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Dr Mark Lorch

Mark Lorch is a lecturer in biochemistry at the University of Hull and a researcher in the field of the structure and function of proteins.  Mark is also a strong science communicator who writes for the Guardian and runs a website showing students simple experiments they can do at home.

The cells in your eye have the same genes as the cells in your skin but they make very different objects.

On becoming interested in science

I come from a family that’s…we’ve had a lot of scientists, and my grandfather was a horticulturalist and he used to…I remember as a boy looking through his lab that he built in a smallholding and it was like an Aladdin’s cave, you know, to a ten year old boy, and my dad was a nuclear physicist and my mum’s a nurse and so there’s a lot of science in my family so I think I’ve always had some sort of interest in it and that was very much nurtured and so from an early age I wanted to do science, I wanted to do research.  I remember even back in school saying I wanted to go and do biochemistry because I wanted to understand how the things that make us live work.

On biochemistry

I am a biochemist and one of my passions in biochemistry is actually trying to solve something called the protein folding problem, which I spent several years researching and still tinker with now.  So the protein folding problem is, basically, how do all the molecular machines in your body come together in exactly the right way to do all the jobs they have to do to work?  

So, proteins are made up of these strings of amino acids, they’re made up of 20 different amino acids that can be in any length in any order, and the amazing thing about them is that they can fold.  They’re produced as these long strings but they fold up into exactly the right shape to do their job in milliseconds.  Now that may not sound amazing, but it is because, actually, there’s more possible ways that a protein can fold than there are atoms in the universe, right, so how then does a protein go from this long string to that folded up structure in the blink of an eye? It’s almost like it knows where it’s going, it’s almost enough to make me believe in God…not quite, but, you know, if there was an argument, that would be it for me. 

So it’s an academic question but also its a really important one because if we know how proteins fold then you can look at the sequence of the genes, because genes tell proteins what order to put their amino acids in, and then you could predict what structure those proteins have just by looking at all the gene sequences.  And if you know that, then you know what they look like and you know what shape you might have to design a drug to bind to them, to change how that protein works.  And also, it’s also important because there’s a whole raft of diseases that are due to mis-folding, so Alzheimer’s disease is a mis-folding disease, there’s a protein that does a very particular job, but sometimes it folds up wrong and then it becomes toxic and you end up with Alzheimer’s disease.  Mad cow disease is another example, and even cataracts, which is caused by milkiness in your cornea, that’s your proteins slowly mis-folding in your eyes. 

 

Well, I suppose the…actually, one of the first experiments in the field is the important one, it’s by a chap called Anfinsen, and he demonstrated this principle that proteins can fold by themselves very nicely because if you think about it, maybe there’s all sorts of other stuff that helps these proteins fold, maybe something comes along and moves it around to put it in the right shape, but what he did is he took some proteins and he unfolded them  and then they were just there, by themselves, a single type of protein, unfolded them and then put them into conditions where they folded and they’re folded into exactly the right shape all by themselves.  Now that’s a very important thing, it tells you that all the information that’s required to fold a protein is contained in itself and nothing else.  So I think that’s the one, that’s the one that flipped a switch in my brain and made me want to study it.

On new discoveries

I think, actually, the thing that I’ve read that’s most changed my view of how science was done actually isn’t a scientific paper, it was actually an article in the New Yorker and it was describing something called the decline effect, and this is something that seems to occur throughout science where the truth appears to wear off, you know, that was the way it was described. You have a theory and it’s published in a great fanfare, maybe in a great paper like Nature or Science, and so everybody really believes in it.  And over a period of time, though, that sort of study is repeated and the effect that was originally reported gets less and less, and there’s countless examples of this sort of thing.  

And the psychology behind it is quite complicated, but you can imagine that sort of what happens is, someone’s reported something, maybe that it’s a fabulous new drug and how well it works, then somebody else comes along to repeat it and their results are contradictory to the first one.  Now that makes it difficult for you to publish it, it also puts that seed of doubt in your mind that am I right, and maybe you subconsciously tweak things a bit so that your results are nearer to the original results and so you modify the original theory but you don’t drastically change it.  And then the next person comes along and does the same, the same, the same and then over a period of time the effect decreases.

And on the first reading of that I thought, oh my gosh, is science broken? You know, when you look at that, because there’s all these examples from anti psychotic drugs to…there’s examples in particle physics etc. where this sort of thing occurs. And after thinking about it I thought, well, no, science isn’t broken, it actually just works on longer timescales, so, you know, eventually science gets to the right answer, but it takes a whole process over a series of time with a lot of repetition because we are just human and we have a bias in our experiments that comes from what we expect those results to be.

On protein folding

Is there something in biochemistry that I’d like to see cracked?  Yeah, I suppose it’s the protein folding problem, that’s the thing, that’s the thing I’d really like to see cracked because then, it would totally change our understanding of biochemistry because…when the Human Genome Project was completed, that was held up as this great thing that would totally change things, but actually the problem is that whilst we have sequenced the human genome, at that point we didn’t know how to read it really, we didn’t really know what it all meant.  Now if you say, well, these genes, it looks like that,  it does this etc., then we’ll have a much, much better understanding of how all these proteins work and how they interact  with each other.  So I suppose there’s that and, you know, the field of proteomics, which is how all these proteins interact because there’s thousands upon thousands and you can imagine the complexity of that system. 

And that’s I suppose the really important thing because, you know, the cells in your eye have the same genes as the cells in your skin but they make very different objects, so how those genes are controlled, and then how all those proteins that they produce fit together, that’s the thing that’s I suppose the holy grail in biochemistry.

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