Associate Professor Bryan Fry, biochemist and molecular biologist

Bryan Grieg Fry was born in the USA in 1970. He graduated from the Portland State University Honours Program with a dual degree in Molecular Biology (BSc) and Scientific Philosophy, with a minor in Psychology (BA) (1990-95). Drawn to Australia by its numerous toxic creatures, Fry completed a PhD from the University of Queensland on the toxic natriuretic peptides of the inland taipan (1997-2000, awarded in 2002). In 2000 he worked as a research assistant at the Australian Venom Research Unit (AVRU) at the University of Melbourne. Fry then took up a postdoctoral fellowship at the National University of Singapore (2001-02) which allowed him to work on Asian snakes and build on his research into snake venom evolution. Fry returned to Australia and the University of Melbourne as deputy director and ARC postdoctoral fellow at the AVRU (2003-06). In 2007 Fry joined the Department of Biochemistry and Molecular Biology at the University of Melbourne as an ARC Queen Elizabeth II Research Fellow (2007-11). Fry is now associate professor at the School of Biological Sciences, University of Queensland where he is group leader of the Venomics Laboratory. His work at the University of Queensland is currently supported by an ARC Future fellowship.

Interviewed by Dr Cecily Oakley in 2011.

Contents

Introduction

My name is Cecily Oakley and I am here at the Australian Academy of Science to talk to Dr Bryan Fry about his life in science. Welcome, Bryan, and congratulations on your Fenner medal.

Toxic first memory

Let’s start at the beginning. Where and when were you born?

I was born in the United States in 1970, just after my parents moved there from Norway.

When did you first get interested in venomous animals?

Toxins have been the abiding theme of my entire life. My first memory is of being torn apart by toxins. That memory is of being strapped to the bed at just under two years of age with spinal meningitis. I had full head and leg restraints and surgery to put tubes into my skull and legs. That’s my first memory – of being torn apart. I have a lingering reminder of that event in my right ear. That ear is useful for hanging sunglasses off and not much more than that. All the neurones have been wiped from that ear, except for one random mid-frequency peak where I have perfect hearing and then nothing either side of that. So I have a daily reminder of the power of toxins and a daily reminder of my own morality.

As a result of that toxins have always been a fascination of mine. I wondered why do these things do what they do and how do they do them? Then I fell in love with snakes and, from there on, it was a given that I was going to make this my career. I think I was around four years of age when I grandly announced that I was going to study venoms for a living.

That is a very early age to know what you wanted to do as an adult.

Yes. I have managed to turn a childhood passion into a career. I used my enthusiasm, my love and my wonderment for the area as my fuel during the very hard times. Science is an absolute emotional roller-coaster. You from thinking, ‘I’m a golden God’ to, ‘Whoops, I missed that piece of data and I’m actually wrong’ – and that’s all before 10am on a Monday. It is a manic-depressive existence. I don’t recommend going into it, unless you love what you are doing, and then it can be the most rewarding existence out there.

Did knowing what you wanted to do from such an early age help to drive you through school in order to get the grades that you needed for university?

Having a goal certainly helps. It gives you something to aim for. It also helped that I was absolutely in love with my area. A key to any successful scientist is that they are seduced by their chosen field. In my case, I kept venomous snakes, spiders, scorpions and centipedes as pets – and anything else I could lay my hands on. I had some very understanding parents. I grew up travelling all over the world because my dad was in the military. We would also go back to Norway in the summers. Because of that, I had a dramatic and unusual exposure to a wide diversity of animals. That gave me a deep and abiding understanding of the animals themselves, their ecology and their evolution. This was a competitive advantage while studying the biochemistry at university. But there are no courses specifically on snake venoms and no courses specifically on snake venom evolution, so a lot of that stuff I had to teach myself out of my own interest.

What did you study at university?

As an undergraduate I did a triple major. I did molecular biology, scientific philosophy and psychology. I then did a PhD at the University of Queensland in biochemistry.

A deadly symphony

Why did you choose to come out to Australia for your PhD?

Moving to Australia was always my long­term goal. I had decided that when I was about 16 and discovered how many venomous animals Australia had, and that was it. I just knew that I wanted to move to Australia, get my PhD and make Australia my home. I bought a one­way ticket. I have a little kangaroo passport and everything now.

