S3, E08: Open Science: The Parallel Universe

Aled Edwards (00:02):
I see open science like we are planting seeds, and if you patent, it's like as soon as the root grows, you cut it and you don't allow branches, where open science allows that tree to grow and branches grow that you never knew would ever grow, and so I think that that's the sort of analogy I like to use and it's all the various branches that have come from one of our little discoveries, and each and every one of those branches is important in its own right and maybe there would've been none had we not shared at the very beginning at the very root of the problem.

Gina Mullane (00:34):
In the United States, Big Pharma is a heavily-regulated industry with a system that attempts to balance the encouragement of innovation with a protection of an intellectual property. When a drug developer introduces a new therapy to the market, they are granted 12 years of market exclusivity, and whatever findings they patent throughout the drug development process are protected for 20 years. A new report found that for the 12 top grossing drugs on the market, there were 125 patent applications filed and 71 granted patents per drug. As a result, breakthrough drugs are developed independently in silos, but what if instead of working behind closed doors, scientists instead share their drug discovery research in the public domain? I'm Gina Mullane, and in this episode of Vital Science, Chris Garcia speaks with Aled Edwards, Director of M4K Pharma and co-founder and CEO of Structural Genomics Consortium, about his open science approach to research.

We'll discuss the limitations of Big Pharma's current system, how public domain discoveries are catalyzing treatment in rare disease, and what's on the horizon in the exciting field of genetic biology.

Chris Garcia (02:05):
Al, welcome to Vital Science. Super honored to have you here. Can you tell us a little bit more about yourself and how you came into the field of genetic biology?

Aled Edwards (02:14):
Yeah, sure. I'm a scientist and I live in Canada, in Toronto, and I had a rather traditional training for an academic. I did my graduate work, and then I went to Stanford to do more research, and then I came back to Canada to be a professor. At the time, after I left my postdoc, as they call it, I was working on one protein. That was a pretty important protein and really diving into the details of it, like how millionth and billionth of a meter things moved, and at the same time, around the world, people were starting to sequence the genetic code of organisms, so instead of working on one thing, we had a glimpse into all the component parts of a being, and I got attention deficit and I said, "Holy crap, that's what I want to do," and so I said, "I'm going to start to move towards working on all the proteins that we now know exist that we didn't know existed a year before and just find out how all these parts come together to make an organism."

At the time, it was yeast, and as you'll hear later on, then we moved into human.

Chris Garcia (03:26):
What is your role at SGC, the Structural Genomics Consortium, and also at M4k Pharma?

Aled Edwards (03:32):
Yes. At the SGC, I was the founder of the organization. I didn't conceptualize it. That was conceptualized by a group of funders, led by Wellcome Trust in the pharmaceutical industry, and they wanted to create an organization that put some of the fundamental knowledge about human proteins, in fact, their three-dimensional shapes into the public domain without restriction, and they sought someone to head it up, someone who had a little experience in academia, a little experience in industry that I had at the time, and so that was in 2003, and so I was the founding, normally the CEO, and I directed it ever since, more like a conductor. There's so many outstanding scientists.

I just watched them do their amazing stuff. For M4K, we spun that out about in 2017. It didn't quite have an organizational structure at the time, like the SGC with a sort of management time. It was more of a concept and a project, but we did create the company. Owen Roberts was the initial CEO.

Owen was a friend from a long time ago. Currently now, I was the Chairman of the board and I'm still the Chairman of the board. Now, I'm normally the CEO as it's transitioning to the next phase of its, from discovery to development.

Gina Mullane (04:55):
Under the Human Genome Project, scientists sought to identify, map, and sequence all of the genes that make up human DNA from a physical and functional standpoint. Likewise, one of the foundational goals of SGC is to put the fundamental information about human proteins, which are encoded by human genes in the public domain. By studying the shape of keratin, insulin, and the 20,000 proteins that make up the human body, SGC hopes to provide researchers with a stronger understanding of human biology and how to treat disease. Let's hear more from Aled on the synergy between the work of SGC and M4K.

