Hello and welcome to my blog! My name is Caroline and I am a PhD student at the University of Sheffield. My research project focuses on Striga - a genus of parasitic plants that devastates harvests by infecting food crops. I am exploring the defence reactions that can make host plants more resistant against Striga. Due to my ongoing battles with anorexia, I haven't made as much progress as I would have liked but I am determined to finish the course.


This blog charts the ups and downs of life in the lab, plus my dreams to become a science communicator and forays into public engagement and science policy....all while trying to keep my mental and physical health intact. Along the way, I'll also be sharing new plant science stories, and profiles of some of the researchers who inspire me on this journey. So whether you have a fascination for plants, are curious about what science research involves, or just wonder what exactly I do all day, read on - I hope you find it entertaining!


Wednesday, 25 December 2013

A merry Christmas to you

Merry Christmas everyone! Thank you for keeping up with my doings by reading this blog. It's strange, usually I am so preoccupied with my research but of late my head has been filled with preparations for Christmas. But  it will be back to work in the new year and I have lots of ideas for ways forward. I sincerely wish you a very peaceful and joyous Christmas and I give you my best wishes for the new year.

Saturday, 7 December 2013

Christmas Festivities...

I am sorry for the long delay since my last post. Things have been a bit manic with trying to finish experimental work, the Literature Review Deadline looming and various one off events that have popped up over the last few weeks.

Firstly, the growth chambers have now been cleared out for their maintenance overhaul between December- January. The remaining potted maize plants were put to good use in the Annual Departmental "Christmas Lecture". Based on a Royal Society Lectutre, but for an audience of primary school children, the topic this year was "Eating Sunlight: How plants harvest energy from the sun". Although I wasn't able to help out in the end, apparently this was a resounding success, in both content and for squeezing 1,200 children into the Octoagon Building. If even one of them is inspired to become a plant scientist, it will have been worth it! This made me consider what made me first interested in science; ultimately, I think my interest was first touched by the David Attenborough TV series, especially "The Blue Planet" with the episode featuring the curious creatures that lived at the darkest depths of the oceans. This does sound like such a cliche though! Even  my supervisor says that David Attenborogh was partly responsible for her becoming a biologist. At that stage, however, I wasn#t really considering the plants (when I thought that studying whale sharks was still a realistic career option and not a chance in a thousand). It took a week long plant-science summer school, hosted by the Gatsby Plants Charitable Foundation, to change my mind. Featuring highly stimulating lectures and practicals (letting young students loose with temperature probes and cameras is always a recipe for madness), gorgeous accommodation, wonderful food, too much frisbee playing... this basically "brainwashed" (albeit in a very agreeable way!) the attendees to devote themselves to a career in plant research. But how did I end up working with Parasitic Plants? My super visor was invited to give a talk at Durham University as part of the Departmental Seminar Series; a weekly lecture conducted by a visiting speaker, followed by questions and refreshments. Many people still remember it as the "best seminar of the year" and after describing her work, she was good enough to mention that she had a PhD available if any undergraduates were interested. Happy twist of fate!

Hundreds of bejewelled fir trees meanwhile, have sprung up everywhere but no one seems to be researching the cause of this phenomenen, as everyone is too concerned about Christmas approaching. Indeed, a veritable scrum of events seems to be jostling for inclusion before the end of term: the Departmental Christmas Seminar, The Animal and Plant Sciences Christmas Party, the Lab Christmas Meal...not to mention the various festivities that postgraduate students organise among themselves!

I hope you are all coping with the mad rush of festivities. I hope I can make it out to the end of this busy term!

Friday, 15 November 2013

An exciting trip to Syngenta.... A vision of the future?


My first taste of travel as part of my PhD ( the World Conference on Parasitic Plants in the summer doesn't really count, being held in Sheffield!) ... A visit to the International Syngenta Research Station in Jealotts Hill, Reading. 

I admit it's not a huge distance but it felt long enough on the train and a worthy enough journey to break by spending the night at my parents  in Knowle. From cosy childhood bed to plush hotel ( on expenses!) where the Complimentary toiletries were so expensive they were bolted to the wall. It was a completely new standard for me at Stirrups Country House Hotel, themed even down to the room Key rings.

Next day, an early start - the taxi whisking us up the gates of the drive. Anne had warned me that the facility was 'in the middle of nowhere' - I hadn't appreciated that this was to the extent that most of the surrounding cottages were owned by Syngenta to house their employees! We were promptly met by Dr David Portwood, who led me on a tour of the site. Although not strictly one of my supervisors, I will be hopefully working with Dr Portwood considerably if I ever get to the stage of generating any data as he has written most of the statistics programmes for analysis. My whirlwind introduction was only really a peek at this company's research capacity: Syngenta employs over 27,000 people in around 90 countries worldwide. Here, the company vision of 'bringing plant potential to life' was realised in the enormous greenhouses and disciplined collections of highly specialised machines whirring away. Although I had hopefully taken my camera, I was warned that photographs wouldn't be allowed. It was quite something to see sugar cane for the first time- the pictures in books don't do the height justice. I especially liked the policy of placing labs next to offices with glass walls in between- a clever way to circumvent the 'no working in the lab alone' rule - as long as a colleague is working late in the office, they can keep an eye on you. 

Then it was back to the meeting room to discuss the 'nuts and bolts' of the project. The cultivars for study were chosen, time plans discussed... It is unlikely that I will get down to Jealotts Hill again in the near future as it will take a long time to perfect the MALDI-MS technique for root tissue...especially when it is infected with Orobanche or Striga. So until I get any data there is no real NEED for me to be there....

But I could certainly imagine it, taking a seat in the cafeteria amid the swirl of agronomists, seed specialists, plant breeders, biochemists, molecular researchers,etc discussing the day's progress. My PhD really is the start of a journey and at some point it will take me on to the next chapter. Who knows if it will be here, back at Syngenta? 

All  too soon, it was time to catch the train back to Sheffield. I really hope to return soon!

Monday, 4 November 2013

Taking my life one section at a time...

Monday 28th October - Friday 1st November

This past week has been a particularly busy one for me. I had hoped to make real progress with the Literature Review but, as all my practical work seemed to come at once, this had to go on the back burner for a while. That is a recurring theme in scientific research - the importance of being flexible and to have plans leap out of the window (especially when your supervisor thinks of another useful assay to do)... nevertheless I have learnt many new skills this week, all of which I will need for my project to come.

I have been performing lots of germination assays on Orobanche and Striga, to see which will be the best races to use for the project. It was just as well; one strain of Orobanche was hopeless, with only about 1 in every 100 seeds showing any response to the germination stimulant, whereas another was really excellent, even though the seeds were actually older. I also had a long chat with Anne, whose PhD forms the basis of the work I will be doing, about the statistical methods she used to analyse her data. Oh dear, my head was spinning after that session...


My favourite part, however, was learning how to cut ultra-thin sections with the cryo-ultramicrotome. As I haven't got any infected rice or sunflower roots yet, I was practising on wheat seeds. It is cold work, as the knife is set at 14 degrees below freezing, and also slightly dangerous. "That Knife is so sharp" Professor Burrell (the Mass Spectrometry expert and one of my supervisors) "you will cut yourself before you know it". Such a fearsome blade is necessary to cut the ultrathin sections required for mass spectrometry - only 50 micrometres thick (where a micrometre = 1 millionth of a metre). After mounting the sample, the handle is turned and the sample slowly drops down onto the blade, which removes a section of the specified thickness. Turning the handle then advances the sample by the section thickness, ready to cut the next slice. It was tricky getting used to it - my thin sections kept curling up - but I did manage to mount some on sticky carbon tape in the end. These have been frozen in liquid nitrogen, to use on the MS later.

Photos:
1. The cryo-ultramicrotome
2. Taking the section...carefully now
3. Final sections mounted on carbon tape




On Friday, I finally infected my young rice plants with Orobanche. This was a very simple process in the end - the seeds of the parasite are suspended in water and brushed on with a paintbrush. It took several hours though, leaving me exhausted at the end of it. Now the plants are back in their rhizotrons in the growing chamber and I shall leave them for two weeks, during which the unfortunate rice plants will hopefully be invaded by Orobanche. To finish this week, I popped back home to Solihull for the weekend to catch up with friends, family and neighbours, which was wonderfully restorative.

Saturday, 26 October 2013

Getting my fingers dirty...

You can't be a plant scientist without plants of course. After weeks of feeling like a "paper student", engrossed in admin and a literature review, I am finally starting my proper induction to the lab.

