Speaking of Science: Discovering a breakthrough in the fight against cancer with Professor Andrew Wilks

Myelofibrosis (MF) is a rare chronic blood cancer that is characterised by the accumulation of scar tissue, or ‘fibrosis’, in the bone marrow which prevents the bone marrow from producing healthy blood cells. The cause of MF is not fully understood due to the complexity of the disease - however, some researchers believe that overactive proteins are involved in its development.

But did you know that both the key underlying cause of MF, and its treatment were discovered here in our own backyards in Melbourne?

For our Speaking of Science webinar, centred around World Cancer Day, we were joined by molecular and cancer cell biologist, as well as PM prize winner, Professor Andrew Wilks. Professor Wilks completed the rare ‘trifecta’ by discovering and patenting several important drug discovery targets and defining their roles in cytokine signalling. One of which was momelotinib which is now used to treat MF.

Listen to how he discovered the drug momelotinib that ultimately led to one of the greatest breakthroughs for the estimated 1 in 100,000 people diagnosed with MF.

Recorded on Tuesday 18 February from 10:00AM – 11:00AM AEDT.

Video transcript

1:30 Professor Steve Wesselingh
OK. I think we might start.

So welcome and thanks for joining us for the first Speaking of Science webinar for the new year and we only started this last year and actually it was really successful.

We've got lots of people online. We had fantastic topics and great researchers and really good questions. So welcome back to this year and hopefully we can replicate it and even grow the Speaking of Science webinar this year.

But before we start, I'd like to acknowledge the traditional custodians of the lands that we're all meeting on. Particularly, I'd like to acknowledge the Ngunnawal people, the Traditional custodians of the Australian Capital Territory of where I am today. I acknowledge and respect their continuing culture and their contributions they make for the life of this nation. I pay my respects to the Elders past, present and emerging and extend this respect to all Aboriginal and Torres Strait Islander people joining us online today.

Before we start today, just a bit of housekeeping. If you want to ask questions, please think about them during the talk and put them in the chat and then we can ask Andrew at the end. Also, if you couldn't join or you know, people who couldn't join the webinar, obviously we're recording and then people can see it later. Or if you miss something, you can watch it later again.

For those who don't know, World Cancer Day was observed on the 4th of February and World Cancer Day raises awareness about cancer, encourages its prevention, mobilises actions to address the global cancer epidemic. And as I'm sure you're all aware, because we've all been touched by cancer, cancer is more than just a medical diagnosis. Behind every diagnosis is a unique human story that involves families and grief and pain and resilience and a patient centred approach to cancer treatment that fully integrates an individual's needs and their family's needs is critical to leading to better outcomes. And that's why this year's World Cancer Day theme was United by Unique, which really places people at the centre of the care and their stories at the heart of the conversation.

One of the really difficult cancers that are is regularly diagnosed across the world is myelofibrosis, a blood cancer that's characterised by accumulation of scar tissue or fibrosis in the bone marrow which prevents the bone marrow from reducing healthy blood cells. We don't totally understand it, but we have increased our understanding dramatically and actually that increasing understanding and the development of some amazing treatments has actually happened right in our backyard here in Melbourne.

And obviously that's a segue into today's speaker, Professor Andrew Wilks. Professor Andrew Wilks is a molecular biologist and a cancer cell biologist who's been involved in kinase research for over 30 years. Firstly, as an academic researcher at the Ludwig Institute for Cancer Research and more recently as a founder or co-founder of a large number of more than a dozen innovation-based companies in the drug discovery space.

He's the founding partner and current CEO of Synthesis Research and Anaxis Pharma and a past or current board member a number of Australian biotech companies. Andrew really has experienced the whole pathway, the whole discovery pathway from being an academic scientist to finding a target to developing a drug and then commercialising the drug. So really for us, it's very exciting for us to hear from Andrew today.

As I mentioned, he's been involved in a number of biotech companies, but he's the founder of one of Australia's most successful biotech companies, Cytopia, where he co invented and led the team that delivered the therapeutic JAK inhibitor that's used to treat myelofibrosis. This JAK inhibitor has recently been approved by the FDA in the United States and is now being considered for listing on the PBS in Australia. So, so really, really exciting.

Andrew was recognised for his outstanding contribution to drug discovery and development in Australia by receiving the 2024 Prime Minister's Prize for Innovation alongside his colleague Doctor Chris Burns.

Even more exciting for Andrew though is he's now on two NHMRC committees, much more prestigious than the Prime Minister's Prize. He's on the Industry Philanthropy Commercialisation Committee and he's on Research Committee.

