Team:Sydney Australia/HP/Gold Integrated
About Our Integrated Human Practices
We spent a considerable amount of time looking out into the real world to figure out how our project would best solve the issues of insulin unaffordability and inaccessibility. Key advisors and stakeholders aided the decisions we made along the way. Not only did our project integrate with the advice of individual people, but these individuals became integrated into a big conversation between us all.
Specifically, these conversations were around how we Apply the design, the Project Design itself and ultimately how we best present this project to the real world as a business.
Under each of the below headings, you fill find the conversations we had with these stakeholders which integrated into our final product. Please enjoy reading through our journey!
Project Design
Our Original Project Design
Originally when we started this project, we were facinated by the idea of single chain insulins, but were hesitant to develop our own due to the vast array of new patent applications that were on the market. Human Insulin was in the clear of any patents, however due to its series of post-purification methods and low thermostability, we thought that developing a business model that had to keep up with high transportation costs, especially when open source, would be a difficult operation.
Read the conversation below to find out how these people influenced our Project Design:
- Anthony Di Franco Our foreign friend began the Open Insulin project.
- Meow-Ludo Meow-Meow Meow-Meow is infamous for his work at Biofoundry.
- Dr Peter Arvan An insulin researcher.
- Nick Coleman Our Supervisor.
- Neil Donelan Neil distributes insulin vials all across the world.
- Jeni A local pharmacist.
- Len Mancini A partner of Maxwells Patent Lawyers.
- Edwina Wang A type I diabetic.
To: Project Design
Anthony Di Franco
We need an Open Source Insulin! We need a team to be able to start investigating methods that could be used to increase the yield, and decrease the post-expression processing steps currently required to produce insulin.
Meow-Ludo Meow-Meow
I've got a team in mind.
Nick Coleman
USYD iGEMers- what do you think?
Team DISCO
We can do that! iGEM is an international competition where teams across the world create and deposit genetic sequences into an open source registry, so that the global community can follow on from a single team’s work.
Meow-Ludo Meow-Meow
That’s fantastic! Keep me updated throughout the project, I’m more than happy to help with this process if I can. Also, good luck with the competition!
After researching insulin a little further, we’ve come to realise that there are a few issues we’d like to address.
Firstly, Human insulin purification takes a long time and, depending on the method used, can be very expensive. We investigated alternatives to this process, and we came up with a few expression systems that could be used to improve the folding of insulin inside Escherichia coli and Bacillus subtilis.
Secondly, insulin is currently stored at 4°C to preserve its activity. Keeping insulin at this temperature in cold storage chains while it’s being transported is incredibly difficult. This is especially so in lower economic countries, where we hope our insulin will be able to be sold.
So we thought, what if we designed our own, single chain, open source insulin that is also thermostable?
Firstly, Human insulin purification takes a long time and, depending on the method used, can be very expensive. We investigated alternatives to this process, and we came up with a few expression systems that could be used to improve the folding of insulin inside Escherichia coli and Bacillus subtilis.
Secondly, insulin is currently stored at 4°C to preserve its activity. Keeping insulin at this temperature in cold storage chains while it’s being transported is incredibly difficult. This is especially so in lower economic countries, where we hope our insulin will be able to be sold.
So we thought, what if we designed our own, single chain, open source insulin that is also thermostable?
Peter Arvan
I have designed a single chain insulin that I won’t be patenting, would you like to improve upon what I’ve developed?
Team DISCO
That would be so fantastic, thank you so very much Peter. We will try and improve the functionality, especially to try and improve the thermostability of insulin.
Neil Donelan
Hi! As a part of the not-for-profit group Insulin for Life, I currently work to export insulin from Australia to all corners of the globe. We haven’t had any issues with the activity of the insulin we distribute, even though we don’t use any cold chain transportation. I think that any insulin you design, just like the human insulin you’re looking to produce, will be thermostable enough for global transportation without cold storage.
Team DISCO
Oh wow! Thanks Neil for your input. That gives us a lot of confidence to say that our insulins should be able to be distributed without cold chain transportation!