It seems ironic that, although these parasites run rampant in the countries they affect, it can be surprisingly tricky to grow them in this country, even under the controlled conditions the lab and growth room allow. Nevertheless, the Scholes lab has got this down to a fine art, with precise timings, meticulous watering regimes, accurate chemical concentrations of germination stimulants...etc. I have grown Arabidopsis (thale cress; the model organisms of the plant science world, with the most heavily annotated genome of any plant), Wheat and Sorghum before but working on multiple systems at once is a new challenge. First there are the crops themselves. I have successfully managed to germinate rice seedlings and am growing these up to infect with Striga next week. The problem is, these plants can take up a fair bit of space...hence the rhizotron system. Rather than growing the seedlings in pots, the roots are trained into large, flat square petri dishes packed with vermiculite (which looks like an inedible form of muesli); these are then covered in foil to simulate below ground conditions. The petri dishes are packed together in trays, the young leaves poking out of a hole at the top, each with a "dripper" for irrigation. The Striga seeds, meanwhile, are prepared in an incubator in the lab; like Orobanche, these require a few weeks of "pre-conditioning" - being coddled in warm, moist conditions. This makes them responsive to germination stimulant. Because parasite seeds are tiny (no, really, miniscule, like dust!), they have little reserves so have developed a clever strategy where they only germinate in the the presence of a suitable host that they can rapidly infect. To do this, they have evolved the ability to recognise chemical compounds naturally secreted by hosts in the root exudates, called "germination stimulants". In the case of Striga, these compounds are classed as "Strigolactones", which also have a role as a plant hormone in the host, to regulate branching. The parasite seed then germinates and follows the concentration gradient of the germination stimulant to reach the root. Synthetic strigolactones are available; we use one called GR24 to pre-germinate the seeds before infecting the plant. This is done by prising the lid off the rhizotron and literally "painting" the seeds over the roots. The poor rice plant hasn't got a chance. At this moment, my Striga seeds are still preconditioning in the incubator and my rice plants propped up in their rhizotrons in the controlled growth room chamber, ready for infecting next week. I mustn't forget I'm on water barrel duty this coming week - if everyone's plants die from drought it will be my fault!
 Preparing the Rhizotron - packed with vermiculite with a strip of rockwool at the bottom to stop it falling out.
 In goes the seedling, resting on a strip of mesh
Rhizotrons wrapped in foil and packed into the Controlled Environment Room (CER)...which is a fair bit warmer than outside!

Meanwhile, I am constantly surprised at how much there is going on (perhaps Durham was a bit of a small University in that respect...)... it can be a bit overwhelming at times and I had to be disciplined in NOT attending all the talks at the book festival. I did catch a highly entertaining talk on science communication given by Ed Young, famous for his Blog "Not exactly rocket science" - it certainly gave me a few ideas for shaping this blog. The Animal and Plant Sciences Department, meanwhile, is keenly committed to public outreach, with a highlight this term being the "Christmas Time Lecture" where close on a thousand young school children are treated to a "Royal Society Lecture" experience before hands-on demonstrations and other entertainments. Past topics have included Birds and Dinosaurs and this year Plants have the starring role... I'm keen to be involved but with this literature review hanging over me, I'm not sure I will be able to spare the time to organise a demonstration so perhaps it will have to be as a steward. It will be worth it to see the unveiling of RoboPlant!

Monday, 14 October 2013

'A PhD should be regarded as a form of training...'

My supervisor was keen to stress that I was unlikely to make any major, enlightening discovery as we mapped the next four years of my life ( well three, I believe the last year will mainly be spent writing up- if I get any results!). But given that I am investigating an area that is largely unknown ( the metabolic response of host plants when infected with Orobanche or Striga), it will be like leaping into the dark. I will be using a technique called MALDI- MS to measure the profile of metabolites ( the end products of the biochemical reactions that occur in living cells) in the infected host plant. My main task is to compare the profiles of susceptible and resistant host cultivars to see if there are any metabolites associated with resistance ( that could POTENTIALLY be exploited into novel control strategies!). Before I can get any data though, I must first optimise the plants for the MALDI technique ( see paragraph below, 'MALDI in a nutshell') as it hasn't been used for these systems before. And this is where science becomes more like cookery, or craftsmanship; tinkering about with protocols, adjusting conditions, tweaking parameters until the process finally works. I spent a very frustrating summer trying to sequence a gene; the problem was that the reaction ( Poly,erase Chain Reaction DNA amplification) was incredibly sensitive and would only work if the conditions were absolutely right, even a single degree difference in temperature could stop it from working! So I am nervous about how long it will take to get this technique to work. When it DOES though, it will apparently spew out so much data that I will only be able to analyse it using the special computers in the department. So I envisage long, lonely nights, after everyone else has gone home, staring at the screen in a darkened room, trying to make sense of it all....
But first I have to get to that stage!
Meanwhile I have been doing more reading for the literature review. If anything, it has made me aware of how many things I don't know. Such as basic plant families....might be useful for general knowledge crosswords too. And sunflowers....the only thing I knew about these before was that my brother managed to grow the tallest one at school. Today I learnt that there are different kinds for making either oil or confectionary. As always in science, one question leads to another.
I have also been trying to do more other things: I attended my first departmental seminar last week on how plants have been key agents in driving global climate changes in the past by David Beerling ( for more information see his book 'The Emerald Planet'). Unlike many of the seminars I attended as an undergraduate, this one was PACKED and I was lucky to get a space to crouch on the floor! I also went to a 'Women in Science and Engineering' careers event. It was heartening to hear from women who had advanced up the ranks of powerful industrial companies, such as Rolls Royce, and by far the best quote was 'I used to work at Microsoft but it wasn't challenging enough...'

MALDI- MS in a nutshell
In mass spectrometry (MS), samples are vaporised and enter a chamber in which they undergo ionisation to form charged particles ( ions). In "positive ion mode", the sample components are bombarded with a stream of electrons which knocks off negative electrons from the sample atoms, forming positive ions. These are then attracted to a source of negative charge and accelerated, so that they each have the same kinetic energy. They are then deflected by a magnetic field, to an extent which depends on their mass; lighter ions are deflected more than heavier ones. This separates the ions by their mass/ charge ratio, producing a 'profile' of charged particles, allowing the components of the sample to be identified. In MALDI (Matrix Assisted Laser Desorption Ionisation), ionisation is achieved using a UV laser. The sample is first coated in a matrix which absorbs the energy from the laser. This energy is transferred to the sample, releasing ions from the surface which are then separated in the mass spectrometer. 

Images: 
1. My bench in lab C45

2.The wonderful collection of fridge magnets in the lab



 

Saturday, 5 October 2013

'Everyone flounders during the first week of their PhD...'

...so my supervisor assured me during our first 'official' meeting together when I mentioned that I was feeling a bit lost. Certainly it feels as though I have been thrown into the deep end a bit. I had got used to the intimate, compact nature of Durham - and being able to get to the science site in 3 and a half minutes- so everything here seems on a much larger scale. My room in the Ranmoor postgraduate village is very pleasant: there are eight of us in total on the floor, all with an en suite room and sharing a kitchen/ dining area. My walk into the department though, now takes half an hour, along streets choked with traffic, litter, students and surprisingly expensive 'convenience stores'. Not to mention SubWay outlets...
That aside, the project itself sounds very exciting. My first tasks will involve becoming familiar with growing parasitic plants to take sections from. Apparently, it can be very difficult to infect sunflowers with Orobanche in the lab- usually in agriculture, the problem is that crops are too EASILY infected. However, this lab contains the world experts in Striga and Orobanche and over the years they have developed tried and tested protocols. I will be benefitting from years of hard earned experience!

The growing facilities will be closed down over Christmas for maintenance so I will have to start preparing specimens straight away to have them ready in time. My Maine ask for is term however, is to produce a Literature Review to place my project in the context of work already performed by others ( with so many research labs in the world these days, it is all too easy for different groups to replicate one another's work). Fortunately, I had to prepare a Literature Review as part of my final year at Durham - I chose to compare the similarities between plant interactions with mycorrhizal fungi and nitrogen fixing Rhizobia bacteria- so am familiar with the paper trail that chasing references entrails. Besides the  wonderful, yet occasionally frustrating, referencing software Endnote. It's difficult to know where to start, so I shall just have to dive in and hope that the way ahead will seem clearer as I read...and read... and read....

