This is George Church’s epoch-changing universe. A scientist/engineer who has been working behind the steering wheel of the human genome for well over 40 years. First on the scene with the genome-editing tool CRISPR, first on the scene with the human genome project, this six-foot-five scientist looms large over his field.
He’s an unorthodox figure, some call him the most interesting scientist on earth, originally flunking out of graduate school, he remains a fervent vegan, a narcoleptic with dyslexia and at any given time is working on a handful of projects that has almost science-fiction altering properties.
Nature has spent billions of years perfecting its own algorithm to an almost harmonious balance. Would editing it produce unintended consequences that we wouldn’t know how to deal with? Perhaps, but with that in mind, George Church is full steam ahead, ready to scale his discoveries should and when the green light is given.
He and his enormous 100 man team at Harvard are heading into a future full of ethical landmines. How they navigate it, Church assures us, involves us all
His signature project GP-Write has just announced they will now attempt to recode the genome to produce cells immune to viral infection. This is a future nearer than you think, the question remains are we mature enough to handle it?
Are we ready for a new era of genome engineering?
You’ve recently created a lot of buzz in the press by announcing that you and your lab plan to recode human cells to resist viruses. Perhaps you could walk us through a vague timeline of how that looks?
Sure, so we’ve done a proof of concept on specific organisms where we can recode the genome. So we’re not just making copies of the genome we’re actually making improvements that require multiple changes all over the genome. And that recoding has resulted in the resistance to four out of six viruses.
The next one we’re doing that we’re finishing now should cause resistance to all viruses. Then the Genome Project-Write will be developing technologies to try and bring down the price of doing that sort of thing in any organism. Microbes, plants, animals, anything with agricultural significance, industrial significance, and human cells both clinical and manufacturing.
So you have changed your original goal which was to synthesize all of the human genome’s 3 billion DNA base pairs, is that right?
No. We still retain this as a major goal. We’ve expanded those goals to include new technologies and synthesis other large genomes (plants and animals). We also want to maximize the opportunities for innovation in the community.
So in the hope of making this technology affordable and ubiquitous across all industries are you hoping that it will be integrated in a positive way that could really be a benefit to humankind?
That’s right. So my career and this particular project has a big emphasis on cost for equity reasons, and safety and security. One of the prime projects that we articulated yesterday was ultra safe human cells. So to make cells that would be typically used in manufacturing or transplantation even safer than current standards, for example making them resistant to viruses.
"I think we could eliminate hundreds, maybe thousands of severe Mendelian genetic diseases within a few years."
So are we really looking at a future where we are able to eliminate really catastrophic diseases like HIV, or hepatitis B, or the common cold? You use the word Ultra-safe cells what does this mean?
The FDA has rules to protect patients from even new, uncharacterized viruses. For example, any therapies called “biologicals” that have been exposed to animal serum is considered a risk of a new virus or prion. We want to make cells that are “ultra-safe” in their resistance to such pathogens, as well as to cancer, senescence, radiation and freeze/thaw cycles.
For some of those viruses we can immunize with vaccines, some we can help with drugs although they typically become drug-resistant eventually. Some of them don’t work with drugs or vaccines yet despite a lot of effort, like the common cold, influenza. So this would get them all at once.
In a synthetic biological sense the work that your team does is really about changing certain aspects of the human. Is that right?
I wouldn’t say ‘the human’, I would say human cells for now. Vaccines in a way are like the most ancient form of synthetic biology. This GP-Write is a kind of vaccine.
So you’re on the cusp of a very exciting new scientific age, especially related to your work. What should we be excited about and what should we be cautious about in your opinion?
I think we should be cautious about all new technologies, and quite a few old ones as well. People should be paying more attention. You don’t want to just leave it up to scientists. You want politicians, religious leaders, everybody to be a part of the conversation.
We also need regulation and surveillance. It’s not sufficient to have voluntary compliance. It’s like with cars, you don’t just say, “that’s great, here’s a license,” and trust that he or she will behave themselves. You have to have surveillance for speeding, alcohol, age and so forth.
What we can look forward to on the positive side is an ability to avoid very serious mendelian diseases by getting your genome sequenced. That’s very inexpensive now, relative to the cost of orphan drugs which can be millions of dollars per child. We can look forward to being able to read and write information to brains more readily, due to the brain initiative, possibly eliminating malaria and Lyme disease, and so forth. The list goes on.
Image: Marius Bugge
So in the future will there be editing systems that are so meticulous in their targeting that we can’t even begin to think of the type of product that it might be able to create?
Well both meticulous and precise in the sense if you want to change a single A to a G, you could do that without affecting adjacent base pairs. That’s what meticulous means in this case. We also need more efficiency, so that you can change hundreds of sites, maybe hundreds of thousands of sites. In GP-Write we’re changing at least a quarter of a million sites.
