Wednesday 30 April 2014

Inside story: Professor Andrew Halestrap - School of Biochemistry

Interview by Melissa Levy

Andrew Halestrap is a professor in the school of Biochemistry as well as as the head of his own research group who are interested in both the role of mitochondria in cell death and monocarboxylate (lactate) transporters. If you want more information about the work which he and his group do then click here.

Where did you go to university and what did you study?
“I was at Cambridge, where I studied Natural Sciences specialising in Biochemistry and then I came here to do my PhD. That was a long time ago and I stayed here ever since! I started my PhD working with Dick Denton (Professor Richard Denton), working on the regulation of fat metabolism in the epididymal fat pad. And then I branched out… I stayed in Bristol, got a fellowship and then a lectureship and I stayed here ever since. I’m very unusual [in that] l I stayed here ever since my PhD.”

If you had to describe the research you are doing to someone who doesn't understand the concepts, how would you describe it?
“Well I’ve got two areas of research that I’m doing at the moment. The bigger area of research is how you protect the heart from damage after a heart attack or during heart surgery. So during a heart attack when you have a coronary thrombosis (the coronary artery is clotted with thrombus) the blood supply stops and then the downstream area is gradually getting damaged because it’s got no oxygen. What they do when they bring you in to hospital is to clear the blockage (we call that reperfusion) and unfortunately the reperfusion, which you’ve got to do to restore the heart function…causes more damage. [It works by doing] something to the mitochondria, it turns them into reverse so instead of providing the energy to drive the cell they actually start breaking down ATP and destroying the cell.  This gives you a damaged area called the infarct, which is just dead necrotic tissue. We are understanding the molecular mechanism and developing treatments to prevent that from happening which will prevent the heart from this damage. And it’s relevant in surgery because when you have cardiac surgery you also have to stop the heart which means stopping the supply of blood, and if the surgery is long then you can get this same reperfusion damage. So we’re also working for cardiac surgeons and applying some of the stuff we do in the lab, understanding the mechanism and how we can prevent it, in the clinical field.  There are clinical trials going on with some of this stuff which is quite exciting! The first clinical trial was successful so we’ll keep our fingers crossed.  And then the other area is in lactic acid production in our cells, which is why I sometimes rabbit on about lactic acid (!!). The process whereby lactic acid gets in and out of cells is a process we discovered many years ago working on the molecular mechanism, and the particular interest at the moment is understanding the structure of the transportes so that we can design better inhibitors that could block the process in tumour cells. If you block lactic acid efflux from tumour cells you can actually kill them!”

How would you describe your typical day?
“A lot of my time is spent writing reviews on grant applications and reviewing papers because I act as an editor and referee of papers. A lot of time is spent writing papers, reading papers, talking with my research group; I don’t get to the bench much now. So I talk with my people regularly about what they’re doing and we think about the next set of experiments. Then sometimes of course (like today) I have a fair bit of teaching and marking to do, some days they’ll be very little teaching. And then there’s administrative jobs, various university committees and things that take up [time]”

What’s your favourite part of your job?
“Oh, well either doing bench research which is really fun but I rarely do it, or just thinking through data and deciding what experiments to do next; it can be very exciting but also very frustrating.”

Do you have any advice for someone who’s looking towards a career in science? 
“The first advice is that if you really want to be active in hands on research you’ll have to do a PhD, and you’ll probably end up doing some post-doctoral work as well. If you’re really good, and that’s only a very few now, you may then get a permanent research position as an academic or in a research institute. Other people will probably realise that they’re not quite good enough to get to the top of the pile so they can go off into maybe an industrial position acting as science officer. Realistically far more people will want to do research than will be able to… So some are going to end up, either after the PhD or the postdoc, going into other science related things. It could be teaching, it could be scientific journalism it could be a rep for a biotech company. There are many levels where you could use your science. And other people change completely and become a managing director and go and do an MBA - It’s very varied!”

What is the most memorable moment of your career so far?
“Ooooooh most memorable? Well I’ve had several that’s the problem! I had a eureka moment; I was literally in the bath and I was trying to work out a way of measuring how much this mitochondrial pore was opening in a heart. I was sitting in the bath and I had an idea, it was just a eureka moment and it worked and it’s one of my most cited papers. That was a good one! But there have been plenty of others.”

If you could do research with anyone in the world, dead or alive, who would it be?
“I was asked this by someone else in a different context and I found it very difficult to choose one person because, when you get to my age, you’ve worked with a lot of good people. I don’t know really… I think the scientist I admire most is probably Fred Sanger (who’s now dead). He took up a challenge that people thought was ridiculous - to sequence proteins - and he succeeded and then rather than capitalising on that he thought ‘well I’ll go off and sequence nucleic acids’. And he went and did that and got a second Nobel prize. He’s [also] a very humble guy, and when he was 65 and he decided it was time to retire he just left science and worked in his allotment. I think that’s a very special person.”

Saturday 5 April 2014

It’s Worse in the Water

by Rob Cooper

The vast majority of the surface of planet earth is covered by water and considering this it should be no surprise that whilst terrestrial (living on land) creatures can get rather frighteningly large, the denizens of the depths are always one step ahead. In this article I’ll examine ten of the most fearsome, peculiar and benign ocean creatures with the hope of showing just how fantastic the diversity of ocean live has been over time.

1. Dunkleosteus
Back in the Devonian a peculiar group called the Placoderms developed to truly monstrous sizes. Characterised by their armoured bodies and bony plates instead of the teeth the Placoderms reached their most terrifying in the killer whale sized Dunkleosteus. Strangely for such a large predator the 8 metre long Dunkleosteus could suck prey towards its mouth by rapidly opening its jaws (in less than 1/15th of a second). Unhealed bite marks on the head guard of younger Dunkleosteus also lend evidence to a theory of cannibalism.