This week has been a whirlwind of registration tasks and compulsory training sessions, everything from fire safety to waste management. 'At one point we had 27 separate waste streams' the Deaprtmental Technician cheerfully stated 'but that was a bit too much to manage'. There still seem to be an awful lot though, with different boxes and bins depending on whether your waste is hazardous, medically related, infectious...etc. Being so used to science paraphernalia, I find it hard to believe that pipettes tips and latex gloves still require special disposal as these count as 'offensive waste' which could upset members of the public if they came across them. Meanwhile, after the CoSHH ( care of substances hazardous to health) session, I feel that I will be lucky to get any actual research done, with the number of Risk Assessments I will need to do!

More excitingly, I have a desk, a locker and a bench to work at. Now I can feel like a member of the lab, even though I still don't know who everyone is and have forgotten the names of those who I was introduced to. The sooner the promised lab photo board is produced the better! And I have attended my first 'Wednesday morning coffee break', held in the departmental common room at 10.30. Coffee break happens every day, but everyone goes on Wednesday because there are free chocolate biscuits. Apparently, it was the only way to get everyone in one place so that any important announcements could be made...

Hopefully by my next post I will have made some progress with the literature and learning names! Thanks for reading!

Sunday, 8 September 2013

Gatsby Plants Annual Network Meeting Thursday 5th-Friday 6th September 2013

Another year, another highly enjoyable meeting of the Gatsby Plants Network. Held over two days,  this year at Queen's College Oxford, the event allows students supported by the Gatsby Plants Charity to present their research to Gatsby mentors and alumni. I am very grateful to the Gatsby Trust for funding one of my previous summer placements (investigating components of the temperature sensing signalling pathway in Arabidopsis with Dr Phillip Wigge at the John Innes Centre) which helped to convince me that plant science research was my dream career. The charity also does much to promote plant science education at secondary school and A Level through the online Gatsby Tree, which provides a wealth of teaching resources. For any teachers reading this, I highly recommend that you see this! http://www.gatsbyplants.leeds.ac.uk/tree.2.0/gatsby_tree.php?theme=null

I found the experience particularly valuable this year as the talks allowed me to gauge what the Gatsby supported PhD students had achieved after one year, two years or even three/ four years. This helped to give me an idea of the rate of progress expected from me when I start my PhD in October. The stand-out talk for me however, was given by Professor Hagen Bailey, of the Department of Chemistry at the University of Oxford. Completely eschewing a plant science theme, he described how "nanopore" technology could revolutionise DNA sequencing. This technique involves introducing membrane pores based on alpha-hemolysin from Staphyloccus into a chip, and feeding DNA through these channels. By incorporating a nuclease which cleaves off bases one by one as the DNA strand emerges or inserting a base reader into the channel itself, the sequence can be read. This avoids the need for using fluorescent bases (required for most sequencing methods) and can be fashioned into arrays with thousands of pores, ultimately capable of sequencing the human genome in 10 minutes. Given that this would be the equivalent of reading a thousand copies of War and Peace, this is quite impressive! Professor Hagen also described how these pores could be used to connect aqueous droplets to form "minimal tissues", which could have potential in organ enhancement or replacement. An intriguing diversion from plant science and an exciting topic to follow in the future...

I must confess that I do enjoy the "Oxford experience" that the meeting gives me - staying in quirky college rooms (no piano this time, but still lots of random doors and a fireplace), listening to the clock bells chiming out over the city at night, the formal evening dinner... I did feel sorry for the vegetarians this year however, who instead of being served "prawn and avocado cocktail" had to make do with "avocado...and more avocado ". I'm already looking forward to the next meeting, and who knows? Perhaps I will be presenting something myself...
 Plant Scientists networking over dinner in the dining room at Queen's College, Oxford
Queen's College, Oxford by night

Saturday, 27 July 2013

IUPS 2013: The closing ceremony

"...a landmark conference for various reasons..." Denis Noble, President of IUPS

How has this week gone so quickly? On Monday, I felt that it would surely take a short lifetime to work through the programme of symposia, plenaries, poster sessions...similar to the feeling I had on starting nursery school, with all those years of compulsory school education stacked up before me. Yet, here we are and I am still surprised to find that I am actually now a 20-something university student and that IUPS 2013 is nearly finished.
But there was still time to be truly inspired, as Professor Karl Deisseroth's lecture "Optical deconstruction of fully-assembled biological systems" demonstrated. The audience were treated to an impressive brain-imaging gallery produced by the novel CLARITY technique, where brain lipids are replaced with a hydrogel framework that allows super-resolution fluorescent imaging. For anyone with an interest in neuroscience, this is a hot topic to read up on. Practical applications of this stunning technique have been limited however, due to the massive data sets generated. Hence, Deisseroth moved on to describe the latest results from the more established technique of optogenetics - where the transgenic introduction of channelrhodopsin allows specific neurones to be stimulated in response to light. This is being used in an intriguing set of experiments where mice are placed in a cylinder half filled with water. At first, the mice swim vigorously as they search for an escape, then they become more quiescent; researchers are hoping to identify the neurones that mediate this transition from active to passive resistance. Preliminary results indicate that neurones of the medial prefrontal cortex are selectively inhibited during this behavioural change and that stimulating these with light can re-induce active swimming. This simple model is complicated, however, by indications that these neurones change the information they represent according to the level of dopamine. It may be that optogenetics, rather than generating straightforward answers in the immediate future, will instead reveal a further dimension of complexity...but this appears to be a reoccurring theme in biology (think of DNA and the gene-->RNA-->protein "dogma").

"...a scientific programme that has brought people from all over the world and stimulated our interest over the past five days..." Denis Noble

After the applause abated, the proceedings moved swiftly to the closing ceremony. IUPS President Denis Noble celebrated the "massive expansion of membership", including Bangladesh, Malta and Nepal. IUPS 2013 also bore the distinction of hosting the largest delegation from Africa so far and for being the first IUPS conference to receive delegates from North Korea. Reference was also made to a comment by the Nobel Laureate James Black at the 1993 IUPS conference in Glasgow that we would see "the progressive triumph of physiology over molecular biology". This might seem counter-intuitive, given the explosion in the field of genetics and molecular biology, however Denis Noble stressed that this was not predicting the replacement of the one science with the other - rather, physiology would be the medium which brought new molecular insights together into a cohesive whole. Bridgette Lumb then extended thanks to the wide number of international organisations and commercial companies who had supported the conference, giving a staggering final figure of 3068 registered attendees.

"...a great and unforgettable meeting...with an atmosphere of friendship and collaboration..."
Benedito H Machado, Organising committee for Rio 2017 "Rhythms of Life".

And then what we've all been waiting for! The grand handover - will this involve flag waving, Brazilian Samba dancers, glorious pyrotechniques? No...a rather more muted affair yet more fitting as the Brazilian organisers emphasised the importance of friendship and collaboration, and extended a sincere invitation for all to join them in Rio 2017 at "Rhythms of Life". A short video, carried throughout by a stomping Samba soundtrack, whetted the appetite with images of an exotic, dynamic city exuding charisma. Finally, the IUPS 2013 organisers gave us one last treat - a round-up movie showcasing the "best moments" of the conference including the delegates' table football skills, dance moves and drunken antics... I do hope they got that man out of the canal....

It's certainly been an experience although I feel some regret that I will probably be unable to join the conference in Rio...but I am sure that the field will have progressed into even more exciting domains by that point.

So it's goodbye from IUPS 2013!