Jeni
Also, just be careful with how much you adapt the insulin you design. Endocrinologists are hesitant to put their patients on biosimilars because they can never be taken off that specific biosimilar. Generally, if a person is taken off one insulin biosimilar and put on a different analogue, they will suffer from an allergic reaction to the new insulin!
Team DISCO
Well we’d better make sure that our insulin is classified as an analogue, not a biosimilar. Unfortunately, Human Insulin will be classified as a biosimilar, but we have designed it to be exactly the same as the human form. Since there aren’t any ‘other’ bits on Human insulin like His-tags or TEV digestion sites, we hypothesise that there will be no adverse reactions or allergies brought on by Human Insulin.
Len Mancini
Would you like some quick tips on how to figure out if you will be free to market the insulin you have developed. Basically we would be looking at the patent landscape including granted patents and patent applications to see whether you wouldcould infringe if your developed molecule was formulated and sold on the market.
Team DISCO
Yes please! We have designed a single chain insulin with a 12 amino acid length linker between the A and B chains, and have made no changes to the human insulin A chain. We have added a glycine to the B chain, as this immensely increases stability.
Len Mancini
The main thing you need to read when looking at a patent to begin with is the claims. If you read a claim, and your proposed product falls within the scope of any single claim, then you would infringe the patent (and could be open to a law suit). However, if your product doesn’t fall within the scope of that claim you would not infringe. One thing to be aware of, howwver, is that “patents” are published at the application stage and also again after they are granted. If they are granted at all. So the first thing you do is check the status of the application at the time it was published. If it was just an application, then the claims may be broader than what would ultimately issue from the Patent Office, or indeed, no claims may gain aceptance and the application may lapse. If you fall within a claim of an application its best to dig deeper and see if the patent is likely to be granted by getting any available examination reports for that application, or any foreign equivalent identified through patent family searches. Its not a quick and easy job!
Team DISCO
Which patents should we be looking at to figure out whether we are infringing or not?
Len Mancini
– If I were you, I’d consider all the insulins on the market, taking a particular focus on Single Chain Insulins. We already know that the human insulin hormone itself is off patent, but you may want to check that subsequent patents on methods of manufacture or particular formulations or compositions weren’t granted and are still active today. Checking process patents in general, especially for your Bacillus expression system, would be important too. Patents for processes and advanced compositions are generally patented by the original owners as a way to extend the monopoly over their product.
Team DISCO
We definitely need to design our insulin after we check all of the relevant patents for single chain insulins. Expression systems and methodology should then follow. How long would it take, and about how much would it cost for your firm to investigate this for us?
Len Mancini
Investigating whether a product is able to marketed legally is a very time intense process invoving muliple searches and months of analysis. The whole process genrally is conducted over multiple years (to account for the patent black spot – 18 months in which applications remained unpublished) and cost over $100,000 if many aspect of the product need to be cleared.
Team DISCO
Ah, that’s a lot of money and time!
Edwina Wang
Hey, also don't forget there are also different types of insulin and we need them for different things - so their actual physiological effect is really important. I’ve used both before but am currently using short acting only with my insulin pump.
Team DISCO
Wow, that’s so helpful! Since you can’t have the same insulin being short AND long acting, its good to aim to create an insulin that’s one or the other. Ruby will be able to do some cool modelling to predict whether our Winsulin will be short-acting or long-acting so we can see which areas would most benefit from our insulin.
Ultimately, we have two insulin products. Our first insulin, Human Insulin, will be exactly the same as the one we produce in our human beta cells. Our other insulin, our newly designed insulin Winsulin, will have the same A and B chains as Human Insulin, but contains a smaller, 12 amino acid length C peptide linker.
From our predictive modelling, we predict the Winsulin will be a short acting insulin. We also believe that our Winsulin will not fall into the ‘biosimilar’ category, as it is not simply an adaptation on a current market therapy, but an entirely new design altogether.
From our predictive modelling, we predict the Winsulin will be a short acting insulin. We also believe that our Winsulin will not fall into the ‘biosimilar’ category, as it is not simply an adaptation on a current market therapy, but an entirely new design altogether.
