Harvard University’s George M. Church is among the world’s leading scientific pioneers in genomics and biotechnology. The genetics professor at Harvard Medical School and Massachusetts Institute of Technology has founded numerous biotech companies that apply his breakthrough technological innovations to medical diagnostics, therapeutics, and synthetic biology.
Church began his scientific career in the mid-1970s, and is the author of 425 journal articles, 95 patent publications, and the book, “Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves.” He developed the first direct genomic sequencing method in 1984, helped initiate the Human Genome Project the same year, and founded the Personal Genome Project in 2005. His discoveries have served as the basis for companies such as Editas Medicine, Gen9bio, and Veritas Genetics.
WuXi AppTec Communications recently held a wide-ranging interview with Church on one of his most recent endeavors – gene editing and its applications. Church observes that there are 2,400 ongoing gene therapy-related clinical trials in which genes are added, subtracted or inhibited to treat diseases. He describes these applications as part of the “new genome technology ecosystem,” which represents an exponential advance in genomics over just the past six years and whose next significant milestone likely will be the technical ability to write DNA for “whatever you want.”
Church also shared a broader perspective on the value of genomics. Although the genomics revolution is realizing its promise, he observes, the public has yet to embrace it.
“Public understanding is a huge challenge,” Church says. “It’s really a pity that genomic technologies haven’t grabbed the imagination of people the way other things have. Nobody really has gotten into (genomics) even though the stakes are incredibly high.”
His advice? “Everybody in the world should get their genome sequenced,” he says. “Learn about yourself; know yourself.” For $999 people can have their whole genome sequenced (or for $80 their exome, and get genetic counseling, he explains, giving them the ability to prevent many genetic diseases. The alternative, Church adds, is paying millions of dollars for a gene therapy to correct a problem that could have been avoided.
WuXi’s interview with Church is part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.
WuXi: Where would you rank gene editing technology in the history of biotech advances and what will be the next significant breakthrough?
George Church: Gene editing in mammals began in the 1980s and has continued to improve since then. Some people consider gene editing to be CRISPR (clustered regularly interspaced short palindromic repeats). I think CRISPR is not as gigantic as some are making it out to be, even though I was involved in turning it into a technology – and that’s not just modesty.
I think the real gene editing revolution happened soon after recombinant DNA, but well before CRISPR, and that was what Mario R. Capecchi and Oliver Smithies got the 2007 Nobel Prize for. That’s real gene editing (Not just gene bashing). That pioneering work was done in mice and to get it to work in other organisms required a series of incremental changes including targeted double stranded breaks via meganucleases, zinc finger nucleases (ZFNs), TALENs (transcriptor activator-like effector nucleases) and CRISPR. They were all part of steadily improving on what Capecchi and Smithies did, so that it works in basically every organism now.
I think that the real breakthrough here is a cluster of improvements on how you read and write DNA. So, to the second part of your question, what’s next; it is the ability to write DNA rather than edit it. There’s this whole continuum – adding genes, subtracting genes (or reducing expression), and precise editing; the fourth and the next thing is being able to write whatever you want.
WuXi: What diseases are best treated with therapeutic gene editing? Do you see any limitations?
George Church: About 2,400 gene therapies have been approved for clinical trials. Almost all of these involve adding a gene. A handful involve reducing gene function, such as RNAi (RNA interference), ZFNs and TALENs. Almost none involve precise gene editing.
WuXi: How do you define precise editing?
George Church:To add a gene you can pretty much put it anywhere on the chromosome. To subtract or knock down a gene you can either put in an interfering molecule or you can bash the gene and make a mess, kind of a random mess. Almost anything will knock out a gene. And precise gene editing means, for example, taking a thymine and changing it to adenine. Or I want to remove exactly four bases, not three, not five. That’s precise editing; and that’s normally what an editor would call editing. I’m sure you are on occasion an editor or deal with editors. They don’t consider ripping a page out of a book as editing. That’s not normally what you consider editing. But we’ve slipped into this world where that’s mostly what people are talking about when they talk about gene editing. They’re talking about making a mess.
WuXi: How would you apply precise gene editing?