Thursday, 25 July 2013

IUPS 2013: The ethics of brain scanning

'Mind reading is one of the most important survival skills for humans' Professor Hank Greely

But we're not very good at it, as shown by our failings in poker and romance. Nevertheless, advances in brain scanning technology, such as PET and MRI scanning, are allowing scientists to 'correlate physical changes in brain states to changes in subjective mental states'. The questions of what this could potentially be used for, and by whom, were discussed in the symposium 'Brain Imaging - An Ethical Time Bomb?'. Companies already exploit emotive reactions when promoting their products - think of McDonalds Happy Meals and luridly coloured sweets for children. It is a scary thought that companies could commission research to understand how to further stimulate cognitive pathways. One researcher even said her group had been approached by a gambling company asking how they could make the appeal of winning £1 outweigh the frustration of loosing £100. Could political parties use brain scanning technology to understand how to manipulate our emotions towards their agendas? Professor Hank Greely, a Professor of Law at Stanford University, asserted that the main use of brain scanning technology in the immediate future would be for prediction. This could have great potential medical benefit: apparently PET scans are now capable of detecting the build up of amyloid plaques that are the hallmarks of Alzheimer's. But this throws up a new snarl of dilemma - if you could have a test for dementia, would you take it? And if you did, who would you tell? Could health insurance companies or employers demand the result of a test if they knew you had taken one? Could they force you to have a test themselves? Given the considerable pressure companies are under to avoid discrimination ( such that they can't ask women if they plan to become pregnant), this seems unlikely, at least in small scale companies. It is more likely that brain scanning will take a dominant role in the courtroom, as a tool to predict the likelihood of re-offence. Greely was keen to stress that, even if these methods aren't 100% accurate, if they are more reliable than current methods (e.g. a defendant's say-so) then they may still be useful. How the information is presented could have a major effect however: a fluorescently coloured brain scan image is much more striking to a jury than a dry report read in a monotone. The issue of lie detectors was also raised - in the USA one can pay to have a test done privately which tests responses to a chosen list of questions. But if the result if unfavourable, the test company will conveniently forget it, allowing defendants to choose what to present in a court as evidence for their case. Greely described how brain scan imaging could be a potent tool in deciding cases where the claimant states they cannot work due to excessive pain. Can a court order someone to have a brain scan? Is there a 'human right' to not have a scan against a person's will?
Besides predictive applications, the use of brain scans for treatment was also raised. Reference was made to the 'paedophile tumour' case in the USA: before sentencing this child sex offender to jail, a brains scan revealed that he carried a brain tumour the size of a chicken's egg. When this was removed, his deviant cravings stopped. He was released on probation; when he reported the impulse to offend returning, a second scan showed that the tumour had returned. After surgery, he was again fine. Could psychosurgery be the future of criminal sentencing? Ablation of the nucleus accumbens can destroy an opiate addiction: could a judge thus sentence a drug offender to surgery? Or will guilty parties be presented a stark choice: go to jail or have brain surgery . Is this fair? Is it more ethical than the death penalty? What else could surgery change - sexual orientation? Should parent's have that power over their children?
A final point was made regarding memory enhancing pills. Will all exams in the future require dope tests? ( surely they are stressful enough?!) Would commercially available pills merely widen the performance gap between rich and socially disadvantaged groups? In that case, should everyone be given them? 
This is a debate that the public needs to be aware of and engage in now. So pleas elevate your comments below!

By far the most impressive aspect of this talk however ... it was given WITHOUT powerpoint slides! And intentionally (not due to equipment failure)! Very admirable in this age.

Wednesday, 24 July 2013

IUPS 2013: Are you on the 5:2 diet?

The 5:2 diet has made the leap from the eccentric circles of celebrities to mainstream public adoption,  and has many supporters who claim the approach can be applied to other areas of life ( e.g. Worry, TV watching, alcohol, shopping). Its popularity stems from the fact that conventional restrictive diets are highly demotivating; eventually the subject tires of the tedium and calorie counting, gives up (possibly in a spectacular fashion) and returns quickly to  their pre-diet state or worse. In the 5:2 method, a limited diet is only imposed on two non- consecutive days of the week; on the other days, the subject is free to eat as they choose. The 'fast days' are fairly severe as intake is restricted to around 25% of the user's energy requirements - approximately 500 calories. This would be punitive over the long term but the key factor here is that the participant knows that they will be able to eat their normal diet the next day and so perseveres. The popularity of the 5:2 diet is such that it could be described as one of the largest unmonitored public experiments.

But does it work?

A considerable audience gathered to hear Dr Krista Varady's lecture 'Alternate day fasting: a novel dietary restriction regimen for weight loss in humans' which described the results of a pilot trial in the USA. In this study, 20 obese makes and females took on a regime where, for three days a week, dietary intake was limited to 25 % of their needs. This was imposed over 8 weeks: for the first 4 week block, the patients were 'control fed' (as it wasn't thought that they would be able to calculate a 500 calorie meal themselves) and for the second half of the trial, they prepared the 'fast day' meals themselves, using dietary advice. I was impressed by what a 500 calorie meal amounted to - a vegetarian pizza, an apple and a handful of peanuts. I would struggle to eat that over a two hour period, which the participants were required to do. Then again, if it was the only meal you had that day...
Only four participants dropped out of the study and at a fairly early stage. The remainder lost an average of 5.6 kg with the rate of weight loss being fairly steady throughout. Nevertheless, in traditional dieting regimes ( especially those involving no additional exercise) this weight loss is usually lean muscle,  rather than fat, which reduces the amount of metabolically active tissue, making it even harder to loose weight.  In THIS case, however, about 90-95 % of the loss was attributable to fat. The subjects also lost about 4cm of their waistline, lowered their systolic blood pressure by 6 mmHg and reduced their LDL cholesterol levels by 20-25%. Subject compliance, as assessed through  feeding diaries, was 87%.

But what was happening on the 'feed days'? One would presume that there would be a temptation to binge...similar to the pancake syndrome before lent. These participants, however, were found to only consume 110% of their energy needs and so didn't make up the deficit. Many of them were even happy to carry on the diet with Varady stating that 'after the initial two weeks most have no problem with the fast days'. Some of the audience were sceptical about the long term effects and Varady admitted that the rate of weight loss did seem to drop after 24 weeks. Perhaps this is only to be expected though- one can't keep going down forever. The most striking thing to me was Varady's self-confidence in  the technique 'I do this a couple of times a year after holidays to shed a few pounds'.

Are you on the 5:2 diet? Do you apply it to anything else? Please comment below!

IUPS 2013: A case of personality driving phenotype?

I wasn't intending to comment on this session but the experiments of Theunis Piersma at the Royal Netherlands Research Institute intrigued me. Red Knots are wading birds that feed on shellfish; their ability to consume larger prey with harder shells is determined by the size of their gizzard. Interestingly, gizzard size can be experimentally reduced by feeding diets exclusively made with either small, soft shelled prey (such as shrimps). Conversely, diets rich in mussels and cockles can increase the size of the gizzard. Piersma et al discovered through tracking experiments that in wild type birds, which show great variation in gizzard size, birds with larger gizzards demonstrate reduced exploratory behaviour. They presumed that this was due to the fact that these birds were capable of handling a wider range of prey than individuals with small gizzards, so didn't need to travel as far to find adequate food. HOWEVER when they experimentally changed the size of the gizzard in captive populations, they observed no change in exploratory behaviour. This suggests, remarkably, that the personality of the individual, I.e. their level of inquisitiveness and thus exploratory behaviour at an early age, influence the development of the gut as these birds will be able  to base more of their diet on softer shelled prey. To me, this is a fascinating potential case of personality influencing phenotype. This opens up other questions, however, such as to what extent are environmental experiences ( e.g. The weather) Or group dynamics responsible for early exploration.
This was followed by an brief discussion by Gaelle Boudry on how  neonatal gut development can be influenced by milk composition to the extent that this has repercussionsfor later life. Piglets fed on high protein breast milk showed a delayed barrier function ( increased gut permeability) and disrupted immune responses. Quite disturbing when human milk formula compounds during the 1980s had protein levels in excess of those in normal breast milk.

IUPS 2013: A Discussion on Science Ethics

Science ethics...perhaps a topic one would rather avoid at a conference exploring the dizzying frontiers of discovery...with too many sessions on outstanding science to choose from, is their time to discuss the more vague and contentious specs of research? A space wa shade for this however, in a session entitled 'Ethical Issues in physiology - synthetic biology: Scientific progress or ethical dilemma?'. A succinct overview was provided of the different ways in which science can be 'owned' or managed but there there was little space for discussion. So I would like to bring that debate here! I'm always intrigued by the question, 'Can you ( or should you) patent a naturally occurring gene?'. You didn't make it but without dedicated, costly study (not to mention specialist equipment), it would not have been brought to public attention. Is the scenario changed if one can manufacture the gene synthetically? This is a debate that will only grow in importance as synthetic biology pervades even more areas of society. So...how should science be 'owned'?

What are the options?

1. State sovereign rights : states and national governments control access through national legislation. Access and benefit sharing agreements are arranged with parties hoping to use the material, such as research institutes.

2. Free access: where the resources are beyond national jurisdiction and can be accessed or used by anyone, e.g. Marine genetic resources.

3. Common Heritage of Mankind: resources cannot be owned by anyone but are effectively managed by everyone. States can only adopt an 'overseer' role. Scientific research is conducted for the benefit of everybody, rather than private gain, and the economic benefits are shared internationally, with the results freely and publically exchanged. 

