Transcript

Exploring Biochemistry with Nick Hoogenraad

Nick HoogenraadNick Hoogenraad
n.hoogenraad@latrobe.edu.au

Matt Smith:

Welcome to the La Trobe University podcast. I'd be your host Matt Smith and I'm here today with Professor Nick Hoogenraad. He's the head of Biochemistry at La Trobe University and also the head of School of Molecular Sciences. Thank you for joining me Nick.

Nick Hoogenraad:

OK. Good.

Matt Smith:

Now, you've been a biochemist for many years now. How did you first get into biochemistry?

Nick Hoogenraad:

I guess quite by accident. Nothing was particularly well planned for me. It's just, I did an agricultural science degree at Melbourne University and we had to do two full years of biochemistry, like any science student and it was a subject that turned me on.

I mean basically once I went into biochemistry, molecular explanations of living processes, I know that that was exactly where I wanted to go.

Matt Smith:

And how long have you been a biochemist for?

Nick Hoogenraad:

Do I have to admit to that? [Laughter] Of course that's fine. Yeah I mean I started my PhD in 1965. So yeah it's a long time.

Matt Smith:

Biochemistry would have completely changed during that time. How has it changed?

Nick Hoogenraad:

Very much so. It's, perhaps most interestingly reflected in the fact that biochemistry as the name provides is the chemistry of biological system, biochemistry. And it had its background really out of chemistry, a branch of chemistry.

And that was in the days when we were defining all the chemical reactions of cells and living species. All of the professional societies, biochemistry societies, around the world had to change their name. Somewhere in the probably 80's, early 80's to Biochemistry and Molecular Biology. And Molecular Biology, it's the molecular studies of the living processes and so it's really the same as biochemistry, but more dealing with the larger molecules of life such as proteins, DNA, nucleic acids and so forth.

And so you can imagine that this came out of the molecular biology revolution where the first genes were cloned in the early 70's. First copies of messenger RNA and so forth and leading eventually into what we might now call biotechnology. Where we can use these tools to actually make biological molecules, which might be of therapeutic value or diagnostic value or other value for commercial purposes using these techniques.

So we can basically do things in test tubes and the test tubes even includes the cells that we work within plastic dishes. So we actually use living cells as a test tube for our research and that's molecular biology. So we call ourselves biochemists and molecular biologists.

So it's changed a lot and there are other times when people asked me what I am and I'm a protein chemist because we actually work on a protein part of things. And other times people ask me what I am, I say “I'm a molecular cell biologist.” I'm working on cells like as I just described to you. And so it encompasses every part of biology where we want molecular explanations.

Matt Smith:

I imagine such a field though wouldn't have been possible say about 15 years ago.

Nick Hoogenraad:

Well, it's probably longer. As I said the first cloning experience, I was actually at Stanford as a post doc originally and an assistant professor in the early 70's when Paul Berg and an Australian who was on sabbatical leave there, fellow called Bob Simons from Adelaide did the very first cloning experiments for which Paul Berg won the Nobel Prize. So it's been around a long time and I learned those techniques while I was there and brought them back to La Trobe with me.

Matt Smith:

So what are you working on now at La Trobe? You're working on mitochondrias.

Nick Hoogenraad:

Well, I say there's two quite different aspects as a technological interest that I have and there's a if you like a biological interest. A biological interest is on these little packages that the cell has thousands of these little packages where the energy is produced out of the energy we can extract out of food molecules. Actually converted into chemical energy called ATP that drives all living processes and everything from bacteria to humans.

Our thinking process requires ATP and muscles contractions does and the process that happen in this particular organelle or this packet. An organelle is really a part of the cell that has its own membrane encasing a whole lot of the enzymes, and if you like nanomachines, molecular machines and so my interest in that is how that organelle reproduces itself, separate from the cell because it's not controlled by the largest cell in that and how it speaks to the nucleus in insuring that there's a coordination.

So, if you need more energy you need more mitochondria. How the hell does that happen? How does a nucleus know to switch on a bunch of genes to make more mitochondria and so does this communication at a molecular level between these organelles and the nucleus where the DNA is. Just how do you actually carry proteins from where they made in the cell into these packages from proteins are so fragile and so prone to come out a solution and to aggregate.

Matt Smith:

You're trying to find out how the nucleus of the cell communicates through the mitochondria. If you do find this out what sort of thing can this tell you?

Nick Hoogenraad:

Ultimately I guess our curiosity requires that have we an explanation for all living processes. So there's a very basic need that we have to try and understand them. So people that go into science are usually pretty curious. They basically take things apart when they're kids and can't put them together but they're interested, they're curious in basic things.