George Church: There are lots of uses. It’s just that it’s so much less efficient, that people tend to play the low hanging fruit game, which is ‘I don’t want that stuff way up there, it might be sour grapes, so I’ll take the ones down here.’ But if we could do precise genome editing as easily as we do knock out, we’d be doing it that way. For example, take sickle cell anemia. It’s a simple point mutation of one base from adenine to thymine. So you might just reverse that. But instead we’re going through all the hoops to figure out, well maybe there’s another gene that we could make a null in it and that would achieve the same result. Cystic fibrosis is another example, with exactly three bases are deleted in the major disease form. There are hundreds of diseases where you would like to put it back to the wild type gene state, and you wouldn’t necessarily want to knock it out.
WuXi: What are the top ethical considerations in gene editing?
George Church: Mainly safety and efficacy, like other new technologies approved by the U.S. Food and Drug Administration and European Medicines Agency. More speculative issues include potential effects that only show up after a few generations, gene incompatibilities or commercial influence on choice of offspring traits.
WuXi: What do you mean by effects that show up after a few generations and gene incompatibilities?
George Church: I prefaced that by saying they are speculative worries. It’s kind of like the worry that the first atomic bomb was going to cause a chain reaction in the nitrogen isotopes of the planet’s atmosphere. Fortunately, it didn’t happen. But people worried about it. They still tried the bomb.
The hypothetical gene incompatibility issue is like drug incompatibility. Like my mother-in-law was prescribed high levels of ibuprofen and when I went to get the prescription filled it was incompatible with the methotrexate drug she was already taking. The same thing can happen at the genetic level. For example, fruit fly P-elements that are harmless in one strain cause vast amounts of random damage when introduced into an incompatible fly genome.
The other – effects that would show up after a few generations; that’s really hypothetical. If you look at people four generations back they tend to be shorter than we are today in a well-nourished country. That’s epigenetics, and somewhat evident in each generation. There are genetic phenomena of “anticipation” in which each generation a mutation grows (triplet repeat expansion) until it crosses a threshold and causes Huntington’s disease.
WuXi: What role does epigenetics play in the applications of gene editing?
George Church: Epigenetics is involved in all genetics. Some people use the word epigenetics when they want to suggest something mysterious, but it has a specific meaning. It’s the way that genetics plays out. Well characterized heritable epigenetics is common in plants and hence a potential alternative to genetic “editing.” We know how to reprogram mammalian cells epigenetically from one cell type to another. It’s relevant to gene editing, but it’s not scary relevant. It’s just another thing you check.
You should always worry about all the ramifications of gene editing. Usually you know enough about the epigenetics. So for example, if I change the promoter of a gene, then it’s going to effect the RNA expression of that gene and the expression downstream from that. That’s all epigenetics. So by making a genetic change in an epigenetic element you can determine what the consequences are.
WuXi: What reservations do you have about the applications of gene editing?
George Church: In addition to the ones I’ve described for human clinical use, there are potential issues with the use in agriculture and wild species, especially gene drives. My group at Harvard was among the first to publicly note these issues and discuss solutions, including biocontainment, reversal drives and daisy drives.
The main issue is that people want to be in control, not just scientists. People want to be in control, they don’t want things escaping into the wild and not be able to bring it back in; and so one of the problems we foresaw when we developed CRISPR gene drives was irreversibility. So we put some effort into reversibility, and containment. How do you keep it in the lab? Or if you put it in the wild, how do you keep it on an island? And so we’ve addressed those issues; especially reversal and containment.
WuXi: What are daisy drives?
George Church: That’s a particular way of doing containment where you basically say gene drive 1 is required for drive 2 is required for 3 and by the time you’ve used up 1 and 2, 3 has spread all over the whole island. But at that point because 1 and 2 are used up, even if one of the mosquitoes or mice gets off the island, it doesn’t have enough critical mass to spread on the mainland. It’s called daisy because it’s like a daisy chain.
WuXi: Is there enough government regulation in using gene drives in agriculture and wild species?