What project did you work on for your PhD?

For my PhD, I worked on the inland taipan, which is the world’s most venomous snake. Specifically I worked on a unique type of toxin that I discovered in these snakes – these very small peptides called natriuretic peptides. These toxins are a mutated form of something that we naturally use in our cardiac system, but they have been tweaked so that they are more potent and long lasting. They are a good example of how venom is not a soloist or a collection of individuals. It is a full symphony, or you can think of it in terms of martial arts where it is a multiple combination of moves.

In the case of the natriuretic peptides, they are one of the first toxins in the venom to exert their effect on the body. They have a very devastating action on the blood pressure. They drop it so quickly that that is one of the things that renders prey unconscious. Natriuretic peptides on their own are not lethal. You could give a big injection of natriuretic peptides to an animal and the rat or whatever will wake up later on. But while it is unconscious, slower lethal toxins have time to do their job. So natriuretic peptides are an immobilising toxin while another toxin comes through and finishes them off.

What sorts of experiments did you do in studying these natriuretic peptides from taipans?

The main thing that we looked at was the effect on blood pressure. We showed that taipan natriuretic peptides acted quicker and lasted longer than the natural form of it. We did a lot of experiments using rat aortas, showing that they can relax the smooth muscle and open the aorta up really wide. So the taipan venom natriuretic peptides have a very specific action on the aorta (the aorta is basically the garden hose running from the heart to the lungs). If you increase the diameter of the aorta, your blood pressure is going to drop very quickly. It is quite simple math. Then I did a lot of different experiments using the snake natriuretic peptides and the human ones. I looked at where there are differences between them and worked out which areas of the peptide conferred a more active molecule. If you understand the structure function relationships, you can start tweaking the molecule and make a more improved version. We are continuing to work on those in trying to make a molecule that is useful as a therapeutic.

For medicinal purposes?

Exactly. It is the silver lining to the dark cloud.

Komodo dragon mythbuster

After your PhD, you went to the University of Melbourne for a year. What were you working on there?

I moved to the University of Melbourne and continued wrapping up a few loose ends. After that, I moved to Singapore for two years. That allowed me to work with a lot of Asian snakes that I couldn’t work on in Australia. The import restrictions were just too much of a pain. So I went over there and caught king cobras and all kinds of kraits and weird vipers. As well as a lot of rear­fanged snakes – the snakes that are traditionally not considered venomous. I showed that, while they are not medically important to a human, they have venom. That venom is toxic from the perspective of a five-gram frog. I even showed that the classic cobra-style neurotoxin was present in some of these nonvenomous snakes. That radically changed our view of the evolution of these animals and of how snake venom has evolved. It also revealed that there is an untapped Serengeti of animals available for drug design development research. Instead of their being 400 or 500 venomous shakes, there is more like about 2,200 venomous snakes. Then that set the platform to return to Australia on a postdoc fellowship from the ARC.

I continued working on the rear fangs and got lots of new stuff out of that. From there, I moved on to a QEII fellowship to develop a general theory of venom evolution. In the course of that, I got really intrigued by the suggestion that Komodo dragons had some sort of toxic bacteria. This never sat right with me. Bacteria don’t work that way. What has been going on all this time has been just breathtakingly simple. You have to view the Komodo dragon in two different ways as far as its predatory ecology is concerned.

Perhaps we should back up a little and you can tell us what the controversy is with the Komodo dragons and how they kill. I was taught that it was the bacteria in their mouths that made them lethal.

Basically, people have been overlooking the fact that the Komodo dragon is not from Indonesia. It is an Australian lizard. There are fossils in Australia from the Komodo dragon. They are forgetting that it is just a big lizard. There is nothing special about it. It is just a very large form of the lace monitor. And it is not even the biggest goanna to have ever lived. There are two larger ones that are extinct. Komodo dragons get to about three to 3½ metres. One of the larger goannas gets to four or 4½ and one of the extinct ones got up to about seven metres. They are all Australian giants. And as for the water buffalo, they are also introduced. They have been in Indonesia for only the last couple of hundreds of years. So there has been no evolutionary impact. It is an artificial situation. What goes on with this artificial situation, the only one that people are seeing, is that a Komodo dragon bites a water buffalo and it dies. But the water buffalo has a 100 per cent escape rate from the Komodo dragon after a bite. They never kill them right out. What do the water buffalo go and do? They go and stand in stagnant faeces-filled ponds.

