Divide and Rules! Sir Tim Hunt at the NLA

On Tuesday (10th May) Nobel Laureate, Sir Tim Hunt visited students and staff at the NLA, not only to tell the story of how he discovered one of the key molecules in cell division (more of this later), but also to meet both young scientists and the teaching team. I think it was a memorable day for all concerned: it was for me and, as Tim emailed on his train back to London that evening: "Thank you for another fascinating day. I hope some good was done!" [The other fascinating day was last year's visit to the UTC]. So here is my take on the day and I hope you will agree, plenty of good was done, but it is just the beginning..... The beginning of a new relationship between school science and world class scientists. As Dr Geoff Wainwright put it to me after Tim's visit: we need an integrated education strategy that takes students from  primary school all the way through to work and University. In my view he is absolutely right!

Sir Tim (or as he prefers, Tim), was born not far from  Liverpool, in Neston on the Wirral, but his life has seen him rubbing shoulders with some of the greatest scientists of the last century. During the day, he mentioned Francis Crick (of Watson and Crick fame) and Fred Sanger (the double Nobel Prize winner from Cambridge) amongst those who have influenced and impressed him. Ms Parker organised the day, which began with a lovely welcome from the Principal, Ms Potter, followed by a tour of the school accompanied by some of the young Science teaching team and students. I have to say Tim and I were both "moved" by the papier mâché Spitfire in the Art break-out space! It was clear that Tim was going to "go off-piste" from the start, but that's the best way to get the feel for a place. And he did. And we were both really impressed with the students' stories of how much the school was shaping their lives. 

After a tour of the teaching space accompanied by conversation, we were treated to a lab class dealing with the principles of diffusion. Tim and I were able to talk with students while they had to carefully cut out cubes of agar jelly, stained with an "indicator" dye. The aim of the experiment was to explore the relationship between the surface area and volume of the small cubes and the time taken for the dye to "diffuse" into the acid (2M HCl), or was it the acid into the dye? This gives me an opportunity to explain why this is so important;  in particular, why it is so important in Biology in general and how it connected with Tim's Master Class on cell division that he delivered after lunch.


Diffusion is simply the movement of a substance from one place to another, which under a set of conditions is constant and depends mainly on the thermal motion of molecules in the liquid. Nothing too complicated so far. This particular experiment (above) relies on the pH-dependence of the colour of the dye. More specifically, the red dye will become colourless when it encounters the molecules of acid. So when the agar cube is dropped in the acid solution, the acid will diffuse through the cube and the dye will become colourless. If the time taken for the colour to disappear is measured, then the effect of distance is obtained. Since at this level diffusion takes place at a constant rate, the time taken to travel 1mm, 2 etc will be a simple relationship, but as Tim pointed out the time taken for a molecule to diffuse is proportional to the the square of the distance. Students were asked to note the time, the lengths of the sides of their cubes and the relationship between the surface area of the cube and its volume, and the time taken for the dye colour to disappear. Then, they were asked to relate the time taken to the ratio of the area of the face of the cube to the volume of the cube.  

The surface area to volume ratio is another important concept in Biology (actually in Science and Engineering!) that is the other side of the diffusion coin. The surface area of a 1cm cube is calculated from (1x1)+(1x1) etc, for its 6 faces; that's 6cm² in total. Therefore the surface area to volume ratio is 6cm^-1, since the volume is 1cmx1cmx1cm, or 1cm³. If you want to calculate the surface area to volume of a sphere, you would need the two formulae: the surface area is given by 4πr² and the volume is given by 4/3πr³. This makes calculating the ratio of surface area to volume just a case of dividing 3 by the length of the radius, and the units are again cm^-1 . [Work through the cancelling out of terms]. A sphere with the same surface area to volume ratio of a cube of edge 1cm (above) would have a radius of 0.5cm. The sphere maximises volume at the expense of surface area.