Our Final Project Design
As you can see, developing human insulin as a therapy became a lot more operational and useful following the discussions with Neil, which showed that insulins do not need to be refrigerated to maintain levels of activity. Furthermore, we developed a series of expression systems to compare the relative yields, and costs of purification, to determine whether or not we could optimise human insulin production. But ultimately, with the blessings of Dr Peter Arvan, we were able to develop our own Single Chain Insulin, and Len Mancini was able to confirm that our optimised Winsulin is in fact outside of all patent claims.
Applied Design
Our Original Applied Design
As technology is evolving faster than therapies can develop, we originally wanted to design an insulin pump to go along with our Single Chain Insulin. This is so that all diabetics are able to utilise our new insulin, and we are not forcing individuals to start injecting themselves again. Furthermore, we assumed that clinical trials would be required in the future for both of our Human Insulin and Winsulin, and that ultimately want to pursue a single one due to the extreme costs of clinical trials. We were also only considering an open source project, as this seemed to fit the most with the international collective movement of Open Insulin.
- Len Mancini A partner of Maxwells Patent and Trademark Attorneys and IP Lawyers.
- Anthony Di Franco Our foreign friend over in the USA began the Open Insulin.
- Edwina Wang A type I diabetic.
- Nick Coleman Our Primary Investigator.
- Biofoundry The local biohack lab.
To: Applied Design
We’ve done a little research into how we could approach the issues of insulin accessibility and affordability, but we aren’t quite sure how we should be approaching them.
Biofoundry
In our opinion, coaxing generic manufacturers to produce your insulin will be a hard feat considering the impassable barriers to entry, including a Good Manufacturing Practice certification for insulin production.
Team DISCO
Hold on, what's that?
Biofoundry
Good Manufacturing Practice, or GMPs for short, are licenses required by a manufacturing plant to produce a therapeutic drug to be sold commercially. This makes sure that the processes used by a plant are meeting quality standards and product specifications. These generally cost around US$100M for a manufacturing plant to receive. This barrier is restricting a considerable amount of small businesses from entering the biosimilar insulin market.
Team DISCO
Wow! That’s a high market-entry expense that we really need to consider! We must consider how we would raise those kind of funds, if we were to eventually build a manufacturing plant in the future!
Len Mancini
But hold on, you guys have something that could be considered a ‘new to market’ drug, which means you could patent this yourselves and raise money through investors who are comfortable that your company will function to produce profits, rather than a single insulin.
Anothony Di Franco
We just raised $16, 656 through some crowd funding though, which is 227% of what we needed to kick start our lab work. If anything, this shows that when moneys needed to be raised, we can raise what we need and more!
Team DISCO
And I guess we wouldn’t really need to ‘build’ a large manufacturing plant. We’d be providing the methods and cells ready to go, so really all a manufacturing plant would need would be the GMP.
Biofoundry
Yeah, you guys really are the proof of concept the industry needs to start seriously looking into insulin production.
Team DISCO
Our YNCM tagged insulins in Bacillus should also provide a much simpler purification process that could be turned into a continuous system with the right optimisations. We should make sure that we spend a little more time making sure that we can compare methodologies between protein extraction when we get up to this stage.
Team DISCO
But wait, hold on. Why are we even pursing to produce an open source insulin, when there might be other alternatives to enter into the market that aren’t the more traditional routes? Could we potentially make an open insulin pump?
Biofoundry
you could, but because of the way that the current pumps are made for a specific insulin analogue, you’d have a hard time selling it without your own insulin. It also wouldn’t really aid the issue of inaccessibility that are currently felt in many places in the world.
Edwina Wang
Hi everyone! As a diabetic myself, I am quite accustomed to injecting myself with insulin, so I wouldn’t worry too much about not having a pump, especially in dire circumstances.
Team DISCO
Len, you’ve said before it would take about a full year and approx. $AU100 000 to fully prepare our Winsulin for patenting.
Len Mancini
Yes. It’s a rough estimate and highly dependent on the product, but generally that’s our rule of thumb.