2. Helicoprion
If you thought Dunkleosteus had strange teeth you may be surprised to learn far stranger tooth morphologies existed in the prehistoric seas. Helicoprion is a fantastic example of this having a ‘toot whorl’ that looked remarkably like a circular saw inspiring many strange artists’ impressions of the creature. The function of the peculiar teeth has yet to be determined but it is thought that the successive rings of teeth are analogous to growth rings in trees and that teeth successively pushed up to replace those that were lost, similar to how its modern day relatives sharks replace their teeth today.

3. Megamouth Shark
To continue from shark like animals to true sharks we next encounter a very rare modern shark colloquially known as the ‘Megamouth shark’. Since its discovery in 1976 only 55 specimens of this elusive shark have been seen or caught. Like its larger relatives, the basking and whale sharks, the Megamouth has an enormous mouth full of very small teeth that are ideal for sieving plankton from the ocean. As it follows the movement of plankton down to over 200 metres in depth it has small photophores (light emitting organs) to attract plankton and small fish to its 1.3 metre wide mouth.

4. Megalodon
It would be an insult not to mention the mightiest of all ocean predators in this article and Megalodon certainly fits that title handsomely. Well respected as the largest and most powerful predator in the history of all life (with one competitor) megalodon is now estimated at lengths of at least 14-18 metres and up to 20 metres and weights of slightly over 100 tonnes. Megalodon has the largest jaws ever discovered in the animal kingdom large enough for a full grown man to walk through without bending down and an estimated bite force of over 180,000 Newtons. This, along with other palaeontological evidence, suggests that Megalodon preyed on large whales until its extinction 1.5 million years ago.

5. Livyatan 'the great whale'
But what animal was big and ferocious enough to rival Megalodon? Strangely enough the answer comes from a contemporary of Megalodon’s the titanic Livyatan. Livyatan was a raptorial sperm whale which lived between 12-13 million years ago in the Eocene period. Akin to megalodon Livyatan remains have been found alongside those of baleen whales, sharks, dolphins, porpoises and many other sea creatures supporting the hypothesis of Livyatan being an apex predator alongside Megalodon. Unlike modern sperm whales Livyatan had the largest teeth of any animal yet discovered (bar the tusks of elephants and walrus) at up to 36cm in length. Livyatan was thought to ambush prey swimming at the surface from beneath much like the modern great white shark.

6. Leedsichthys 'monster fish'
From two rather fear inducing giants to a rather more benevolent one. Meet Leedsichthys, the largest bony fish to have ever lived. Leedsichthys ranged from around 10 to nearly 15 metres in length so probably rivaled the modern whale shark in size although a heavier bone skeleton likely made Leedsichthys considerably heavier. A strange tendency in large oceanic animals is that of eating remarkably small prey and Leedsichthys was no different and likely fed on plankton either by pumping water through its huge mouth or actively swimming to filter small organisms from the water around it.

7. Giant Manta Ray
Benevolent giants still exist today in the form of the majestic manta ray. Gliding through the waters like marine birds these gentle giants can have a wingspan of up to seven metres and weigh over a tonne. Manta’s are also filter feeders and typically herd their tiny prey into tight balls and swim through at speed with their large rectangular mouths open. On occasion Manta’s have been observed somersaulting through particularly tight balls of prey presumably to catch more prey.

8. Predator X
Leaping back 155 years to the late Jurassic period we come to a group of marine reptiles called the Pliosaurs. Pliosaurs were characterised by short necks and immensely powerful large jaws, the largest specimens having estimated bite forces comparably or far greater than Tyrannosaurus rex. Predator X was one of the largest of all Pliosaurs reaching between 12-15 metres long and possibly weighing up to 45 tonnes. Strangely, compared to modern day marine species, Pliosaurs used their four flippers for locomotion and had no tail fins to speak of; two of these fins would be used for normal locomotion whilst the other two would be used to create a burst of speed when ambushing prey.

9. Plesiosuchus
Crocodiles are often said to be living fossils and quite rightly so for modern crocodilians have hardly changed at all for hundreds of millions of years. However back in the Jurassic period, something very strange happened in crocodilian evolution… They began to adapt fully to living in the sea. At around 6.8 metres in length Plesiosuchus was one of the largest marine crocodiles and like its kin had shed the heavy, restricting armour of its forebears in favour of a streamlined body. The skull of Plesiosuchus shows many similarities to modern killer whales implying it regularly predated on large marine reptiles of the time.

10. Shastasaurus 'ocean giant'
On the topic of marine reptiles, it would be immensely uncharitable of me to finish this article without mentioning the largest marine reptile yet discovered. Shastasaurus was a primitive ichthyosaur, a group of marine reptiles that in their later stages would bear many similarities to dolphins yet the primitive forms were quite unique. The prey base and feeding method of Shastasaurus remains a mystery as it seems to have had no teeth and the suggestion that it fed on soft bodied molluscs is generally not supported by ichthyosaur skull morphology, what this strange animal was specialised for we may never know but that hardly makes it a less thrilling creature to imagine.

The oceans simultaneously offer some of the most fearsome and most benevolent creatures that planet earth has ever harboured. From gentle filter feeding giants to titanic ambush predators lurking beyond the reach of light the oceans are a place where life has fully explored the limits of size. No dinosaur has even come close to the largest baleen whales of today and whilst we may be thankful that many of their huge predators such have Megalodon have finally passed on; we do ourselves a great service by remembering just how rich the oceans are and how important they are as an ecosystem to us and other terrestrial species.