4. Intellectual Property Rights: the classic practice of protecting property with patents. 

5. Mixed systems: combinations of the above. An example is the International Treaty on Plant Genetic Resources, which concerns over 30 crops pertinent to food security. Nations put forward a list of their genetic resources but still exercise state sovereign rights. The treaty aims to facilitate rapid access- benefit sharing agreements between countries to allow genetic material to be disseminated among research groups. A strong feature of the treaty is the protection of farmer's rights and their contribution to protecting germ plasm. Another case is the International Pandemic Influenza Prepardness Framework, set up in 2011 to allow the rapid exchange of viral material between member states to accelerate vaccine development. Both these treaties seek to avoid the 'Patent Thickets' that can delay research; in the case of food security and vaccine production, such beureaucratic encumbrances can cost lives.

So which method is the best to take forward into the future? Should different areas of science adopt different approaches? What are your thoughts? Please leave your comments below or your experiences of systems that you believe in.

Tuesday, 23 July 2013

IUPS 2013: A fascinating diversion into bears...

I was fortunate enough to catch the last bit of a session led by Henry Harlow of the University of Wyoming, describing his work on hibernating bears. Amazingly, during their winter slumber, bears loose only 20% of their muscle mass, whereas equivalent confinement in humans (e.g. Remaining on a hospital bed for 150 days) results in 70% loss of muscle. How do they do it? During the 5 months of their hibernation, bears do not urinate at all: by using radioactive isotopes, Harlow and his colleagues showed that the urea is broken down by gut microorganisms to release ammonia, which is recycled into building muscles. This session almost made me regret moving away from zoology and animal physiology although the idea of performing surgical implants on hibernating bears doesn't appear entirely risk free to me. Although some may argue this research is purely 'academic interest' understanding the physiology of fasting in bears is highly relevant in a world where we are limiting the hunting season for polar bears through our impact on global climate.  A sobering thought for the bears' futures - can their remarkable physiologist help them pull through?

IUPS 2013 The Public Lecture: The Rhythms of Life – What your body clock means to you from eye disease to jet lag

'We think we are the same creature throughout the 24 hours of day. We're not, we're fundamentally different...we are an extraordinarily dynamic creature, constantly changing and that impacts how we construct our society'.

Speaker: Professor Russell Foster, Professor of Circadian Neuroscience at Oxford University and a Fellow of the Royal Society. A passionate advocate for communicating science to the public, with a strong YouTube presence.

The impact of body clocks and sleep regulation on our everyday functionality... A more inclusive topic for a public audience would be difficult to find. We all know that sleep is important and many of complain  that we suffer a lack of it, yet this behavioural habit, which makes up around 36% of our life, remains a mystical realm that eludes understanding. Robert Foster provided a stimulating exploration that emphasised how we constantly undermine the value of slumber.

Professor Foster opened his lecture with an introduction to the endogenous body clock, demonstrating that different aspects of our physiology, such as body temperature, alertness, growth hormone levels, peak at different times of the day. These natural ocissilations, he explained, are endogenous and would be maintained even if we took up refuge in a permanently dark cave system. Not surprisingly, these variations have functional consequences. Core body temperature shows an approximate one degree fluctuation over 24 hours, reaching its lowest level at night, before climbing in anticipation of waking in the morning. This is thought to explain why swimmers are, on average, 2.7 seconds slower over 100m at 6 'o clock in the morning compared to 8 'o clock at night - I wonder if this has any influence on deciding when to hold competitions or training sessions. Blood pressure shows a similar rhythm, rising in anticipation of waking. Clinical studies have found that this is correlated with a 49% increased stroke risk between 6 am and 12 noon, prompting Foster to comment that each day you should rejoice each afternoon for you have 'survived the most dangerous part of the day'. 

Cognitive performance is another area highly related to sleep patterns; we all know that we perform less ably when sleep deprived but the reality appears to be more complex. In one study, cognitive ability was assessed in individuals at different parts of the 24 hour cycle. Frighteningly, performance at 6 'o clock in the morning was WORSE than the level expected for a blood alcohol concentration of 0.08% ( the legal limit for driving). Because the participants were kept awake until they were tested, it could be argued that poor performance was due to fatigue. Bizarrely though, those tested at 10 ' o clock int he morning performed BETTER than those at 6 ' o clock, despite missing more sleep. So perhaps you should be more worried if someone offers you a lift in the early hours rather than if they are under the influence...

Having established the existence of these endogenous rhythms, Professor Foster Proceeded to describe how they are produced. The main orchestrator of the body clock is the supra chiasmatic nucleus (SCN) in the brain; although this is composed of billions of single cells, each one is capable of generating 24 hour oscillations, hence this mass of individual clocks are coordinated together to make the 'master' body clock. Tying in nicely Sir Paul Nurse's lecture describing living organisms as information systems, Professor Foster outlined how 24 hour rhythms are driven by a conserved set of clock proteins operating in a feedback loop. The proteins produced by clock genes act as transcriptional activators for genes involved in metabolic processes however they also translocate into the nucleus and turn OFF the original clock genes. This causes the concentration of clock proteins to decrease ( as the existing proteins are degraded in the cytoplasm), reducing the inhibition of the clock genes until they can become active again.  Subtle modifications in clock gene proteins are being linked to distinct sleep patterns such as 'morning' and 'evening' sleep types, demonstrating their central significance.
 Are we thus driven by our genes? Does is master clock FORCE a 24 hour rhythm on all the other organs? 
NO... A key development in circadian research was the discovery that ALL cells in the body can generate a 24 hour rhythm. So...why have an SCN at all? It clearly has a fundamental importance as it's destruction ( for instance, by a tumour) results in all 24 hour rhythms being abolished. It seems that the SCN functions as the grand conductor of an orchestra composed of billions of individual cells, and provides a regular tempo for each cell to refer to. As Professor Foster summarised, this enables the body to produce 'a glorious symphony...rather than a cacophony of sound'. 

Following on from this succinct summary of how sleep/ wake patterns are produced, Professor Foster moved on to explore the importance of sleep in our functioning and society. Sleep, he argued, has become undervalued in recent times. Traditionally, it had been viewed as an essential, restorative behaviour worthy of diligent practice; as Benjamin Franklin said 'Early to bed, early to rise, makes a man healthy, wealthy and wise'. There was however, no scientific evidence for this argued Professor Foster, allowing sleep to viewed in an increasingly negative manner over the modern era, culminating in a view best summarised by Thomas Edison 'Sleep is a criminal waste of time and a heritage from our cave man days'. Many of us are guilty of 'burning the candle at both ends', feeling a pressure to rise early and end our working days late. Yet scientific research suggests that sleep has important roles in cellular repair and brain function, particularly laying down new memories. The human endogenous rhythm, however is longer than 24 hours; if this was not reset daily, we would rise later and later, becoming out of synch with the light/ dark cycle. The signal for entrainment appeared to be natural light as removing the eyes prevented sleep/ wake cycles from being maintained. Hence the eye is a dual function organ, forming images and perceiving brightness. The process of image production using rods and cones has long been known, yet in mutant mice whose rods and cones have degraded, sleep patterns are not disturbed; as Professor Foster summarised 'these mice are visually blind but not clock blind'. This suggested the existence of a novel photoreceptor - a furious controversy among ophthalmologists at the time, who had been studying the inner eye structure for 150 years. Foster persevered in his reasoning however and was eventually proved right with the discovery that 1 in 100 of the ganglion cells that connect rods and cones are photo receptive - now known as photosensitive retinal ganglion cells. This knowledge helps to explain how in certain diseases, such as diabetic retinopathy, patients may be essentially blind but show natural sleep/ wake patterns. In addition, it can be used to improve advice for such patients- rather than wearing dark glasses, patients ought to expose their eyes to natural light to re- set their endogenous clocks. In this light, giving glass eyes appears almost criminal as it replaces a partially functioning organ with a dead, totally useless vehicle. 

