Being bold in medical research

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

Lupus is a severe syndrome affecting more than five million people worldwide. Most are women; but men can carry the burden of more severe symptoms. The work of Professor Fabienne Mackay, Head of the School of Biomedical Sciences at the University of Melbourne, led to the development of the first new treatment for lupus in more than 50 years.

Professor Mackay has also recently received a Lupus Research Alliance Award to explore a new therapeutic strategy for the treatment of the disease. Through this award, she and research partners will investigate depletion drug therapy together with a nutrition and gut microbiome methodology. It is the first time this approach has ever been taken.

Professor Fabienne Mackay sat down to chat with our reporter Dr Andi Horvath.

ANDI HORVATH
Tell us about your area of expertise.

FABIENNE MACKAY
So my area of expertise is immunology, in other words, the study of the immune system, but most particularly in disease. So the disease I've been focusing on is an autoimmune disease and it's called lupus, and lupus is basically - to explain simply, it's a disease whereby the immune system, for whatever reason, is turning against a person. So an immune system is designed to fight infection. It's designed to fight cancer, but in patients with lupus the immune system for a very strange reason is attacking the normal tissue of the patient.

ANDI HORVATH
Which tissues in particular does it attack?

FABIENNE MACKAY
So it may vary from patient to patient, but a very normal manifestation or a very common manifestation of lupus is a red face, a form of a butterfly on the face, which is basically skin inflammation, but there can also be a problem with the kidneys, problem with the lung and occasionally problem with the brain as well, and various other organs and tissues in the body.

ANDI HORVATH
How do we know we have lupus?

FABIENNE MACKAY
Well it's an interesting question because it takes a while to diagnose it, simply because each patient is different. A lot of the symptoms may make the practitioner think about something else, and it will take a number of tests, in particular a blood test, that will detect a form of antibodies called autoantibodies. They are diagnostic markers that usually suggest the person is having an autoimmune disease. Then there is a further clinical assessment looking at different parameters of health or disease or symptoms, and depending on how many symptoms the patient ticks, it may be characterised as lupus.

ANDI HORVATH
So this is a disease where our own immune system attacks our body?

FABIENNE MACKAY
Yeah.

ANDI HORVATH
Is there a cure?

FABIENNE MACKAY
No there is no cure. There are - in fact there are not great treatments either.

ANDI HORVATH
So let's say we're diagnosed with lupus; we've detected a certain antibody in a blood test that's at high levels showing that the body is under inflammatory attack. What happens next?

FABIENNE MACKAY
I think clinicians will do a number of tests. As I said, they need to be sure they're dealing with the kind of disease such as lupus, and it takes a while to be sure. Should they be diagnosed that it is lupus, then the practitioner will have to decide on the kind of treatment is best.

ANDI HORVATH
I want to jump to your success. You have created a lupus treatment and we've not had lupus treatments for 60 years. So you've really broken open the whole treatment of this currently incurable disease.

FABIENNE MACKAY
So I think the one you're referring to relates to a discovery I've made nearly 20 years ago. I mean time flies. Really what I was looking at - I was looking at a family of natural factors that we all make, and this family is called a family of Tumour Necrosis Factor. It was an important family because Tumour Necrosis Factor - the first one was discovered, or for short TNF. It's very important for inflammation. In fact there's been treatments development for TNF which block TNF and they are given to patients with rheumatoid arthritis for instance.

So I was in the United States and as you can imagine, because TNF was so successful, it was such an important factor in disease, many teams around the world were looking for the next TNF. The way it happened is quite interesting. At the time, the human genome, in other words all the genes in humans, were not known. We only had bits and pieces of information about that. In other words, the whole human genome was not sequenced yet, so we only had partial information about partial genes in the human body.

But those were listed in a computer and people were going to that computer and fishing for anything that looks like, smells like TNF. So it was a big race because everyone was after the next billion dollar molecule; the factor that's going to lead to the next blockbuster treatment.

So I was assigned particular bits of DNA and that bit of DNA was interesting because it appeared to correspond to a gene that's expressed a lot in the human spleen. The reason why it was interesting is because my previous work in the United States led to a really important paper in the prestigious review, Nature, on the spleen.