We're really privileged today to hear from Andrew about that whole process of you know, being in the lab, finding the target, developing the drug, and then the whole challenges that we know exist in Australia around commercialisation, developing companies and developing new drugs. Really looking forward to Andrew's talk.

Thank you for coming to our webinar today, Andrew. I'm really looking forward to your talk. Thanks.

7:12 Professor Andrew Wilks
Terrific. I'm going to put my presentation up. Can we get a thumbs up if we got the presentation up?

So well, thank you, Steve, and I really appreciate the opportunity to talk. This is a terrific platform for us to sort of evangelise some of the more important things that we're all thinking about, and I guess give people the opportunity to give feedback.

I having agonised over it, I'm going to be quite self-indulgent and tell that story that you just spoke about those sort of bench to bedside story about the JAK Kinases and the inhibitor we built and Momelotinib.

I'm going to try and decorate that story with some of my, well, some soapbox moments. I think there's a lot to evangelise about in terms of this translational piece that Australia has such promise in but is rather under delivered on, I think. Perhaps I can share that there is, there's two versions of this presentation. One I give around coffee time, which is the one you're going to see and one I give around cocktail time and that's a rather different proposition.

You can certainly ask me questions in the question time and I'll give you the gory details of some of the things that actually happened on the way through here. But I think it is a bit of an object lesson in translational piece and so if you'd indulge me, I'm going to speak about that for the majority of this presentation.

I want to do a couple of things at the start of this and one is a bugbear that I have. I often quite facetiously say that I went to the dark side in the late 1990s to the company side and I often hear that I'm doing commercialisation. I think the word commercialisation is wrong.

I actually quite resent the use of the word commercialisation in the sort of thing that I've been doing it. I think it presents a barrier to creating some cohesive translational piece. I much prefer to think of myself as a translational scientist, a preclinical translational scientist. I've done the discovery piece, and we'll talk about that. But translating those early discoveries into actual therapeutics is what I do that there's no difference in the quality of the science that's required. There's a slight difference in focus and sort of application of the techniques but that translational piece is where I am at and that's where my passion is.

I think we can do much better and taking advantage of that amazing basic discovery research in the life sciences that we have in, in translating that and coming out with good outcomes. Then of course, there's clinical translation, which of course we're all very much aware of. Then finally, if you get the package right around the discovery and the preclinical translation and that clinical translation. Then finally, as patients are being approached, that's when the commercialisation piece happened.

There's a role of course for two streams of research here. Academia of course has a huge role in the discovery piece and increasingly is leaning into that translational piece and there are a number of mechanisms that, you know, MRFF and other sort of funding bodies that can actually support that translation of by academia. Of course, in the clinical sector that's always been the case, but biotech is a separate and a separately funded stream of research in that translational space and we've been very, very poor, I think, at finding funds for that.

I think part of the problem is that barrier between discovery and commercialisation, but part of it is also a lack of cohesion of academia and biotech and about how we can make the most of that discovery and early stage translational work. There's a, you know, there's a little bit of a soapbox thing, but I'm more than happy to discuss about, about my thoughts around that. There's so much more that we can do.

I'm not just sucking up to the NHMRC. Part of the research that I'm going to talk about, the early-stage stuff was very much funded by the NHMRC with no strings or attachments to it. The Ludwig Institute was of course incredibly important, but we tapped into the NHMRC as a funding source at the Ludwig Institute quite early on and then through the early discovery work, you know there's a Manhattan Project that involved ourselves and people at ICRF and the Rockefeller was funded by a Human Frontiers grant.

You know that there is a saying in, in this business that, you know, too much money is never enough and of course that's as Roy and HG would say, and that's definitely, definitely true. And I think one of the big problems in this translational journey that we all need to go on is finding that cocktail of funding sources that would appropriately help us progress the work that we're interested in delivering. But I just wanted to acknowledge that because it really is was an important part of what we did.

The other piece to recognise, I mean, we've had all of these gongs and awards and stuff, Chris Burns and me and others, but it really does take a village to create the drug. There was a whole bunch of people at the Ludwig Institute who are part of that academic discovery piece that ought to be acknowledged in all of this. Then Chris Burns and his team at Cytopia on our biology team and then collaborators at the Monash Institute of Pharmaceutical Sciences and Monash University who delivered the crystal structures and then our collaborators. I mean this, you know, I could probably fill this slide with 100, 150 people who actually had contact with this molecule as it's been brought forward. I just want to make sure that there is love to go around for everybody who's been involved in this and quite justifiably so as well.