George Church: I think the government is just right, in a Goldilocks sense. Every government has rules. For example, if you want to release a wild animal in the U.S., you have to get approval from the Food and Drug Administration (FDA), the Environmental Protection Agency (EPA), the Department of Agriculture (USDA). The FDA wants to protect the welfare of the animal, the USDA wants to protect the existing livestock, and the EPA wants to make sure it doesn’t spread without control. The combination of those is pretty potent for wild release.
I think that gene drives will be improved, but also even if the daisy drives work, you still have a possible escape from one country into another, which means you need to have another whole layer on this that is international; where you say we have approval from all the countries of the world that we should do this. In principle, for example, the United Nations should be able to get approval from all countries for mosquito gene drives for malaria because the medical need is so overwhelming.
WuXi: What are the major challenges in helping patients understand how gene editing will affect them?
George Church: All potential parents, not just those with family history of genetic disease, have a 5% risk of having a child with very challenging genetic diseases, with $20 million in costs. So we should all learn more about our own DNA via genetic counseling – sequencing nearly all genes costs $80 and whole genome sequencing costs $999 – to prevent such diseases, generally without editing. Groups like the Personal Genetics Education Project are creatively working to increase genetic literacy.
WuXi: Do you mean that if people were more aware about their genetic make-up they could be more cautious about passing on genetic diseases?
George Church: That’s mostly what I mean. There are communities that have essentially eliminated Tay-Sachs disease and they did it, in part, by who they marry. It doesn’t greatly restrict your choices of who you meet and date and fall in love with. It may be a small percentage of people to whom you are not introduced by the community. But that’s currently a lot cheaper than therapy. Getting your Tay-Sachs diagnosis is $80 and dating services are almost free. Where if you get a Tay-Sachs baby, you’re talking about millions of dollars and a lot of pain and suffering for the family. And a cure doesn’t even exist for Tay-Sachs, and even if it did, it would probably resemble currently approved orphan drugs, which cost hundreds of thousands of dollars per dose for life.
WuXi: What concerns you most about potential side effects of gene editing, short-term and long-term?
George Church: Ideally, we should do tests in large human organs without putting humans at risk. This is needed since off-target effects are very genome-specific, not just target gene specific.
There are two kinds of side effects. One is off-target cutting of target editing and the other is you do exactly what you intended to do, but it has some complicated physiological effect you didn’t expect. That second one is unlikely if all you’re doing is returning the gene back to its normal state. In other words, you’re taking the bad Tay-Sachs gene and turning it into the common Tay-Sachs gene.
So I think the first one is the most likely problem, which is you have off-target editing, and if you have off-target editing the only way you can find out – you can’t really compute it yet – is to edit a lot of people. Well do you don’t want to edit a lot of people because then you get a chicken and egg problem so you edit a lot of human organs. So where do you get human organs without people? Well you could manufacture them in the lab, like give me a thousand hearts or livers. Those may not be good enough to transplant, but they are good enough to do preclinical trials on. This is just my speculation. I’m not representing an industry consensus here. You would probably need to test for safety, and ideally before you test in humans you’re going to test in human organs.
WuXi: How will gene editing technology evolve over the next five- to-10 years?
George Church: Exponentially, as has happened with reading and writing short pieces of DNA, where we have helped bring out a million-fold improvements in a few years. Reading and writing DNA are key parts of the new genome technology ‘ecosystem’ which includes editing.
WuXi: What do you mean “as has happened with reading and writing short pieces of DNA, we have helped bring out a million-fold improvements in a few years?”
George Church: It’s sometimes called next generation sequencing where we brought the price down of sequencing the human genome from $3 billion to $1,000 – and most of that occurred over a six year period. That’s what happens with exponential change. It just gets better and better by many factors of 10. In addition to reading short pieces of DNA, we also learned to synthesize short pieces of DNA a million times more easily during the same few years. In both cases the enabling revolution was via “molecular multiplexing.” I just gave those as examples of exponential technologies and I think that genome editing, assembling and writing will follow similar rapid change cost curves.
WuXi: What do you mean by “new genome technology ecosystem.”