So the team in Boston told me well you know what, you're the spleen queen, you're working on this bit of DNA. So I thought okay, well let's do that. So working with another team in Boston we only had a bit. We needed the full lengths of that gene, so we work on that. We eventually got the full lengths.

Then I worked with a great person in Switzerland, Pascal Schneider, and we collaborated together, and he got the full lengths of the human version and got the full lengths of the mouse version. Then I had a very simple idea. I knew that the original one called TNF is bad when you have too much of it. So I said to Pascal you know what, I'm going to engineer a mouse model which expresses too much of that new factor which we call BAFF, B-A-F-F. So let's see what happens when we have too much of that new factor.

Is it as bad as TNF? Is it doing something different? Let's see. So we developed that model and as the mouse model aged, we figured they were not well. Then a long story short, we did the whole pathology and we realised that these mice were developing a pathology that was very similar to lupus in humans.

ANDI HORVATH
So you had the TNF gene that inspired you to look at the BAFF molecule it makes. You engineered a mouse that made too much of it. You found the mouse model for lupus. What happened next?

FABIENNE MACKAY
So this was published. There was a race because I wasn't the only one doing this, but I was the only one who knew what it was doing. Everyone had the sequence, everyone knew what BAFF was and we were all competing for it, but I was the first one to tell the world what it did. So I was the first one to publish the article that demonstrated that having too much BAFF is bad for you because it drives an autoimmune disease very similar to lupus.

So this particular article was cited more than a thousand times. It's a blockbuster. It's been very, very highly cited. But that kicked off a race. So the industry out there, pharmaceutical industry realised that targeting BAFF was a therapeutic target. We have to block it in patients with lupus.

So this happened - the story of BAFF happens when I first came to Australia so that's where I found what it did; what we had in the first place. It's important actually in the first place. We need to have this factor because without it we don't have a normal immune system. We won't have antibodies, but too much of it is bad because you're going to have lupus.

ANDI HORVATH
Oh right, so you can't really shut down the immune system because otherwise you'll get other diseases…

FABIENNE MACKAY
That's right.

ANDI HORVATH
…which is why it's so difficult to treat.

FABIENNE MACKAY
That's right. So anyway, we knew that BAFF was bad and I collaborated with clinicians in Australia and we found that patients as well have a high level of that factor BAFF in the blood. So that told us it was the right thing to do. We had to develop an inhibitor of this factor.

So many did. Many companies started the race to develop an inhibitor for BAFF, and so it was done eventually by one of those companies and we participated as part of my previous employer in the United States.

In 2011 in March this new treatment called Belimumab was approved by the FDA in the United States to be commercialised and to treat patients with lupus. So it was the first treatment in over 50 years. It actually succeeded in a clinical trial. Before that it's been a very sad story and it continues to be a sad story of many, many different prototype treatments being tested in the clinic and not showing any effects in patients.

ANDI HORVATH
Are some patients treated via diet?

FABIENNE MACKAY
Look that's still controversial because again being a scientist and knowing a lot about clinical intervention, the power of diet at the moment it's negligible. The real power of diet can only be demonstrated through a proper clinical trial, so with proper design, standardised diet and to see really the benefit. But having said that, there are a number of studies at least with animal models of disease that are showing a benefit in having a certain type of diet.

ANDI HORVATH
What type of diet's that?

FABIENNE MACKAY
The type of diet that is really effective is what we call a high fibre diet. We hear that all the time. When you read magazines or listen to the TV or the radio that eating your greens is good for you. Less fat, less sugar but more greens, more salad, more vegetables is good for your intestine, your gut and your health in general. So there's a bit of truth in that, but to really unravel that truth we need to do a lot of research to understand the mechanism of action. You see there's a lot of hype out there, were we know that a good diet is going to change the kind of gut microbiota. So what is microbiota? It is all the little bugs that live in our intestine. For a long time we knew they were there but we never really paid attention to them. In fact they're very important because they break down the food and they break down the food into small species of metabolites. Those go into the bloodstream and they have mostly beneficial effects in the blood and in tissues all over the body, especially if you have a good diet.