Chris Garcia (05:38):
How do those two organizations work together, SGC and M4K Pharma?

Aled Edwards (05:43):
They actually don't work together, but they're connected, in that M4K was created from a project at the SGC, and one of the SGC projects was on a protein that is mutated in a childhood cancer, and we'd taken it to a certain point and we were just hoping that the business world would take it on and try to make a medicine, except that unfortunately, that the mathematics don't work, or the economics don't work. There are too few children with the disease, thankfully, because it's a bad one, and we couldn't think of a way to advance it into a medicine in the traditional way, so M4K was a solution, actually. It's sort of like a business solution to a wicked problem in that if there's no market, there's not going to be a way to invent a medicine in the old system or the traditional system, shall we say.

Gina Mullane (06:42):
Under this traditional system, the expense of drug development is often a hindrance to the development of treatment for rare diseases. While policies to support rare disease research have improved in recent years, there are still 7,000 rare diseases that have been identified, and only 5% have treatment. Instead of relying upon the industry to act on the protein discoveries made by SGC, M4K Pharma is designed to pick up where SGC has left off, creating a mechanism for these drug discovery findings to be leveraged in bringing rare disease drugs to market.

Chris Garcia (07:21):
Tell us about that open science approach. One of them is developing childhood cancer drugs. How did that come about?

Aled Edwards (07:29):
And so when we did that exact analysis, as you say, everybody's working on the same thing, how do you construct a system that allows you to work on things that no one's working on, and you can create different kind of stories. Well, the way that does work is that if you invest in that area, you might also make the research open so that only one person needs to do it and everyone can benefit, and then you can sort of create a return on investment argument that, "Well, instead of 500 people working on gene 15,000, one person works on it, does it well, puts it all into the public domain so no one else has to do it," and if you're going to spend global money the most efficiently, that's the way to do it, and so we started off with that as the rationale, do it once and well. What we've learned in the interim period is that by making it open, it actually makes it a lot easier for people to study the protein and share because all of the encumbrances that are in the system that the lawyers put on it are gone, and so you can save a hell of a lot of time and effort by avoiding all the sort of barriers to collaborate that the world is constructed over the last 30 years. The more and more biomedical research becomes linked to commercial endeavors, the more legal things that we've had to do to do our science. I mean, if I want to transfer a thing of no commercial value to my friend at another university, I actually have to do that through legal contracts.

I mean, officially, you have to. Sometimes you just do it, but if you're going to follow the rules, you have to go to your university, get them to talk to the other university, put legal contracts in place so I can pass something worth 30 cents over to the other university. That's the world we live in.

Chris Garcia (09:24):
Do you think this open science approach can be applied to all levels of drug development in different therapeutic areas?

Aled Edwards (09:30):
Absolutely. You see, the National Institutes of Health now is funding an Alzheimer's initiative called Treat AD, where one of the centers there has explicitly said upfront, "We're not going to file patents on any of the chemistry we do all the way up to a lead." That grant was reviewed and was given a humongous thumbs up. There were two grants given, and it was one of them, and it explicitly said, "We're doing open science." In one of the new proposals put in to make antivirals, you know, these pandemic prevention things, I know at least one of the initiatives that explicitly wrote in their grant, "We're not going to file patents on any of the molecules that we create, and we're going to share them so the world can use them and discover stuff," and I'm pretty sure that one's going to get funded.

Aled Edwards (10:21):
There's a COVID Moonshot project led from the UK and Switzerland now, and they explicitly said the very same thing, "We're going to start to make a COVID drug without patents and sharing all the data so everybody can contribute to the cause," and that's working well. It's like when we started, we were like the camel's nose in the tent pushing to try and get in, but I think there's a hell of a lot more projects now that see the wisdom in it, and it makes sense. They do it because it's easier to do science when you share. I think the best open science story actually was Heidi Williams, who was now a professor at MIT. What she did was when the human genome was being sequenced, at the time, people thought you should patent genes. It's like a gold rush patent, the human gene.