So, what implications do these insights in circadian rhythms have for everyday society? Professor Foster was keen to stress how a 'whole cocktail' of neurotrasmitters is involved in regulating sleep patterns, making sleep very susceptible to disruption. During our waking hours, sleep pressure accumulation is thought to be mediated by adenosine- normally the body clock mechanism prevents this from inducing sleep until the correct time. Many of us are at war with our clocks, however, using alarms to jerk ourselves awake and caffeine ( which blocks adenosine receptors) to fight off fatigue. This results in a vicious 'stimulant-sedative' cycle. We do not allow natural light to harmonise our internal rhythms, flooding our bedrooms with harsh lights, bright technology and entertainment. As Foster argues, we could sleep better if we cleaned our teeth before bed in semi- darkness.  This is poor comfort for shift workers, who are denied access to natural light rhythms ( the best advice seems to be 'don't do shift work'). Other practical measures are to avoid caffeine ( which has a half life of 5-9 hours) after lunchtime and not to nap for more than 20 minutes in the day - any longer would counteract the sleep pressure that helps us nod off at the opportune time. Chronic sleep deprivation is a major epidemic, rarely noticed except when it is implicated in disasters such as the 2010 Air India crash. As scientific evidence for detrimental health effects increases, however, people may become prompted to take better management of their sleep patterns. For one thing, sleep deprivation affects the balance of the satiety hormones Ghrelin and Leptin; the former stimulates apeptitie whilst the latter suppresses it. Chronic sleep deprivation tips this balance in favour of ghrelin, supporting the argument that lack of sleep can predispose to obesity. Deprived sleep can also amplify the stress pathway and elevate cortisol levels: this has myriad implications including suppressed immunity, hypertension, gastric acid production and glucose:insulin imbalances. More disturbingly, sleep deprivation is now being implicated in many mental health conditions as scientists move from the view that disturbed sleep is the result of anti- psychotic medication towards an argument that it may actually be a primary cause of these diseases. Psychological illnesses, such as schizophrenia, and sleep regulation appear to share common neural pathways and experimentally disrupting genes affecting sleep/ wake cycles impacts mental health. Meanwhile, improving sleep patterns in human patients has had some success in improving mental illness symptoms. Sleep may thus prove an effective therapeutic target in these cases.

As Professor Foster stated 'we are now on the point of understanding the fundamental neuroscience of these systems'. So how can this be put into useful practice? An example is provided by a study on teenagers, which found that the teenage clock is intrinsically delayed by 2 hours; whilst the average adult becomes fully alert by 10 'o clock, most teenagers take up to 12 ' o clock to do this, with 10-20% only becoming fully awake at 2 'o clock. In an intriguing experiment, cognitive function in adults showed a 7% decline between mid- morning and mid- afternoon, whereas teenagers showed a 10% INCREASE in function. Could this explain why teachers find it easier to control ( tired and subdued) classes in the morning compared to ( boisterous and rowdy) classes in the afternoon? Perhaps the whole school day should be restructured as in Monkseaton School in Newcastle. When the school adopted 10 o' clock starts, the GCSE scores showed a marked improvement, particularly among socially disadvantaged children. 
As these examples show, better understanding of our circadian rhythmns, the harmonious counterpart to our conscious disorder, could help us to structure our daily lives and societies to enable us to function most optimally and enjoy long term health. This fascinating lecture has certainly made me examine my own lifestyle more closely (should I stop using my iPAD in bed?). But the audience clearly had other concerns on their minds- when the floor was opened for questions, the first was 'Has the Royal Baby been born yet?'

Monday, 22 July 2013

IUPS 2013: Is online learning the future?

A slight departure from the general programme: a discussion on the effectiveness of online learning resources and how they can be developed most effectively. Although I was only able to attend part of this session, many pertinent points were raised. Online learning platforms can offer great flexibility, allowing students to pick and choose modules tailored to their requirements, and can reduce travel costs. Achini Vidanapathirana gave her own experiences of online learning, including the APS course on writing abstracts. She was able to benefit from the input of experts located in completely different sectors of the globe and emphasised how being able to take the modules at her own pace was an enormous benefit due to English being her second language. Nevertheless, she made the point that knowledge retention was heavily influenced on how important students viewed the course to be for their development. This is particularly relevant as most online learning resources are heavily based on 'low retention' methods of learning, such as recorded lectures and Audi-visual aids, rather than 'high retention' activities, e.g. Demonstrations, hands-on practical activities and discussions. Furthermore, there is limited face-to-face interaction, which reduces students' motivation to contribute to any discussion formats and the opportunity for peer learning. Networking is an increasingly vital skill for the aspiring researcher and online courses rob students of the chance to develop this at an early stage of their career.
David Dewhurst, of the University of Edinburgh gave an evaulation of online medical programmes offered by his institute. He described how online scenarios could allow students to conduct 'experiments' that they couldn't otherwise do, working on tailored 'virtual patients'. This certainly has the advantage of avoiding costly and time consuming ethics procedures. Not ALL practical skills can be learnt online though - a fish dissection I did in my second year springs to mind. But online resources can certainly be useful in supporting limited wet lab sessions. In this case, watching a video uploaded onto the University online network was invaluable - when practicals are typically hectic, cramped, rushed affairs with the demonstrators struggling to turn everybody out after three hours, any advance preparation helps the experiment to go more smoothly, allowing students to learn more from the experience. perhaps a good example of online/ practical complementation is the 'Hazard Perception' element of the driving test. Exposing learner drivers to these situations ie real world would be frankly dangerous, yet it cannot replace the practical 'hours behind the wheel' ( more like days in my case) needed to master the skill. 

Dewhurst cited studies which found that online lectures or practical simulations were at least as good as (if not better) in terms of data interpretation, communication and knowledge acquisition. Nevertheless, most students preferred the actual lectures (to get hints of what may come up in the end of year exam, perhaps?). Students also seemed to access online resources at different times of e day/night, supporting the view that greater flexibility complements student lifestyles. On the other hand, the success of online platforms very much depends on the dedication and expertise of the institution. In some cases, whole modules can be put together out of lectures or resources cannibalised from other courses. Hence, the student pays for a course that lacks coherence and is not tailored to their aims. It takes time to master the skills required to develop online resources, placing researchers and teachers under additional pressure - it is much easier to put together a series of lecture slides. The more creative the course developer, the more interactive the module will be, containing more quizzes and self-assessment tests to aid knowledge retention. Dewhurst made the interesting point that, despite these time constraints, teachers/researchers often reject imposed third party designs, seeing them as unfit for their needs. Success is also dependent on the student's ability to manage their own learning progression - making the transition between spoon- fed GCSEs and independent study at University even more important. Should Sixth Form schools thus be introducing more independent and online elements in A Level provision? Most of the students subscribing to the Online modules offered by e University of Edinburgh are apparently professionals in full time work, roughly 30 years of age, that pay their own fees, with an approximate 50:50 male/female ratio. Many are internationals, who benefit by not having to travel or obtain a visa. It seems that a desire to remain in full time work is a key attractant of online courses, especially for those just advancing their careers. 
For myself, I believe that online resources can be very beneficial in supporting practical lessons, especially where time and cost can be factors that limit the learning experience. But they can NEVER  replace actually DOING the skill. I learnt a fair bit about hygiene and bacteria when I took an online course in food preparation so that I could volunteer with a student cookery group. But I only gained confidence in the kitchen by cracking eggs, making a mess, burning myself and getting over my fear of turning the oven on. What do you think? Comments below please!

IUPS 2013: Trade stands and exhibitors

As if the frightening amount of symposia weren't enough, IUPS 2013 is also the host of an industrial-scale trade exhibition, featuring companies producing the latest, cutting- edge research equipment, worldwide physiological societies and the eminent journals that many of the delegates will be aspiring to publish in. The key event on Monday was the launch of Physiological Reports, an open access journal and joint venture between The Physiological Society and the American Physiological Society. Although the ebullient atmosphere was probably mostly due to the free alcohol and canap├ęs, this event represents to me an exciting trend in publishing. Moving away from restricted access and yearly subscriptions towards more freely available platforms is surely the way to facilitate wider participation in all areas of science, besides physiology. For the GCSE or A Level teacher that doesn't have access to journals through Univeristy membership, this gives the opportunity to explore the latest developments in their especial areas of interest and pass these in turn to their young students. Likewise, diligent  pre-Univeristy  students can access high quality material to assist in producing coursework ( especially those taking the Advanced Extended Project). Greater scientific understanding is also available to nurses, journalists and the average member of the public who has been inspired by a scientific programme or news feature. As long as rigorous publishing criteria and the peer reviewed process is maintained, I believe these platforms will be instrumental in disseminating scientific discovery. I shall follow the success of Physiological Reports with interest!

Meanwhile I had to resist the temptation to pick up EVERY back- issue of physiology journals and posters that were freely available ( I still have a stack of Nature Journals to sort through at home...). I couldn't resist a brain cup from Novusbio Antibodies but I was disappointed not to win a cuddly giant neurone. I did manage to have a lovely chat with Peter Wagner, Editor-in-Chief of the Journal of Applied Physiology (which I have used more than once in Univeristy assignments!) who emphasised how physiology acts as the central bridge between molecular discoveries and clinical care. 

