The Most Impactful Startup Pivot in Human History | Moderna and mRNA Treatments

If you've been following the news at all over the past year, you've undoubtedly heard of Moderna. They're a biotech company with one of the most promising coronavirus vaccines, and they developed it in record time. But they weren't founded with the explicit goal of developing vaccines, and the company is over 10 years old now. So I thought it would be interesting to explore some of the company's history and see how they wound up in such a prime position to win the fight against COVID 19. I'm John Coogan, and while I've never worked in biotech, I do have a passion for understanding how companies grow. So today we're exploring Moderna's pivot into vaccines and what this means for the future. I first started really digging into the Moderna story after I saw the founder of Stripe, Patrick Collison, tweet that he had added Moderna's MRNA vaccine to his running list of people quickly accomplishing ambitious things together. Reading Patrick's summary and it's clear that this is a huge accomplishment and something everyone should look to when undertaking any ambitious project. But a little research into Moderna shows that there is obviously much more to the story. This will be Moderna's first commercial product ever to make it to the market, and while it might be a stretch to call this vaccine a true pivot, it does differ pretty significantly from what the founders had in mind when they started. Moderna was founded in 2010 as Mode RNA Therapeutics in order to commercialize the research of stem cell biologist Derek Rossi. The promise of MRNA based therapeutics is huge, and the CEO of Moderna, Stephane Bensel, explained the general opportunity really well during this 2013 TED talk.

Your body needs protein, tons of protein to survive, to function like insulin, growth hormone and thousands more. So when your body needs a protein, what it does is he basically use the information of the genes in your DNA and not to damage the DNA. It makes a little copy of only what it needs, only the gene it needs. And the copy is made in what is called messenger rna. The messenger RNA goes inside your cells and in its own machine called the ribosome, it makes a protein. So if you want to think about insulin, the way it works gets the insulin message from your DNA, makes a copy messenger RNA and the ribosome makes a protein. Et voila, you just made insulin.

So if you have a disease that causes your body to fail to make a specific protein, most treatments will involve injecting that protein to supplement your body's production. That's how Synthetic insulin treatments work, but the biotech industry has also been working on gene therapies that seek to replace the genes that code for proteins. In theory, this would allow your body to create the missing proteins directly, but the approach hasn't been widely applicable yet. There are thousands of rare genetic diseases, but the FDA has only approved 18 gene therapies for treatments as of today. So Moderna targeted a third option. Instead of creating the proteins directly or trying to modify the DNA that codes for a protein, they focused on creating MRNA treatments. This has always been seen as a bit of a moonshot, since MRNA triggers an immune response and was thought to be unstable. Since viruses are made of mRNA, your body will think that you just got the flu and you will quickly develop flu like symptoms. And the instability problem meant that the treatment could break down in minutes, meaning that you would need many injections per day for it to be effective. Moderna has fortunately found reasonable solutions to both of these problems, but they still pose major barriers to broader applications of the technology. Moderna's MRNA approach still has major advantages over other drug development strategies. As we are seeing firsthand with the coronavirus vaccine. Development can be extremely fast and production could be much more scalable. There are of course, trade offs, like the freezing cold temperatures that each dose must be kept at to remain stable. But what's most interesting about Moderna's COVID vaccine is that it creates a secreted protein as opposed to an intracellular protein. In that same TED talk, Stephane Benzel describes the difference between secreted and intracellular proteins and why the latter is so important to Moderna's long term vision.

And the beauty, and this is a piece that we did not expect initially, is we can do two things with this technology, two unbelievable things. The first one is we can make secreted protein again. Think insulin, think growth hormone. And so what happens here? You inject the mRNA, let's say for insulin, it's made in this cell, and then we tell the cell how to secrete the protein inside the blood to go at the right place in your body. So we just mimic what your body does when you're not sick. But the big bingo is on the right, where we inject the mRNA, the little guys, the ribosome, they make the protein, but we are able to tell the cell, do not excrete, do not secrete outside of yourself the protein, leave it inside, so it's trapped inside the cell, meaning we can make intracellular protein, which are most of the proteins you have in your body. And today there is no way. With no technology available from either the big pharma companies or the biotech companies to make intracellular protein, those proteins that are needed for your protein to function.

Unlocking therapies that can deliver intracellular proteins would be a massive development. This problem hasn't been solved yet. And if MRNA treatments work, a huge number of diseases could be treated for the first time ever. But the Moderna COVID vaccine doesn't create intracellular proteins, only secreted proteins. So they haven't fully proved that MRNA is key to those kinds of treatments yet. I'll let Moderna explain how their vaccine works directly, since they do a better job than I ever could.