As Tim showed in some beautiful slides, the approximate shape of an egg cell prior to fertilisation is spherical! And when fertilisation triggers cell division without growth, the volume of a single egg cell is approximately the same as the 2, or 4, or 8 (up to 16, I think) cell developing embryo, or morulla (see the figure on the RHS). Successful evolutionary mechanisms are generally mathematically rational. Can you make sense of this observation? Now Think about the different shapes of cells in different organisms (or tissues), and ask yourself whether it makes sense. A plant leaf cell is a flat rectangular shape, a red blood cell is a flat disc, a white blood cell is a sphere and some bacteria are spherical (cocci), while others are cylindrical (bacilli). 

We can thank Euclid and his colleagues (see the shapes RHS) for providing us with the geometrical rules for calculating all of the necessary areas and volumes of spheres, cubes, pyramids etc. And of course, where would we be without pi! 

Interestingly, as 3D printing becomes more common, I wonder whether drug manufacturers will change the shape of their tablets? If you look here, you'll find some unexpected results! It seems that the capsule and the button shape may be the best compromise between surface area:volume ratio and the manufacturing constraints? But 3D printing is about to change all of that: paracetamol pyramids, just like pyramid-tea bags?

Tim's presentation after lunch took us on a chronological journey from the discoveries of cells several hundred years ago, through the drive to understand the consequences of exposure to nuclear radiation (Hiroshima), to the part he played in identifying the molecular basis of cell cycle decision making: the discovery of cyclins. Linking the class practical on diffusion to cell division and surface areas etc prompts a thought that we raised in discussion. How do you set up polarity in the developing embryo? How does a symmetrical process suddenly become asymmetrical and one side becomes the head and the other the tail (or the feet, if it is a human)? Again diffusion plays a key role. If you add a small amount of a molecule that promotes the development of brain cells to one location on a sphere, it will not reach the other side until some later time. If the first contact changes the biochemical activities in the embryo locally, asymmetry can develop against the so called "diffusion gradient". 

 

Much of our current thinking on embryo development centres on the differential diffusion gradients of growth factors at this critical early stage. The result of this can be seen in the amazing transition from Blastula to Gastrula, shown above. In fact the "enigmatic" mathematician Alan Turing turned his thoughts to these phenomena just after the second world war. 

In summary, diffusion underpins many Biological processes, and while it may be a complex phenomenon to explain and understand, with the help of Physical Chemists, we are beginning to understand it. [Again, as Tim pointed out, diffusion is a very useful means of regulating events in cells at the molecular level, but "help" is needed in large organisms. Think about the heart as a pump that makes up for the short-comings of natural diffusion of nutrients and oxygen around the tissues.]

I must of course take a moment to remind you of the beauty of cyclins. Tim described the need (in the 1960s and '70s) to determine the composition of a "substance" that the Biochemist, John Gerhart predicted (and called MPF, for maturation promoting factor) would trigger cell division. Using Biochemical methods (Tim showed protein extracts separated by a method called gel electrophoresis (actually SDS PAGE, which stands for sodium dodecyl sulphate polyacrylamide gel electrophoresis). He pointed out that there was an alternating pattern of appearance and disappearance of a protein that he eventually realised, correlated with cell division (and the cell cycle). As he said: I managed to win a share of the Nobel prize for identifying something that is effectively not there for cell division to take place! The work of two great yeast geneticists, Lee Hartwell and Paul Nurse, combined with Tim's work on sea urchins, led to the realisation that two key molecules come together, and the cyclin component must be removed for the cdc2 protein to trigger cell division. The diagram shows our understanding of the role of cyclins in the cell division cycle. The complex of cdc2 and cyclin is shown below (the sharp eyed ones will notice that there is a black inhibitory molecule included, since these complexes are targets for anti-cancer drug discovery.)