OK, so Once Upon a time, so if you go into the Royal Melbourne Hospital and you go onto the 7th floor in Ward 7B which is the leukaemia ward and you look down, you go to the corner office ward and you look down. You can look into the office of what was Don Metcalf's office. I had the rather unfortunate opportunity to be down there with, with my son in law who had leukaemia and he had Neupogen, Phil Grasstein, GCSF going into his body helping recover his neutrophils, having had chemotherapy.

You could look down into Metcalf's office where he discovered all of that stuff. My office was on the other side, but you couldn't see it. But that should have a blue plaque on it, I think that building, because there's such a lot of contribution to haematology and to the treatment of various types of cancer.

This man Don Metcalf, so famous was he that he had his own postage stamp was the father of haematology. When I give this talk to undergraduates, of course I have to explain what a postage stamp is. But he really was an extraordinary influence and a whole bunch of people and there's a whole clade of scientists like myself and Doug Hilton and Nicole and others who came through the Metcalf empire and benefited enormously from it.

But his masterpiece was of course, this sort of cellular description of hemopoiesis. From hemopoiesis stem cells that were self-renewing and somewhat differentiative all the way through to the mature T cells, B cells, red blood cells, cells of the macrophage and neutrophil phenotype. He actually with others opened up this whole cascade of differentiation and more importantly even also was able to define some of the small molecules or the proteins actually drove this process and there's a couple there, GCSF and GMCSF that of course were actually discovered by that microscope down below Ward 7B. GCSF was the molecule that was going into my son in law and that was an extraordinary contribution to science. and again, as I said, we all sort of benefited and, and lived off that those discoveries.

My own role when I came, which was 1983, was to try and figure out what their cellular receptor for some of these cytokines actually looked like. The notion was that these molecules would have specific impacts on various precursor cells and cause them to differentiate and proliferate in certain directions and therefore there must be a cellular receptor that helped determine that process. I tried for five or six years to  figure out what those receptors, were banging my head against a wall and not quite succeeding until I had an a brain wave, until I had an idea that it was perhaps the case that these cellular receptors might be kinases.

Kinases in those days were, was a pretty underpopulated family of molecules that would have been 20 kinases that we were aware of. Some of them were oncogenes had been captured by viruses and were transforming in their nature. Some of them were receptors and so the EGF receptor for example, and the PDGF receptor were known to be protein tyrosine kinases. The notion was that, well, it's entirely likely that these cellular receptors for these stimulating factors were going to be CFS as well.

I invented a technique using PCR probes to create a library of related kinase molecules using these highly conserved regions that were found in all kinases. I applied that PCR, cloned them all out and you know, this was one of those sliding door moments for me in my life. Went from having, you know, one student and a technician to having probably 35 people in my lab.

Because what came out was a whole bunch of receptors that were really very important in determining fate of endothelial cells and other cell types. Then these scruffy little kinases that didn't quite fit, we call them FD17 and FD22. There was a harvest of new molecules that came out and from there my lab expanded and I was able to sort of work in all these different areas.

But FD17 and 22 were kind of strange. They clearly weren't receptors. They had a kinase and a pseudo kinase and a bunch of other domains. They had no external domain and so I called them just another kinase, just another kinase 1 and just another kinase 2 and that's where the acronym JAK came from. JAK1 and JAK2. It wasn't too long, having consigned them to the bin for a while that we realised how important they actually were and started to work on them.

When I published them, I had to come up, I love the acronym, it was a great acronym, but I had to come up with another justification for it and so they became the Janus Kinases. There are 2 kinase domains here that sit back-to-back and if you squint, you can imagine this chap on the right here, the Roman God of Doorways Janus, that they kind of look like that having 2 faces, 2 interacting faces. And so, they became the Janus Kinases. When I published them, rather cowardly, I felt I justified that acronym with the word Janus Kinase and so that's where the JAK came from originally.

Then there was a whole Manhattan Project working with people like Ian Kerr and George Stark.

There were a whole bunch of interferon signalling mutants and we were complimenting that those mutants with full length clones for the stats. Jim Darnell was providing that and we were providing all the JAK stuff and we were showing that whilst they were mutant in their interferon signalling, we could replace that mutation. We could complement that mutation with full length JAK molecules and so we could replace that with JAK1 and recapitulate the signalling.

That put some real nice genetics into trying to understand how these molecules fitted into cytokine signalling. Of course, the irony of it was that the original goal of trying to find cytokine receptors as tyrosine kinase failed miserably because they weren't tyrosine kinases, but they did use these JAK molecules as the intracellular signals downstream to deliver those intracellular signals through the STATS and so forth. That was, I think, a good demonstration of how this works.

