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!