We talk to Professor Massimo Hilliard and Dr Steven Zuryn about the importance of fundamental science – what it is and why it is critical for generating discoveries that may have huge impacts to your health. Both researchers use roundworms to tackle some big problems in neuroscience. They study the basics of how cells in the brain and nervous system work in a simple animal to gain insights into how our brains work.

Transcript

Neuroscientists have to be fairly creative when coming up with ways to study the brain because it’s so inaccessible. Some discoveries, especially new tools or methods, are so huge that they have a significant impact on research for decades.  Often they take advantage of simple organisms – like worms – to explore how brain cells work when they are functioning normally, and also when things go wrong.   

I’m Carolyn Barry. Welcome to A Grey Matter, the podcast of the Queensland Brain Institute at the University of Queensland.  In this episode, we are exploring the concept of Fundamental Discovery Science – what is it and why is it so incredibly important, and why focusing on fundamental research will helps us understand the very building blocks of our brains. 

I’m joined by two of our research leaders: Professor Massimo Hilliard and Dr Steven Zuryn. They both use  C. elegans, a tiny nematode worm, to tackle some pretty big problems facing our society: Massimo and Steven, welcome.

Carolyn: Let's begin by explaining where fundamental science fits in to the research field. Massimo? 

Massimo: Broadly speaking, research can be divided into basic (also called fundamental science) and translational (also called applied science).  For translational science we mean research with a focus on an immediate clinical application, and that is driven by the need to be applied.  For example, developing a vaccine for COVID-19, or testing a new treatment for cancer.  Whereas fundamental science is what we would broadly define as curiosity-driven science that aims to understand a specific biological phenomenon.   For example, studying how cells divide, or how neurons develop and function.

Carolyn: Why is fundamental science so important?

Massimo: Both types of science are important and should co-exist.  Unfortunately, however, there is a damaging and unbalancing trend in our society to focus mostly on translational science.  The main reasons for this are that it is more intuitive - because there is a clinical application - is politically more justifiable, and it fits better short-term goals.  However, shifting away from fundamental science is really counterproductive and problematic, because when we reflect historically on how we have progressed in treating or curing diseases, real game-changing discoveries have come from fundamental science.

Carolyn: Can you give us some examples, Steven?

Steven: There are some very important and commonly available treatments that many people might now take for granted, but which weren't available 50 years ago.  These treatments only came into existence because of fundamental research that led to a basic biological discovery, which was then used to design a treatment – this is the same type of fundamental science we do at the Queensland Brain Institute. 

For example, Lovastatin, which treats high cholesterol, is a drug that was born from the discovery in 1957 of an enzyme, called HMG-CoA reductase.  This enzyme produces cholesterol in the cells of animals and Lovastatin blocks this enzyme and therefore reduces cholesterol.  This drug was FDA approved for medical use in 1987, and  Statin-based drugs are now a very commonly prescribed treatment that would not be here if not for the fundamental research into metabolic enzymes done 30 years earlier.  In fact, this Statin-based molecule prevent around 80,000 deaths by heart attack and stroke each year in the UK alone.  Statin-based drugs which are available at your local chemist for about $7 is just one example where a basic biological discovery, not driven by a medical need, led to a very commonly used treatment.

There are many other examples, and it has been estimated that 80% of the world’s most transformative medicines can be traced back to one or a few basic science discoveries, which were turned into treatments with translational research.  So, just to list a couple of other examples, you have:

  • HIV protease inhibitors for AIDS
  • ACE inhibitors for hypertension
  • Omeprazole for acid reflux

Carolyn: Are there more recent discoveries with the potential to transform medicine?

Massimo: Yes, there are. One example is the discovery of RNA interference or RNAi, which consists of a novel way to block the function of specific genes.  This discovery was made in 1998 by two scientists, Andy Fire and Craig Mello, while they were studying the nematode worm C. elegans.  They were awarded the Nobel Prize in 2006 for their discovery.  Importantly, their discovery was not motivated by a specific medical application or need, rather by their curiosity and pursuit in understanding the function of specific genes in the worm.  Just a few months ago the first RNAi treatment was approved to treat a serious human disease called amyloidosis, which is fantastic. 

A second and also very remarkable example is CRISPR.  This is a gene editing technology, discovered in 2012 by Jennifer Doudna, Emmanuelle Charpointier and Virginijus Siksnys, who will likely receive the Nobel Prize in the next few years, which gives scientists the ability to change specific genes in the genome.  CRISPR was discovered by these reserachers while studying bacteria, such as those that are used to make yogurt, and how these bacteria defend themselves from viruses – there was no medical application in mind. This discovery can be compared to having found a precision scalpel to modify the genome at will, and potentially allows the treatment of a very large number of human diseases and disorders in an unprecedented way. Importantly, CRISPR is already in the clinic, with the first patient, Victoria Gray from the USA treated in 2019 for sickle cell disease, and from a current report she is doing extremely well.   