I think that technology is right around the corner. If you look at the trends in molecular biology, and the kind of work that my lab has been doing, we helped bring down the cost of reading genomes by ten million fold, and the cost of synthesizing DNA by a similar amount. But actually changing DNA in living cells and determining that it’s doing what it should do there is a new revolution called GP-Write.
So what does it look like when GP-Write is working? A patient comes into the doctor’s office in 10 or 20 years, what does an optimal GP-Write situation look like?
One scenario is that GP-Write has done its job even before the patient comes into the office. Or maybe they don’t even come into the office but get it at home. And that is that some stem cell has been engineered to be virus resistant, and cryo-preservable and programmable to make any organ you want. That’s just popped in the patient so there’s no real genome engineering at that time. It’s been done in advance.
The other possibility is that there’s some customization that might occur in the clinic if things get fast enough, for example, the speed of sequencing a genome has come down from 10 years to minutes. So the same thing could happen for writing. If reading can go down from a decade to minutes then writing may be able to do that as well. You could also imagine that you might have a lot of really high-quality, semi-personalized therapies prepared in advance. Universal transplantable cells which we’re starting to see already in the form of Universal’ CAR T which are used as cancer agents.
So would you be confident in telling someone that we would be able to eliminate diseases like cancer from the earth in a certain amount of time, considering the acceleration of technology that’s happening amongst the community right now?
I think we could eliminate hundreds, maybe thousands of severe Mendelian genetic diseases within a few years. We have the technology already, it’s just that people aren’t tapping into it. For example, I launched Nebula Genomics recently that is going to pay people to get their genome sequenced. That’s a prerequisite for most of the stuff we’ve been talking about today.
They can learn with whom they are compatible genetically and thereby avoid the five percent of babies that are born with severe genetic diseases. So that’s something that could essentially happen as fast as people sign up for it. We’re going to try and pay them for their genomes rather than wait for people to notice that the price is already pretty low.
There might be some residual kinds of cancer that are very hard but we’re making such great strides now with universal CAR T cells and with cancer vaccines, I would not be surprised if we have a completely different relationship with cancer in the future. Also with genetic predispositions to cancer. All kinds of preventative methods that are suddenly popping up about which most people are unaware.
This revolution has been so fast. It’s been 14 years and we’ve brought down the price of these things ten million fold. I wouldn’t be surprised if in another 5 – 14 years almost everything listed here is happening.
This might sound like a bit of a naive question but considering everything you’re saying, that we can eliminate certain diseases that are prevalent amongst the human population, could hypothetically certain mutations arise as a consequence of eliminating that could pose an even bigger threat?
Like I said, we should worry about everything, but that particular thing is very unlikely because our sequencing is quite accurate, and we do a lot of testing. This is exactly the thing that the Food and Drug Administration is in charge of. Making sure that you test new therapies in animals and then in small clinical trials. Also, just the thousands of research studies on the subject of genome engineering over the last couple of decades would argue against it as well. I’m not saying it’s impossible, I’m just saying we have mechanisms and a lot of data.
Considering you were one of the early pioneers in the development of CRISPR, in hindsight would you change anything about the development of this project, how fast it’s come out?
No, I think it’s come out fast enough, in fact probably faster than most technologies. It went from the first proof that it could work in human cells in 2013, to four companies in a few blocks of each other in Cambridge that have a market capitalization north of 2 billion dollars, just in a couple of years. That’s fast enough. There are four companies working on editing and it’s curious that these four companies are all near one another in Cambridge. In addition, many genetic diseases might be handled cost-effectively with genetic counseling via Veritas Genetics and Nebula genomics.
"I think we’re talking about in the next few years seeing an aging reversal in 12-year-old dogs."
George Church on age reversal technology
What would you do to educate scientists that are now taking the torch so to speak and using it for whatever kind of work in this area? Secondly, some geneticists have thrown around fanciful ideas of editing the genome in the future where we can engineer humans to get energy from photosynthesis or to create plants that can walk. Are we on the cusp of that kind of Frankensteinian revolution?
Well, the first part, I certainly recommend to the next generation that they focus first on safety engineering. There’s safety engineering in almost every field of engineering, civil engineering, bridges, aviation, electricity, cars and so forth.
To your second point of whether we can do truly revolutionary constructs like photosynthetic animals, there are already photosynthetic animals on almost every major phylum in the animal kingdom. Mollusks, salamanders, insects, etc.. The real question of all these things that sound strange is, “are they useful”?