We had a small boating accident on one of my expeditions researching the Komodo. I got shells driven up against my knee bone and some of that same water went into my leg. Thirty-six hours later I was unconscious, in the Bali SOS clinic, getting emergency intravenous antibiotics. So I know how quickly that infection can happen. But the infection is from an environmental source. It has nothing to do with the lizards themselves. It is no different than if I took a surgical knife and cut your leg and you went and stood in that same water. You would get infected. So that has been the source of that infection all this time. And, as I have said, that is an artificial man-made encounter that has no evolutionary basis.

Komodo dragons naturally evolved to feed on 40 to 50-kilo prey animals like pigs and deer. When they feed on their natural sized prey, they kill 90 per cent of that prey in the first three or four hours. 75 per cent of the prey bleed out in the first 30 minutes and another 15 per cent continue bleeding and die within three or four hours. That is one of the things that people have seen, but haven’t clicked on. When a dragon bites something, it keeps bleeding. Its victim seems to rapidly go into shock and bleeds and bleeds. That is what is the venom is doing. We have shown that the Komodo dragons have an anti-coagulant in their venom as well as other venom components that drop the blood pressure. It all combines to a steady march towards unconsciousness. The dragon can then tear the head off at its leisure.

The primary Komodo dragon weapon is actually the teeth. They have these very flat, large, double-serrated teeth. When they bite, they bite and they pull straight back, so they leave parallel deep cuts. It is like with a saw, each cut follows the other one and each notch goes a little deeper. It is the same thing with their teeth. It is basically grip and rip. The mechanical damage alone from the teeth wounds is enough to kill in some cases. For example, on Rinca, where we do a lot of our research, an eight-year-old boy was killed there a couple of years ago. He went and squatted in the bushes and a big dragon came up, got him and cut right here (indicates). The dragon sliced right through the boy’s femoral artery. That mechanical damage, the tissue damage, is enough to kill. The blood spurt was about two metres from his leg. But it was a little unclear whether he died from that or from when the dragon then grabbed him mid-body and smashed his head against a tree. That caved in his head and the dragon ran off with the body while being chased by the family.

They are very formidable animals and they can kill in a multitude of ways. The venom is that it is not like a death adder or a taipan venom, where the venom is the only weapon. The Komodo dragon bites, sits back and its victim dies. Here the venom is to support or to supplement the tooth damage. It is a combined arsenal system. You have the teeth as the primary weapon and the wounds which don’t close up. If you don’t die outright from cutting a femoral artery, you are going to keep bleeding until you are out of blood and then you are dead.

If the animal survives the initial attack, the Komodo dragon can follow afterwards?

Yes. It will hang around and do multiple attacks. It is a sustained, vicious attack. But the natural scenario for death is blood loss. And the same dragon that attacks will get that same animal. However, this fairytale of dragons all over the island, with buffaloes dropping dead randomly and other dragons benefiting... Nature doesn’t run a charity shop. There is no altruistic behaviour amongst dragons. The situation with the dragons and the buffalo is evolutionary irrelevant. It is a man-made situation and it has always had an environmental source.

Yes, the buffaloes do get infected. But all the studies that purported to show dragons having bacteria in their mouth didn’t sample the water that the dragons were drinking. Any bacteria in their mouth are a transient source of infection. Dragons actually have very clean mouths. After they have made a kill, they will sit there and lip lick for 15 or 20 minutes. Meanwhile they also rub their head inside the leaves and really clean everything up. Whenever I open up the mouth of even a wild Komodo, the gums are nice and pink and the teeth are shiny and white. They have much cleaner mouths than that of your average five-year-old brat chewing on your ankle.

Suffering for science

Have you ever been bitten?

