Proteins in cells underpin many of our most important functions, from muscle contraction to breaking down food. In a new study published in the journal Science, researchers from the universities of Oxford and Massachusetts explore how these proteins assemble into the 'complexes' that allow them to perform their specific tasks. Two of the paper's authors, Professor Justin Benesch from Oxford's Department of Chemistry and Dr Georg Hochberg, formerly of Oxford and now of the University of Chicago, discuss the study's findings.
What are proteins, and what role do they play within organisms?
Proteins are the biochemical workhorses of cells. They make muscles contract, break down food, replicate genetic material, and underlie our senses. To perform these important functions, most proteins assemble into so-called complexes. A complex consists of several individual proteins chains that associate in a precise and stable geometrical arrangement.
What did we previously know about how proteins assemble and interact? What didn't we know?
Protein complexes are incredibly specific. Each cell contains thousands of different proteins, each of which is only part of a small number of complexes. So proteins have to be able to recognise their assembly partners with incredible fidelity, excluding from their assemblies the vast majority of other proteins. In general, proteins that interact to form a complex have three-dimensional structures that fit together tightly, with surfaces that display a high degree of shape and charge complementarity – that is, they fit together in both shape and with charges attracting rather than repelling each other.
But somehow many proteins also exclude other proteins from their complexes that have very similar shapes compared to their proper interaction partners. This happens because new protein complexes are often created by evolution through gene duplication, a kind of copy-paste mechanism in which two initially identical copies of a single ancestral complex are produced. Because their three-dimensional structures will be identical at first, the two copies initially always co-assemble into a complex together. But in many cases, they gradually 'forget' how to do this, and eventually only form two separate complexes – one containing only protein chains from the first copy, the other only chains from the second copy. Why proteins become selective in their assembly like this, as well as how they achieve it structurally, was completely unknown.
What did this research find?
We first found, by looking at many proteins from a variety of organisms, that proteins avoid co-assembling with the majority of their gene duplication copies and that this allows the two copies to carry out different biochemical functions. This means that 'forgetting' how to co-assemble with their gene duplication relatives is a key step in the evolution of novel biochemical functions.
We then worked out exactly how selective assembly is achieved structurally between two small heat-shock plant proteins that were created by gene duplication. Small heat-shock proteins protect other proteins from the dangerous effects of heat stress. Both proteins we studied assemble into complexes with only their own protein chains, but do co-assemble into complexes containing both kinds of chains.
To our great surprise, the two proteins had near-identical structures, with no clear sign of an absence of shape or charge complementarity that would prevent them from co-assembling. Instead, we found that evolution achieved selectivity in the most economical fashion, modifying only a minimal number contacts between the proteins, and exploiting very subtle differences in the way the two proteins deform as they assemble into their specific complexes. We could also show theoretically that such selectivity should be easier to achieve for complexes containing fewer protein chains, and that this has left a measurable imprint in the number of chains selective complexes actually contain in nature.
This was a highly collaborative piece of work, between biophysical chemists in Oxford and plant scientists at the University of Massachusetts, and required us to use a broad range of methods, from theoretical statistical mechanics, to computer simulations and experiments to determine the molecular structure of the proteins, to functional investigations on pea leaves.
What are the implications of this research?
Our results imply that a major rethink of the determinants of molecular selectivity in proteins is required, away from simple shape and charge complementarity. In addition, our data has demonstrated the selectivity in assembly of small heat-shock proteins is an important part of their function, and may give us new opportunities in developing more thermally resistant plants.
Dr Kamal R. Mahtani, an Oxfordshire based GP and deputy director of the Centre for Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, discusses the pressures on GPs and the factors affecting patient waiting times.
Over 50 million people in England are cared for by the NHS and at least 90% have their first NHS contact with a GP. However, getting to see a GP is increasingly becoming more of a challenge. The latest NHS patient survey showed that about one in five patients had to wait one week or more before they could see or speak to someone at their GP surgery. Ominously, the British Medical Association have added that patients should expect current waiting times to “rocket”. The Royal College of General Practitioners now estimate that by 2022 there will be over 100 million incidents of a patient waiting a week or more to see a GP or practice nurse.
