s son) with cowpox then deliberately exposed him to smallpox
repeatedly, showing that the vaccine worked and Phipps was immune to smallpox.
The practice of deliberate infection for scientific benefit really
took off after the demonstration by Pasteur, Koch and others that microbes
cause disease. In the early 1900’s, Walter Reed, the American public health
pioneer, was trying to understand where yellow fever came from – he had a
suspicion that it came from mosquitos. This was important because identifying
the source could alter behaviour and reduce the incidence. To test his
hypothesis, Reed recruited 11 volunteers to be bitten by mosquitos that had
previously bitten a yellow fever patient; two of the volunteers contracted
yellow fever, strongly supporting his idea. One important development in Reed’s
infection studies was informed consent. The volunteers were told about the risk
to themselves of participation. Sadly, later in the 20th century,
some human infection studies entered a darker chapter where this consent was
not sought, such as experimentation on prisoners in Nazi Germany and Imperial
Japan.
Informed consent is the bedrock upon which all modern
research involving volunteers is built, and infection studies are not exempt
from that. The landscape of human infection studies has changed dramatically
since the middle of the 20th century; now, ensuring the health and
safety of participants is of paramount importance and trials are carefully
designed to minimise any potential risks. Studies are only performed following
extensive ethical review by an external body, for example all human infection
studies carried out at Imperial College London have ethical approval from the
UK Health Research Authority. There is ongoing debate whether infection studies
can ever be ethical, in terms of deliberately exposing someone to the risk of
harm; even in the context of minimising the risk. However, there are many
benefits to the studies and when volunteers understand the risk and choose to participate
for the greater good, they can achieve important things.
One of the ways in which deliberate human infection studies
are most beneficial is in the testing of vaccines. Vaccines are tested in the
same way as any drug, the first studies involve a small number of participants
who are closely monitored to check first and foremost whether the vaccines are
safe. These early studies (called Phase I clinical trials) can also inform
about whether the vaccine is making an immune response. However, in order to
demonstrate that the vaccine can prevent disease, much larger studies are
needed. These, phase III, studies are often very large, the Pfizer COVID trial
had 43,548 participants and Moderna 30,420. One of the reasons for these large
numbers of participants is the uncertain nature of infection. Even during a
pandemic, most people will not be exposed to the infectious agent (particularly
if other measures, such as stay at home and social distancing are in place).
This means that to get to statistically meaningful numbers to compare infection
rates with and without the vaccine, you need more subjects. Infectious
challenge studies can get around this, especially when the pathogen being
tested is rare. One example of this is typhoid, a bacterial infection that
causes diarrhoea in approximately 10-20 million people a year, mostly in low
and middle income countries. A research team in Oxford gave volunteers a
typhoid infection and tracked them till they had clinical symptoms before
treating with antibiotics. Again, pausing to think of the volunteers – knowing
that you are likely to get a bout of diarrhoea and going ahead for other
people’s benefit takes a special mindset. Indeed, without volunteers, modern
medicine would falter, so we all owe a large debt of thanks to these selfless
individuals. Having shown it was possible to infect people in a controlled way,
the group tested whether 2 new vaccines could reduce disease. They showed that
whilst 77% of the volunteers without a vaccine developed typhoid, only 35% of
the vaccinated volunteers did. Deliberate infection studies have also been used
to support the rollout of vaccines for cholera, malaria and shigella.
Another important benefit of deliberate human infection studies
is in understanding how specific viruses cause disease and how we can be
protected against them. The common cold unit was a British research centre
operating on Salisbury plain between 1946 and 1989. It set out to understand
respiratory infections; being somewhat isolated it was able to look at
transmission of colds, by infecting one volunteer and then housing them
together with other uninfected volunteers. It also provided us with important
information about the levels of immunity required to protect against influenza.
By measuring antibodies in the blood of people before they were infected it was
possible to identify a threshold above which infection was unlikely to occur;
this threshold is still in use for the development of influenza vaccines.
Some diseases have more challenges than others in setting up
the infections. Whilst respiratory viruses can be grown and dripped into the
nose, other infections get into our bodies through a third organism, called a
vector. In the case of schistosomiasis (sometimes called bilharzia), the
parasites live in snails before infecting people. To help develop drugs and
vaccines for this neglected tropical disease, researchers have had to learn
snail husbandry!