Not by a Komodo. I have had a couple of big monitor lizard bites. I had a lace monitor destroy my hand, so I got to see what arterial spurts look like. You get really excited and spurt just goes faster! I don’t want to see that again. It took two surgeries to put that back together. It sliced the tendon, nerve bundle and artery in two places, while splitting both knuckle capsules down to the bone and grooving the bone on both sides. I’ve had a few snake bites and I have broken 23 bones in the field, including my back. I’ve had 400 stitches, three concussions, a near fatal scorpion sting in the Amazon, a nasty centipede sting in Costa Rica, a stone fish sting and a few other things that I can’t remember off the top of my head.

That’s a lot of damage!

Oh yeah. By the time I’m done, we should just donate my body to science fiction! But I am having a great time. I am absolutely living every single day to its fullest. Certainly I have a daily reminder of my own mortality. But I am having a lot of fun. I am getting to play with the animals that I am absolutely in awe of and, because they are my passion, I have been able be successful.

Do you spend most of your time collecting samples or in the lab?

My travel rate can depend. Last year, I was away for 10 months of the year. I can be gone for very long periods. I am off to Heron Island next week, then home for a couple of days, then back off to Komodo Island and then over to East Java to play with slow lorises (the only venomous primate in the world), then over to Arizona to catch coral snakes and then off to a conference in Spain. So it’s a really tough gig!

Yes, I feel sorry for you.

Venom evolution

You were awarded the 2011 Fenner Medal from the Australian Academy of Science for research in biology, specifically for advances in our understanding of venom protein evolution. How did venom evolve? What did you find?

Venom doesn’t come out of thin air. There isn’t a little intelligent design fairy that comes by and goes ‘Poof, have another venom molecule.’ The building blocks come from the body somehow. A perfect example or, two good examples are from tiger snakes. Their venom does absolutely devastating things to the blood chemistry. Their venom has a mutated form of a blood coagulation enzyme called factor 10. It has been mutated so that it is 1,000-fold more active and 100-fold more resistant to being broken down by the normal regulatory enzymes. It is a good example of a massive overdose. In fact it is no different than if we just kept infusing you with massive amounts of normal human recombinant factor 10. You would have the same clinical pathology as you would from a tiger snake bite, which ultimately can involve bleeding in the brain and other fun and exciting things like that. But it shows the very simple way that venoms evolve from other things.

Another way for the venoms to evolve is to make a molecule that gives you an underdose. With things like a death adder, their venom is chockers full of a modified neuropeptide, so instead of turning something off, it just sits there and blocks the receptor. Therefore none of our normal acetylcholine can get through and none of the messages can get through. You lose all control of the muscles and death is from respiratory arrest. If you can’t move the diaphragm, you can’t inflate the lungs. If you can’t inflate the lungs, you don’t get any air. If you don’t get any air, you are not going to live very long. So the tiger snake and the death adder are good examples of the two basic ways that venom evolution happens – an overdose scenario or an underdose scenario. The venoms evolved to use the body’s building blocks against its victim – weaponising the proteins. There are lots of different mutations selected by evolutionary processes after that, to confer entirely new activities.

Conservation through commercialisation

I understand that there are also medical applications. Perhaps you could explain some of those.

Venoms already have had a very long and profitable history in drug design development. There are two good examples. If you know of anybody taking high blood pressure medication, the odds are that they are taking a class of compound called ACE inhibitors. The medical importance of the drug class cannot be overstated. A founding member of that entire multibillion-dollar drug class that has saved countless lives was a snake toxin. That has been one of the rampant drug development success stories not just of a venom-derived compound but of any drug class. That is one of the most successful. There is also now a new diabetes treatment that is from the venom of the Gila monster, one of the lizards. That is also drug yielding multibillion-dollar profits.

You have all these natural resources waiting for you. When people ask me, ‘What’s the best way that I can convince people to conserve?’ I say, ‘Your weakest argument is to talk about how beautiful and wonderful these animals are, because the only people who are going to appreciate that are the people who already think that way. You are preaching to the choir.’ Your strongest argument is basically conservation through commercialisation. People who don’t care about venomous animals or nature in general are not going to be swayed by the argument, ‘We need to conserve because they are awesome.’ That is not going to get them. But, if you talk to them about wiping out a forest being no different to taking our mineral wealth in the Kimberley and blowing it up or throwing it in the ocean – it is the same economic destruction. You can’t predict where the next wonder drug will come from. Often it is from the most unlikely of sources, like an ugly lizard or a horrible snake, that we have these wonder drugs that aren’t just saving lives but are making a lot of people a lot of money. You therefore need to view it as a resource. Imagine if we treated our banking sector the way we treat our environment. Oh yeah, the banking sector is a bit of a mess too, isn’t it?

