What is basic science? Dr Steven Zuryn explains the slow burn of basic science and how it is the building block for many of our current scientific endeavours and has the ability to affect generations to come.

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Donna: We humans are curious by nature. We want to understand the world around us. Why is the sky blue? How did we get here? Our greatest thinkers have never shied away from asking the big questions. For neuroscientists, understanding the brain and how it works comes from examining the basics of science, the fundamental building blocks that are crucial for great discoveries to occur in the future. In common parlance, the word ‘basic’ has become something of a slur in recent years. In popular culture, calling someone a ‘basic bro’ implies that they’re predictable and devoid of defining characteristics that make a person interesting or extraordinary. But in the science world basic means the exact opposite.

In this episode, we hear from Dr. Steven Zuryn, a laboratory leader here the Queensland Brain Institute. Steven talks to us about the importance of basic or fundamental research. What this type of research means to science and well, the fact that basic science is anything but.

Steven: So basic science doesn’t simply mean that easy and it’s simple to do. Basic means that we are looking at the very fundamental aspects of what's happening in biology. So, we’re looking at how nature works. Our theory is that if we can understand how nature works, we can understand what happens when nature goes wrong and you obtain a disease or some other kind of pathology. And by understanding how the underlying nature works, we can then work out a logical way to cure that disease rather than just guessing and doing trial and error. We actually form a logical hypothesis of how we could cure a disease; and in the beginning, we actually know what the disease is doing and how it’s actually disrupting - for example, your brain - and only by understanding how the brain works can we even begin to think about how to repair that. So, basic science has a post of translational of applied sciences we want to understand the very fundamentals of how the system works before we start to tackle what goes wrong.

Donna: Can you give some examples of what translational research involves?

Steven: Sure. So, translational research is basically gathering all the information that we've obtained from basic research and then formulating a way to use that basic knowledge to tackle some applied problem that could be health and disease. It maybe in environment and technology. So, it’s basically using what we've learned in the basic sciences and then applying it to a human problem. However, it would be naive to think that we know everything and we know the fundamental aspects of any field, let alone biology, so we have to maintain that basic science and we have to keep going with basic science, otherwise there would no such thing as translational science.

Donna: Basic science historically has led to some pretty amazing discoveries. CRISPR is something that comes to mind, can you talk a little bit about what CRISPR is?

Steven: Sure. So, CRISPR is a very new discovery only in the past few years and basically, what it is, it’s a mechanism that microorganisms can use to defend themselves against invading DNA from another species.

Donna: So, by microorganisms do you mean things like bacteria, for example?

Steven: Exactly. Like what simple organism, but they have quite complex ways that have been, like I said, that have been evolving for billions of years. And they have very elegant ways of dealing with pathogens and other types of threats to their own integrity. And so CRISPR is one way that they do that; they actually design a way in which one of their proteins can stick to a piece of nucleic acid and then that nucleic acid can go and then recognise the nucleic acid of a foreign organism, stick to it as well, in a sequence-specific manner, and then actually chop that piece of foreign RNA or DNA up. And so recently, that was discovered and now it’s actually been applied. So, we can hijack that technology that was found and identified, and use it for our own means: for example, we can now use that to chop up other pieces of DNA that are in any organism essentially - even humans, mice, a whole range of organisms. It’s a very highly conserved mechanism. And so, the idea is that in the future we will be able to actually go through and edit genes in the human body that may be mutated and cause a disease, such as cancer. So, theoretically, you could use this technology to repair genes as well as destroy genes.

Donna: So, you can use CRISPR to potentially treat disorders, but could you also use it to potentially bring back an extinct species?

Steven: Yes, so you have been doing that for a while now. CRISPR is just the latest type of editing technology that's become available since this new discovery, but there are other types of technology that have been around for much longer. The difference between CRISPR and order technology – and what I mean by older is that means that it’s just discovered by humans a bit earlier than CRISPR – is that CRISPR is a little bit easier and more flexible to utilise; and so it’s vastly cheaper and it’s quite highly conserve, so you can do that in another species. To bring back an extinct species using CRISPR is a little more complex than that cause we have to reassemble many different genes and DNA sequences to do that; and at the moment, CRISPR is quite limited in the fact that we can just edit maybe on gene at a time. So, it will take a lot of work.

Donna: I wanted to jump back to something you said earlier about you know the things that we don’t know when it comes to research. There are so many moments in science that have come about as a result of a eureka moment, almost serendipity. Are there examples that come to mind when you think about basic science?

