Hans Krebs, from Hildesheim to Sheffield

The Widnes Sci Bar provided an opportunity for me to try out my talk on Sir Hans Krebs from a wider historical perspective as well as trying to communicate the impact of his work. As usual, the audience was good in number and searching in questioning, after the drinks break! It is really rewarding to talk to a group who have such a range of life experiences and who can call up memories of school, university and science from the work place. The talk included a few items to demonstrate the changes in technology associated with Biochemical research: from the Warburg flask to the fluidic microchip which stirred up a few memories of the craftsmanship of the scientific glass blower for some. Following last night's talk, which is provided as a presentation labelled Krebs Talk (on the right hand side-bar), I have provided some of the requested information at the foot of this post. This includes a summary of the knowledge base in metabolism at the turn of the 20th Century, from my undergraduate Blog site, together with a set of links relating to ATP and energy production in the mitochondria and in relation to photosynthesis. The body of the post summarises some of the main points from the talk and includes selected images (all of which are in the attached power point show). 

Hans Krebs was born in Hildesheim, north Germany in the first year of the 20th Century: his father Georg was a surgeon and his mother was Alma Davidson. Hans attended the local grammar school and subsequently studied medicine medicine at a range of University locations including Göttingen, Freiburg-im-Breisgau, Hamburg and Berlin, where he eventually joined the laboratory of Professor Otto Warburg. Warburg (right) was both a technical and intellectual genius; and in his laboratory, Krebs acquired the cutting edge experimental techniques of the era and soon developed a keen interest in the major biochemical challenges of the day. Key to the work that Krebs was to pursue first at Freiburg (1930-33), then Cambridge (1933-5) and finally at Sheffield (1935-1954), which would lead to the Nobel Prize in 1953, was the Warburg flask and manometer. This device enabled Krebs (and most Biochemists of the day), to make careful measurements of carbon dioxide release and oxygen uptake, by thinly sliced tissues incubated with a range of carefully controlled metabolites and inhibitors. 

In 1937, in association with William Arthur Johnson, a PhD student in the laboratory (you can read a nice appraisal of Johnson here, by my colleague at Sheffield, Milton Wainwright), Krebs published a manuscript entitled 

"The role of citric acid in intermediate metabolism in animal tissues" (1937) Enzymologia 4 148-156. Krebs H.A. and Johnson, W.A.

A summary of his work in the context of the field is available as a transcript of his Nobel Lecture as a pdf here. The original manuscript was rejected by the journal Nature, through an apparent lack of space! Krebs immediately submitted his findings to Enzymologia and rapid publication ensued. The Krebs cycle is also referred to as the citric acid cycle or the tri-carboxylic acid cycle (TCA for short) and occupies a central position in the metabolic "circuitry" of the cell. The image below (which a number of the audience were keen to obtain a large format print!) gives some indication of the incredible complexity of metabolic pathways, much of which would not have been unlocked without the incredible experimental insight brought by the work of Hans Krebs. (I came across this Blog site where those of you who wish to try and obtain a printable file can contact the Blogger).


I realise that the resolution is too poor for a detailed analysis, but it does create quite an impression!

The problem that followed on from the Krebs Cycle, was how do the products generate energy in the form of adenosine triphosphate (ATP). It was clear from the questions that this was of interest to many of the audience, so here is a summary of my response to the questions and some links to further reading.

The "products" of the Krebs Cycle are carbon dioxide (waste) and importantly "reducing power" in the form of NADH and FADH. The electrons that are conducted along a series of electron carriers associated with the inner membrane of the mitochondria, are punctuated by a series of large rotary enzymes that harness the differences between the proton concentration on the inner an outer face of the membrane to catalyse ATP synthesis from ADP and inorganic phosphate. You can read about NAD and the enzyme that finally catalyses the synthesis of ATP by following the links to a series called molecule(s) of the month. As I said, it was a radical rethink of methods and aspects of physical chemistry that led Peter Mitchell to propose the chemiosmotic theory of ATP synthesis. This had a bumpy ride at first with most "old school" Biochemists, but the subsequent joint award of the Nobel Prize for Chemistry in 1997 to Sir John Walker (Cambridge) and Paul Boyer (USA) gave a molecular basis for the Mitchell hypothesis. The MRC website has some animations  and this youtube movie is breathtaking! I hope it explains the phenomena better than my hand-waving!

