Straight from a Nobel-Prize winner's mouth....

It's not every day a Noble Prize-winning scientist visits town...but as part of  the KREB FEST (a science-extravaganza celebrating the life of pioneering biochemist Sir Hans Krebs), the University of Sheffield has been inviting distinguished researchers to explore 'Big Ideas in Science' in a series of public lectures. I went along to hear Professor Sir Jules Hoffman discuss 'The Innate Immune Response - From Insects to Humans'.

As human beings, we often like it think of ourselves as somewhat more 'sophisticated' than other organisms. The truth, however, is that many of the most fundamental processes that keep us alive are common across the whole Kingdom of Life, making us not so very different from plants, fruit flies, bacteria ...etc. And the immune system, as Professor Hoffman explained, is no exception to this.  

Humans display two types of immunity - innate and adaptive immunity. The innate system is a generalised set of responses to infection - including the production of antimicrobials compounds - that takes place rapidly, within hours. This is activated by common features shared across pathogenic organisms. Adaptive immunity, on the other hand, is a more specific response and involves the production of an army of specialised immune cells ( such as T and B lymphocytes) that destroy the invader. Although this response takes longer to initiate, some of these activated immune cells remain as an 'immune memory' against that particular pathogen. Adaptive immunity is generally thought of as a more complex, 'higher' response as it is only present in vertebrates, whereas innate immunity is found throughout the animal kingdom. Yet for a long time the innate response remained a mystery - we knew the OUTCOMES ( e.g. Antimicrobials production) but not HOW exactly it is activated. 

Eagerly awaiting the start of the lecture

When Professor Hoffman started his career, insects were the model of choice for investigating this: they show strong innate immunity responses, making them highly resistant to infections. For instance, just pricking a fruit fly with a needle that had been dipped in a microbial solution is enough to prompt the production of a wide range of antimicrobials, belonging  to seven different families. To find out what triggers this, the gene of one antimicrobial, called Diptericin, was cloned and found to contain distinct elements in the promoter,later called NF-KB elements. When these are mutated, Drosophila fruit flies are unable to mount such a strong innate immune response, and become vulnerable to infection. It turned out that many antimicrobial genes are recognised by a transcription factor called NF-KB which recognises and binds to NF-KB elements to activate the gene. Normally, NF-KB is held inactive in the cytoplasm by an inhibitor protein ( IF-KB) ; during infections, this inhibition is lifted and NF-KB can move to the nucleus to activate antimicrobial genes. But what was detecting pathogenic attacks in the first place and controlling IF-KB?

It took years of painstaking research, by groups across the globe, to identify these receptors - a problem complicated by the fact that different receptors seemed to activated different antimicrobial compounds. To cut a long story short, Toll receptors were found to be the main agents in activating the production of antifungal and antibacterial compounds in Drosophila ( actually, Toll Receptors do not sense pathogens directly but are activated by cleavage of another protein called Spaetzle....but that's another story!)

A giant model of Green Fluorescent Protein (GFP), commissioned for the Krebs Fest ( see my previous post for the giant E.coli!) 

You might be thinking - 'years of work - just to work out the immune system of a fly?' However, Toll receptors were found to have their counterparts in mammals, controlling similar pathways of innate immunity. However, it has recently emerged that Toll- Like Receptors (TLRs) have an importance that goes far beyond anything previously envisaged. "The initial notion that TLRs were sentinels against microbes turned out to be too restricted" Professor Hoffman said. Now it appears that TLRs play a whole variety of crucial roles, including allergies, neuro-regeneration in the central nervous system and kidney function. It just shows how years of incremental research, putting a puzzle together piece by piece, can open up whole new vistas in areas you would never have guessed at first.

This has promoted a paradigm shift that has seen the innate immune system garner much more respect, rather than being simply a 'primitive' relic. In fact, this response is so effective, that out of millions of bacterial and fungi species, only a handful can evade innate immunity and must be dealt with by the adaptive immune system - the pathogens that we regard as key problems. Evolutionarily speaking, adaptive immunity is a relatively 'late player', only appearing 450 million years ago in the ancestor of vertebrates, compared with innate immunity which has been present for approximately 1 billion years. "Essentially, we survive microbial infections through innate immunity" said Professor Hoffman. Without this "brilliantly successful" system, we would all be dead by lunchtime - each person produces roughly 10 g of antimicrobials a day, to fight off invaders they will never be aware of. Perhaps you may feel it is demeaning to compare a human with a fly....but in this case, I'm grateful that our immunity shares so many similarities!

Next week, Sir Paul Nurse will be coming to speak about his groundbreaking work elucidating how the cell cycle in controlled in mammals - and how this goes wrong in cancer. I'll be there! 

How can scientists engage with the new Parliament?

