Genetics Unzipped is the podcast from the Genetics Society - one of the oldest learned societies dedicated to supporting and promoting the research, teaching and application of genetics. Find out more and apply to join at genetics.org.uk

017  Happy 100th Birthday To Us

017 Happy 100th Birthday To Us

Kat: Hello, and welcome to Genetics Unzipped - the Genetics Society podcast with me, Dr Kat Arney. In this episode we’re celebrating the actual birthday of the society - founded on the 25th June, 100 years ago - with past president, Nobel laureate and winner of the Genetics Society’s first centenary medal, Sir Paul Nurse.

On the 25th June 1919, the Genetics Society was born. The brainchild of Edith Rebecca Saunders and William Bateson, the pair convened a meeting at the Linnaean Society, based at Burlington House in London, to propose founding a 'Genetical Society'. The idea met with broad approval from the assembled leading lights of the fast-growing new-fangled discipline, and the first meeting of the Society was held a couple of weeks later in Cambridge.

To celebrate this auspicious day, the Genetics Society held a very special birthday party at the John Innes Centre in Norwich, where Bateson was director. First we were treated to a wonderful exhibition of artefacts from the society’s history, including Bateson’s original microscope and fascinating photos. Then past president of the society and Nobel prize-winner Sir Paul Nurse unveiled two blue plaques dedicated to each of the founders, followed by the first ever Centenary medal lecture. 

We can’t bring you the whole of Paul Nurses’s brilliant lecture, which covered his life in research and discovery of the key genes that drive cells to divide, but I have picked out a few highlights. Afterwards, we sat down properly to chat about his thoughts on serendipity in science, the craziest experiment he ever did, and his favourite gene, so stay tuned.

Paul started by talking us through his early work carrying out genetic screens in fission yeast in search of genes which, when broken, meant that the cells couldn’t divide but just kept on growing, appearing down the microscope as unusually elongated cells. But, as he explained, a chance observation led to the discovery of something new and unexpected, which was quite the opposite….

 Paul: Doing forward genetic screens of this sort also had the potential to bring about serendipitous discovery. That is; discovery of things that you've never thought of before.

Such open-ended searches allow what I like to call ‘nature’ to deliver unexpected mutant phenotypes so the geneticists. If you keep alert, you can see things that you hadn't imagined that might well be informative.

An important example of this in the fission yeast screens that we were carrying out was the serendipitous finding of a microcolony of small cells during a screen for elongated cell cycle mutants. Seeing such cells led to the realisation that they were advanced into mitosis and cell division and divided before they could grow to the normal size.

This was a chance observation but having seen these mutants which were called Wee mutants, because they were isolated in Scotland, in Edinburgh, and I thought it was funny at the time. I no longer think it's funny, now I've been saying it for 45 years, but it did seem funny at the time.

I just want to say, for those of you who like the idea of cute names for genes or proteins, just ask yourself whether it is likely to still be cute and funny 40 to 50 years later. Mostly, they are not.

Kat: Paul found his first Wee mutant, and went hunting for more - but that second Wee gene proved to be frustratingly elusive.

Paul: Now, this screening for new Wee mutants - I'm getting a bit personal here - was extremely laborious. It was a visual screen and I could only get about one to two mutants every week. I couldn't cope with more than five hours on the microscope. It took a long time. The goal that I set myself was to isolate 50 such mutants. This took about a year.

What eventually turned out to be the Wee2 mutant isolate was spotted late on a rainy Friday afternoon in Edinburgh. It was November, and for those of you who live in Edinburgh you may remember how miserable November is, especially when it's raining.

It was on a plate which was terribly contaminated with a filamentous fungus. As many of you will also know, it's very difficult to sort that out, as the fungus just grows everywhere. As it was a Friday afternoon and as I was tired, I threw it away in the rubbish bin.

I cycled home, I had my tea and then I felt guilty. I felt more and more guilty as the evening proceeded and then I cycled back about nine o'clock. And because it was the 1970s, certainly the rubbish bin hadn't been emptied by that time.