Finally, for those of you who want to read more about photosynthesis, there are the usual wiki links, but you might like to look at Neil Hunter's web site, a colleague of mine at Sheffield who was awarded an FRS for his work on bacterial photosynthesis a few years ago. There are some powerful new microscopy techniques that are beginning to provide molecular insight into the molecules in vivo and I recently attended a lecture by the Baumeister group from the Max Planck Institute in Munich. The images on the left are visualisations of the thylakoid stacks that form the structural support for the light harvesting complexes that feet photons into the chloroplasts and the photosystem which runs alongside the fixation of carbon dioxide into a reaction catalysed by the most abundant enzyme on the planet Ribulose Bisphosphate Carboxylase, or RUBISCO! 

I hope this provides a helpful addition to the talk material and any comments are most welcome. You can also read more about the Sheffield Krebs Fest in this pdf version of the small brochure I passed around.

Symmetry is the key to everything Widnes SciBar, 9th Sept 2015

 Symmetry is the key to everything

Peter Rowlands

Honorary Teaching Fellow

Department of Physics, 

Liverpool University

Peter said that his interest in the history of science leads him to believe the conventional teaching of physics is not the source of the deepest creativity in physics and that this is part of the reason why there has been no really new ideas at the fundamental level since the appearance of the Standard Model over 40 years ago. Whilst it continues to be widely accepted, with numerous experiments since then verifying it, there has been no progress in explaining this theory. Many efforts to do so have involved ‘string theory’ despite the fact that such an ‘explanation’ is more complicated than what it seeks to explain.

When Peter did his Phd, he designed and built his own apparatus for carrying out his research project, and computers had little relevance - he recalled they were so primitive he could work out his calculations easier by hand.

In contrast, the Phd student in high energy physics today has little contact with setting up the apparatus - that is done by large design teams and specialist engineers working to specifications prepared by lead scientists. A student will often spend a year working in shifts at a laboratory such as CERN monitoring the experiment from a control room. They have access to huge stores of data on which they perform endless computer analyses. Before any results are published they are subject to significant internal scrutiny.

Peter doesn’t work like this. He doesn’t use computers and ‘work’ for him involves thinking, writing and discussing. ‘I don’t work away at the same problem, I wait until something creates link in my brain’. He is interested in the big questions & in using a more philosophical approach than is normal for physicists.

Climb the Mountain or Cross the Valley?

Lee Smolin, an American physicist, suggested there are two types of scientist. Most scientists are ‘mountain climbers’ who work in a particular area of their science throughout their career and gradually attain a summit of perfection. Much less in number, ‘valley crossers’ look for connections between different areas. Peter is a ‘valley crosser’ and, he believes, the really major breakthroughs nearly always involve ‘valley crossing’.

For example, Isaac Newton stands out from other physicists of the past in that he described the seemingly intangible world of the falling apple in totally abstract ways. In so doing, he defined mass on the same basis as time and space. He thought outside the paradigm (or the conventional thinking), but not contradictory to it.

Peter recalled that at the age of 12, rather than playing with Meccano, he played around with mathematical equations, such as those from Einstein’s Special Relativity theory. He noticed that if he kept increasing the speed of light, mass became imaginary - his first ‘discovery’. This was an early example of his desire to find out what happens if you theoretically push things to extremes.

Whilst Peter’s first interest was in using maths to get to the most fundamental laws, he realised that physics was the setting where he could do this. From an early stage he thought that symmetry was the key to making breakthroughs and his talk was about the results of a very long term personal and unique project in this area. Currently his proposals are seen as ’interesting’ by other physicists but they could become an alternative to the Standard Model if confidence in it fades, e.g. due to results from the Large Hadron Collider not supporting it.

Example of Symmetry in Particle Physics

Symmetry is everywhere in physics, especially in particle physics. For example, being negative the electronic charge has the characteristics of an imaginary mass. Similarly, in relativity, time behaves as though it is an imaginary dimension of space - there is some kind of symmetry there and it must be there for a reason! Peter proceeded to present his theories but as this involved complex mathematics, this is far enough for now! As commented by one of those present, ‘I found his mathematics and matrices a bit beyond my immediate comprehension although I could see how it had resulted in a mathematically beautiful result. Whether this symmetry analysis is a true representation of nature remains to be seen, but I am tempted to hope so.’ 
 

Bob Roach

roach36@talktalk.net

23rd September 2015