But what do these game-changing discoveries have in common?  First, they were not born out of translational projects.  They were basic projects motivated by curiosity and excellence.  And second, they took many years, 10-20 years before they made their way to the clinic.  So, taken together, these examples remind us that, contrary to intuition, fundamental science is probably one of the best long-term investments for humankind. 

Carolyn: So, the focus of fundamental science is really curiosity-driven research. Is that how you see it Steven?

Steven: For me, fundamental science is learning and discovering how nature works. In the biological sciences, this can occur at different levels – from the most basic molecular level by which proteins and other molecules such as DNA interact inside of our cells, to the cellular level by which cells interact with each other, and then to an organism level by which animals, such as us, interact with others and with their environment. If we focus on the molecular scale of events, there is exceptional similarity between all forms of life, even if we do look very different on the outside. These microscale events evolved a long time ago, so they became firmly established before we split away from the other animals. Most of the basic mechanisms of how cells work for instance are shared between humans, mice, birds, fish, and even fruitflies and the microscopic C. elegans worms, which are all organisms we work on at QBI – and as you will hear in this podcast series more about them.  So, when we discover a new molecule, such as a gene or protein, and learn what it does and how it works, we are revealing a fundamental piece of how nature works - a cog in an extremely complicated clock - which was several hundred millions of years in the making. This knowledge helps us to understand how the human body works and can therefore help us to understand how a disease or any other pathological process disrupts normal processes.  Then we have a better chance of rationally designing treatments using translational research.  

For example, one of the main discoveries in cancer came from studies in yeast focused on understanding how yeast cells divide, a discovery for which Paul Nurse received the Nobel prize for in 2001.  This has allowed us to define the genes that control this process and develop drugs and treatments that can stop it.

Importantly, I don’t think we shouldn’t fall into the trap - and it would be naïve to do so - to believe that we now have a complete understanding of biology and can go straight to the translational research. The simple answer is we don’t. There is much we still don't know about how cells, the body, and the brain work, and we need to keep investing in fundamental research as a human endeavour. 

Carolyn: So here at the Queensland Brain Institute's focus is on fundamental discovery science, which gives you scientific and creative freedom to build a really strong knowledge base of how neurons and the brain works. Does this freedom change the way you work, Massimo?

Massimo: Yes, absolutely.  Having a place with a culture in which fundamental science is seen to be as important as translational science is essential to promote and support those researchers who are willing to ask major unsolved questions in biology, which inevitably will have a significant impact on how we solve medical problems.  The freedom to pursue curiosity is the main driver of creativity, which is a key attribute needed for outstanding science and ground-breaking discoveries.

Carolyn: Massimo, you study roundworms to see how their damaged neurons repair. How does using a tiny worm help you to understand nerve cells recover from this damage?

Massimo: Neurons communicate with each other through long and thin cable-like filaments called axons, which transmit electrochemical signals.  They function like electrical cables, which conduct electricity.  A nerve is made by dozens or hundreds of axons bundled together.  During nerve injury or in spinal cord injury, these axons are severed and the communication between neurons, or between neurons and their targets, such as muscles, is lost.  Unlike other tissues, such as bone that can regrow, or blood vessels that can be repaired, the nervous system does not regrow well and it’s difficult to repair due to the minute dimensions of the axons - think that the diameter of an axon is 1/50 of an average hair! - so neurosurgery is very difficult, if at all possible.  C. elegans neurons and axons are very similar to ours, and a number of molecules and mechanisms in worms, such as how axons develop, grow, find their targets and communicate are essentially the same to ours.

In 2004, a technical advance allowed us to sever individual axons in C. elegans, which in turn allowed us for the first time to study axon repair in real time and now in a genetically accessible organism, which meant we could alter specific genes and ask how they affected the axonal repair process.  Now, remarkably, what we and others discovered is that these animals have a superb ability to spontaneously repair their injured axons by stitching them back together, just like you would do with an electric cable to repair it.  If we could make this type of repair occur in humans that would be revolutionary.

Carolyn: So it seems like a bit of a stretch, you have this tiny round worm, it is transparent, it is less than a millimeter long, how does that relate to humans? 