If you have a bad diet, like a lot of meat, a lot of fat, a lot of sugar, you can have bad metabolites and those can be bad for your heart for instance. But we're only at the beginning of understanding the bioactive nature of those metabolites, and unless we do this we're not going to be able to treat people properly.

ANDI HORVATH
What are some of the misconceptions about lupus? Does it get confused with other diseases and other treatments?

FABIENNE MACKAY
It can be because people are not always 100 per cent lupus. Some of them may have arthritis. They may have other manifestations.

ANDI HORVATH
Like?

FABIENNE MACKAY
Like inflammatory of the salivary gland which could be - which is another disease called Sjogren. So some of them can have a mixed presentation.

ANDI HORVATH
Is it like celiac's?

FABIENNE MACKAY
Celiac is slightly different. So celiac is related to the gut and…

ANDI HORVATH
That's the gluten reaction to…

FABIENNE MACKAY
Yeah, so it's more than allergic type reaction, although it's a bit of a component of immune reaction to the gut.

ANDI HORVATH
Tell us about the prevalence of lupus.

FABIENNE MACKAY
It's actually quite prevalent. It's a disease that is female-dominant so it's more frequent in women than men. I think it's one in 600, about 20,000 in Australia and five million worldwide, but the incidence is increasing, so there's more and more patients developing this disease.

ANDI HORVATH
I've heard Indigenous populations also.

FABIENNE MACKAY
That's right. So it's actually - the general population may not know that, but Indigenous Australians are four to six times more likely to develop this disease than the general population.

ANDI HORVATH
Tell me about, Fabienne the young scientist. Where did it all start? Where was this passion for science?

FABIENNE MACKAY
Actually my first passion wasn't for science at all. It's a long story but when I was let's say - I was probably 16, 17 - I was always a good student. My passion was around math and physics. I come from France, but you can tell from the accent I'm sure. So anyway, in my country, there are specific schools that train engineers. It's a specific system in France. They're called grandes écoles and I always looking at becoming a mechanical engineer and developing fast trains and airbus planes. So I was fascinated by the mechanical industry in France because we're quite good at it with the Germans and in Europe in particular.

Then unfortunately last year of high school I became sick. I had to stop for a few months and I was on and off school.

ANDI HORVATH
It wasn't lupus was it?

FABIENNE MACKAY
No it wasn't lupus. So that put a break in a particularly bad time; the last year when you're about to do - it's called baccalauréat in France which is the final degree in high school. So what I didn't expect - I was expecting to repeat that year and go again for the entry for that engineering school, but at the end of that year I was feeling better and my parents said well why don't you go and do the baccalauréat; you won't get it but you're going to repeat the last year; you'll get it the following year.

So what I did a lot when I was sick is read a lot and I didn't realise how well I - I was very much of a sponge and I remembered a lot of things. So when I went to do the baccalauréat I actually got it. I wasn't expected to get it but I did get it. The problem is you see my parents were happy for five minutes. We went to a restaurant that evening and at dessert time my mum said where are you going now? So I said to my parents do you know what, maybe I should go to a faculty of history, become an archaeologist or maybe become a lecturer in history or an historian. My parents were not too keen on that particular path because job prospects were not great.

The other alternative was medicine. So I had special consideration I could do medicine, so I decided okay. I wasn't sure about medicine because medicine meant after being sick, going back to hospital was the last thing I wanted to do. But I had to be somewhere, and my parents said well just do that; you're still convalescing and if something goes wrong the faculty of medicine is right next to the hospital, so they can catch you on the other side. I said okay I'll do that for a year and see what I'm going to do.

What I didn't expect is actually I really liked studying medicine. I really enjoyed it. I don't know what it is about it. I liked discovering maybe because of my own experience being sick. I was fascinated about understanding pathology in particular, you know why things go wrong. This machine is so beautiful, so well done, so sophisticated and yet why do things go wrong? So I was fascinated by that and I think that was a trigger I think.

Personal journey through being sick and then discovering a passion for medicine in a way, but I still wasn't keen on becoming a doctor because of my particular lack of appetite for a hospital environment. So I thought I needed to do something different, and I was a bit concerned in France at the time. We're talking the early '80s.

