Lab Times Summer Read (2) - “For Science, Play is Not a Luxury”
(July 14th, 2017) Digging deep into our archive, we found quite a few gems from the past, worth a second read. Here's an interview with the inventor of the Southern blot, Edwin Southern, from 2013.
The Southern blot is a well-worn, standard instrument in the molecular biologist’s toolkit. It is what duct tape is to DIY enthusiasts. The Southern blot provided one of the first, if not the first, ways of detecting a specific DNA sequence in a soup of DNA fragments. Like all neat inventions, its simplicity makes you wonder why it took so long to think it up. Take your DNA, cut it up, electrophorese it. Press an absorbent membrane on top of it to soak up the DNA fragments, then probe it with labelled complementary DNA. Simple – but it doesn’t end there.
The basic idea of probing DNA soup with a labelled molecule paves the way to microarrays and all their opportunities. The river feeding modern molecular biology has one of its sources in the work of Lasker Award-winning scientist, Edwin Southern. Realising I was about to meet someone who has played a huge role in the bio-informatic revolution, I took a couple of minutes to compose myself as I sat waiting in the meeting room of Oxford Gene Technologies, a University of Oxford spin-off that develops molecular tools for biologists, of which Southern is a founder. But if I had any nerves to suppress, they soon evaporated when I saw the man himself. A gentle, gray-haired and bearded gentleman held out his hand and offered me a cup of tea. And then the conversation began...
What environment did you grow up in?
I grew up in a small town near the Northern city of Manchester. My father was a typewriter mechanic, and eventually became self-employed. His father owned a laundry in the city of Manchester and was a keen photographer. My parents brought me up in a council house, so we were definitely not privileged in that sense. I would say they were working class, aspiring to be middle class. However, my great grandfather was a councillor and his brother, Sir James Southern, was an Alderman in Manchester and, as I discovered as an adult, raised the funds to build the Manchester Ship Canal. My parents certainly had aspirations for me – my mother in particular encouraged me to do well.
So how did a working Northern boy get to where you are now?
I went to the local Church of England primary school, a very small place. As a child we had a remarkable amount of freedom. From a young age, I tagged along with my brother and his friends roaming around the fields at the edge of the town. When I was about 6, I remember being left alone in a wood in the dark while the older boys went home to collect blankets so we could all sleep out under the stars! I helped my father on his allotment and we kept and bred budgerigars. I passed my 11-plus exam, which meant I could go to the local Burnley grammar school. I did well at Burnley, left school at 16 and went to Manchester University when I was just 17 years of age.
You started University at 17?
Yes. I think it was too young, and I was young for my age, so I didn’t do too well there. I came out with a 2.2. I found the way chemistry was taught at University very boring. It didn’t hold you back, though.
Looking back, what factors shaped your career?
Probably my primary school. It was a very small, Church of England school, headed up by a very special headmaster called Teddy Allen. I remember him well. It certainly wasn’t a very conventional school, but most importantly they taught me the value of play. As I remember, we spent a lot of time working in the garden and raising animals – there were rabbits running round the classroom as we sat the 11-plus examination. I owe a lot to other teachers, too. Burnley Grammar was a good school, and there were several teachers, who took me under their wing and brought the best out of me. I was put up a year, so I was the youngest in my class from the age of 12. I was a regular visitor to the public library and consumed a large number of text books! Of course, we specialised very early, and by the age of 13, I had abandoned most subjects and was concentrating on the sciences. I did not study biology at school – this was only available at the girl’s grammar school, as back then it was classed a girls’ subject!
Why did you go into chemistry? Was it the bangs and smells?
Oh, definitely. At school, I made up my mind that I wanted to do chemistry. I remember making our own fireworks and trying to blow up the wall of the workhouse at the end of our street. We didn’t quite succeed but we had a good try.
You said you only came out of University with a 2.2, but you managed to get a PhD place in Glasgow.
I was there from1958 to 1963. But you know, the environment then for a PhD student was very different to today. It was very hands-off – you were just left alone to try things out. I very much believe in the importance of play as part of the creative process. Today, as soon as you start your PhD you are put through an organised training programme and straight away you will be working as part of your supervisor’s team. But there is no room for play, and I believe that for science, play is not a luxury, it is a necessity. In your second or third year you may be on a couple of papers along with several other lab members. I was sole author of the first paper I published. It is not the fault of the supervisors; it is just that there is no risk-taking any more. And I think science should be fun.
You are best known for the famous blot named after you. How did you develop it? Was it a carefully planned search for a solution to a problem, or was it a serendipitous discovery?