Then we worked a lot on the biochemistry to show how these molecules phosphorylate each other and the choreography and the dimerisation and so forth. And so fleshed out this pathway, this JAK/STAT pathway, which has since been much amplified, and all the details have been put into it. But it became clear that this was a central and important pathway in the decision making of a whole bunch of different processes, hemopoiesis, for example, almost all of the cytokines that control hemopoiesis use this pathway to one extent or another and then a whole bunch of differentiative processes and so that became the work of ourselves and others.

It's interesting to note that part of this, that the reset switch, which was actually something that was discovered at WEHI as well by Robin Starr and Doug Hilton and others. So this became very much a Melbourne based pathway as we went through.

At this point I think I became slightly bewildered, slightly giddy with all of the opportunity here. I started to work very much on the genetics of this and trying to understand what was happening. It was clear that there was a JAK Kinase in Drosophila and that was playing an important role in segmentation. Really amazing work by some, some colleagues in Boston, Rich Benari and Norbert Perriman. Then it became clear that there was a mutant allele of this same Drosophila gene that actually caused cancer and so that was really interesting. This was, I think, the first example of a dominant oncogene to be found in Drosophila and these melanotic tumours were actually caused by mutation in the JH2 domain.
Hold that thought because we're going to come back to it in a minute, that this mutation here caused a dominant allele to be formed and that drove these cancers in the embryos of the Drosophila and demonstrated that there was something interesting going on with how these proteins were regulated.

Then finally I started to work on zebrafish in a genetic system and looking at the epistasis of the JAKS with all these mutants that were being created by various people around the planet as a way to try and tease out what other interactions there were with this pathway and other pathways and how this crosstalk actually happened. But as I say, having a whale of a time, and this is by the middle of the 1990s, just a really fun time. I then had some kind of midlife crisis or epiphany, I'm not sure which. We were having such fun, but what impact were we actually having on other humans? I decided somewhere around the mid-90s that I really wanted to translate this work.

I really wanted to find a way to take these learnings that we'd come through all of this wonderful basic research and see if we could actually change therapy, change treatment for patients and sort of improve the quality of life for other humans. There's a whole as a cocktail hour discussion of the psychology around that, but it really became the thing that I most wanted to do to the point where I decided I was going to leave the Ludwig Institute and start this company Cytopia.

I thought that was going to be the only way that we could take these discoveries and actually create new medicines and see if we could make that impact that needed to be made on the back of the discoveries that we've made. This is the translation piece of the work.

I had a bunch of patents, I had a benevolent VC team, 2 words you don't see very often together benevolent and VC. But there was a chap called Kevin Healey there who put dollar one into the company, a very important contributor from Medicare holdings. Finally, having been told that I couldn't do Biotech and stay at the Ludwig, the upper management of Ludwig came in behind and gave me the licences to all of this technology. I jumped ship completely from being a full time academic to being a full time translational scientist under the auspices of Cytopia.

There was quite a lot of learnings, as you might say, from that process. It's not, it wasn't an easy time. It's an extremely difficult time. But that commitment to the translation piece was really what was driving me to actually make that transition and see what we could do. I had no experience in it whatsoever and so I was on a very steep learning curve.

What came, I mean, clearly knowing the involvement of these proteins in blood cell development and also therefore inflammatory processes, it was obvious that we could direct some inhibitors in that direction, JAK inhibitors in that direction were we able to develop.

But what really transformed the sector really was this discovery by a number of different groups in Boston and Paris and other places that there was a single point mutation in JAK 2V-617-F that was the predominant driver of Myeloproliferative Disorders, now known as Myeloproliferative Neoplasms.

So Polycythemia rubra vera, essential thrombocythemia and idiopathic myelofibrosis of the bone marrow cancer that we heard from Steve at the at the very start of this. All of these are driven by this hypermorphic JAK allele, which causes the hyperproliferation of precursors to red blood cells and causes that bone marrow scarring.

If you think back to that Drosophila experiment, we kind of knew this already because this was exactly what was happening in those Drosophila mutants that were driving those melanotic lesions. There was a hyper in exactly the same place. There was a mutation in the Drosophila that was causing those cancers in the fruit fly that were also causing cancers in the human. So, the notion was now we had a very specific target that we could direct our JAK inhibitors against. A single point mutation that was driving these MPNs. This is what's happening here. This hypermorphic JAK2 allele is pushing those cells to proliferate and causing the problems.

This is what PRV looks like. It's a very rare disease, 80,000, maybe 100,000 people and they basically get too many red cells and too many platelets and that is a problem that causes viscosity problems, when the hematocrit goes up and it also causes problems with clotting and so forth because of the thrombosis. Then there's a propensity to progress to leukaemia and to myelofibrosis.