Team DISCO
We are already starting to see just how costly these kinds of endeavours are, without even including the biosimilar trial and clinical trials required for both of our insulins. Surely there are some other alternatives? Could we not just start producing insulin in bathtubs all around the world?
Nick Coleman
Guys, that’s a great idea, but we have GMPs for a reason. Safety is more paramount than simply meeting demand. Regulating something like that would be way more of a nightmare than it’s worth.
Team DISCO
Yeah, we guess you’re right. Recombinant methods of production of an open source insulin seems like our best option moving forward. Market hurdles included! We should probably investigate how an open-source business would function though with a few more experts.
Our Final Applied Design
Following these discussions, we decided to follow the mantra "Keep it Simple, Stupid" and just focus on synthesising insulin from bacteria, rahter than producing an insulin pump alongside it. We also decided to model the activity of our Winsulin to determine what kind of insulin it is. This will also be important information for future endeavours. Furthermore, we became a little more comfortable with the idea of going open source with our Winsulin also. However, these talks also demonstrated that raising the initial capital for manufacturing plants may be a little difficult given the start up costs, specifically Good Manufacturing Practice approvals.
Entrepreneurship
Our Original Entrepreneurship Plan
Originally, we were full steam ahead on the open source direction. We planned on raising capital through crowd funding measures and with angel investors. Other open source tools were considered, such as Public Investment 'matching' schemes and Private Trading Schemes.
- Mike Nichols A local entrepreneur mentor at the INCUBATE Hub at Sydney University.
- Narcyz Ghinea A specialist in access to high cost medicines (specifically cancer drugs).
- Neil Donelan Neil distributes unopened, unexpired insulin vials all across the world.
To: Entrepeneurship
We’re at the point where we’re pretty sure we have a couple of awesome products, but we need to make sure that our project will be effective in the future and doesn’t simply mimic another business or open-source project out there that wasn’t successful!
Mike Nichols
In order to make a global impact, you really need to build a business around your products, patents and all. Raising funds will be a lot easier when you start a start-up in conjunction with us, as many businesses with much less appeal have made millions of dollars after just a few years here.
Team DISCO
Wow that’s amazing! It would definitely be easier to raise the funds as a company. Much of the price of insulin comes from manufacturers and patent holders adding huge mark ups on the product that the governments and consumers then must face. If we were to design a business, obviously we wouldn’t impose those kinds of mark ups.
Narcyz Ghineaa
Hey guys, slow down a little. Discovering promising compounds is only one step in the process. It is the in-human trials that are needed to convince regulators the drug should be registered that is the real challenge for open source drug development. How are you going to fund that? If you want to get a drug to market entirely open-source without industry involvement you will probably need to consider “open source clinical trials”, and organise a network of people that are willing to do the necessarily research on a non-profit basis.
Team DISCO
We hadn’t considered that. I guess that we need to think about all the potential options for funding that doesn’t necessarily involve us making it directly to fund the project.
Mike Nichols
You should also start thinking about how the initial manufacturing plant begins. If I were you, I’d find a country that has a high demand for insulin and is currently very undersupplied. Build your plant there, following the regulatory guidelines required for that country. Once your Human Insulin production starts making a profit, you can begin phasing in your Winsulin. Get Winsulin off the ground with your human insulin production.
Neil Donelan
This might be a nice way to start. We currently have a large amount of processes that we have to go through in order to transport insulin from one country to another. Custom imports are different between countries, some of which are time and resource intensive to manoeuvre through. Localising your operation in one location may be a better way of organising this before expanding.
Mike Nichols
Would you have anywhere specifically in mind?
Neil Donelan
We have had huge demand for insulin in Tanzania in Africa. Their diabetic population is quite large and is expected to grow significantly as better diagnostic tools are implemented, as estimated 2/3rds of their diabetic population are currently undiagnosed in Africa alone. The South East Asian, and Pacific rim regions also need to be closely monitored.
Mike Nichols
So, maybe Tanzania or somewhere similar would work? You should strongly consider forming a start-up, and withhold Winsulin from the open source sphere to pursue this. Global impacts require profit margins and intellectual protection.
Team DISCO
These are all such great insights. We really need to consider our options.