You'll control it and you'll make lots of money and blah, blah, blah, and so a lot of biotech companies came out and started patenting our genes. Now, the legal system 10 years later said, "You can't patent a gene because it's natural," but at the time, that's after, so they're patenting, patenting, patenting, and some genes were never patented, so you presumably, the biotech companies patented the genes they thought were important. Then, they realized, "Oh my gosh, this is spending a lot of money patenting stuff. We're going to let them lapse," but you had two sets of thousands and thousands of genes, one that had a brief period in the time, being the subject of a patent, and these had never been patented. What Heidi did is quantified economic activity in the subsequent 10 years.

The genes that had never been patented, these are the ones that were not important because they would've patented the important ones, 30% more economic activity subsequent from the genes that had never been the subject of an intellectual property. That's kind of the branches that I was talking about, right? If you think of a gene to a product or that, if you cut it off at the gene, you don't know what you never meant.

Chris Garcia (12:18):
It's obvious this old way of doing things has had an impact on the scientific research community, but how do you think the open science approach will benefit patients with these diseases?

Aled Edwards (12:28):
Well, we don't know yet, to be honest, because the average time between a discovery, which is where we play in the little universe and a drug make in the market is probably 15 years all in on average, like it's a distribution. Some are very fast, some are really slow, and most drug discovery projects fail anyway, and so you're asking, "Oh, so you're pregnant, and how many lottery tickets did you win?," and so it's a really hard question to ask, so there are proxy measures of how well this impacts translational science so we can quantify how many new clinical trials have started. We can't say they made it to the end, but how many have started built on top of the open science foundation and the stuff made, and there's 50, 100 clinical trials that have been launched based on the kind of science we do in the open. I see open science like we are planting seeds, and if you patent, it's like as soon as the root grows, you cut it and you don't allow branches, where open science allows that tree to grow and branches grow that you never knew would ever grow, and so I think that that's the sort of analogy I like to use and it's all the various branches that have come from one of our little discoveries and each and every one of those branches is important in its own right, and maybe there would've been none had we not shared at the very beginning at the very root of the problem.

Chris Garcia (13:57):
Al, what would you say are some of the other major challenges of the industry actually adopting open science?

Aled Edwards (14:04):
Well, let's call it the sector as opposed to the industry, because we, as a society have created the drug discovery sector as is. We protect the intellectual property with government patent. Patent is a government right, right? The right to exclude people from using is a government right. We have created the mechanism of reimbursing drugs, you know?

We, as a society condone the idea that a drug is a product that needs to be sold and a profit needs to be made. You start putting that in place, and then universities plug themselves into that system saying, "Well, if that's the only way drugs are going to be made, we have to become part of it. We have to," and so you have this really interesting ecosystem that's been put into place that we all condone, and so what we're trying to do is to create a parallel universe that plays to different kind of drivers and different expectations, where in my fantasy world, I have a rich fantasy life, FYI, in my fantasy world, medicine is a human right, and that's the starting position, and then we create an economic model that is consistent with that. I don't see a way it's possible without open science. I think if individuals keep trying to get as much as they can, it won't work at all.

You have to have sort of folks that want to go in there and contribute, and they're doing it for the scientific excitement that they get on route and for the fact that at the end of the day, we create a medicine that everyone on the planet can have.

Chris Garcia (15:38):
M4k Pharma's current funding comes from government grants and donations paired with a range of organizations performing pro bono research and development work to deliver drug candidates. How has M4k Pharma's blended collaboration with patient groups, foundations, and academia resulted in the development of small molecule inhibitors designed to target diffuse intrinsic pontine glioma or DIPG?