Presenting a brief round up of our last Science in Policy Session - 'Engaging with the New Parliament'. Our guest speakers Lynn Hobson (Parliamentary Outreach), Dr Grahame Danby (Science Clerk from the House of Commons Sci and Tech Committee) and Dr Cat Ball (Science and Technology Policy Analyst) gave us a masterclass in how scientists can engage with policy makers and submit evidence to influence key government inquiries. 

First Lynne Hobson from Parliamentary Outreach gave us an introduction to the structure of Parliament, and in particular, how the work of the House of Lords complements the House of Commons. Although the House of Lords can have an elitist image, Lynne argued that it is actually more representative of British society than the Commons, representing a wider range of ethnicities, professions and industries. She also disagreed with the view that having the two houses is an idiosyncratic system that slows down the process of law-making. "The Lords aren't there to cause trouble - it is about creating a debate to get the best laws possible, ones that are robust and fit for purpose" she said. 

Both the Lords and Commons have select committees, who commission inquiries into specific topics. Some of these committees are permanent, such as the Committee for Human Rights, whereas others are reactive, formed in response to major events, such as the banking crisis. The only committee which has the same name for both houses is the Science and Technology Committee, and we were very lucky to hear from Dr Cat Ball, Policy Analyst for the Science and Technology Committee of the House of Lords. 

After introducing us to the committee members (an eclectic bunch including a former head of MI5!), Cat described how their work reflects the most topical issues of the moment. "We are currently taking oral evidence for the potential uses of GM insects and our next big inquiry will investigate the relationship between EU membership and science". During these inquiries, members of the public are invited to submit evidence - this can be from world- leading experts, people who simply have an interest or even PhD students! Even though thousands of people may submit evidence, the administrative staff "read and consider everything and unless it's completely balmy, we will put it forward to the committee". But do these enquiries actually make any difference? Cat gave us some compelling examples that they do, including a 2011 enquiry into nuclear research which the Government used to develop its nuclear strategy up to 2050. Nevertheless, Cat stressed that the committees are strictly limited to an advisory role. "We have much more of a scrutinising function than one of law-making" she said.

For all these inquiries and for informing parliamentary debates, it is vital that MPs and select committees have all the information they need right at their fingertips. Not surprisingly, Parliament is supported by a huge army of administrative staff who play a critical role in 'keeping everything working'. Dr Grahame Danby, Clerk to the Commons Science and Technology Committee, gave us an insight into this behind the scenes work. Part of his role involves signposting MPs and ministers to the correct department that can answer their questions and to retrieve key information from the vast repositories stored in the Government libraries. In one famous example, an MP once asked which department he should go to for information about asteroids. The reply: "Well, the DTI (Department of Trade and Industry) deal with space but if it comes closer to earth, it might become an issue for the Ministry of Defence". 

Grahame stressed how the pace is in a completely different league to the sometimes ponderous world of academia. "An MP might literally only have a few minutes before they have to be in the Chamber" he said. "I don't have time to commission a PhD for every question I'm asked". The libraries get a lot of use, with the clerks receiving enquiries on every topic under the sun. "MPs get approached with all sorts of problems, especially from their constituents" Grahame said. "If one of David Cameron's constituents complained to him about the height of their neighbour's hedge, he would almost certainly refer to the library for guidance". MPs also 'like to know what they are talking about' for media appearances and public debates. Hence, Grahame found himself writing briefing notes on the Higgs Boson the day before its discovery was announced! More recent examples of issues that have drawn heavily on published scientific research include plain packaging for tobacco, ash dieback and how neonicinotoid insecticides affect bees.

It was a fascinating overview of a little- known and often unappreciated range of careers which cross the boundary between being a scientist and being a policy maker.

Meanwhile, keep watching, we're off to Westminster on 17 th Novemebr!

Highlights from the questions:

Do select committees like receiving evidence from academics during an enquiry?

Grahame: "I personally like getting information from Academics as you can tend to trust them to be impartial and their research is put to a rigorous peer review process"

Can even PhD students submit evidence?

Grahame: "The select committees tend to go for heads of departments and Professors but there is no reason why a PhD student could not submit evidence"

Cat: "We welcome input from early-career researchers. In many cases, they will be the ones most affected by new legislation". 

What happens if someone submits untruthful evidence?

Grahame; "You used to be locked up in Big Ben....that doesn't happen now but 'contempt of Parliament' doesn't look good on your CV!"

Do you have any advice on how to contact MPs with scientific issues?

Lynne: "Be BRIEF - ask yourself, 'Could my MP read this on the train?' Tell them who you are, why you are contacting them, what the issue is and why it is relevant to them now. And certainly don't use any academic lingo!"

What is the main limitation of the select committees?

Cat: "The main limitation is that, despite putting a lot of time, detail and trouble into our recommendations, we can't force the Government to do anything. All we can do is hope things move along".

Grahame: "Yes, but it does take forward the public debate. E only way things happen in a democracy is through public debate".