When the bone marrow starts to get exhausted from that so much activity in producing those cells, you get this extra medullary hemopoiesis, you get expansion and growth of multiple abdominal organs, the spleen in the liver particularly, but the splenomegaly is a huge problem where we're trying to replace that the bone marrow as a source of hemopoietic cells.

Of course, the sad part is that having progressed from the initial disease to the myelofibrosis, ultimately these patients have a relatively short life expectancy and will die if they're not treated. We had this in mind now as we drove our discovery programme. This was in the good old days, old school medicinal chemistry, you know, plausible, robust, scalable chemistry, adding functionalities to scaffolds and sort of growing out the molecules using standard med chem technology.

Assaying them on the other side, exploring what fitted well and what didn't and very much as I said, old school med chem, you know, we made somewhere in the region of 15 hundred, 18 hundred molecules before we came up with the actual drug itself. We were monitoring those biological properties of the molecules through cell assays and biochemical assays. You can see here that the changing this this functionality on the left improves various properties of the molecule.

Then what also helped enormously, of course, was as we started to get a good understanding of what the structure of the JAK2 kinase domain actually was and how certain functional groups fitted particularly well into the binding site and how that improved potency and specificity. We were able to generate this molecule, CYT 387, which ultimately became known as momelotinib, and it was not a bad inhibitor. It was a pretty good inhibitor. But what really made this a drug was its ability to exist and survive long enough in the blood system to actually have an impact. But also, you could take it orally. It was pretty much 100% orally available.

Then we did a whole bunch of biochemistry arrived at the conclusion that this was the molecule to go with. Then here's the PK, 100% bioavailable, half-life 2 and a half hours in the rat which scaled to once a day oral for the human at all the best behaviours in terms of its inhibition of various metabolic enzymes like CYP and a very clean background in terms of some of those toxicities that you might want to avoid including genetic and so forth. The molecule really was a bit of a standout from what we've been developing.

Did it work? So we had to collaborate with Mike Denninger from OHSU. There was a model where they didn't stall that mutation in a murine system using retroviruses. They got pretty much the same sort of symptomology as the humans did. We were able to show our molecule when applied both orally and also IV, that you could reduce the spleen weight very, very nicely. That extra modality hemopoiesis no longer happened. You could see that the white blood cell count came down to completely normal levels and that the inflammatory cytokines, which are a feature of all this disappeared. That became pretty encouraging news that the molecule was going to behave itself and do what we'd hoped it would do in patients.

We went into the human in 2009. It was really well tolerated and quite safe. But most importantly from day one, we were already starting to see some important changes in the pathologies of the patients with these diseases. You know, the night sweats, the bone pain, the itchiness, the fever, were all starting to disappear. The spleen in a great majority of patients would come down. The splenomegaly would disappear. Famously one of the slides that we were shown by some of the clinicians had a patient in in bed prior to the treatment with a spleen the size of Tasmania, clearly a death's door and then the next slide that was shown was him playing the backhand on a tennis court and that was kind of a nice moment of realisation that we were actually starting to have some impact on the actual patients.

There were phase two trials that were run very successfully. Then phase three, there was a kind of a stall in terms of how the phase three trials went. There was some issue around, you know, the scoring function that was used to assess efficacy, but the molecule was ultimately acquired by Sierra Oncology, and they took it through this momentum trial, phase three trial against standard of care. You can clearly see the difference between the treatment of patients with momelotinib and the standard of care which was done as on. All those symptomologies, the night sweats and stuff, the spleen size and the anaemia were starting to come down and these patients were making great progress in terms of their outcome.

We subsequently realised that we'd accidentally improved the profile of this molecule through enough target activity that was present in the kinase profile. The JAK1 and JAK2 activity were on target and was what we wanted to do to actually target those mutated JAK2 genes and the JAK1 was to improve the inflammatory profile within the bone marrow and other organs. But there was another activity called ACVR1 which was also present in the molecule and that conversely improved the outcome for the patients because it reduced hepcidin transcription and improved iron homeostasis and increased haemoglobin.

JAK2 would actually cause a reduction in red blood cell and haematocrit because it inhibits erythropoietin function, and this would reverse that and recreate the haematocrit as it needs to be. Fortuitously in in some sense, there was both a therapeutic effect on the molecule, but also an improvement in terms of allowing the patient to have a much better haematocrit than what was out there.

You can see this in this experiment where the blue line is a patient on momelotinib. This is another JAK inhibitor, ruxolitinib and you can see these patients become quite anaemic and need to have transfusions on a regular basis. They finally realised that the patients on momelotinib didn't need that and so that was a much better outcome for them.