Returning to the coronavirus infection study, this looks to
address both the development of vaccines and improve our understanding about
infection. In the earliest results from the study, it was seen that volunteers
who had not had COVID before could be infected with an extremely low dose of
the virus, which might help to explain why SARS-CoV-2 is so infectious. It can
also inform more generally about the behaviour of respiratory viruses. These
studies are now progressing to help in the design and testing of the next
generation of vaccines and drugs. As we have seen in the last 2 years,
infections can be extraordinarily disruptive; studying how they behave, why we
get infected and how to prevent this is extremely important – when performed safely
and ethically, human infection studies are an important part of our toolkit.
Originally published in Nature: https://www.nature.com/articles/d41586-022-03216-3
Is the stream of negativity around academia putting people off?
It’s no secret that an academic career has many challenges,
short-term contracts, low pay, long hours – as well as in the uncertain,
exploratory nature of science. And they don’t go away with tenure: academic
time is getting increasingly proscribed, funding is reducing, more is expected
from less, management are more remote. As a principal investigator I am
constantly juggling and hopping from one uncertainty to the next: yes I have a
job, but I still need to find money to pursue my research and develop the
careers of my team.
As with most academics, I have often considered quitting
because of these challenges. The three times that I came closest were six
months into my doctorate, when absolutely nothing was working,
finishing/writing-up my PhD thesis, which drove me to despair, and the first
big grant rejection early in my PI position. I still wonder about
other/different career paths. I’ve worked in academia my whole adult life (+/-
a period in the army reserves). The little voice suggesting
something better definitely gets louder when I am weighed down with admin or
stresses about how to keep the lab going.
The structural challenges in academia are not going away any
time soon. In the UK, where I work, an increased workload, reduced pensions and
destabilisation of long-term positions are making academia as a career
increasingly unattractive. Recent survey data paints a picture of a substantial
number of mid-career scientists who are extremely dissatisfied with their
career opportunities https://www.nature.com/articles/d41586-022-01512-6. Data from Advance HE, a British organisation
that champions improvements in higher education, suggests a slight decline in
postdoc numbers between 2019 and 2021 https://www.nature.com/articles/d41586-022-02781-x.
The net impression is that early career scientists are being deterred from
academic careers.
This drift from basic science begins before students even go
to university. There is a lack of understanding in schools as to what
scientific careers involve. I only did a science degree because it was what I
was best at, I did a PhD because I didn’t really know what to do with my life
after my degree.
To improve understanding, increasing numbers of academics
are doing outreach programmes in schools to describe the career and paths into
science. But in my experience enthusiastic high school biologists are more
interested in careers in medicine than in biological research. I can see their
reasoning. A career in medicine, as a doctor or a surgeon, has a structure and
a job plan that’s likely more attractive than ‘scientist’ which let’s face it
is pretty nebulous even to those of us who are doing it as a career. Of course,
‘scientist’ is not the same as ‘academic’. Academia is the alternative career,
with most science post-graduates employed outside of universities.
That all said, focussing solely on the negative is I think
problematic, especially when people are discouraged from trying an academic
career at all. We need to celebrate the good parts, and by that I mean not just
successes in terms of papers or grants, but celebrating where academia brings
us joy – an experiment that surprisingly worked, a colleague who helped you, a
student who got you to look at a problem with a different light, a trainee who
flourished.
And there are many good bits to academia. For me, it’s the
science, the freedom and the people. And by freedom, I don’t just mean the
freedom to research what you want, but also the freedom to choose how you spend
your time be that teaching, researching, writing a book.
These good bits come with a cost, but in the end, nothing of
value ever came easy. Academia is hard, there are no two ways around that, but
so is working in a biotech, or a charity, or a school, or a hospital, or a
publishing house. Jobs outside the academy come with their own list of
challenges. These might be softened with increased pay, but the pound of flesh
expected in return can be more substantial.
It comes down to making choices. And to make those choices,
you need the best, most accurate information. For this I would recommend
applying the same scientific method as you might to the day to day workings of
your career.
For those of us who are more established, to enable others
to make those choices, both sides of the argument need to be presented. After
schoolteachers, academics are the most visible scientists to students and
trainees and therefore do have an influential voice. It needs to both bemoan
the hard parts and celebrate the good. My constant moaning about paper portals
needing fax numbers and the committee I am on over-running but not telling
about the things that bring me joy only paints one side of the picture. As with
most things, academia is a mixed bag, so let’s celebrate positives in equal
measure to bemoaning the negatives.