It was still in the rubbish bin, I got it out. It turned out this was the 47th or 48th mutant to be the only mutant allele that I got which wasn't Wee1.

Kat: Paul went on to investigate the role that all his new genes were playing in cell division, leaving his favourite - cdc2 - till last. And it’s here that he ran into another frustrating problem. He was carrying out an experiment where he switched mutant yeast to a high temperature, to see whether they would create spores or not. This should have been a yes/no answer, so he was baffled when he realised that only 20 per cent of the cells were behaving...

Paul: Now, the only permissible answers were 0 per cent or 100 per cent. Being a biologist, anything less than 5 per cent will count as zero, as far as I was concerned. Anything over 80 per cent would count as 100 per cent, but even I had trouble with 20 per cent.

So I of course did what we would all do, I did it again. I got 20 per cent. It involved doing shifts between temperature of water and the accuracy mattered, so I bought a bigger thermometer for checking the temperature of the water. I did it again and I got 20 per cent.

I then got depressed and put it away in a drawer and left it for a month. I realised I was getting increasingly close to the end of my contract, got it out again, did the experiment again and got 20 per cent.

Then I had a light, light up in my head. What about if 20 per cent was the right answer? (Laughter). That had absolutely never occurred to me. I was convinced it was the wrong answer and I was just looking for the right answer, which was zero, or 100 per cent.

Kat: A valuable lesson in challenging your assumptions - and investing in decent lab equipment- something that Paul could have done with when he and his team were trying to develop a technique called transformation - something that had never been done before in fission yeast. This involves trying to sneak some DNA into the cells to see whether it contains the gene you’re interested in, and requires breaking through the thick yeast cell wall. They’re not very happy about this situation, and need to be kept in soft nutrient jelly, known as agar. And it’s here that there was a problem.

Paul: Unfortunately, I used a cheap soft agar. I was in the University of Sussex at the time and we couldn't afford the more expensive soft agar. This led to it solidifying in the tubes before plating.

But I had done all the work up until that point, so what I did was I got the tube and sort of banged it like tomato sauce. It sort of all came out in a heap on the plate. Then I used the petri dish to squash it all over the plate. Now of course any sensible scientist would have thrown it all away, but I just put it in the incubator just in case something arrived.

To my amazement, all these colonies started to appear in all the goop that was on the plate. It turned out in the end that these weren't contaminated, but actually were transformed fission yeast, and the first ones that we had ever made. 

Kat: After those early days of transformation came the advent of reliable DNA sequencing, finally allowing scientists to start reading the genetic code of yeast and all its genes. Paul was obviously keen to get the fission yeast genome sequenced, but had a problem extracting the cash - until he came up with an ingenious plan.

Paul: The problem we had there was as usual, fission yeast was not on the hotlist for genomic sequencing, at least for the genomic sequencing community. Whilst I applied for money to try and get it sequenced, unlike the budding yeast in the worm and the fly for example, let alone humans, I could never get any funding to get the organism sequenced.

Then luckily, I met somebody called Bart Barrell, some of you may know him, he worked with Fred Sanger. Bart had applied and got a grant from a funding agency - in inverted commas, you'll see why in a moment - to contribute to the sequence of the budding yeast genome, the first eukaryote to be sequenced.

But Bart had rather too much money for the budding yeast, so between us - in the pub actually - we cooked up the idea that we could use the excess funding to sequence fission yeast because I suggested that maybe the funding agency wouldn't notice. (Laughter)

Unfortunately they did notice, because we did about half the genome sequence in a few months, then I said, "Well, we'll go back to the funding agency and they will see they'll have the second eukaryote entirely funded by them, if they just give us a bit more money. They're bound to do it."

Well of course, they weren't amused. I got dressed down and they said they had no intention of providing the extra money. Nor would they let me apply for the extra funding.