GSK having seen this data bought Sierra Oncology for about 2 billion U.S. dollars and then took the programme to the FDA for approval.

We had the great news in September last year that momelotinib have now renamed as Ojjaara and God knows where they come up for the names for these drugs. It's beyond me. Momelotinib is molecule from Melbourne, by the way, so that that's where we got the name for that. But Ojjaara was approved by the FDA, was approved by the EMA in the middle of last year, and then finally was approved by the TGA earlier this year a couple of weeks ago. We’re still waiting on the news of whether this is going to go on to the PBS and be funded by the government. We hope for good news in the near future, and we'll see where that comes from.

But the molecule itself is actually having a terrific impact on patients. Our motto, having made that psychological trans transformation to the translation piece is the patients awaiting. I had a couple of amazing bits of interaction recently.

This young lady here, her name is Deb. She was the first patient I'd ever come across and we were introduced a couple of weeks ago when the TGA approved momelotinib. She pretty much made a proposal of marriage to me. She asked my wife if she could take me home and my wife said that's a great idea, but he's very high maintenance so I wouldn't do that if I was you.

But I mean, for me having done a lot of this in the silo of basic research and also in that biotech setting, meeting my first patient was a really extraordinary moment and very moving and quite transformational again for my future intent on doing more of this.

Then just yesterday, this is Chris Burns and me, met another patient, Charlie, who is significantly better from having had the drug and looks forward to the chance to get the drug on the PBS.

I think pretty much every basic scientist should get an opportunity to see the humans that they can have an impact on. I think for me, you know, forget about the Prime Minister's Prize. This was the great prize for the work that we've done to actually meet people that we had a real impact on. So that was a red-letter day for me.

I could speak on, and I realise it's now 20 minutes to go, I'm more than happy to keep talking on. But I think Steve, if you wanted to, we could open it up for questions and we could share a little bit more of people's thoughts and impressions.

40:23 Professor Steve Wesselingh
I think it's a great idea. No thanks, Andrew. What a what a wonderful story, what a fantastic story and I think really important to the audience that we have today to understand that story.

I just encourage everyone who's been listening, and I know who no doubt have been blown away by this story, to think of some questions and put them up in the chat then I'll move them into verbal questions for Andrew.

Maybe I'll start though, Andrew, I guess the point I think that affects a lot of scientists. You're at the Ludwig presumably in a fairly secure position, no scientists are really secure, but I imagine you had a few years of a contract with the Ludwig, presumably had family to support, etcetera, etcetera but you made the courageous decision to move from that to what I think must have been a fairly unstable position to start Cytopia and start developing a drug.

What went through your mind then? What were you thinking? How did you work that out? How did you, you know, develop the courage to do that?

41:45 Professor Andrew Wilks
I mean that's a fabulous question and there's a whole seminar on that. I mean I had long term funding from the Ludwig, six or seven years out of guaranteed funding for my own self. I had funding from all of those funding bodies. We had 35 people in my lab. We were going gangbusters.

What actually happened was I went to the Ludwig and said, I want to start a Biotech, and they said that you can either stay or you can go, but you can't do both, that's a conflict of interest. I think that's the opposite. I mean we shouldn't let synergies of interest get in the way, or conflicts of interest get in the way of synergies of interest. There’s a much better way of thinking about these things.

But I don't know whether, I certainly was very highly personally motivated to have that impact that. I mean, my own stubbornness, I think is, is what's driving that and so it became just sheer bloody mindedness and wilfulness, so this is what I was going to do.

The word conversation, shall we say, with the Ludwig hierarchy about how this happened, and I found myself saying, well, OK, that's it, I'm going. Then on the other side, so this was in December on the other side of Christmas, of course, I don't have a job. I'm starting to think, oh my God, what have I done now? If it wasn't for the support of my wife and my family, of course, we wouldn't have gotten through that.

But there was a six-month period where we were completely without funding until Medic Holdings came along. Should never happen. It did happen and what doesn't kill you makes you stronger, I think. The resilience was actually learnt post hoc from having made the decision and trying to survive.

I wouldn't recommend it to anybody. I would certainly recommend the translation piece, but we need to find a way to make it a lot easier for people to make that transition. For me, I just think, you know, I was so committed to the idea of translating this stuff that I wouldn't let anything else get in the way of it and the consequences fell and flowed from that. But that was what my wife calls the baked bean year, where we only had baked beans. We used to go to Prahran Market with all the free food on a Saturday and that was our treat to eat out. It was really quite difficult stuff.

44:26 Professor Steve Wesselingh
Just rephrasing one of the questions on the chat.