A bit of both. At the time, we were interested in the relative abundance of 5S RNAs. It was known there were different sequences in oocytes and somatic cells. We wanted to find ways of isolating the DNA – we knew that there were multiple copies in tandem arrays – and detect specific genes. This was up in Edinburgh, where I was in contact with Ken Murray. He was in the molecular biology department and I was in zoology. At the time, restriction enzymes (endonucleases) had just come onto the scene, but the standard approach of separating out DNA fragments by gel electrophoresis was not straightforward. When you are working with complex DNA you just end up with these rather featureless smears. So I thought I could find a way of using RNA hybridisation to find genes. I tried ways of drying out the gels but the fragments would just come out during the hybridisation process. So that came to a dead end. But funnily enough, I found out later that Oliver Smithies in the US had got it to work but it didn’t lead anywhere. I often wonder how things would have panned out if that technique had worked for me! So instead I followed a different track. It was well known even then that you could get DNA to stick to membranes, so I fiddled about with laying the gel on top of a membrane and floating the whole thing on top of a bath of sodium perchlorate, which dissolves agarose gels as Charlie Thomas had shown. As I sat watching my little boat, I noticed little droplets on top of the gel – then came the epiphany: the gel was porous. That is how the idea for the blotting technique took off. But it took me two years to get the original paper published in a journal! In the meantime, it had been publicised by word of mouth and was already in widespread use.
The way we do science has changed a lot even in the few years since then. Do we do it better now?
I think science has become too industrialised. As I said before, I am a great believer in play. So much of what we do today is rather predictable. I almost laughed when I read in the newspaper recently the big piece of science news of the year: a report about the publication of the first hot results of the ENCODE project. There were some 430 authors on the papers. To find what? That there isn’t as much junk DNA as we thought! Now where’s the fun in that?
Tell me about your role in the development of the microarray, and how that led to your involvement in industry.
I was sitting in a meeting in Japan in 1987, called to discuss how to sequence the human genome. Then, the Sanger method was seen as the ultimate tool, but it was thought to be too expensive. It dawned on me there and then that oligo hybridisation could be a way to speed up sequencing and make it less expensive. I came back home and sent in a grant application to the Medical Research Council. Later on, we worked with the University’s ISIS outfit, which helps launch University startups, and with their help we filed a patent on the hybridisation technology.
You took on Affymetrix in a legal battle over that patent, didn’t you?
Yes, and I won. I have nothing personal against them – I know their founder, Steve Fodor, well and we get along fine. But the cash settlement funded Oxford Gene Technology, which is doing very well.
I have just remembered my manners – I was forgetting your knighthood. I should be addressing you as “Sir Edwin”!
Well, I don’t normally use the title and given my political position it was difficult to accept. I was about to turn it down, actually. But I have a friend, Paul Nurse, who has at various stages of my life offered me valuable counsel. He said to me, “Ed, you have always been complaining how little scientists are recognised by the establishment and this is one way they have of giving us recognition.” Although I don’t use the title normally, it can open doors, particularly in my work with the Trusts.
Was that the end of the interview? Your Lab Times reporter thought so. Thinking that the meeting was drawing to a close, I began to shuffle my notes, preparing to thank this amiable luminary for his time and openness. But Southern was not yet finished,
“Oh, but let me tell you about Kirkhouse and Edina!”, he insisted anxiously. My fears that I was about to learn about two favourite pet cats were allayed when he told me how in his retirement he, “wanted to do something that was totally under my control”. My interest aroused, I quickly put my notes back on the table and learned what Southern has done with the Affymetrix cash settlement mentioned above.
“The Edina charity provides help for science teaching in primary schools,” he explained.
Ah, the church school near Manchester, I thought to myself. “We provide cash to primary schools for all sorts of science-based activities, like outings or shows at the school or to put equipment into the science cupboard. They have made an amazing difference.” But Professor Southern was saving the best until last.
“And there is Kirkhouse,” he continued. “Another place where Paul Nurse influenced me. Kirkhouse is about improving crops in the developing world, by developing genetic resistance to pests and diseases.”
But isn’t GMO just a way of locking farmers into proprietary seed? I grabbed my chance to exercise my role as righteous defender of the poor.
“Oh no, this isn’t GMO at all. We provide the molecular tools to speed up traditional breeding. We find molecular markers that are close to the resistance gene, so that you can see which seedlings to select, without having to spend the time to grow them to maturity. The resulting seed belongs to the farmer, not to us.”
Southern told me of the aptly-named “witchweed” of Africa. Striga, as it is less poetically known, lies hidden in the soil, for years if need be, waiting for the staple crop, cowpea, to be sown, then wiping out some 30% of the crop yield. The €12,00024,000 spent in setting up each laboratory in African centres is already paying off and the project has led to resistant crops, which are now in farmers’ fields. This success has attracted interest from the Bill and Melinda Gates and the Rockefeller Foundations, to help distribute the seeds more widely.
You aren’t making any money out of this, and it isn’t earning you any more mega-papers. So why are you doing it? “Fun,” he smiles.