Steven: Well, of course. I think the most famous example is the discovery of penicillin. I can’t remember the exact story, but I believe it has to do with mould growing; and that was where the mould was growing you didn't have the bacteria growing close to them. So there are these discoveries, but there are many like this where it’s not just serendipity; it's actually just a curiosity where a researcher is just trying to understand how nature works. They see something interesting, it doesn't make sense usually and it’s actually… it’s harder to work out when it doesn’t make sense, but when you actually work it out you’ve actually discovered a whole new idea, a whole new pathway, something that was never known before. It’s very different. And at the end of the day biology can be quite messy because we weren’t designed; we were actually evolved layer upon layer, upon layer of many, many years and because of that we're essentially a tangled mess. And so you see things that are completely unexpected and sometimes not logical, but it’s a whole new pathway that we would never had predicted if we didn’t just tinker in there, going there, try and work out what's happening bit by bit and that's basic sciences is trying to just work out how things work.

Donna: It’s kind of like having a jigsaw puzzle you’re putting together the pieces bit by bit without knowing what the picture is going to look like and you mentioned before that you worked on epigenetics, as well. Can you talk a little bit about what that is?

Steven: Sure. So, everyone knows about DNA and we have DNA code, a DNA sequence which is four letters: GATC; but on top of that there is another layer of complexity and one of those levels is that these letters can actually be modified. So you don't have to change the code itself but you modify the code; and these modifications can be induced through the environment, for example, an organism’s experiences. So, epigenetics is essentially these types of modifications that can be inherited, as well. So, for example a parent experiences a certain environment, their DNA would be modified during their lifetime and these modifications can actually be passed down to subsequent offspring. So, it’s a fascinating field where you can actually influence the genetics of your future generations just perhaps through the environment that you live. There's different types of pathways. It’s all not just modifying the DNA, it’s much more complex than that. There is at least four pathways that are well understood, but they all involved changes to gene expression that do not involve a change the actual code. So, these are things that can change during the lifetime of an organism and then be inherited down. So it’s quite a fascinating field and it’s beginning to explode now. All the ramifications of what happens during your lifetime may actually be passed down and that's quite interesting.

Donna: So, a researcher is able to tease apart exactly what kind of things, or stresses, or factors in the environment can modify the epigenetics?

Steven: Yeah, sure. So, one of the most sort of famous example is dietary intake. So, I work on a tiny organism called C. elegans which is a little worm, but this worm has been quite instrumental in this field because some of the pathways were actually discovered in C. elegans and led to Noble prizes. And one of the things that’s one of the most dramatic types of influence of the environments, is starvation. So, if you're to deplete the food of the worms and then re-feed them as if nothing happened, they would keep that memory of that period of starvation and that would transmit through at least three generations that were never exposed to starvation themselves. So, it’s quite amazing. There's other types of stresses, as well; and what we’re studying in the lab actually is wondering if the mitochondria have some influence over epigenetics, as well. If mitochondria become dysfunctional, can that also be transmitted to subsequent generations via epigenetics and that's one thing were looking at right now.

Donna: For a lay person, can you explain what mitochondria are?

Steven: Sure. They’re actually very fascinating little things that live in pretty much every single one of our cells, not just down your arms but along muscle cells or intestinal cells and they’re also in every single species that you see. They’re in plants, animals, everything. And what they are is they are little organelles that live in each cell, and they actually turn the food that you eat and the oxygen that you breathe into energy that the cell then uses to power things, like muscle movement or neuron firing, basically, every single thing. And without them you would obviously die. But the cool thing is that we never used to have them…well it’s a long time ago, but around a billion years ago, we actually up-took another bacteria into our cells. They started out as a pathogen and then, a symbiant and now we can’t move without them, basically; and they actually have their own DNA still. So, they're almost semi-autonomous.

Donna: So basically, this crucial part of each and every one of our cells now actually started off as a bacteria that our bodies took on?

Steven: Yeah. That's what the theory is. It’s called the endosymbiosis theory and that's what we still believe now and happened a very, very long time ago, but the fact that we did take up another bacteria and some of its genes got into mingle with our genes, but it still has its own genes, led to this very intimate relationship that is probably the most intimate relationship between any two, well at the time separate organisms, and now one organism. So, it’s quite a remarkable thing. But it allowed us to produce ever more energy and that's why we are so complex today – completely dependent upon this mitochondria for all of our energy needs. And our brain and our nervous system is probably one of the most if not the most energetically demanding organ systems in our body. So, if the mitochondria become dysfunctional, straight away would develop brain and nervous and muscular diseases. And right now, there's a lot of evidence suggesting that these mitochondria actually degrade overtime. They start to become more and more dysfunctional and that leads to this progressive nature and late onset of neurodegenerative diseases, like Alzheimer's and Parkinson’s. So, the mitochondria themselves are very important for maintaining neuron function. Neurons need a lot of energy. They constantly firing electrical pulses and it’s these mitochondria that power them and so, by studying the mitochondria and the function of the mitochondria –  and what goes wrong with the neurons when the mitochondria become dysfunctional – we can start to work out how the cells can counteract those effects and then hopefully use those counteracting effects to help cure diseases later on.