So at that time you need, as you said, you had six months with no money, you obviously needed to sort of go from clearly being very good at writing NHMRC grants and getting NHMRC money to getting investment money from a totally different sort of culture and genre.

I guess firstly, how did you learn that skill? Then secondly, and this goes to one of my thoughts, do you think the fact that you were in that precinct that you showed the picture of, the Parkville precinct, did that give you a bit more confidence than if you were perhaps not in such, you know, in a precinct that's got, WEHI, the Murdoch, the Florey, now the Doherty, etcetera. Do you think the precinct sort of helped support you, whereas, you know, if you were in a smaller university, you might find it more difficult.

A 2-part question, how did you learn to get the money from a totally different group of people than the NHMRC peer review process?

45:38 Professor Andrew Wilks
The first thing is that I probably didn't. The first draft of the research plan that I gave to Kevin Healey from Medic Holdings, he looked at, he says that's a great NHMRC grant, but that's not, that's not a business plan. He tutored and helped shape the document into a proper business plan. The investors want to know a couple of things, they love the idea of impact, of course they do. But how do I get in and how do I get out? I mean how are you going to look after my money and how we're going to deliver the thing that you're promising they’re the questions.

They don't care whether you know, JAK1, phosphorylates JAK22 and all that sort of thing. That's very much a skill that was learned on the hoof and sort of evolved in my mind through tutelage of people who knew what was required and what needed doing.

That's the first thing. The second question was, did being in Parkville help it? Certainly. Well, I think the opposite. I didn't go back to Parkville for a long, long time, largely and part of it was paranoia. I felt something of a pariah there, having gone over to the dark side. Certainly, and I haven't talked about this with, with many of the people who were in my lab, but I'd love to hear what their point of view actually was. It was really a very difficult circumstance, and we ended up around Saint Vincent's Hospital, Saint Vincent's Institute. That's where we put our labs rather than in Parkville, rather than actually be in Parkville.

Interestingly, those 35 people in my lab, it seems like I was just slowing them down because all of them are blossomed into their own fantastic careers as scientists. Everything turned out all right for them as well. But there was a big psychology or psychosis really of you know, going back to Parkville that was a really quite a difficult thing. I finally did it. I'm back there now, of course, but you know, difficult times.

47:57 Professor Steve Wesselingh
Really interesting. Michael's actually put up a question about the IP and everyone else can read Michael's questions. Really great question, but really goes to the issue about your IP.

You mentioned in the talk that the Ludwig sort of pushed back for a while, but then just gave you the licences and allowed you to move on.

Do you think that Australia does that badly and that our universities and our institutes don't easily give up, or allow a smooth route of intellectual property to move from the basic side to the more translational side?

48:39 Professor Andrew Wilks
I think the evidence would say that that is the case.

I mean they can't win the tech transfer offices at university. You know they give it to the people and that's not a great idea or they find some way to get in the way of giving it and that's not a great idea.

I do feel that they are in a very difficult situation, but they are also in a position where that process can be quite facilitatory and making that a smooth transition throughout licencing and so forth really would make a huge difference. We dealt with a whole bunch of universities, and it takes huge amounts of time and effort to actually get the licence thing sorted out. That's not how things operate in the US.

For some reason the speed and enthusiasm is very different and I don't really know what the secret sauce actually is. Interestingly, the patents that I had in the late 90s, everyone had patents on genes that they were, you know, groups like Insight and others, that were their whole business model was the fact they had patents on various important genes that were involved as drug targets and so forth and they were the nature of my patents as well.
I had patents on the JAK family members, and I had patents on the assays that you could use and for a brief window there, I could use that as a token upon which to base the investment that people were going to give me.

It turns out that just on the other side of 2000, all of that went away. There were some changes in patent law that suggested you can't patent a protein because it's a natural product. I'd use them as a token to get the money and then they disappeared, so I was kind of in, in a lucky window of opportunity there and we'd already moved on to actually discovering the proteins anyway. But you know, the patent stuff is really, really important.

No one's going to invest in any company unless there is IP, both in terms of knowledge and sort of know-how, but also in terms of protection and freedom to operate sort of constraints. It's a really important tuition, how the universities actually facilitate that. Again, a very important and crucial thing that can be improved.

51:05 Professor Steve Wesselingh
Yeah. How, how do you think we could, what processes could we put in place?

I mean, I just put a plug in for NHMRC. We give out money, we don't ask for anything. We just ask you to do great research, which I think is an important process actually, because if we asked for the IP, it would be terrible. But what about the universities? How could we get them to do it better?

51:28 Professor Andrew Wilks
You’re touching on a really interesting point there.
I do think funding bodies deserve something from having contributed because the NHMRC gives the money to the institutes, or the university and the university does the work, and they claim some proprietary ownership of the intellectual properties that generated having done the work. But not having the money's come from the NHMRC I think there's something interesting going on there.