Massimo: Study in C. elegans, as well as in any other model organism, is relevant to humans for two reasons.  First, because of evolution.  As we mentioned before, most basic processes, such as cell division, cell migration, neuron development, cell death, are in common among species and use the same or very similar molecular machinery.  So, the knowledge we acquire from model organisms informs us on our own biology.  Second, being much easier to access and manipulate, they provide us with a window or a lens through which to discover new biological tools that can be then used in medicine.  CRISPR-CAS9 and RNA interference discussed earlier are perfect examples in which new critical genetic tools would have not been discovered if those studies in worms and bacteria were not conducted. 

Carolyn: So, Massimo, tell us a a little bit more about the techniques you use to study these nerve cells in the worms.  How do you actually sever the axons?

Massimo: This is a great example about how fundamental science becomes the foundation of discoveries.  We use a laser mounted on a microscope, so we can visualise the worms and their neurons, and use the laser to selectively sever individual axons.  Now, behind this simple statement there are decades of fundamental science discoveries.  Our animals are transgenic and fluorescent, which means that to be developed they required knowledge of DNA and how to manipulate it, how to insert fluorescent molecules into the animal; and cutting the individual axon required engineering of a specific laser.  None of these advances were done with a translation purpose in mind.

Carolyn: What do you believe are some of your major discoveries that will have impact – what are you most proud of? 

Massimo: We have identified the molecules that in C. elegans allow the severed axon to stich back together.  These molecules function as the necessary molecular glue to repair an injured axon.  I think this discovery is fascinating per se in biology and has the potential also for a practical outcome, if in the future we can apply it to humans for nerve and spinal cord injuries.  

Carolyn: What about you, Steven? Why do you find C. elegans, this little worm, such an important tool for your work?  

Steven: As we have both mentioned earlier, many of the molecules are shared between C. elegans and humans - I guess we are both animals after all.  But the big difference is that C. elegans is extremely accessible to study and investigation and humans are not. We can easily access their genes, proteins, and cells and determine how they work, and not only that, but can do so very quickly, much faster than in other species like mice for example. We can edit genes, delete genes, add genes and measure the effects on cell function so that we can discover what they actually do and how they do it. They are also transparent, which means we can literally see inside of their cells and watch what is going on while they are still alive. This type of accessibility allows us to be very creative in the types of questions that you ask but also on how weaddress them, and that’s mostly due the fact that you are not costrained by any technical boundaries, or at least not as many as in other species.

Carolyn: Steven, tell us about your research and what discoveries have you made that you are most proud of? 

Steven: My team studies mitochondria. These are microscopic structures inside of our cells that generate the chemical energy through an extraordinary process called oxidative phosphorylation. Essentially, mitochondria use the oxygen we breath to burn the calories that we eat to generate a highly energetic molecule called ATP. Our bodies use so much energy that we actually generate our own body weight in ATP everyday.

Interestingly, however, mitochondria used to be a separate organism – a bacterial-like organism - that our cells engulfed about 2 billion years ago – this was when every animal and plant on Earth was still single-celled organisms, so a very ancient process. From there, a symbiotic relationship formed between mitochondria and the host cell and this provided the energy for evolution to produce the complex animals and plants that we see around us today. The mitochondria still actually have their own DNA, and this is what we study. We study this DNA and it mutates quite rapidly as we get older, which is bad for us and can cause disease. One thing we have discovered in the lab quite recently is that a couple of genes function to prevent mitochondria that harbour these mutations from being inherited to the next generation. This is extremely important, as these genes potentially help stop the spread of diseases to our children and then to their children. We used C. elegans to discover this process and the same genes also exist in humans, meaning that translational research could be performed at a future date to determine whether this new knowledge can be used to develop treatments for mitochondrial diseases as well as other diseases. We would never have been able to find this out if we worked on humans directly.

Carolyn: How do you see what is going on inside the worm and its mitochondria? I mean the worm already is really tiny, how on earth do you see the mitochondria inside the worm?

Steven: So C. elegans are transparent, which is a good start, but so is every other molecule – DNA, proteins, mitochondria - they are all transparent. So, we have to label them with something so that we can see them. In the 90’s scientists discovered the gene that made jellyfish fluoresce bright green and they then figured out that they could express this gene in C. elegans and make C. elegans fluoresce like a jellyfish – this actually led to Nobel prizes in chemistry because it was such a valuable revolution in biology, allowing us to label individual proteins and other pieces of the cell, such as the mitochondria and visualise them in the cell – not just in C. elegans but in other animals as well. In our lab, we simply take this jellyfish gene, which is called GFP – standing for green fluorescent protein, we link it to our gene of interest and express it in C. elegans. In the case of mitochondria, we attach the GFP to a protein that normally is found in the mitochondria and this essentially decorates the mitochondria with bright green fluorescence, which we can see under the microscope. They are really quite beautiful.

