Science Interviews

Interview

Mon, 15th Aug 2016

Most science isn't groundbreaking...

Patrick Short, University of Cambridge

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Most science isn't groundbreaking; it often builds a picture, pixel by pixel, to Light bulb momentscomplete our understanding of the world, as Patrick Short demostrated to Graihagh Jackson on a whistlestop tour of genetics...

Graihagh - Hey.

Patrick - Good morning, how are you?

Graihagh - Iím good, how are you?

Patrick - Great! Good to see you again.

Graihagh - I have a present for you.

Patrick - Wow! Pea shoots - this is great!. Where did you get those?

Graihagh - Iím glad you recognise theyíre pea plants and not brought along to woo you.

Patrick - Iím a terrible gardener; everything I touch dies!

Graihagh - Meet Patrick Short - heís doing his PhD in genetics at Cambridge.

Patrick - This is actually, probably the first time Iíve closely studied a pea plant. I wish I was more of a pea plant expert.

Graihagh - So can I start by asking you why are we talking about peas? I know I know why Iím talking about peas but Iím just thinking no-one else will know why weíre talking about peas.

Patrick - Weíre talking about genetics and for most people the timeline of where genetics really begins is with a monk called Gregor Mendel. He grew up in - itís modern day Czech Republic -  but the Austrian-Hungarian empire, and he was the first one to really study this idea of inheritance.

Graihagh - By the time Darwin and Wallace had come along and said new species evolved via natural selection but not how and this is where Gregory Mendel fits in.

Patrick - At the time they had some idea of inheritance. They knew that things were passed on and the dominant model was kind of a blending thing; if you had white flowers and red flowers they became pink flowers. But he was one of the first to really systematically study this phenomenon and he did it in his garden with pea plants.

Graihagh - It was something like 36 varieties that he studied for 8 years and he cross-bred them didnít he to work out how they were changing colour and how the leaves changed in length or fatness - itís quite a meticulous bit of work?

Patrick - Yes. Apparently, if I remember correctly, he originally wanted to study animal breeding but the monastery wasnít particularly comfortable with him study animal sex, so they said why donít you just focus on the plants and, eventually he stumbled on something really fascinating.

Graihagh - And what was that?

Patrick - I think his main two contributions are this idea of the segregation of alleles so you can essentially study the first generation, second generation, third generation and you see some that are dominant. If dad has brown eyes and mom has blue eyes, then the child is going to have brown eyes. But if you keep watching then the blue allele actually doesnít disappear - it sticks around so then, if you go another generation down, you actually see children with blue eyes pop out again. He was the first to pinpoint this idea that some traits are dominant and others are recessive and you have this dance, so this balance over time of these things being passed on.

Graihagh - The one thing that I find pretty staggering is that he worked out not only do you get one gene from mum and one gene from dad, and then that there are dominant and recessive genes, but he managed to work out, in a pea plant, which ones were going to be dominant and recessive - thatís insane to me.

Patrick - Yeah, itís good. At its most basic level itís fractions and itís maths - yes itís simple but Iím sure it was very difficult for him, at the time, to wrap his head around.

Between the time of Gregor Mendel around the 1960s to around the mid 1900s there were a lot of incremental changes like -  science always works in small steps.

Graihagh - For instance, in 1866, Ernst Haeckel theorised that the stuff of inheritance would be found in the nucleus of a cell. Three years later, the young Swiss physician Friedrich Miescher had shown the stuff in the centre of a cell nucleus was nucleic acid - one of the building blocks of DNA. Things were moving fast and by 1944, DNA was determined to be the thing that held this genetic material. Lots of small, incremental stepsÖ butÖ

Patrick - Sometimes there are really big leaps, and one of those big leapswas in 1953 when Watson and Crick, with the help of Rosalind Franklin, published their structure of DNA - so this is the double helix that we are all familiar with.

And I donít know if you realise it but just around the corner up here is the Eagle pub in Cambridge where itís said that Watson and Crick announced their discovery of the double helix.

Graihagh - Patrick says Ďitís said thatí because recently, well, Watson changed his mind and said that actually, he didnít announce the discovery in the Eagle pub. Nonetheless, we went over to have a gander at the big blue plaque outside.

Would you like to do the honours and read the sign?

Patrick - Yeah, sure.

DNA double helix 1953 - the secret of life. For decades you go to the local pub for scientists in the nearby Cavendish Laboratory. It was here on February 28th, 1953 that Francis Crick and James Watson first announced their discovery of how DNA carries genetic information.

Unveiled by James Watson on the 25th April, 2003.

Graihagh - Itís a beautiful, blue plaque.

Patrick - It is. As everything in science, we recognise a few people but thereís always tons of researchers involved, so the three people who shared the nobel prize were: James Watson, Francis Crick, and Maurice Wilkins.

And it was Maurice who was the one who pushed this idea from the beginning and ended up convincing Watson and Crick to jump on with him. And then, of course, youíve got Rosalind Franklin who did a lot of the work on the X-ray crystallography and diffraction that was really the catalyst for this whole thing to take off and so itís quite amazing. And Iím sure there were students, and researchers, and all sorts of people that were there along the way questioning assumptions and coming up with ideas and, after all this time, the structure was discovered here in Cambridge.

Graihagh - Understanding the structure as this double helix - what did that enable; how did that improve our knowledge?

Patrick - We have this idea of inheritance and the most important thing, and what was probably on everybodyís mind was how do we read this stuff. So we know itís a catalogue, or an instruction manual, or a recipe book, but we canít really understand its secrets until we figure out a way to manipulate it, understand it, see whatís happening. And, from a chemistís point of view, or from a biotechnologistís point of view, knowing the structure of this molecule makes it a lot easier to manipulate and design technology to actually better understand it. So this discovery paved the way for everything that weíve been able to do in the last 60 or 70 years to understand this promise of genetics.

Graihagh - So while scientists now knew the structure of DNA, they didnít actually know the code - the letters or base pairs - that pair together to form a gene or a word if youíre using that analogy. This was found out in the 60s and then the first entire piece of DNA was sequenced by Fred Sanger in 1977. It was a bacterium though, so naturally, human DNA was next on the agenda but not for another 25 years or so... A train ride later, and Patrick and I found ourselves in that Ďpromised land.í

Patrick - Alright, so weíre at the Sanger Institute which is in Hinxton, just outside of Cambridge. So you may be familiar with the Human Genome Project; this is a big international effort to sequence the human genome. And incrementally we figured out more high throughput ways to actually take this molecule and convert it to some sort of digital information that we could analyse. So Fred Sanger worked with a funding body in the US (The National Institute of Health) as well as the Wellcome Trust and they opened the Sanger Institute where they did, I think actually, more than a third of the total sequencing of the project worldwide.

Graihagh - And when you say sequencing - what do you mean?

Patrick - If we think about the genome as a recipe book, so Watson and Crick, in some ways, showed us what this recipe book looked like and sequencing is what allows us to read the letters. So at the point of sequencing you still donít know what it means; you just have a string of information. And then the next job, once youíve got the the technology to sequence the first person, then you start to understand what are the patterns in the data; what do these letters mean. How does that information get transferred is the next step but you have to be able to read it first.

Graihagh - And that is where this happened?

Patrick - Yes, thatís right. Since then, the Institute's been involved in Thousand Genomes Project as well as a project thatís going on right now to sequence one hundred thousand people here in the UK. So it keeps scaling and itís always been at the forefront of this genetic technology.

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