So then Bart and myself had to go to the European Union and we produced a cottage industry initiative where we deployed it all out to a dozen labs. I think some of you may remember this - a dozen labs around Europe, to get the damned thing finished. It took another two years to get it done, but it still ended up being the fourth eukaryote to be fully sequenced. 

Kat: After a dazzling trip through his discoveries, Paul ended his lecture with an exhortation to the audience about the power of genetics and his advice for those working in the field.

Paul: I've tried to demonstrate how genetics can help understand biological processes and phenomena. Key to this is genetic thinking, powerful classical and molecular genetic methodology and its ability to toggle genetics, biochemistry, cell biology and theory in silico.

But for this type of approach to work, it always requires a clear focus on what you're trying to understand, embedded in a good understanding of the physiology of the organism under study. As Barbara McClintock so aptly said, the maize geneticist, the researcher needs to have a true feeling for the organism. Geneticists need to engage with the whole organism.

Genetics is a wonderful discipline, for me it's the queen of the biological sciences. Thank you for listening to me and happy 100th birthday to the Genetics Society. Thank you.

Kat: And finally, I just had to include this anecdote that he told at the end of the Q and A about being a very young scientist meeting Barbara McClintock - the pioneering maize geneticist whose phrase, “a feeling for the organism” is such a touchstone for biology. 

Paul: I was back at Cold Spring Harbor and there was a really terrible talk going on at the front. You know how that happens. It was a terrible session and so I'd gradually moved further and further back.

I was in the back row and obviously fidgeting. Then this old lady next to me said, "Do you think it's terrible too?". I said "Yes." And she said, "Would you like to come and have a cup of tea with me?" I looked at her because it was a bit unusual. I don't normally get old women asking to have tea with me, or young women, for that matter.

I went out with her and I realised it was Barbara McClintock. She took me back to her maize lab and showed me all of her cobs and gave me tea and biscuits.

Kat: Rather than tea and biscuits, we headed off for a drinks reception, where some of the finest minds in genetics were tasked with making cocktails out of frozen strawberries, pineapple juice and chilled overproof rum, in the hope of extracting some DNA. I dragged Paul away for a slightly rum-fuelled chat about all things genetics, starting with what he saw as the role of serendipity in science.

Paul: Well, I think serendipity is quite important. I want to make it clear that not everything driven is by serendipity, of course.

Kat: It's all just luck!

Paul: Trying to do something sensible but in an open-ended way that allows you to pick up things that you perhaps couldn't imagine. Could classical geneticists do so many visual screens? What that means is that you actually see things that you hadn't imagined.

So, doing a decent screen looking for things you have imagined is the starting point, then the serendipitous bonus is to see the things that you hadn't imagined. That may take you in completely different directions.       

The other aspect of serendipity you talked about was meeting people who can stimulate in ways you didn't expect. That certainly was the case for me. People working in different areas, you come across them and you learn from it.

We're here in Norwich, I was a graduate student - a biochemistry graduate student and I was only really exposed to genetics by going over to the John Innes and talking to people and realising what it could do. That made me think I ought to do genetics from that point on.

When I was thinking about what is controlling the cell cycle, I was hugely influenced by rate limiting steps in metabolic pathways, which is something that a professor in a completely different department was thinking about in terms of metabolic pathways.

So these sorts of things are not exactly chance because you're actually looking for different things, but they are not things that you have imagined before. Laying yourself open to what nature delivers you actually can lead you in very new and interesting ways.

Kat: I remember in my very first year at university, I was lectured by Ron Laskey. His phrase that always stuck with me was the Pasteur phrase, "Fortune favours the prepared mind".

Paul: Yes. That's a quote from Pasteur, if I recall correctly. And Ron, who I first met in about 1976, 1977 - he's a biochemist rather than a geneticist, but he's always been attentive to things that are a little different because he worked with xenopus -

Kat: The weird frogs!

Paul: - the weird frogs and the extracts there. It's half biological, half biochemical, so I'm not surprised he said that.