Donna: So, how does the work in terms of epigenetics relate to the brain or understanding how brain cells work?

Steven: It’s not exactly my field, but there's a lot of people studying how learning can occur and learning, it seems, can influence the epigenetic state of a neuron. So, if you learn a particular task, for example, the DNA can be modified and that modification persists, so that you have a memory. So, there's a lot of work now going into epigenetics and learning in memory. I think Associate Professor Tim Bredy at the QBI, he's into studying that. He has a few papers on this very interesting topic. So, I’m sure that epigenetics is gonna be involved in pretty much every single biological phenomena there are. It’s a highly conserved; it’s all the way from bacteria up to humans. So, it's a very ancient mechanism, but we've only recently discovered it. So as you can see with basic science, there's this basically an infinite amount of new discoveries to be made and if you would've think anything else it be quite naïve. So, there's much more to discover that will completely be different to what we’ve ever seen before.

Donna: I want to talk about C. elegans again. You said it's a small worm, but it is very, very tiny. It’s actually only several hundred neurons long, isn’t it?

Steven: Well, it’s about a millimeter long when they are full adults. So, you can see them with the naked eye, but only just .But that's right they only have 302 neurons, exactly. So, the interesting thing about this nematode is they basically clone themselves. They’re genetically identical. They're hermaphrodites, so they can mate with themselves and produce genetically identical offspring and they each have the exact same number of cells and exact same number of neurons and they…all these cells derive from a single cell in the exact same pattern of lineage. So, we can trace every single cell down to a single cell precision. That means we can really start to tease a part what cell does what and what gene does what in each cell. And that's why so many fundamental discoveries are made in such simple microorganism. They’re very easy to tease apart.

It’s like if you were a child and you're looking up at a tower clock and you're wondering how a clock might work. You just can't access it. You're too small, the clock is too big, but if you have a watch on your hand and you have the small little tools to open your watch you will basically understand how the big clock works based on how your watch works. The mechanisms are very similar just different sizes. So, by studying these very simple systems with only 300 neurons we can really understand how each component works, rather than something as complex as a whole brain which is a hundred billion neurons is so complex and it’s very hard to develop the tools to understand how it works.

Donna: If there's one thing you wish everyone knew about basic science, what would it be?

Steven:  Yeah. I think one of the big things is all basic research will most likely end up benefiting the human endeavour in some way or another and it's usually unpredictable, but it’s usually quite dramatic. So, we have to keep an open mind to where we invest our taxpayer dollars. Applied research into curing a particular disease is important, but so is the basic science that will lead to cures not right now, but at least in a decade or 2two decades or even longer. So, we have to keep an open mind and not just count on research to benefit ourselves or directly our children, but the future generations. And there are so many examples in the past where the basic research perhaps may not have benefited the immediate contemporary generation at the time, but has is now with us right now and we're benefiting from that. So, we have to keep an open mind about where our money goes and we have to think long term not just short term. Things take time and research is extremely complex.

Donna: Can you give some examples where a research fifty or a hundred years in the past has now led to benefits for us today?

Steven: If I was to pull out one example, the people that were studying yeast. So yeast is what we use in bread and beer, very small simple single-celled organism, microorganism, but they divide quite rapidly. Three people were studying how these cells divide and they started to tinker with them and work out what genes were actually necessary for these yeast cells to divide and they figured out the molecular machinery, the proteins that were required for cell division. And these proteins are what we now realise today are mutated in certain forms of cancer and when they mutated the cancer can uncontrollably divide and that's why we have tumours that grow. And if it weren't for these discoveries in yeasts, these were done fifty or so years ago, we wouldn't have any idea about the molecular machinery and its now because we understand that machinery we can design drugs to target that machinery, to try and either inhibit it or activate it. So, there are actual drugs on the market now that treat cancer that would not be here for it wasn't for people just trying to work out how this yeast cells divide.

Donna: That was Dr. Steven Zuryn explaining the slow burn of basic science and how many of our current scientific endeavours have the ability to affect generations to come. If you want to know more about basic science and the research we do here in the Queensland Brain Institute, visit qbi.uk.edu.au. I'm Donna Lu and our podcast is produced by Jessica McGaw. If you enjoyed this episode, let us know on twitter or Facebook. Tell you friends or you can give us a review on iTunes. Thanks for listening.

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