Stéphane Bancel (Chief Executive Officer – Moderna): We have a lot in common, more than you think 22,000 genes, that would be three billion base pairs of genetic information.
But one mistake, one mistake out of three billion bases, can change your life, can be fatal. For example, if you are unlucky, and if you have a mistake on the gene UGT1A1 on chromosome 2, that is Crigler-Najjar, a fatal disease. Basically, you are unable to process your red cells. There is no treatment. The only thing that clinicians have found to save the people who have this disease, is to have them 12 hours a day in a photo-therapy.
12 hours a day! And by the time this little guy is 18 he is going to die because his body is going to be too big, the phototherapy will not work any more. It’s only one of more than 6,000 rare diseases. 6,000 rare diseases! and the number is going up. And by the way, cancer is also a disease of the genome. So that matters.
We have a lot in common. So let me maybe spend a few minutes, zooming in and walking you through the basics of molecular biology, the human cell, the basic unit of biology. Your body needs protein. Tons of proteins to survive, to function, like the insulin, growth hormones, and thousands more.
So when your body needs a protein, what does it do? It basically uses the information of the genes in your DNA. And in order not to damage your DNA, it makes a little copy of only what it needs, only the gene it needs. And the copy is made in what it’s called messenger RNA. The mRNA gets inside your cells, in a little machine called the ribosome, and it makes a protein. So if you want to think about insulin, the way it works is the insulin message gets from your DNA, makes a copy messenger RNA, and the ribosome makes a protein, and Voilà!, you’ve just made insulin.
Based on those discoveries, the biotech industry started 40 years ago. Think Genentec, Amgen. And what they did was they made those proteins in yeast or in bacteria cultures, in the factory, then they put them in a syringe to inject them to patients. And you got the first human insulin, human growth hormone, and so on. So it was a fantastic revolution.
Then scientists kept pushing the envelope and asked themselves: “Well, what if we could get the DNA inside the patient’s body for if the information is missing it can make its own protein?” And this is when gene therapy started. The only problem is we are 40 years after those first discoveries, those first biotech products; but is it a success? 6,000 rare diseases and the number is going up every week. As we understand more and more biology, there is only one gene-therapy product approved for patients. One! There are only 20 recombinant products approved for patients with rare diseases, but 6,000 rare diseases.
Is it enough? So few of us, couple years ago, sitting in Cambridge, Massachusetts, thought about the following crazy idea: “What if mRNA could be a drug?” And the reason why people haven’t developed mRNA drugs in the past, –because from what I’ve explained to you is pretty obvious, mRNA are drugs, why not?– it’s because of these two things, and the first is mRNA creates an immune response. Why? Because a virus is made of mRNA, like flu. So if we inject mRNA in a patient, what happens? Your body thinks you’ve just got the flu. And it’s not very good for a drug. Because you know, all the symptoms of the flu are not super nice.
The other reason is that mRNA was thought to be very unstable. Minutes, in vivo I don’t think a drug that you have to inject yourself every couple of minutes would be a good drug either. So those two reasons are really the foundations of why we never made mRNA drugs before. But we ask ourselves “what if”? We worked tremendously hard for two years, and we are happy to report that we found a way.
We have a way to work through those two barriers and what we do now, we made mRNA drugs. So how do we do that? We make mRNA in a reactor, in a factory, we put it in a syringe, and then we inject it into animals, patients down the road, in your belly fat or in your thigh, you inject the mRNA and what happens then? Inside the cell, the little guys in Grey, the ribosomes, read the mRNA we’ve just injected. They read your mRNA all day long. Trillions of time a day, they read your mRNA. And so, what they do here is they read the mRNA we’ve just injected, and they make the protein we tell your body to make. On demand.
Think insulin. And the beauty of it is that there are two things we didn’t expect initially we can do with this technology. Two unbelievable things. The first one is that we can make secreted proteins. Again, think insulin, think growth hormone. This has been grown by biotech industry but again, there is not a lot of products that have been made. You have in your body around 4,000 secreted proteins. That’s less than half the products that have been made by the entire biotech industry over the last 40 years. So there are still a lot of drugs that are needed by patients.
And so, you inject the mRNA, for insulin — it’s made in this cell, and then, we tell the cell how to secrete the protein inside the blood cell and to go at the right place in your body. 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 ribosomes, make the protein, but we are able to tell the cell “Do not secrete outside of yourself,” so the protein is kept inside, it’s trapped inside the cell; meaning we can make intracellular proteins, which are most of the proteins you have in your body. And today there is no way to do that with no technology available, either by the big pharma companies or the biotech companies, — to make intracellular proteins, those proteins that are needed for your body to function.
What I have just told you about at the beginning, the Crigler-Najjar disease, and the gene with that one mistake, UGT1A1, well, we are able in animals today, to make that mRNA for UGT1A1, inject it, and it makes the protein which then is trapped inside the cell where it has to be so the disease is not spread. This is really the big breakthrough, and again, if you think that your body has 22,000 proteins only 4,000 are secreted. Most of the proteins you need to be healthy, to live, are intracellular. Totally undrugable with any technology available today. This is the big breakthrough.
So let me walk you through one example of an application that has been tried over the last 40 years across many companies and that has always failed is about how you regrow the heart after a heart attack. So Dr Ken Chien, who is one of the Moderna’s academic co-founder and a professor at Karolinska in Sweden, has spent his life studying hearts — he’s a cardiologist — and taught me that on everyone’s heart there are stem cells until the day we die. All your life, you have stem cells sleeping on your heart tissue.
And what Ken taught me is that there is one protein in the body, called VEGF-A, and that if you send that protein to the stem cell it is going to tell it: “Go back to work make more heart tissue.” And so, what Ken has done, four years ago, was he tried to make a drug with recombinant proteins, the technology that the biotech industry has used. He made the protein for VEGF-A, in e-coli, in a reactor in a factory, and injected it in a heart after a heart attack. The problem is that when you inject it, it goes into your blood circulation way too quickly. To have enough VEGF-A, for the stem cells to wake up, to make a new heart tissue, you need a high dose.
The problem with it, as blood circulates through your body, is that it has a ton of side effects, so the drug failed in trials. And 10 years after, when gene therapy was discovered, Ken jumped on it again, said: “I am going to try gene therapy for my VEGF-A.” And the problem with gene therapy is once you inject it, you cannot stop it. It keeps making VEGF all the time, and that’s not good either. When Ken saw that technology, mRNA, he said: “That’s exactly what I’ve been looking for for the last 30 years!” And he tried it.