Kat: And when you look back over your career, are there any particular events, any serendipitous meetings or things that really stand out as a turning point for you?

Paul: Well, the one that I talked about a little bit today was spotting these mutants that were dividing into small size but it must be said that most people wouldn't probably have taken too much notice of.

Because I had noticed in the yeast that I was studying that they always divided at the same size, somewhere in the back of my head I was thinking that the cells were finishing their cell cycle when they reached a certain size. Therefore, when I suddenly saw cells dividing at a much smaller size, it made me instantly think they must have been advanced into mitosis and cell division, because they hadn't grown to the right size.

That immediately connected to rate-limiting steps and some rate-limiting components. It was there in fifteen seconds in my head. I then remember trying to explain it to everybody and they weren't really following me. They just thought these were some contaminant that had come in. But I was instantly converted. That’s probably the best example.

The other big change which isn't entirely serendipitous - in fact it's not serendipitous but it was ludicrously bold, was when I wanted to ask whether human cells had the same gene - before everything was sequenced, long before.

The reason why it was bold and therefore serendipitous to even try it, was because nobody thought for even one moment that a complicated process like cell reproduction could be the same in a simple yeast and a human cell. It was thought ludicrous.

Kat: We are way more sophisticated than yeast, you crazy man!

Paul: It really didn't seem worth doing but I realised that if it worked, this would be spectacular.

Kat: Plane tickets to Sweden time…

Paul: Well, I'm not sure I thought that exactly but it would be spectacular. We struggled with conventional methods and then the method that we tried that again, nobody thought would work, would be that I got hold of the first human cDNA library. It had only been made a few months before by Paul Berg and Hirota Okayama, who gave it to me straight away, as soon as they had made it, very generously.

I transformed it together with Melanie Lee who was in my lab. We transformed it into a mutant of the key gene cdc2, a temperature sensitive mutant. It couldn't grow at the high temperature because the cell cycle control was defective - reasoning that if human cells had a gene with the same control, then we might fish the gene out.

Of course, people thought this was crazy. I was talking to my friend Peter Goodfellow in the audience today. I remember him thinking that this was completely barking mad and I had to agree with him. It was pretty barking mad, but it actually worked. We got colonies growing up. I can tell you, when I saw that I thought, my goodness. Serendipitous not quite true, but luck and bold and everything else.

Kat: Audacious.

Paul: Yes.

Kat: That is one of my most favourite ever science experiments - to make that leap from so many million years of evolutionary time and say maybe it will just work.

Paul: We're not talking -- just to emphasise, it's 1500 million years, 1.5 billion years divergence. Dinosaurs went extinct 65 million years ago. It is deep in the depths of time.

Kat: You could do that same experiment with dinosaur cdc2. It would work.

Paul: Yes. It would be less interesting than 1.5 billion years. Think about it; there's been 3 billion years of divergent evolution, yet it's still conserved to the point where the cells even divide at more or less the same size. It's madness. It's madness.

Kat: It blows my mind. Evolution is incredible, biology is incredible. But we are here to talk about genetics, it's The Genetics Society’s centenary. What do you feel is the purpose, the role of societies like The Genetics Society? It's been going for a hundred years, what do you feel it does for the genetics community?

Paul: The first thing I want to admit, is that I am so fond of The Genetics Society. I remember when I was a graduate student, not even doing genetics and wanting to learn about it, I would go along to the meetings. It was so community based.

Kat:  Good parties?

Paul: There were parties too, it's true, but the regular meetings - you could talk about things, you could meet people who were much more experienced and quicker in thinking about these issues. It was a real education for me.

Then when I became President in about 1990, 1991 - a long time ago, over a quarter of a century ago now - I remember it was so amateurish. We would have meetings and I remember making the tea for the tea break, in lots and lots of big kettles, just to make tea for the 50, 100 people that were there. It was an utterly community-based society and still is. It serves the community, does a fantastic job of it in my view, very friendly.