This is bad news for patients. Longer waiting times mean that fewer patients will be seen and - for those that do get an appointment - severe constraints on the time that a GP can devote to each appointment.
So what is driving these pressures? One obvious reason is that patient demand has increased substantially. A recent analysis, published in The Lancet, and led by a team at the Nuffield Department of Primary Care Health Sciences, examined over 100 million NHS primary care consultations. The analysis showed that between 2007 and 2014 there were significant increases in both the numbers of consultations being requested by patients and the lengths of the consultations; the system, the researchers suggested, was reaching a “saturation point”.
Along with increasing demands to see GPs, the complexity of patients’ problems has also increased. A 10-year study of more than 15,000 people in England, aged over 50, showed a 10% rise in the number of patients who have two or more long-term conditions, so-called “multimorbidity”. NHS England has suggested that this is currently the greatest challenge facing the NHS, a challenge largely being managed by GPs. Patients who live longer, but with more health problems, also face the potential problem of polypharmacy, the use of multiple medications, sometimes justifiably, sometimes not. A 15-year study of over 300,000 patients in Scotland showed a doubling in the number of individuals who were taking five or more medicines. Avoiding the harms that medicines can cause, while maintaining their potential benefits by optimising their use, is a challenge faced by every GP every day, and one that can rarely be managed during a typical 10-minute consultation.
With rising demands and clinical complexity, the number of UK GPs continues to fall, a trend that, unless adequately addressed, appears likely to continue. A 2015 survey of over 1000 GPs showed that 82% intended to reduce direct clinical work within the next five years, citing work-related pressures, the changing nature of the job, and stress as contributing factors. A King’s Fund report has emphasised other problems contributing to the current pressures facing GPs: high levels of deprivation, a decline in self-management of minor illnesses, higher expectations, particularly of new services, and a fall in general practice funding.
If these pressures continue to mount, patients will suffer more than just longer waiting times. The Royal College of General Practitioners has suggested that the growing GP workload may affect patient safety. Empirical evidence suggests that this may already be happening. In a survey conducted by the British Medical Association, 93% of GP respondents reported that their workload had had negative effects on patient care.
Depending on what you read, the UK National Health Service is either one of the best health care systems in the world or one of the worst. Nevertheless, when the NHS was founded in 1948, “the most civilised achievement of modern Government” according to Nye Bevan, egalitarian implementation of the best standards of health care was expected to lead to reduced demands. The opposite has happened. The NHS has been hugely successful and is widely admired, but few will deny that it is suffering from its own success. For that success to be maintained, the factors that are harming it must be recognised and remedied. Given the number of patients served by general practice, this should be an obvious priority.
Luke Jackson from the Institute for New Economic Thinking at the Oxford Martin School explains how achieving the Paris Agreement could help to slow sea-level rises.
Achieving the aim of the Paris Agreement, to hold the rise in global average temperatures to well below 2 °C above pre-industrial levels and to pursue efforts to limit the temperature increase to 1.5 °C above pre-industrial levels, by the end of this century could dramatically reduce potential sea-level rise compared to projections based upon business-as-usual scenarios.
A lot of research on sea-level change had previously focused upon high future Global Warming. Since the Paris Agreement was signed in late 2015, there has been a switch in focus to think carefully about how the climate (including sea level change) will respond if we succeed in achieving Paris’s aims.
Future sea-level rise has the potential to affect millions of people and billions of dollars’ worth of infrastructure world-wide by increasing the vulnerability of coastlines to flooding from tides, wind-driven waves and storm surges.
In our own study published this month - 21st century sea-level rise in line with the Paris accord - we apply a novel method to project future sea-level rise at a global and a regional level for the two temperature levels stated in the Paris Agreement.
The new research shows that achieving a 1.5 °C or 2 °C temperature rise by 2100 could result in a global sea-level rise of 44 cm and 50 cm respectively. This is in contrast to a rise of 84 cm for a business-as-usual scenario if temperature rises around 4 °C by 2100. The difference between achieving Paris and a business-as-usual scenario is even more marked when comparing low-chance (1-in-20), high impact projections. In this case, the global projections are 67 cm versus 180 cm for 1.5 °C and business-as-usual respectively, a difference of more than 1 metre.