If they’re not useful it’s unlikely there’s going to be a lot of effort put into them. The amount of surface area you would need to make a photosynthetic animal is pretty large. I would say the usefulness trend would be towards a very efficient photosynthetic production of all kinds of food. Vegan based foods are about 20 times more efficient in terms of photosynthesis than animal based. Combining photosynthesis directly into animals doesn’t make as much sense as making food that really tastes great that skips the animals. That would be my guess.
I know you’ve spent a part of your career working on reproducing a wooly mammoth, would you say that is useful?
We wouldn’t be working on it if it weren’t. The utility argument, which is certainly not airtight but is I think compelling, is that the Arctic has 14 hundred gigatonnes of carbon, much of it in the form of methane which is 30 – 80 times higher global warming than carbon dioxide.
And the 14 hundred gigatonnes for perspective is equal to all the carbon in the atmosphere already, plus all the carbon in all the rainforests in the world if they were burnt to the ground. So it’s a lot of carbon that is simply escaping due to the melting. It’s kind of a positive feedback loop. Even if humans disappeared from the earth we might still have this positive feedback loop where we spiral out of control, which occasionally changes a planet as it did on Venus.
So how the mammoths come in is, not so long ago they kept the tundra colder by punching down the snow in the winter — an insulating blanket that delays loss of warm summer ground temperature. Mammoths are very closely related to modern elephants. They’re more or less the same species so if you could make them cold resistant. . . So that’s what we’re looking into, that possibility of simultaneously adding features to endangered species of elephants and doing work to pull carbon out of the air and prevent methane being released into the air.
Mammoths could be brought back from extinction to help stabilize climate change.
This wouldn’t be an interview about synthetic biology if I didn’t ask you a question about the ethics, naysayers, and skeptics have warned of a very dark future around this domain. So what is your answer to the ethical side of all this in terms of the work that you do?
Well, I raised most of these ethical issues first, simply because I happened to see them first, being in a position where the technology is being developed. I think that most of the scenarios you described are unlikely to be useful, like photosynthetic animals. Most people want their children to be much healthier rather than less healthy so I think there will be a trend for using it for public health benefits worldwide. Eliminating poverty will allow people to get a better education. So that’s my prediction.
But we need to encourage these kinds of ethical conversations by bringing in lots of voices as you’re doing today, reaching out and making sure that people know what’s going on. It’s in people’s control if they’re adequately up to speed. It’s a multiple way conversation. We need to listen carefully to what people want.
I’m all for your work, I think it’s incredible and revolutionary, but we’ve opened a Pandora’s box of sorts. Some people might not want healthy kids. There’s a lot of strange people with strange intentions out there is all I’m saying.
I totally agree, and I’m not trying to paint a utopia. What we have is a real world that requires watchdog agencies (FDA, USDA, EPA, FBI), as I mentioned earlier doing surveillance and making sure that parents who abuse their children get locked up. That’s already the case with the Food and Drug Administration making sure that any new drug or device gets tested and anyone who uses it without testing also gets penalties. So I totally agree. Every new technology and old technology needs to be paired up with government regulation, and surveillance and enforcement.
I have one last question for you. A lot of people out there reading this would love to know about aging. Where are we at in terms of your domain in fighting aging?
My lab works on aging reversal. We’re emphasising aging reversal rather than longevity because you don’t want to live a long time in a decrepit end of life situation. Also it’s easier to do experimentally. And finally, it’s easier getting an FDA approval. If you say, I’m going to extend your life by 40 years, the FDA is going to say, fine come back with your 40 year study. But if you say we’re going to do ageing reversal that’s something that could happen in months, and it’s much more feasible technically.
Where that stands now is there’s a great deal of information about ageing related genes. Ageing reversal has even been demonstrated in about eight different ways in mice. So we’ve been modifying those genes and doing gene therapy trials on mice that are two years old, almost dead from ageing. We’ve been doing ageing reversal on a variety of different traits — cardiac disease, kidney, obesity, diabetes and so forth, and we have examples of gene therapies that can affect all of these simultaneously.
I don’t think we’re done by any means but we’re entering a whole new era where it becomes very easy to test lots of different combinations of genes. We’re moving from mouse experiments into experiments on dogs. People care about aging in dogs. And then from there, we’ll move to humans. We’re already starting the dog clinical trials now so this is not something that’s far off in the distant future.
"I wouldn't be surprised if in another 5 - 14 years almost everything you can imagine is happening."
On the future without severe genetic diseases
So would you say that we will be able to at least extend our expected lifespan in our lifetime by a huge amount?
I think we’re talking about in the next few years seeing an aging reversal in 12-year-old dogs. Then human trials will start immediately so it could be as little as four years before we see the first clinical trials and the first people being positively impacted. Now that’s not going to be the whole population, it’s just going to be however many it takes to do a clinical trial.
Feature imagery: Marius Bugge