George Church: It’s more like a community of technologists and clinicians and so forth; that we have an ecosystem of genome technologies that some people call editing, but it’s not just editing. You can’t edit unless you can read. So it’s a combination of new ease of reading and synthesis of DNA to make large libraries; and this collection of genomic tools now that are amazing are fueling the next round of the exponential improvement.
WuXI: Would you say we are finally realizing the promises of the human genome sequencing project?
George Church: First of all, I’m not one of the ones who promised cures. My group focused on improving the technology. And, by the way, no one ever sequenced any human genome. Some people say we never landed on the moon. I think we did land on the moon. But we did not sequence a complete human genome yet. My group has new approaches that might finally do it.
So yes, I think we’re getting close on delivering a package of technologies, not just turning a crank and saying I did 3 billion of something. It’s being able to read genomes over and over and find out who’s got what and how it’s related to disease and how to fix it and with that whole cluster of reading and writing technologies, I think we are delivering on that now. We now have a healthy industrial collaboration that is working. For example, there are millions of women who get non-invasive prenatal testing (NIPT). There was zero of that a few years ago. Now there are millions. But why isn’t everyone taking full advantage of genome sequencing?
WuXi: What will be the biggest challenges in bringing gene editing therapies to patients?
George Church: Clinical trials. Clinical trials are expensive. They cost money to get FDA approval and they take time. It’s unusual to get something passed in less than eight years. You start curing people as soon as you start the clinical trials. If the drug is incredible, then you’re going to start curing people in the first year. But it’s not on the market at that point. It’s still going to take years to get it on the market.
WuXI: Will that process ever change?
George Church: Well there’s part of me that hopes we get so good at it, that we can do it quickly. But I certainly hope the laws don’t change before we get good at it. There’s always somebody who wants to go a little faster, cut some corners. This happened in gene therapy in the year 2000, and we got three people dying in two different studies. It set back gene therapy and I think it was because researchers were rushing a little bit.
I think right now most of the countries of the world are pretty cautious. Thalidomide is another example where Europe rushed a little more than the Americans did. But it could have been the other way around. Every time we seem to get lax a little bit we have a crisis. I think we stay tough on the regulations. What we need is innovation. If we have innovation, the regulations will embrace therapies and diagnostics that work really well.
WuXi: Do you see public understanding of all these new technologies in the ecosystem as a challenge?
George Church: Public understanding is a huge challenge. It’s really a pity that genomic technologies haven’t grabbed the imagination of people the way other things have. People are jazzed up about celebrities, sports and consumer goods.
Nobody really has gotten into this even though the stakes are incredibly high. If you are a parent who has a sufficiently challenged child you basically drop off the radar. That’s why nobody thinks about it. But parents who have a child with a genetic disease often have to quit their jobs to provide care or raise funds. People seem to feel that it can’t happen to them. But it happens to 5% of families and they say well I’m in the 95%. How do they know? We have no idea until we look.
And so we need something like what happened with air bags. There’s still a million people worldwide who die every year in automotive accidents, but relatively few of them die in cars that have air bags, and certainly a lot more would die. So what we need is something like that, where people say, I know it’s rare but I know I’m not immune to it, so let’s just do it. It’s cheap enough now. We’re just going to do it.
Everybody in the world should get their genome sequenced. That’s the first thing they should learn – genetics 101. Get your genome sequenced. Learn about yourself; know yourself.
WuXi: Will cost be a major challenge in bringing gene editing therapies to patients?
George Church: We brought the cost of sequencing down to less than $80 for all genes and $1,000 per genome. But the gene editing therapies, those are in the order of $1 million and the rarer the disease, the more the therapies cost. These genetic diseases are individually rare, but collectively common. They are collectively 5% of all births worldwide each year. But they are individually rare so they are costly, but that could change with time. We haven’t had time for that cost revolution to occur like it has for sequencing. But yes, cost is a problem.
And that’s why genetic counseling is very attractive, or should be attractive. But people don’t want to think about it until they have the disease. Once they have the disease in the family, then they say, ‘Okay where’s my gene therapy?’ Before they had it, they could have had their genome sequenced for $80 to $1,000. Instead, they’ll take a $1 million solution once they have a problem, but they won’t take the affordable preventative route to avoid a problem.