Currently, yes.

Why invent the wheel? Collaborate!

Do you have other people that you work with in your experiments – collaborators perhaps or PhD students?

I have an extensive variety of collaborators. If you look at the papers I publish, often they have a cast of thousands. I have had a few papers with over 20 authors from 13 different labs and six different continents. That is very deliberate because I have a very simple philosophy of ‘why reinvent the wheel?’ If I want a certain technique done or a certain assay performed, I will find out who is the best in the world and I will go there and do it alongside of them. In that way, I can learn it and bring it back. I go there because there are always some little tricks that they have, their own little innovations, which you are not going to get just from reading the protocols in the paper. You have to see how they are actually working their magic. I end up collaborating on multiple studies with a lot of these people. I have some very good friends in Holland with whom I do my magnetic resonance imaging of the venom glands. We have had half-dozen papers so far on that imaging, including two Nature papers. So I like to collaborate. I don’t like to compete. I like the idea that, if you collaborate with the proper people, it becomes a case of one plus one equals three. You get this beautiful emergent property that happens and things get done faster and with greater efficiency, which is all that I’m after.

A lot of people are very insular. They try to do their own little empire building in a closed-door lab and everything is all hushed. But I have the luxury of having a monopoly on an area, so I can relax. I have samples that nobody else has. So I don’t need to worry about any competitors. I am the only person in the world with Antarctic octopus venom glands, courtesy of going down to Antarctica with the Australian Antarctic Division. I am the only person in the world with Komodo dragon venom glands. I have all these resources that are only mine. It means that I have something that other people want. And it also takes a lot of pressure off me. Versus if I was working on something like drosophila. My definition of a model species is that it is the same animal that everyone else is working on.

Most of the scientists who work on venoms are very restricted in the number of animals that they can work with, because they don’t go out and collect them themselves. They have to buy the venom from Sigma or from a serpentarium. This means that any of their potential collaborators have access to the same resources. That is not going to give you a competitive advantage. Also they don’t understand the animals. It is like they think: ‘All right, let’s keeping working on cobras,’ ‘Why?’ ‘Well, 80 per cent of the articles are on cobras. That must be the hot area.’ No, it just means that it has been raked pretty heavily. Also they don’t think about: ‘Well what about this remote population over here?’ For example the king cobras that we are working with over in the Andaman Islands off India. They are a very unique population. We have worked out that they are not from India. They have swept over on the oceanic currents from Burma. The Andaman Islands population is an isolated population. That is where you are going to find the greatest biodiversity.

I have a very simple philosophy with the drug development side of things: ‘that will naturally take care of itself’. That is basically my view of it. I am not motivated by that. I am motivated by working out the evolutionary hot spots. The venoms from the biodiversity hot spots are going to be the most unique. And they are naturally going to have the most novel compounds, which will therefore be of greatest use in therapeutic development. As opposed to finding a whole bunch of me­too compounds that are quite similar to the whole bunch of things that we have known about since 1930.

Your research has taken you from Antarctica to Norway and to the oilfields of Palestine. Could you share with us some of your experiences there?

Some of the things have been surreal. Like our safe house getting blown up in Karachi, Pakistan, three days after we left. That was interesting. There has been a long list of smouldering wreckages of rental cars along the way, but we don’t mind that. ‘Zero deductible’ means never having to say you are sorry. Going to Antarctica was as close to a religious experience as I am ever going to come. It was so breathtakingly beautiful. I was in awe of this place. I am very privileged in that I get to see a lot of these places before they’re wrecked. I get to see the disappearing natural world, and that is what motivates me. I want to get out and see and experience and live in the nature that is still there. I will spend the month of July tucked away in the rainforests of East Java playing with slow lorises, the only venomous primates. I get to have these wonderful experiences because of what I do as a scientist. That is what makes it all worthwhile. It makes the career uncertainty worthwhile – all the dramas that come with being a university scientist. There are a lot of very trying things that we have to put up with. But, done right, we also get the greatest benefits.