The life of a doctor in France is pretty - they're all concentrated in cities. You can live in a village, but in some ways a lot of elderly people live in the village so you'd be doing palliative medicine more or less – not quite but a lot of it – and not advancing medicine personally. Doing a great thing for the local population, which I thought attracted me - to be someone important who plays a big role in the life of these people, but not being to make a difference just using medicines that are just available, I wasn't satisfied.

So I thought I needed to do something different, and so I met with, funnily enough, some of my lecturers and they said you can make a difference, you just have to do medical research. I think that just did it for me. I said, yeah, I think I want to change. I don't like the treatment we're having. I was one beneficiary, I hated it, so I think if I've got to do something useful for mankind that would be a new treatment, something much better.

ANDI HORVATH
You certainly have. You've created a treatment for lupus that suits quite a large subset of the lupus patients.

FABIENNE MACKAY
Not all of them and this is another problem with the disease. As I mentioned earlier, it's very heterogenous so the biggest barrier we have is trying to determine when you see a patient will that patient respond or not to an expensive treatment. We have no way at this stage to really guess whether that person will benefit from a particular treatment.

I think there's a lot more work. We're doing that in my lab actually. Trying to understand heterogeneity better and use that information to do what we call personalised medicine. In other words, better predict the kind of drugs, so the kind of treatment that's going to work the best in the particular patient.

ANDI HORVATH
Tell me about what's changed since you were a young scientist to your laboratories now.

FABIENNE MACKAY
I used to love being hands-on on the bench doing my own experiment. I used to do a lot of them, being very efficient. Now you are trusting people to do those experiments for you, so it's different. It's good too because you're mentoring young people and you're sharing your passion and they're enthusiastic so that's good, but because I'm also very busy being a head of school I think perhaps there is sometimes that time frustration. Not having enough time to read; not having enough time to reflect about the experiment or the kind of the direction the research should take.

I manage a lot of after hours work because I still love it and I'm still passionate about it, but I think as you become more and more senior there's a lot of things that get in the way.

ANDI HORVATH
Has big data made a difference to your area of research?

FABIENNE MACKAY
Absolutely. Actually, I was mentioning better understanding heterogeneity in patients with lupus - that's big data. It's basically putting in a big computer every single bit of information you have per patient and has the computer to create pattern and tell us can you define subgroups out of all this mass of semi-disparate information on every patient. Can you compute that hours and hours and hours and come back with something that looks like a stratification? That's exactly what we've done.

The computer says yes, I can see things actually that can - I can put a group of persons in certain groups; I can stratify them a lot better.

ANDI HORVATH
What advice do you give to your students?

FABIENNE MACKAY
I think in terms of how to succeed and how to become a successful researcher, I think the main thing is to be passionate about this. This is a long journey being a scientist and it's not an easy journey. You spend your time convincing the world that what you do is very important to get funding, so that's one way, but I think what makes you succeed is to be convinced that what you do is really fundamental; that the questions you ask are really important questions.

I said to my students don't do minutiae. No one's interested in the little details. You need to sit back and look at the mysteries of the world and the things we still don't understand, and yet if we were it would make such a difference for patients or for our understanding of the human body or nature for that matter.

I think always go for the big questions. Always be bold. I think blue sky, a bit of risk is - I know it's never something that students are comfortable to do, but I think that's where you find the most valuable new discoveries.

ANDI HORVATH
You inspire your students by asking them to reflect on the bigger picture. Who inspired you?

FABIENNE MACKAY
I had many mentors along the way. I think my first mentor was a great researcher, really brilliant. His name is Jeff Browning. He was my first really significant mentor at Biogen in Boston. I think what I like about him - I'll tell you a funny story - that's how I managed to work on those big questions, and I managed to lift my game in a way. I thought I was pretty good. I did a good PhD in Switzerland and I had a very good mentor there, although he was very busy. I was very proud of papers I'd published and I thought I was reasonably good, but when I went to Biogen I realised that I wasn't so good.