It relies on its income from journals. Which - I mean, Plan S is a real danger for it. People talking about open source and Plan S have not understood what damage this might do to societies like The Genetics Society. It's a serious, serious problem.

It's a wonderful thing, I love it. I do a lot of things now, but it is my intention - I run an institute called the Crick Institute, which when it is on firmer ground, I intend to re-engage with The Genetics Society and do whatever I can to help others in the Society too.

Kat: You'll come and make a nuisance of yourself.

Paul: I always do make a nuisance of myself, yes.

Kat: Finally, it would be remiss of me if I didn't ask you, as past President of The Genetics Society, a Nobel Prize-winner, do you have a favourite gene?

Paul: Well, the gene that has made me famous, if I am famous, is this gene called cdc2. It's a protein kinase, it controls all the events of the cell cycle in the fission yeast and relatives do it in other organisms, it has to be my favourite gene.

If I didn't work on that then I think it would be one of the homeotic genes in drosophila. When the homeotic guys and girls - because it was also Janni Nusslein-Volhard - were looking at the developmental mutants and looking at mutants which would make an antenna, put a leg on an antenna - I'm not sure that happened but something like that -

Kat: Legs out of the eyes and double wings.

Paul: It's amazing. I love those mutants.

Kat: A single gene can just rearrange your entire body plan.

Paul: Exactly.

Kat: Biology is amazing.

Paul: There's no question. Biology is amazing which is why we are biologists and genetics is the most amazing part of biology, and that's why we are geneticists.

Kat: Sir Paul Nurse - past president of the Genetics Society, Nobel laureate, and - as it turns out - a fan of fruity cocktails. 

After that, we all headed off for an excellent dinner complete with a pea-themed starter, a Punnett square of puddings, and cakes bearing a secret birthday message written in the triplet code. And that’s not all...

[music]

Kat: That’s the sound of science troubadour Jonny Berliner, who entertained us all during dinner. But he saved the best till last, with a specially commissioned song about the history of genetics taking in everything from peas to fruit flies to bacteria, worms, yeast and more, written with a little help from Alison Woollard, a former PhD student of Paul Nurse who’s now professor of biochemistry at Oxford University, and her PhD student Emily Baker. We’ll be making a proper recording available in the near future, but for now here’s a little taster. 

[Sung]

Now flies are fine to study but their chemistry’s complex, 

So George Beadle and Ed Tatum mutated moulds to test.

Leading to the famous ‘one gene, one enzyme’ hypothesis

And showed genetics and biochemistry are one…

It’s the greatest thing a Neurospora has ever done!

Kat: Thanks to all the members of the Society’s centenary committee for their sterling efforts in creating such a fantastic celebration, and particularly to centenary project manager, Cristina Fonseca and Alison Woollard.

That’s all for now. Next time we’ll be back with more stories from our series exploring 100 ideas in genetics. For more information about this podcast including show notes, transcripts, links, references and everything else head over to geneticsunzipped.com You can find us on Twitter @geneticsunzip https://twitter.com/geneticsunzip or email us at podcast@geneticsunzipped.com with any questions and feedback. Please do take a minute to subscribe on Apple Podcasts, or wherever you get your podcasts from, and it would be great if you could rate and review - and more importantly, please spread the word so more people can discover the show.

Genetics Unzipped is presented by me, Kat Arney, and produced by First Create the Media for the Genetics Society - one of the oldest learned societies in the world dedicated to supporting and promoting the research, teaching and application of genetics. You can find out more and apply to join at genetics.org.uk  Our theme music was composed by Dan Pollard, and the logo was designed by James Mayall, transcription is by Viv Andrews and production was by Hannah Varrall. Thanks for listening, and until next time, goodbye. 

Cupcake photo licensed from Envato.

018 Cut. Paste. Pair. Repeat.

018 Cut. Paste. Pair. Repeat.

016 Genetics By Numbers

016 Genetics By Numbers