Lunch preceded Tim's Master Class, but I wanted to draw together the discussions we had with the teachers and the session with sixth form science students. The centre piece of lunch was an "organic" cake. Well it was decorated with an organic molecule that probably sits in the active site of an enzyme. The library provided a nice back-drop for discussions about the challenges of finding time in the curriculum to provide the context to some of the key concepts. We also learned of the forthcoming difficulties in providing some students with access to Science in the sixth form as the BTEC route begins to move closer to the A level pathway. It will be interesting to monitor, and important to anticipate some of the consequences of the introduction of examinations into what was originally designed as a coursework and practical experience pathway for sixth formers. 

I think the most common issue that cropped up was time, or rather the lack of it. A common problem I think for everyone; but getting the balance right in delivering course material and stimulating students to identify and develop their interests has to be a priority. Both Tim and I were fortunate to have had more time to think deeply about Science, at a time when there was much less hard  information. As Ms Parker pointed out, the moves towards mastery in subjects like maths might bring a deeper understanding of the curriculum material. I wonder if simplification of experimental work with more time to provide an explanation of context would help? 

Discussion with the teachers was not too different to the final end of day open session with a sixth form group. It took a little time to "warm the students up", to be honest, no less than many groups of undergraduates! Once we got going, Tim was quizzed about the value of his research on the cell cycle and new medicines for cancer. I thought this was a very nice question, and we learned that analysis of the genomes (the sequences of all of the chromosomes) in a group of cancer patients revealed that there were 25 000 mutations in the cancer cells compared with normal cells. Since we have around 25 000 genes in total, this is a huge number; and this makes the job of identifying the critical genes and the critical mutations something of a mountain to climb. 

The questions gathered momentum and I will pick out two that gave us both considerable food for thought afterwards, when we were joined by Dr. Geoff Wainwright for a "post match discussion". The first one was prompted by me and directed at the students. What do you enjoy in Science classes? Experiments! And the example that came back, with nods of agreement, was a class in which students had to determine Young's Modulus and investigate the differences between stress and strain. Tim was quick to point out that he was pretty rusty on this area of Physics, and indeed Physics in general; citing examples of his failure to "get school physics", unlike a good friend of his. What I also felt was interesting, was that the Young's modulus experiment clearly left a strong (and positive) impression amongst the class. The Physics teacher had clearly done a great job. It is such memorable classroom experiences that are well known to spur people on in their adult lives. In Tim's case, a motivational Biology teacher, in my case an adventurous junior school teacher and an inspirational University tutor. 

The second question probably elicited the most profound (and rapid) response from Tim. What is the hardest problem you have faced in your Scientific career? Tim retorted "finding a problem worth solving". The discussion was opened up by Ms Parker which led Tim to consider the value of a crisis in focusing minds, such as Ebola or AIDS. Sometimes the need to solve a problem stimulates creativity: radar in WWII and the return of  Apollo 13? In fact I ended up discussing this with some postgraduate students the following day and I realised I completely agreed with  Tim. Methods exist to tackle many of the problems in Science, some simple and some like the Large Hadron Collider, big and expensive! However, it is the problem that is most important, not the execution of the experiments. There is no doubt in my mind (let alone the Nobel Committee!), that determining the molecular basis of cell division was a problem of huge significance. But is all experimental Science as valuable, supported by the tax payer? These are important issues to ponder: however, Tim cautioned against to consider becoming too "application focused" (or as they say at the moment, too translational). He argued passionately that serendipity still has an important place in scientific development. I am with him there, but when we teach science at school and university, I think we also need to provide the context for the curriculum material. Discussions of this kind allow students to begin to develop their own thoughts on such matters. Indeed, many eminent scientists are advocates of translational priorities, while just as many argue for a serendipitous approach. As usual, a combination of the two is likely to be the most appropriate approach! 

In closing, I would like to say a personal thank you to Tim, for taking a day out of his hectic international schedule and a big thanks to the staff for looking after us and organising such a great programme. Mostly I want to express my thanks to the students who made it such a memorable day off for me! As Tim embarks on a new phase of his career in Japan, I am sure we all wish him well and I know he will carry with him a splendid impression of the NLA, its students and its staff.