Back to UQ

You recently moved from the University of Melbourne back up to Queensland. How did that come about?

It was always my grand plan to return to UQ. That is where I did my PhD and I would have to say that the happiest time of my life was doing my PhD at UQ. It is such a magical campus. But there came the sad day after I graduated that I had to go out and make my own name before I could return. It goes to the very heart of scientific discoveries – it has to be an exercise in intellectual pollination. People stay and they stagnate. People that I knew who did their degrees at the same time as mine at UQ and who have stayed have definitely stagnated. They are not getting the big papers out, they are not taking risks and they are not getting the rewards because of that. Because they are playing it safe they are not getting the fellowships and they are not moving up their career path. So I had to go out and take my risks, I had to do all that to make my own name. Now it’s sort of the prodigal son returning, and I am absolutely thrilled to be back up at UQ.

Where do you see yourself in 10 years time? Still at UQ or having moved on again?

I would be quite happy to stay at UQ. I love Brisbane. I have bought a house at the top of Mount Glorious, tucked back away among the trees. Suburbia stresses me out. I hate seeing neighbours. But I’m very happy to be back at UQ. It is a great campus. I have moved to a different department, so I haven’t moved back to the same one that I was at. I did that very deliberately. I am at the School of Biological Sciences now. It is a young department. I already knew some of the people there. Everyone is very like-minded and evolutionary driven. A lot of them are quite mad, so I am not the only inmate in the asylum. I am really happy to be back up there. That was my major goal. So, if it is the last university that I am at, I will be satisfied with that.

Cheerfully insane

Do you have any interests outside of science?

Yeah. They seem to suspiciously involve large amounts of adrenaline. I race my motorcycle and sky dive. I do a lot of big wave surfing and other pedestrian, sane activities.

In preparing for this interview, I googled you and one of the first things that came up was a picture of you and your tattoos. When did you get those?

My first tattoo was a colourised version of the logo of the Australian Antarctic Division. That is over my heart. I got that after my trip to Antarctica because it was such a special trip for me. But I waited a year before I got that first tattoo. I had the idea of getting it while I was in Antarctica. I told myself, ‘Tattoos are forever. So it’s not going anywhere and time will pass regardless.’ So I waited a year and a year later I still wanted it. I knew that, once I had got one, I would get more. I just wanted to make sure that I properly wanted them. I have the chemical formula for adrenaline tattooed on my neck. I have two Komodo-dragon CT skulls on my shoulder blades like angel wings. They are actual data from one of our dragons. I have a very abstract snake that was drawn by a girlfriend in Italy. I also have biohazard symbols on each shoulder. I now have all tattoos that I want and I am done with that – I have got the imagery.

Actually, Carl Zimmer, a very well known science writer, is putting out a picture book of scientists and their tattoos. He has collected thousands of images from all over the world. People are very inventive and often these tattoos are very personal. All my tattoos are very personal in that way. But scientists and tattoos seem to go hand in hand. It is this little quiet secret.

Perhaps the tattoos are a bit more creative too?

Yes, exactly.

Finally, you work with creatures that are specifically and beautifully designed to kill. Are you mad?

Yeah, I would say that I am cheerfully insane. I think that is a fair description of me. No­one has ever accused me of being normal. But I am also one of the happiest people I know. I am doing what I love. If I had millions of dollars, I would be doing exactly the same thing. I am not motivated by money. In fact, I am dreadful with money. I make sure that my bank account doesn’t drop below an arbitrary number and then I have all the bills set to auto pay. As long as the balance doesn’t drop below that arbitrary number, I don’t care. Of course, it is easy not to care about money when you have money. But I am not driven by a need to buy another stock or another bond or a need to invest. I am not worrying about that. I am living. I am not working to survive. I am enjoying life. I think that I am one of the most self-fulfilled people that I know because I have stuck to my childhood dream. I have stuck to my passion. I haven’t used the same amount of academic training to go and become a doctor instead. I could have been very good at that, but I also would have been dreadfully unhappy.

It is lovely to talk to somebody who is so passionate about what they do. Thank you for coming and talking to me today, Bryan.

My pleasure.

For more information about Dr Bryan Fry and his research check out his website Venomdoc