Carolyn: Can we really apply what we learn in worms to ourselves? 

Steven: As Massimo mentioned earlier, RNAi-based silencing, which was discovered in C. elegans in 1998, was medically applied to humans 20 years later. What we are researching in my lab with mitochondria, and what Massimo is uncovering with neuron repair, has the potential to have the same result, and perhaps even quicker considering that the timespan from discovery to clinic is shorter than ever.  Just going back to the CRISPR DNA editing as an example of that, the timespan was only eight years from discovery to successful medical use.

Carolyn: You've mentioned timelines like 10-20 years from the lab to the clinic. To an outsider, that seems like that's a long time. Can you explain a little more about why it can take this amount of time?

Massimo: I think the answer will depend on the specific disease, but why it sometimes takes so long is because we often still do not understand the basic biology of the specific disease.    

Steven: If I can add that once we do understand the basic biology, the translational research does take time as well and we then need to be sure that whatever therapy is developed, it is proven to cause no harm and actually work through clinical trials

Carolyn: Steven, why study mitochondria? What about them is so fascinating to you?

Steven: I think mitochondria are interesting because of the history of this 2 billion year relationship between what used to be two separate organisms that have come together to form one single organism. The relashionship between the mitochondria and our own cells is quite fascinating and there are a lot of different interactions, and those interactions are important. You have to imagine that there are two separate genomes, the mitochondrial genome and our own cellular genome, and they have to coordinate and express certain proteins that come together with really nanoscale precision in order to get the whole thing working. It is just fascinating that we have this very ancient endosymbiotic relationship; that relashionship is the source of a lot of human diseases, because things do go wrong between them.  Infact neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease are actually being linked closer and closer together with mitochondrial dysfunction, and mutations in the mitochondrial genome itself, suggesting that there is this really strong and intimate link beween mitochondria and human disease.

Carolyn:  Massimo, why do the type of research that you do? Why does it interest you?

Massimo: I am fascinated by neurons and by the mysteries they still hold.  Their incredibly varied morphologies and tree branches structure which are beautiful to observe, their diverse functions, and the idea that to some extent neurons are really the essence of what we are; we are our brain, and being able to study and understand what we are is incredibly fascinating. 

Carolyn: Massimo, much of your research is funded by you applying for government grants, but it doesn't cover all of the costs, right? In fact, about 17% of our Institute’s research funding comes from philanthropy.

Massimo: I feel very privileged and most grateful, and I am sure I am speaking also for Steve and other colleagues at QBI, to the Australian scientific community and to the National Agencies such as the NHMRC (National Health and Medical Research Council) and ARC (Australian Research Council) to consistently fund our research.  We are also very grateful to our philanthropic donors, who allow us to conduct studies that would be impossible otherwise.  Now, looking forward, there are two issues that need to urgently be addressed.  First, in Australia the expenditure for research measured as a proportion of the GDP has decreased over the years, and it is currently set lower than 2%, at 1.79% precisely.  This value is somehow reflective of the importance that a country places in a specific sector.  As it currently stands, Australia is in position 15 or so, and in disadvantage compared to other developed countries, such as US, Israel, Japan, Germany, China and others, which invest between 2 and almost 5% of their GDP.  Ans second, the Government provides our Institutions approximately 30 cents for every dollar that comes in from grants to cover the essential costs of research facilities and admin.  This is not close enough, it should be at least doubled, to support the important and continuing infrastucture and personnel costs that are required for the actual research outlined in the grant to proceed. Inevitably, these two factors have forced our Institutions to rely heavily on students’ fees to cover some of their expenses, and this is a problem that has been strongly amplified by the current COVID19 situation.  Generating awareness in our communities and persuade stakeholders on the importance of investing in research for our future economy, is thus paramount.

Steven: I agree with Massimo.  To appreciate the value in fundamental science as an investment in our long-term future, it is important that we remind ourselves of the past discoveries that have led to today’s treatments and cures.  A nice way to think about it is - “Someone is sitting in the shade today because someone planted a tree a long time ago”. The science that we do now at QBI, as well as other institutions around the world, is planting those seeds that lead to improvements for all of humankind in the long-term.

Carolyn: That was Professor Massimo Hilliard and Dr Steven Zuryn discussing their views on the importance of fundamental science and where they hope their research will take them. If you would like to learn more about Massimo’s and Steven’s work or any of the other scientists at QBI you can download our new magazine The Brain: Nature of Discovery at qbi.uq.edu.au/nature-discovery. Thanks for listening. 
 

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