Aled Edwards (16:07):
Yeah, so you're asking an interesting question because it's actually broader than M4K. M4K is one example of what you just said. I think that over the last, I would say 15 years, as the pharmaceutical industry has been sort of distributed into academia like contract research organizations like Charles River, patient organizations even have drug discovery expertise now, it's the idea that what used to be in one house, like Pfizer would have everything in-house, is now distributed, and so things like M4K and many other biotech companies, they collaborate among these partners now to be able to run specific projects, like very focused collaborations, and so with M4K, that's exactly what we did. We sort of found the network of folks that would be interested in this as a problem, and then M4K and the open science created a mechanism for us to align them towards a cause, and it's been super fun to watch folks collaborate freely because the ground rules of open science means that nobody is going to benefit more than anybody else and it's really fun. I like to say that...

Especially professors and doctors. We're like kindergarten kids, right? If Johnny gets more candy than us, boy, are we angry. We'll complain. That's our core competency as professors, is to complain, but if everybody gets nothing or of the same, in this instance, nothing, everyone's happy, because you feel you're really as a team contributing to a common cause and nobody is benefiting more than anybody else and it's fair, and so that's the kind of spirit that M4K was formed under, and it's worked remarkably well.

Gina Mullane (18:01):
This fair collaborative approach doesn't mean that researchers don't get credit for their work however. In academia, being able to attach a name to your findings is often a critical component of advancing one's research. The M4K business model encourages researchers to take advantage of molecules that, for example, Charles River has made, test them and publish their own data. Let's hear more from Aled on the potential role of CROs in this new approach to drug development.

Chris Garcia (18:32):
In what ways can contract research organizations help programs like those being done at M4K Pharma?

Aled Edwards (18:39):
It goes back to the deconstruction of the sector, which is a 50-year deconstruction, or I can't know if that's the right word, but like what used to be in-house is now distributed and contract research organizations, my naive view over the last 50 years is they usually focused on one thing at the time. They were very good at one step, and rather than all the companies have individual labs, they just have one lab that does it outside the company. Then, all the contract research organizations started to be good at that, then bolt on, and now they're almost integrated companies from beginning to end, and they've recruited super skilled people who have experience in the sector, and so now, you could almost run a drug discovery project from your garage. If you have enough money and a starting material, an organization like Charles River could do soup to nuts, beginning to end just as well as a large company could. Now, they don't have a factory and a sales force to make and sell the drugs, so there is a need for other partners, but certainly, for the discovery and development aspect of making a medicine, contract research organizations, many of them, including Charles River, can do it all and they're extraordinarily talented, and so you might see more M4K things emerging in the future where, of course, the business model still has to be worked out, but that a contract research organization is the engine that drives a drug discovery project.

Chris Garcia (20:16):
It sounds like you see the business model of drug development evolving quite a bit in the future. What do you see on the horizon for genetic biology?

Aled Edwards (20:24):
I'm hoping that the scientific community can appreciate that human biology or genetic biology hasn't yet adjusted to the fact that the human genome was sequenced, and it goes back to the diagram that we spoke about earlier, where most of the research in the world is focused on the 20% of the genes that have already been studied. That, I think is a result of how folks of my generation were trained, right? The scientific method is you generate a hypothesis and you test the hypothesis, and it's impossible to create a hypothesis about a protein about which you know nothing. What's your hypothesis? It does something, and we also give grants as to the elegance of the hypothesis, so, "I don't know what it does," "I want to find out what it does" will not get to your grant, and so what we want to think about is the human genome as a finite area of biology.

It's not if you study the stars, there's another star to study. You don't know. There's an infinite number of stars. You can't conceptualize how to end it. Similarly with chemistry.

There's an infinite number of compounds you can make. There's a finite number of genes, and we have resources that are finite. We should map the resources on those genes and make a much more structured and organized way to tackle human biology. Right now, we're attacking this problem with a thinking of 30 years ago, and we haven't been able to change the way we think. I think that's a mistake, but when it does happen, then we'll be able to say, "Okay, there's 20,000. We understand those," mic drop, we're done, so why don't we start to allocate resources more appropriately as a global community across this landscape and discover more faster, and if we share, we don't have to work on much about competition?