It all started with isolation of the virus from an infected patient in China. The coronavirus was sequenced and its genetic information was uploaded to a public datab. Working together, scientists at the NIH and Moderna identify the sequence for a key protein on the surface of the virus called the spike protein, as a good vaccine candidate. The instructions for making the spike protein were then encoded into an instruction molecule called mRNA, which could be administered directly to patients as a vaccine. The vaccine is injected just like other vaccines. The MRNA is taken to immune cells where it instructs cells to make copies of the spike protein as if the cells had been infected by the coronavirus. Other immune cells, shown here as red and orange figures, are then able to learn about the spike protein and develop ways to protect the person if they ever come into contact with the actual coronavirus.

Getting such an advanced product to market as quickly as Moderna has should be applauded, and it clearly bodes well for the future of the company. Their stock has been surging since the start of the pandemic. And perhaps most importantly, because of the high profile nature of this treatment, the American public is becoming familiar with the idea of MRNA treatments. In 2018, when Moderna went public in what was the biggest biotech IPO ever, they actually flagged the potential negative perception of MRNA based treatments as a major risk factor. With the US government purchasing 100 million doses of their vaccine, MRNA is going to be a lot more familiar to America. Americans in 2021 and beyond. I think they have essentially de risked this issue entirely. But there's still a question of where Moderna and MRNA treatments go from here. Earlier in the company's history, they set their sights as high as creating a vaccine for cancer. And there are still a number of hurdles ahead of them on that front. First, it appears that delivering MRNA treatments requires the use of a lipid nanoparticle, which can cause toxicity at high levels. This is a big problem for diseases that require ongoing treatment. Moderna was testing an MRNA treatment for a rare genetic disease called Kriegler Najar, but abandoned the project after failing animal trials. Essentially, the liver struggles to break down these lipid nanoparticles, causing a whole set of separate issues. A few years ago, Moderna was starting to get criticized heavily by the biotech community. A lengthy 2016 article in Stat News chronicled numerous problems the company was having both in product development and talent retention. Aside from issues about a high pressure culture, it looks like Moderna was running into some serious problems when trying to apply their MRNA technology to rare genetic diseases. The company had also become extremely secretive about their work, which drew unfortunate comparisons to Theranos. Employees were required to sign highly restrictive non disclosure agreements and Moderna refrained from publishing data in peer reviewed journals. Nature, one of the premier scientific journals, actually wrote an entire article calling them out for failing to publish data and let the scientific community wait in on their approach. It looks like it was around this time that Moderna pivoted to vaccine development. Although vaccines weren't considered as big of a business opportunity to the biotech industry, MRNA treatments seem to be the perfect solution. The Stat News article quotes an industry insider who says MRNA is better suited for diseases where treatment for short duration is sufficiently curative, so the toxicities caused by delivery materials are less likely to occur. Essentially, vaccines are the lowest hanging fruit in mRNA, so it makes sense that Moderna would start trying to commercialize products there. While it's only a slight pivot from their original vision, I think it's an incredibly impactful one. Financially, Moderna had set their sights extremely high with the aim of essentially curing cancer. Flagship pioneering the Biotech fund that backed the company has a long history of swinging for the fences, and Moderna is no exception. What's interesting is that while the market for vaccines might be smaller than cancer treatments, 2020 has shown us how impactful rapid vaccine development technology can be. Moderna was clearly in the right place at the right time to deal with the coronavirus pandemic, and now that they have this experience, future vaccines could be developed even faster. Everyone is now well aware of the threat posed by novel viruses, but with Moderna's ability to rapidly develop and produce vaccines, humanity is in a much safer place now. I for one am extremely excited to receive the vaccine and really hope that it can roll out quickly and make 2021 a great year for for America and the entire world. The Moderna story is inspiring because it shows what can happen when a company works extremely hard on a big problem. For years and years, even though they had to reduce the scope of their initial ambitions, they wound up having a profound impact on the world. And they certainly proved all the Theranos comparisons wrong. But let me know what you think. Was there anything interesting I missed about the Moderna story? Please leave a comment below and if you liked this video, please consider subscribing to the channel. Subscribe I've also created a YouTube playlist of Moderna related videos you can check out if you want to learn more. Thanks for watching.