So in the end I remembered Jeff saying to me - I was very proud of an idea I had one day so I came to his office. I said, Jeff I think we should do this experiment because I think I'd be fantastic, and he looks at me and he's saying, wake me up when it becomes interesting.
So I realised it wasn't bold enough and so I spent time in the library and did more research, and came back with something a bit more substantial and had a more risky, more sophisticated - but boy it would really get us a really interesting answer. So I went back with that and then he was very appeased - this is exactly what I wanted.

ANDI HORVATH
Tell me Fabienne what has surprised you in your journey?

FABIENNE MACKAY
What surprised me - surprises me and still surprises me today - is the fact that the human body and nature still has a lot of secrets to tell and I think - I thought we've done a good job understanding the immune system in my case. I thought now we're into the minutiae there's not much more to discover, but when you realised all the diet and the microbiome and there's a new dimension we completely missed, now it's coming back to us telling us well there's a whole story we didn't realise was there and now it's just excitement all over again finding out how is these layers working on top of all the layers we've already unravelled. So how do the two work together?

So I think that's what fascinates me, it is the fact that you think you know it all and then there's always something that comes and surprises you telling you well I actually you don't know a lot. There's a lot more to know.

ANDI HORVATH
You're a very celebrated scientist. Tell us about your awards.

FABIENNE MACKAY
Well a lot of my awards were big grants from the National Health and Medical Research Council. It's a very important support and it's been helping me in the last 20 years I've been in Australia, so it's very significant and particularly important form of support.

I've been recognised in a few awards. I had the Martin Lackmann Award. Named after a wonderful researcher in cancer who unfortunately passed away way too young. He was passionate about translating research into a new treatment, and this award recognises work that led to the development of a new therapy. This is aiming to develop new therapies.
I had a trophy from France. The French Government and the Minister of Foreign Affairs recognised my contribution as an expat in research and education as well, so that was done. The latest one is the Lupus Research Alliance Distinguished Award. I guess I've been in this field for many, many years and I came to New York – I presented to the society in New York a new project in collaboration with two brilliant scientists at Monash actually – Charles Mackay and Margaret Hibbs.

The three together came with really interesting projects and we all contribute something that will combine diet intervention and eliminations of harmful inflammatory cells together to really tackle lupus.

ANDI HORVATH
So the University of Melbourne and Monash University tackling lupus?

FABIENNE MACKAY
Yeah.

ANDI HORVATH
Next time we hear about lupus and autoimmune diseases what would you like us to think?

FABIENNE MACKAY
I think I would love the public to realise that lupus is actually very prevalent; that the therapies we have at the moment, even though I worked towards one, is not serving everybody. It's not helping everybody. It helps some patients but not all of them. One thing that you may not know and the general public may not know, but Indigenous Australians are four to six times more afflicted by this disease than the general population.

ANDI HORVATH
Are there clues that it's got to do with western diet?

FABIENNE MACKAY
It's still very early to tell. I think we need to do more studies on this, but the role of lifestyle - certainly lifestyle and the environment play a role. The genetic makeup of the individual plays a role. Which one is more important? It's still too difficult to tell and nobody knows really, but I think what's important to say and for the public to understand is in Australia not many people working on this disease - I'm one of the rare ones but a few others - but not many of us do that, and yet it's a significant burden for the general Australian population and certainly our Indigenous Australians. Yet we still have a lot to do to improve treatments and care of these patients.

As I mentioned earlier, the BAFF inhibitor is the first new treatment in over 50 years. The only one too. We haven't made any progress except this one and this one, as I said, helps some people and helps well when it does, but there are many others out there who have no more new treatments than the one that's been given for over 50 years and is not great.

ANDI HORVATH
Professor, I feel like I'm holding you up and I'd better let you go back into the lab.
[Laughter]

FABIENNE MACKAY
Okay, thank you.

ANDI HORVATH
Professor Fabienne Mackay thank you very much.

FABIENNE MACKAY
Well thank you for having me. Thanks a lot.

CHRIS HATZIS
Thank you to Professor Fabienne Mackay, Head of the School of Biomedical Sciences at the University of Melbourne. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on November 11, 2019. You’ll find a full transcript on the Pursuit website. Audio engineering by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2020, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.