And although it is very hard to sell the notion that the curiosity driven research, basic research is of any value to humankind. It really is because things go wrong and these aspects are basically valid yet it goes wrong and results in disease. OK that's one thing and so by understanding the basic biology only can you come up with therapeutic outcomes or diagnostic outcomes.

So, the big farmer, the big companies like Amden who's our partner in the CIC, which is a market capitalization of $80 billion dollars. Really big company. They're only interested in working with people that understand basic science well. They don't want some therapeutic that they go into a billion dollar clinical trial that can cost up to a billion dollars and get $500 million into that and find that they, if they did know more basic science they would've predicted bad side effect. They have to cancel the trial after having spent up that much money. So basic science very much underpins therapeutic and medical benefits, if you like. But in the planned area also, this basic knowledge helps us to design better ways to treat patients and get better products out of it and on the technology side, we can absolutely utilize our knowledge of basic science to actually make products. You sell satisfactory as I said before or you know as test tubes and we can make a erythropoietin for example. Then a hormone causes it to make red blood cells which the cyclists like to use illegally, but it's people with kidney transplants and so forth. There are products which can earn companies money that come out of good basic research as well.

Matt Smith:

If you manage to find you how a nucleus of a cell communicates with mitochondria, can you tell it to produce more mitochondria, which would maybe produce more ATP?

Nick Hoogenraad:

If that was beneficial to the cell. But one of the pieces of the puzzle I didn't describe to you to start off with, that I said all the DNA, the genes are in the nucleus but I was being inaccurate there because the mitochondria have their own set of genes. Very small number. Only 12 in humans. And the whole machinery for making proteins, are the information carried in those genes. So when the mitochondria has to reproduce itself it has to coordinate the activity of those 12 genes and about 1500 genes in a nucleus to make new mitochondria.

They can't do this without talking to each other, in a molecular sense. And so understanding that communication between the mitochondria and the nucleus is important. One could predict the sort of scenario that would occur and that is we would have a sensor in a cell that would say the ATP levels are too low, the energy levels are too low.

And one can design a sensor like that and that leaves to signal transvection pathways that's signaling to tell the nucleus and the mitochondria to switch on those genes that are needed to make mitochondria. So that means you need molecules that came from the sensing to the signaling, to receptors that can receive messages and then switch on what we call transcription factors, the machinery that switches control gene activity.

So we know what the components are going to look like. We have acquired a lot of information already about the basic processes. But the interesting thing if you think about it in the way I've been describing it, is it's all really a chess game. We can't see these molecules. If you purify these molecules and see in the synchotron that they exist in the cell as single molecule and so, can't see them, not under even the most powerful microscopes.

And so we have to design our experiments as a thought experiment, where we design in such a way that the answers we get out can only mean one thing and it takes us a step forward. And if the answer is no it doesn't happen, it also takes us a step forward because we can try an alternative now. So experimental design, exquisite experimental design so that you, it's like the game of battleships, so that every hit you make you know exactly where that hit is.

And I give my first lecture to honor students and we talk about philosophy of science. We're all amateur philosophers without being formally trained in it. But you just have to look at the progression of science you know exactly the sorts of things that happened that push science ahead. Why we have a scientific revolution that basically now will probably threaten our survival unless we wake up to ourselves very, very quickly. We live longer lives, good for us, good for the planet.

Matt Smith:

So down to our judgment really.

Nick Hoogenraad:

So my interest in that from a biological point of view and that takes me all the way from prodding chemistry to molecular or gene cloning and understanding genes. The other side is in the Corporate of Research Centre for biomarker translation which is a headquartered at La Trobe. Where all the technology that we need for all this biological projects, whether it's my project or anyone else requires a technological base such as a mass spectrometer, machines that are wonderfully sensitive. Where you can look at a very, very small number of molecules and identify them just purely based on their mass.

It sound simplistic but it's quite a complicated process and the machines they're wonderful, they're expensive, up to a million dollar a piece and we have built a facility with five of these instruments in it and it's a really state of the art facility and so this technology really underpins a lot of the research, a lot of people do in the department. So having a good technological base and people who have technological expertise to get the best out of these instruments is part of the foundation on which we've been build good biology or biochemistry if you like now.

Matt Smith:

Are you teaching students how to use this technology?

Nick Hoogenraad:

Yes, we even have kids in from high school who come and make aspirin in the lab and then they put it through the NMR machine to see, to prove that it's right, that what they've made is correct. And they go to the Mass Spec lab and they put it to the mass spec and see. And this is way to turn students on.

Scientists as I often say, actually partially think through their fingers and through their hands. You've got to be working at the bench, doing things to get those neurons firing in the right way. So students coming in and doing little experiments and seeing this technology and how they can use it is certainly part of turning kids on to science.

Matt Smith:

Professor Nick Hoogenraad, thank you for your time.

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