We often find talking to universities, there is a very strong sense of proprietary ownership of intellectual property that often gets overvalued, and those negotiations can become quite difficult. I really don't have a solution around that other than trying to align incentives in some way certainly with the universities. I don't see why the NHMRC shouldn't get something out of this. It would certainly help fund stuff, wouldn't it?

The other thing is, of course you know, that we having discovered these JAK proteins and stuff that there is presently now something like $30 billion worth of drugs that work on those JAK inhibitors. Wouldn't it be good if Australia got the benefit? Not least to say me got the benefit, but saying Australia got the benefit of the underpinning science that led to such large income streams that other people are taking advantage of.

It's one of those missed opportunity things. Maybe it's a good thing or a bad thing to think about, but I don't know.

53:25 Professor Steve Wesselingh
No, very interesting.
I think that might be some topics of conversation for our Commercialisation committee.

53:32 Professor Andrew Wilks
I didn't want to spoil the surprise, I'm going to bring this up next week.

53:35 Professor Steve Wesselingh
Fantastic.

Richelle has asked, based on your experience, do you think business studies, IP law, etcetera, should be an element of a health and medical research postgrad degree?

53:50 Professor Andrew Wilks
That slide I showed at the start, I mean, there were so many people with each of them had an individual contribution to make. I wouldn't change my phenotype as a scientist to learn business or to learn IP law, particularly when you're very good at antibody production.

I mean, you certainly need to be aware of these things. I've done no MBA studies, I've learned all this on the streets, as it were. Maybe that's a good thing, maybe that's a bad thing. I don't know. But I very much try to stick to my knitting, which is still as a molecular biologist, as a cell biologist. It's certainly worth improving the awareness of anyone who plays any role in these translational projects. That I think is a very useful thing.

You definitely don't need to become an expert, or you know in all of these things. You know, stick to your knitting. Make sure that the thing that you can contribute, that you offer the best proposition in that piece of the jigsaw puzzle because the team will form around you. It's certainly well worth making yourself aware of these other dimensions to the translation commercialisation process.

55:18 Professor Steve Wesselingh
I just want to go to the process. I mean really after Cytopia, one of the observations that that I occasionally make is that Australia lacks large pharmaceutical companies. I mean, we have CSL, but we really don't have anyone else. A number of Australian discoveries have gone to GSK as an example actually.

Would you have liked to have had your drug developed by an Australian company or do we have to use global pharma?

55:53 Professor Andrew Wilks
Oh, I mean, we have to use global pharma.

But I mean, this is one of the things that still burns with me that we didn't actually play more of a role in that later stage development piece that was largely done. Gilead took the thing early on and then Sierra Oncology was a NASDAQ listed company and then GSK.

We're definitely missing a big piece of the ecosystem here, both in terms of trickle down funding, but also aspirational sort of hope and anticipation for your project.

We tend to go very early in terms of partnerships, you know, even preclinical. I'm to blame as much as anyone. I've done three or four of these things, so not having the ambition to sort of develop these things further within Australia is a function of lack of opportunity, lack of capital, but unfortunately lack of ambition as well.
I mean, changing that would, I think, have a big impact on the ecosystem that we're trying to build. Let's be more ambitious about these things.

57:05 Professor Steve Wesselingh
Alright, on that note, I think that's a really important note. I think your talk has just been fabulous and the courage you showed, and we just talked about that and the ambition you showed. But I think it's a great example of the sorts of things that Australians can do, that with courage and ambition we can develop. Fabulous talk, Andrew.

I think everyone online would have really, really enjoyed it and it's just a great story with, as you said, a patient centred outcome actually, which is what World Cancer Day was all about. As you said, the biggest gift to you was to meet those people. All in all, it's one of those terrific bench to patient stories and thank you so much for sharing it.

57:55 Professor Andrew Wilks
Oh, you're welcome. I don't know if people give my email out. I'm more than happy to help other people start their own journey on that. That's become quite a passion as well.

58:10 Professor Steve Wesselingh
Alright, well, thank you everyone. Thanks everyone who's been online and listened to this. I'd like to thank the staff for organising all of this and obviously, Andrew's volunteered actually, because normally we say if you didn't get a chance to put your question up, you know, send it to us and we'll try and get the speaker to answer it. Andrew's even offering some counselling and mentoring. So fantastic.

If you do have any questions for Andrew, we're happy to share Andrew's email with you. Then just finally, to encourage you to come to our next Speaking of Science webinar. Thank you all very much.