You guys work on that, you guys work on that, and organize it all, and open science is so key to that because if one thought, "Oh my gosh, the guy got the part of the land with the gold underneath it. I should go over there because," then we'll have everybody working on the same thing over and over and over again, so open science is kind of a fundamental tactic in doing this, but until we understand what each and every one of those genes do, we're not going to be able to cure a disease. Most of the medicines we take into patients fail to do any good because we didn't understand the biology, not because people like Pfizer or Charles River can't make a great molecule. The molecules are great. The drugs are great. They're just doing the wrong thing, and they're not doing the wrong thing because they messed up, is because we don't know a lot about how the body works.

Gina Mullane (23:28):
A prime example of the problem Aled is speaking about is Alzheimer's disease. In 2021, there were a total of 126 agents in 152 trials assessing new therapies for Alzheimer's. It is Aled's dream that by studying human proteins and sharing research in the public domain, we can understand the biology of Alzheimer's faster, that by collaborating and sharing knowledge, rather than working behind the closed doors of individual labs, we may work more efficiently in identifying a cure.

Chris Garcia (24:03):
It sounds like this approach can potentially revolutionize how affordable new treatments are discovered and developed.

Aled Edwards (24:10):
Revolutionize is a word that I don't like to use too often because that's oversold. If you were to ask me what's the big problem in drug discovery, I would say we don't understand disease. As I said before, Parkinson lived in 1816 or something, and we still don't know what causes Parkinson's disease. We have a bunch of genes we don't really know, and so we really need to think about focusing as academics on the big problem is. What causes these diseases?

Aled Edwards (24:47):
Once you have the cause and you pretty well understand the mechanism, the drug discoverers can do the rest, but we need to provide them with the knowledge, and once we provide them with the knowledge, then medicines will fail. New medicines will fail less frequently. The process will become more efficient. Medicine prices hopefully will come down as the sort of macroeconomics change, but until we, as basic scientists provide that fundamental information to the community, I don't think we're systematically going to have affordable medicines. Now, for areas of market failure, pandemic prevention, antibiotics, childhood diseases, I do believe we have an opportunity to convince governments that it is in the social interest and the public interest to support drug discovery projects for those things that cause societal harm but that industry is ill-equipped, or the industry system is ill-equipped to tackle, so I think we should continue to push hard on that, that it's our collective responsibility to make medicines for these folks and these children, for example, and we shouldn't point to industry and ask them to use the old business model, which is just frankly, it's inappropriate for the problem at hand.

It's a very difficult question you ask because it sort of talks about the macroeconomics of how society's put together and the beliefs of the industry and the universities. They all sort of aligned in direction one and it's incompatible with affordable medicines. I believe that you have these institutional barriers, but if you walk into any one of my colleagues' offices, any one of the students, the postdocs, the professors, would you like to participate in a drug discovery project where we put things in the public domain and we ensure that the medicine is affordable? No one's going to say no. They'll say, "Oh, but the system doesn't allow us to do that," so they'll blame some shadowy being out there that doesn't allow them to do them, but at a personal level, every single one would, every single person at Charles River, every single person in Pfizer, every single person in Merck would say, "I'm in."

"Tell me how," and that's what we need to do. We need to create a how, because once we've done that, we're going to have literally hundreds of thousands of scientists all in.

Chris Garcia (27:23):
Al, thanks so much for your time on Vital Science today and for sharing your fantasy world with us. I'm really hoping it becomes reality.

Aled Edwards (27:31):
You're welcome. That was a hoot.

Gina Mullane (27:35):
Aled Edwards is the Director of M4K Pharma and co-founder and CEO of Structural Genomics Consortium. In our next episode of Vital Science, we'll talk with Nick Brown from Charles River's High Peak site about Retrogenix Cell Microarray Technology and how it can help us better understand potential drug candidates earlier in the drug development process. Until then, thanks for listening.