Sunday, 21 July 2013

IUPS 2013: Sir Paul Nurse and Denis Noble

Sir Paul Nurse: Awarded the 2001 Nobel Prize in Physiology and Medicine for his post-doctoral research on the protein components that govern the cell cycle. Current president of the Royal Society and Director of the developing Francis Crick Institute (scheduled to open in 2015).

Key point: "We need to focus on the management of information to understand biological complexity".

As a researcher of molecular mechanisms governing cell function, Sir Paul Nurse may not be an obvious choice to open a Physiology Conference. He argues otherwise, however, stating "I'm always a physiologist - I want to understand how cells function, how they work, using whatever tools are available". He highlighted the importance of physiology using the Oxford English Dictionary definition "a branch of science that deals with the normal function of living organisms and their parts..." - in his view this encapsulated the central quest of biology. The second part of the definition bothered him however - "...in so far as it is not dealt with by more recent sciences". This gives the impression that physiology is merely there to "fill in the gaps" left by molecular biology, immunology, genetics, etc. Instead, Nurse argued, these other fields enhance our understanding but cannot substitute for physiology in meeting the key aims of biology. Having established the importance of physiology, he now asked: Where is this science going?

In the second part of the lecture, he emphasised how living organisms can only be understood as networks of interacting components, stating that higher order processes (such as homeostasis) can only be understood as the result of the gathering, storing and processing of information by a system. He cited DNA as an example of this- essentially a digital storage device. In addition, the Lac Operon (a genetic "switch" mechanism modulating metabolic control in E. coli) provides an exquisite instance of a negative feedback system, which responds to a flow of information. Future advances in physiology must be based on translating the chemistry of systems into modules that manage information. Nurse was keen to draw a distinction between metaphors relating biological systems to electronic machines or circuit boards, the key difference being that these are "hardwired" whereas biological systems are "wet wired"  - the components can be connected differently to change the information received. Information processing was so central to biology, he argued, that understanding how complex networks function in general - including models of airport hubs and ecological or sociological networks - can illuminate aspects of the physiology of cells & organisms. He rather daringly stated that our thinking must be more "feminine" - the point here being that men are supposedly more simpler systems, being "either off or on" whereas women have more complex constitutions. Rather than considering biological systems as simple, linear, input-output pathways, we must imagine an intricate network with superimposed levels of feedback control. Key questions to address in future include how the flow of information through such a system can generate fine spatio-temporal control, and how introducing dynamics can allow a greater degree of information to be transmitted. A formidable challenge is to place these complex systems within the evolutionary context. Nurse described the case of "John Harrison's clocks" who developed a series of machines to measure longitude in response to a commission from the English Admiralty. Each of these was intelligently designed and used to inform the development of the next with the clockmaker able to go back to the drawing board and start from scratch between each prototype. Biological systems, Nurse stated, do not have this luxury - they must carry the remnants of their evolutionary history. This constrains evolutionary development, rendering many physiological phenomena inefficient or redundant. As a result, "complexity may lead to counter-intuitive explanations" and we "cannot assume that the simplest explanation will be the adequate one" in each case. Nurse related this to physics, where "when dealing with the very big or very small, we are lead into the increasingly bizarre". Similarly, the evolutionary complexity of living systems may draw biology into "new worlds of strangeness", away from what we can understand counter-intuitively. This may require increasing assistance from mathematicians and physicists to understand a new level of abstractness. Nevertheless, Sir Paul Nurse's message was clear; physiology can only advance further if it embraces a view of living organisms as dynamic, intricate systems responding to a constant stream of information.

"Physiology moves back onto centre stage: a new synthesis with evolutionary biology"
Denis Noble CBE FRS. About: Eminent researcher in cardio-vascular physiology, current president of the IUPS.

Key point: New insights in physiology are exploding the traditional concepts of Neo-Darwinism evolutionary theory, and opening up a new world of hereditary mechanisms.
"If physiology has moved off centre stage, it is coming back with a vengeance".
"The genome is an organ of the cell, not a dictator. Control is distributed".

The focus of this lecture was in demonstrating how the classic views of evolutionary theory are being pulled apart by new physiological advances. According to Neo-Darwinism, evolution is primarily gene-centred and occurs through the gradual accumulation of random mutations. According to the Weismann barrier, the germline is completely isolated from the parent, hence there is no possibility of acquired traits being inherited. Noble first asked "Are genetic mutations actually random"? Current evidence indicates that genetic mutations follow distinctly non-random patterns throughout the genome. An example of this is P elements, DNA transposons in Drosophila fruitflies - demonstrated to hone in on functionally related areas as they jump between parts of the genome. Noble then explored whether evolution only occurs through gradual assemblies of single mutations. Analysis of the draft human genome sequence in 2001 indicated that the evolution of transcription factors and chromatin binding proteins could not have proceeded one amino acid at a time - rather whole areas and domains must have been shuffled to obtain the current conformation, indicating that mechanisms of reconfiguring the genome must exist. This was illustrated by the example of domestication, a process of introducing changes gradually through generations. However this form of selection "has never led to the formation of a new species. It is a purifying force, not a creative force". Compare this with hybridisation, which involves mixing up two distinct parental genomes. Noble also described how our very concept of a gene has changed and the classic linear progression of DNA --> phenotype has been abandoned in favour of a three way interaction between DNA, the environment and the phenotype via a biological network. This explains why knocking out genes rarely reveals their function as the network can compensate for their loss. This was demonstrated effectively by Hillenmeyer et al. who showed that approximately 80 % of knock out gene mutations in yeast are silent unless additional environmental constraints are imposed.

Noble then moved on to ask "Why should a physiologist be concerned with evolutionary biology?". Traditional evolutionary views are gene centred, yet physiological research is demonstrating that organisms can "immune themselves from the genome". Furthermore, information transmission is not a one-way process as organisms can impose downward control onto DNA through cell signalling, transcription factors and epigenetic modification. An example of this is provided by work on rats showing that regular grooming in early life makes the mature adult less fearfull - is grooming time limited in colonies stressed by predation or starvation? Another exciting illustration is the production of cross species fish by placing a carp nucleus into an enucleated cell from a goldfish. In the rare circumstances when this produces an embryo, the skeletal configuration is intermediate between the two, but much more similar to the goldfish. Hence, information cannot be transmitted solely by the DNA but must be influenced by maternal factors in the egg cytoplasm. Work on the nematode worm C.elegans meanwhile, has revealed that epigenetic changes can be incredibly robust. Here the inheritance of antiviral RNA molecules was demonstrated for up to 100 generations, even though the DNA template had been lost; inheritance had been achieved through RNA polymerase amplification in the cytoplasm. Our view of the DNA machinery should echo that of Barbara McClintock, who viewed DNA as a highly sensitive organ that can detect and respond to unexpected events. Noble cited how genome reorganisation may also occur through the lateral acquisition of new DNA material from unrelated cells, such as the ingestment of the prokaryote cells which became reduced to mitochondria and chloroplasts. The central concept of this stimulating lecture was clear: the genome is NOT isolated from the environment and furthermore, acquired characteristics can be inherited. Perhaps Lamarck wasn't so wrong after all.

IUPS 2013: First impressions and Opening Ceremony

"Five days of Outstanding Science" Professor Walter Boron, Secretary General of the IUPS

From the outside of the ICC Exhibition Centre and Symphony hall , there is little to bely that the major event in the Physiological Sciences Calendar - the 37th International Congress of Physiological Sciences - is on the brink of launching. Inside however, the flow of international arrivals, babble of foreign tongues and dynamic mixing of reunited colleagues is reminiscent of a thriving airport, as is the long line of "check in" desks, where badges and conference packs (containing an impressively stodgy abstract book) are being rapidly distributed. I particularly like the stairwell listing the previous venues - it gives a feel of continuity as one ascends to register. As one familiar with the Birmingham area, I wonder what impression "the city of a thousand trades" has had on the foreign delegates. In the Opening Address, Professor Bridget Lumb, Chair of the Organising Committee, sets the event in context through some select statistics; 2020 abstracts submitted,  535 lectures, 202 symposia and over 700 speakers, not to mention industry sessions, workshops and the public outreach activities. What really strikes me, however, is that this singular event has been in the planning process for eight years, on a par with the Olympic Games. Professor Walter Boron, Secretary General of the IUPS emphasises how such events don't happen through "the random aggregation of particles" but rather rigorous and comprehensive preparation. It is thrilling that the congress has arrived again in the UK, the last time being in Glasgow twenty years ago. Professor Jonathan Ashmore, President of the Physiological Society, outlined the historical presence of the congress and how the event had consistently attracted the leading physiologists of the time. This was portrayed succinctly by a photograph of delegates at the 1923 gathering in Edinburgh, which featured, among others, Ivan Pavlov, Edward Sharpey-Schafer (a pioneer in endocrinology who gave us the word "insulin") and Archibald Hill (a founder of Biophysics). Such an introduction lent a natural progression to the opening lecture, given by Sir Paul Nurse, winner of the 2001 Nobel Prize in Physiology and Medicine for his research which identified the protein components which regulate the cell cycle. The opening event had a refined, restrained feel - there was no attempt to enforce awe through special effects or overbearing graphics. Instead, the palpable excitement tingling in the audience as the lectures started made it clear that this was a group who had converged from all corners of the globe to hear great science and discuss it - and that they were very much looking forward to doing so. Bring on the next five days!
Delegates "checking in" on arrival