Differences of this size are significant for decision makers regarding Climate Change mitigation (achieving the Paris Agreement will require rapid, deep emissions reductions) and coastal adaptation strategies.
The full paper, ‘21st Century Sea-Level Rise in Line with the Paris Accord’, by Luke Jackson, Aslak Grinsted and Svetlana Jevrejeva, can be read in Earth’s Future.
Thursday 8 March marks International Women's Day, a global commitment to honouring the cultural, social, economic, political and academic contributions of women. Over the next few weeks, Science Blog will start the celebrations by shining a light on the incredible women of Oxford and some of their achievements.
Despite the different backgrounds, motivations and journeys that brought them to the University, each of the women featured have one important thing in common: success. In a field where women are still woefully underrepresented, they are rapidly carving their own niche, inspiring budding scientists of tomorrow in their own way.
Science Blog meets Layal Liverpool: 'I can't wait until there are no more firsts'
Representation is often discussed in today's society, but it means something different to everyone. Its impacts though are undisputed, taking hold from a young age and rippling out to shape the rest of our lives. Lack of representation can distort our understanding of people who are not like us and prevent some from imagining themselves in a situation - blocking their talent from developing into an opportunity in the process.
One person who understands this well is Layal Liverpool, a 24-year-old DPhil student investigating virus-host interactions at the MRC Weatherall Institute of Molecular Medicine. In addition to her studies, Layal is a committed science communicator and STEM ambassador. She shares her experience as a young woman of colour navigating the world of academic science.
I've been to a few career seminars, but only ever seen one woman of colour presenting. I can't wait until that changes and there are no more firsts.
What inspired you to pursue a career in science?
Even at the age of five I had a natural interest in learning new things and solving problems, to the point that I was obsessed with encyclopaedias - my parents were worried I wouldn't read anything else.
I also had a great A-level biology teacher, who had a PhD and happened to be a woman. Having her in my life meant that I never saw science as not being for girls.
How did you come to specialise in infectious diseases?
My parents are originally Ghanaian, so as a child I spent a lot of time there. Ghana was significantly affected by the HIV pandemic and growing up I saw marketing about using condoms and how to stop the spread of HIV. I was just a kid and had no idea what it was, but I was curious and wanted to find out more. During my bachelor's degree at UCL, I took a brilliant course on infection and became absolutely fascinated by viruses in particular. I find the way the human body works - particularly disease and why things go wrong - fascinating. I chose to study immunity against viruses in general, to learn about multiple infections.
Viruses are not even alive and yet they can cause such complicated diseases - that fascinates me.
What are you working on at the moment?
At the moment I am building on a lab project established by a previous researcher, aiming to better understand how viruses are detected when they first invade our cells. You can read more about our research in this blog post.
Do you think diversity is an issue in STEM?
Absolutely. Just the other day I attended a career seminar - I've been to a few of these, but this was the first time I had ever seen a woman of colour presenting. I felt so inspired and was really struck by the fact that she was the first highly successful woman of colour that I had seen giving one of these seminars. I can't wait until that changes and there are no more firsts.
It was really interesting to hear from her about how much the world has changed since she first started working - for example, she shared some past experiences of overt discrimination in the workplace.
My advice to anyone considering a career in science is don't let self-doubt stop you. The only way you definitely won't get in is by not applying.
Would you say that role models are important in science?
I've been fortunate to have wonderful role models so far that I truly appreciate, but very few have looked like me and I hope that changes. I think that would be really great for the younger generation because representation matters.
I love my field and feel very fortunate to be here at Oxford, but if I could change one thing about my experience it would be to have and interact with more women like me at different stages. The University has a mentoring scheme, and I think it would be great if that ran across all levels. For example, as a doctoral student I could be mentored by someone more senior, but equally I could mentor new applicants and people just starting and help them navigate the University.
How would you describe your experience at Oxford?
I am constantly grateful to be here, and get to work alongside world-leading researchers, but I think university is still a very elite environment, and there is a way to go to improve diversity - especially at my level. I have noticed that the higher you go within the University, the diversity decreases, which is a shame. There are a lot of talented people working in STEM who I think could be there, but the opportunities need to be available to get them there.
