Omar Abudayyeh & Jonathan Gootenberg: Manipulating DNA, RNA, and Cellular States to Cure Genetic Disease and Prevent Aging – Ep. 151

1:48 – (Jonathan) “Right now medicine is kind of going through a lot of changes with new technologies. And in the past, many people who are born with genetic disease could have treatments, but it was impossible to actually go into their genomes and fix that letter or problem in their genome that led to that disease. There were no cures available. And now we’re seeing technologies that are truly programmable that allow us to program those technologies to go into the genome, which is really 3 billion letters in all of your cells and be able to actually change any errors that lead to this specific disease and then actually cure it.”

2:40 – (Jonathan) “The technology that’s gotten the most coverage that does that is called CRISPR, the genome editing technology, is really the first wave of a whole slew of different programmable medicines. So in our lab at MIT, we work together to develop new programmable medicines that we hope someday will be therapies for genetic disease, for other common diseases like cancer or cardiovascular disease, and enable a new wave of treatments and medicines that can really help alleviate a lot of the suffering that people have from many of the health problems that come from these causes.”  

5:06 – (Jonathan) “I think that science fiction is a great path line to what could be possible. And so thinking about different ways that in different pieces of work that genetic disease is cured or that disease is diagnosed, the tricorder often comes up, from that Star Trek inspiration, it’s nice to imagine what’s possible because then it actually can motivate people to work towards that.”

7:32 – (Omar) “It took a really long time to understand what CRISPR was. I think as we started sequencing more and more life in the 90s and starting looking at the genome and people just started sequencing all sorts of bacteria and environmental samples, you start collecting this repository of genome information and one thing people quickly notice, I think the first observation was actually in the late 80s and people started seeing it more in the 90s was that bacteria had these really weird repetitive sequences in their genomes and no one really knew what they were. But it took the sequencing revolution of the late 90s and early 2000s to basically start noticing that the repeat sequences, in fact the sequences between the repeats that were in bacteria were starting to show up in the viruses that infect bacteria. And people thought that was really curious that there was this connection between bacteria and viruses. And I think in one paper someone even remarked, ‘Well, maybe this could be some sort of immune system in bacteria.’”

11:13 – (Jonathan) “If we really want to make the medicines against the diseases that everybody, whether they’re cardiovascular disease or they’re genetic, cancer, we need the ability to program biology just as we program computers. And part of that is going in and using the code of life to make proteins, to edit genomes, to target specific cells, to do things that we want. And that’s going to be the really powerful layer of medicines in the future.”

13:15 – (Omar) “I think there’s still a lot more biology that’s needed, in understanding why it is that people age, right now a lot of the common things in aging where – heart attacks, cardiovascular disease, strokes, brain degeneration, which is a really tough one. So the question is, if you solve those diseases, how much longer can you live? And then, what happens after that, right? Are there new diseases we can’t even think of today that if you live to 130–140 years old, for example, then hit you, right?”

(Ross) “Then it kicks in? I love that idea.”

19:41 – (Omar) “I actually think in general, gene therapy DNA tools for cancer treatment directly are harder because the difference between treating it like a genetic disease and a tumor is a tumor you have to get every single cell. With genetic disease, right? You’re missing a protein, maybe only like 1% correction, now you have enough of that protein to survive, but if I only got rid of 1% of your cancer cells, you would still have the cancer. If I got rid of 99.99% of your cancer cells, there’s a good chance that cancer might come back. And so you have this problem where you really have to get it into every single cell. And that’s hard. And that’s not a problem necessarily with gene editing technologies, it’s a problem with our current ability to deliver these technologies inside the body, two different cell types.”

23:33 – (Jonathan) “The thing about science that separates it from pseudoscience is that you have data and you have mechanism where you can one say, if I do a randomized controlled trial where I can take half of the people and treat them with this thing and half the other people treat them with the comparator or the placebo, I can actually see the change. And then I know also that there are intermediates, there’s biology there. Why that’s happening. It’s not just that they’re getting better, it’s that their cell is secreting this thing and can measure that. And so everything makes sense with everything we’ve tested in the lab. So it matches a hypothesis, a falsifiable hypothesis. That is really useful. So that’s the gold standard.”

45:22 – (Ross) “There’s this belief, I think, in the general human population that, ‘Oh, someone, somewhere is solving all of the problems,’ in this case, those some ones are you two. Someone, somewhere is working on cancer. Someone, somewhere is fixing sustainability. But not me, and not my life. I just trust. But I think there’s danger in that kind of thinking that somebody’s going to solve everything. However, I also think there is tremendous upside in the sense that a breakthrough can really change everything in a very short period of time. I mean, even looking at the iPhone, how it changed things or the invention of the car, how it changed the streets of major cities that were only horses just a few years before. It’s clear to me that a few things can change everything in a very rapid period of time.”

46:44 – (Jonathan) “I think that we’re starting to really be able to develop medicines that can actually approach these areas that we’ve had good treatments, but not total treatments, that will have large impacts. Cancer is a big one. I think that now we’ll be able to program cells and develop vaccines against cancer. So you see that, you know, Moderna, Pfizer, BioNTech were able to make these programmable vaccines we talked about for COVID. And now that, we’ve kind of proven the concept there, these companies are now turning to things like can we make personalized cancer vaccines? And so these technologies may usher in an additional era of new cancer treatments.”

48:23 – (Jonathan) “You may be familiar with the drugs Ozempic or Semaglutide or that Wegovy are burning through Hollywood because everyone’s on them. Those are actually incredibly impactful ways to manage appetite and diabetes that have had really impactful outcomes on people’s weight where they’re losing 20–30% of their weight. So it’s kind of crazy that people can just get an injection that helps them manage their weight. So we’ll probably see more of those as well. One last one is pain, being able to develop new drugs for pain, non-opioid pain where obviously the opioid epidemic was terrible to this nation. But new drugs are able to manage chronic pain, which is an outstanding issue. Those are also in development. So we’re going to see lots of very compelling new biotechnologies and medicines coming through in the next 10–15 years.”

51:35 – “When you take on any difficult journey just from a strategic standpoint, you want to be able to digest that into small parts that seem like they can be conquered. You know, to eat an elephant, you have to break it down into all those small parts and then you can actually do that. It’s not great for you. But so it’s really taking a problem and factoring down and also learning from those things. So if you try and experiment and you fail and you learn from it, it can direct you new directions to be able to actually overcome those challenges. So it’s really how do you plan and strategize well, how do you make alternative plans that you take that data and just know when to give up on a small subset of something and try a different route? Because these ambitious goals, there’s many different ways to attack them. And some will fail and some won’t. So failing fast, understanding, which are the best paths and how to iterate these small steps can get you a lot of progress in that direction. As long as you have that plan there, even if you’re failing, you’re learning.”