Latest insights into parasite control

Understanding the fundamentals of parasite development, metabolism and function is fascinating in itself... but the real driving force behind all such research is HOW it can be applied to control these agricultural pests.
This was one of my favourite sections of the meeting and is a topic close to my heart. Here are some of the highlights for me from the session:

Precision control for Orobanche: The herbicide Glyphosphate can be used effectively to control Orobanche, yet can also induce damage for the host & environment and is expensive for small-scale farmers. Extensive studies in Carrot (a major crop in Israel) have identified that applying low doses of herbicide at 600 growing degree days (an early stage of Orobanche development) is the optimum time for treatment; later applications are significantly less effective (Cochavi et al. Neww Ya'ar Research Centre, Israel). Such "precision timing" enables limited stocks of herbicide to be exploited to their full potential, whilst minimising host damage. But how to estimate the developmental stage of a below-ground parasite? A comprehensive study of Orobanche infestation of tomato in Israel  demonstrated the potential of mathematical modelling to address such issues (Eizenberg et al. Newe Ya'ar Research Centre, Israel). For irrigated crop systems, the main constrain on Orobanche development is the soil temperature , rather than moisture availability. In this project, a "drone" device was used to provide aerial mapping of the infected fields - the images provided such good resolution, that the infection stage could be visually assessed (whilst avoiding the need for laborious ground-level assessment). By correlating this to real-time soil temperature data, a model was formulated which could calculate Orobanche development based on the soil temperature. Hence, these methods can empower farmers with the knowledge of when the parasite is most vulnerable to herbicide treatment.

Combining resistance to drought and Striga: when considering methods for parasite control, these should not be isolated from other environmental or biological challenges constraining production. This was demonstrated superbly in a study which quantified drought tolerance among cultivars developed originally for Striga tolerance (Menkir et al, International Institute of Tropical Agriculture IITA). Striga itself is adapted to thrive in regions erratic rainfall and plants weakened by drought have been shown to be more susceptible to infection. The most drought-tolerant cultivars were crossed to produce hybrids, some of which demonstrated an incredible yield increase under infestation conditions (in one case 4113 kg/ha compared to 875 kg/ha for the parent line). As the speaker noted, selecting for these plants could address the dual problem of low moisture availability and parasite control in a way akin to "carrying two goats on the same motorbike" (the image helped to explain this!). Nevertheless, it was noted that the selection mechanism may simply be for higher yielding lines if the relative loss of yield between well irrigated/drought or uninfected/Striga infested conditions was the same as that experienced by the parents. Based on the significant differences in yield however, I'm not sure the farmers themselves would be too concerned about this point.

Arbuscular Mycorrhizae to the rescue? Having based my final year Undergraduate literature review on Arbuscular Mycorrhizal Fungi (AMF), I am perhaps slightly biased towards their intricate lifestyle and benefits. These fungi form intricate symbioses with most plant species, providing nitrogen and phosphorous in return for photosynthate sugars; the development of this association was thought to be instrumental in allowing plants to first colonise the land. Louarn et al. (INRA, France), have demonstrated however, how AMF may also have a practical use in controlling agricultural parasites. Strigolactones are produced by plants to recruit AMF but these have also been exploited by parasites to induce germination (allowing parasitic seeds to remain dormant until an available host is in close proximity). AMF colonised sunflowers were shown to be less susceptible to infection by Orobanche, yet this may simply be a consequence of decreased strigolactone production (if the roots are already colonised, the need to recruit AMF is reduced). In accord with this, root exudates from AMF colonised roots show lower germination stimulation of Orobanche than non-colonised root exudates. However, complementing the AMF root exudate with the classical synthetic strigolactone GR24 did NOT fully restore germination to the level of application of GR24 alone, suggesting that AMF produce a germination inhibitor which passes into root exudates. Characterising this inhibitor could offer an exciting avenue of research into parasite control, at least for Orobanche cumana.

Finally, the most popular talk was "Shoot the mistletoe", which described the development of a novel mistletoe controlling device at the University of Sao Paulo, Brazil. Gregorio Ceccantini humorously described how, at a different scientific gathering, involving considerable consumption of alcohol, an idea was born to use an air-triggered paintball gun to fire pellets of herbicide at mistletoes attached to commercially important trees. Besides proving that scientists love their toys (also justified by the "drone" study above - we were treated to many videos of it in action), this method does actually seem to be effective! Perhaps a way for bored teenagers to work off aggression?

Friday, 19 July 2013

What exactly do plant parasites take up?

By attaching themselves to an unwilling host ( either through a direct connection to the phloem / xylem or indirectly via other cells such as parenchyma tissue: this remains an area of debate and may vary between species), parasites are able to access water and, in the case of holoparasites photosynthate sugars, yet what else do parasites expose themselves to by establishing this conduit? Although much evidence suggests that uptake is an active process and that the haustorium ( penetration organ) can show selective nutrient uptake, various other substances have been shown to accumulate int he parasite from the host. An intriguing example is plant toxins secreted by the host to deter herbivore predators: by taking up these compounds via the haustorium, such protection can be conferred to the parasite. The holoparasitic stem parasite Cuscuta ( dodder) supports greater numbers of feeding aphids  when grown on tomatoes compared to turnips. Turnips belong to the same family as cabbages ( Brassicas) , which are known to produce glucosinolates as a herbivore deterrent. To investigate the basis of aphid defence in Cuscuta, Smith et al. ( Pennysylvania State Univeristy) grew the parasite on wild type Arabidopsis or mutants deficient in glucosinolate production. Predation by pea aphids was greatly increased on Cuscuta grown on the glucosinolate deficient Arabidopsis, suggesting that parasite uptake of host toxins can provide protection against herbivores. Evolution however, has rendered this interchange more complex however: certain insects, such as monarch butterflies, have developed a tolerance to plant toxins and specifically feed on these to make themselves unpalatable to birds. Similarly, peach aphids are stimulated to lay eggs by glucosinolate compounds. Consequently, peach aphid fecundity was increased on Cuscuta grown on glucosinolate deficient Arabidopsis. Hence, whether these commands are actively taken up by the parasite or accumulate in a passive manner, these seem to act as a double edged sword in the battle against herbivory.

Perhaps more intriguing is the evidence that RNA* from the host can also be transferred to the parasite; there are thought to be over 2000 phloem mobile RNAs yet even RNA sequences thought to be immobile have been detected in parasites. This raises the exciting possibility that parasites could theoretically be controlled using RNA interference** using transgenic hosts expressing siRNAs or shRNAs. This has successfully been demonstrated against Triphysaria versicolour grown on the legume Medicago truncatula. The host plants were engineered to express an RNAi construct against the enzyme acetyl-CoA carboxylase, a key enzyme for plant metabolism. Triphysaria parasites that infected these hosts were unable to survive and died (Yoder et al. Univeristy of California). It is clear that understanding the flow of traffic between host and parasite could afford greater insight into potential mechanisms for control.

* RNA: an intermediate ' messenger molecule' transcribed from the DNA sequence of a gene.  The RNA then translocates from the nucleus to the min body ( cytoplasm) of the cell, where organelles called ribosomes read the RNA sequence and assemble the amino acids of the protein the original gene encoded.

** RNA interference: a mechanism to effectively silence a gene by destroying all the proteins produced from it. Unlike DNA, RNA templates are single stranded and double stranded RNAs are incompatible within the cell. By articially introducing an RNA construct that is complementary to the RNA of interest, these can anneal together to produce a double stranded molecule that is targeted to destruction by the cell. This prevents the ribosomes from manufacturing the protein encoded in the RNA.
 
Plant Scientists love to network! This example comes from the Stables Courtyard at Chatsworth House, venue for the Wednesday "cultural excursion".