If I could change one thing about my experience it would be to have and interact with more women like me at different stages.
Are there any changes that you think would make a difference?
More representation is not easily achievable, unless more young people are inspired to pursue science careers. I have volunteered at Saturday Science Club, a science activity programme for families run by Science Oxford, and my hope is that when the children in the group are asked 'what does a scientist look like?' they will say 'anything'.
What does being a woman in science mean to you?
I view my studies as an important step along the road of using scientific research to benefit society. It wasn't that long ago that women didn't have these opportunities. I like to reflect and recognise how far we've come, but also how far we still have to go. There are some incredible women doing incredible things in science and I feel fortunate to have the opportunity to work alongside them and contribute.
How did you first get involved with science communications?
I actually auditioned for FameLab, where you have to explain a scientific concept of your choice in three minutes to a general audience. I spoke about HIV and made it to the regional final. A key element of understanding something is being able to explain it in simple terms, and the experience really improved my science communication - I really enjoyed it.
Why is communication so important in science?
Perhaps they have always been there, but nowadays there seem to be more misconceptions around science that can lead to dangerous ideas, such as the anti-vaccine crusade. Better communication about science would give people an understanding, so that that they can hopefully appreciate the benefits of vaccines and other important interventions.
What has been your biggest learning curve so far?
I learn a lot from my outreach work with children - they are so smart. As you grow older you have more to lose, so you develop a sense of fear and stop asking important questions. I think they ask more probing questions than adults, and I find they inspire me to change my approach to my work.
A key element of understanding something is being able to explain it in simple terms. A good scientist should be able to explain their work to anyone.
Who inspires you?
I've been fortunate to have lots of great role models - male and female - but my parents are my biggest inspiration. They are both immigrants that have overcome their own share of challenges to build a life for my sister and me. Education was a privilege that they worked hard for so that we could have more opportunities than they did. Both are half Ghanaian, but my mum is half Lebanese and immigrated to the UK. My dad is half Dominican and immigrated to the Netherlands - which means that I am fortunate to have claim to five nationalities.
What gets you up in the morning?
In the world of science things don't always work the first time, but I love the feeling of carrying out an experiment and getting an unexpected result. Often that is where new discoveries are made.
What are you most proud of?
Honestly, I am just proud to be here. We often doubt ourselves, particularly if there aren't role models that look like us. But my advice to anyone considering a career in science is don't let that stop you. The only way you definitely won't get in is by not applying.
WATCH LAYAL EXPLAIN HER PHD IN THE PUB:
An image of a single positively-charged strontium atom, held near motionless by electric fields, has won the overall prize in a national science photography competition, organised by the Engineering and Physical Sciences Research Council (EPSRC).
‘Single Atom in an Ion Trap’, by David Nadlinger, from the University of Oxford, shows the atom held by the fields emanating from the metal electrodes surrounding it.
The distance between the small needle tips is about two millimetres. When illuminated by a laser of the right blue-violet colour the atom absorbs and re-emits light particles sufficiently quickly for an ordinary camera to capture it in a long exposure photograph.
The winning picture was taken through a window of the ultra-high vacuum chamber that houses the ion trap. Laser-cooled atomic ions provide a pristine platform for exploring and harnessing the unique properties of quantum physics.
They can serve as extremely accurate clocks and sensors or, as explored by the UK Networked Quantum Information Technologies Hub, as building blocks for future quantum computers, which could tackle problems that stymie even today’s largest supercomputers. The image, came first in the Equipment & Facilities category, as well as winning overall against many other stunning pictures, featuring research in action, in the EPSRCs competition – now in its fifth year.
David Nadlinger explained how the photograph came about: “The idea of being able to see a single atom with the naked eye had struck me as a wonderfully direct and visceral bridge between the miniscule quantum world and our macroscopic reality," he said.
"A back-of-the-envelope calculation showed the numbers to be on my side, and when I set off to the lab with camera and tripods one quiet Sunday afternoon, I was rewarded with this particular picture of a small, pale blue dot.”