Our chat with the man who helped develop CRISPR

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Yesterday, we started our interview with George Church, professor of genetics at Harvard Medical School. He’s one of the developers of CRISPR. That’s the biggest story in biotech, this side of the millennium.

I’ll let Eoin continue, where he left off yesterday…

Q: In April, Chinese scientists announced that they edited genes in non-viable embryos. In November, British researchers said they’d successfully treated a one-year-old girl who had leukaemia using gene-edited T-cells. Are these in your view positive developments?

A: They’re two different things. [As regards the] editing of the T-cells, you can treat Aids patients and you can treat leukaemia and various cancers using gene editing. You can basically make T-cells coming in seem less foreign, less rejected, so they can do their job with killing the cancer. I think that’s probably quite good. It’s starting to save lives. But it has to go through FDA approval like everything else. This is me saying: let’s be cautious as usual. It doesn’t require a new law. Just make sure that your leukaemia drugs are tested. Don’t rush anything.

The Chinese did something, and a lot of people are confused as to whether it’s legal. It’s perfectly legal in most countries of the world, including the United States and England. They didn’t do anything out of the ordinary. They used triploid embryos, which are essentially a waste product of the reproductive medicine, but it was also legal to have done diploid embryos. It’s just not legal for any new medical technology to be applied in the broad population without government approval.

Sometimes China is characterised as being a lax, loose regulation [environment]. They are not. There is not loose regulation in China. I don’t understand how people can be confused about that. They shut down all of genetics, country-wide, in an instant, which would be very hard to do in other countries. This is for genetic analysis, not just therapy. Furthermore, they have very tight regulations on the internet. They’re not a lax regulation state.

Your question is whether that’s a good thing. Again, you need to ask specifically, what are they trying to cure? Plausibly, they’re curing or preventing, better yet, many of the things we were talking about. So the scenario I talked about before – using sperm to prevent serious diseases like Tay-Sachs, which kills babies by four years and is very psychologically detrimental to the whole family – seems like a good way of reducing abortions and increasing the health of children.

Q: You alluded earlier on to the dispute over which team developed CRISPR-Cas9. You were a significant contributor to that development, yet are not one of the names frequently quoted. Can you talk a little about this?

A: We have patents that were issued for CRISPR in my group. We were arguably one of the first three. I’m glad that we’re not part of the dispute. Our patents are unchallenged, which could mean that we added value that was recognisable and unique.

There are the other two groups: Jennifer Doudna’s and Feng Zhang’s. Jennifer came up with a way to cut DNA, and proved it in a cell-free system, and hypothesised how it might work in human cells. Then our group and Feng Zang’s showed how you could use it for precise gene editing, meaning homologous recombination and how to do that. So it boils down to, do you want to reward a prophetic and incompletely worked-out protocol, or the actual protocol that does precise gene editing?

By the time we all published in January 2013 – all three groups published in that month – there was only one group that had done precise, homologous recombination in human stem cells, which was ours. And there was only one group that had the guide RNA that turned out to be the one which everyone used, which was ours. Feng Zhang’s had done homologous recombination, precise gene editing of human cells, but had not yet done stem cells and had not yet developed the right guide RNA. Jennifer’s group only did cutting, not homologous recombination, and again did not have the first guide RNA. So that’s what was proven in public at the time.

In most fields, there are lots of inventions that are required for practicing – actually practicing. This will probably be no exception. We’ve already got some [patents] that are granted and not under contention, and those will be valuable. To make a cellphone, you need thousands of patents. This [CRISPR patent] happens to be one that’s getting a lot of scrutiny, but I don’t think it’s going to be of great financial significance. I could be wrong.

The three companies that started up to do gene therapy are all in Cambridge [Massachusetts], and they’re not really interfering with each other. This is a purely academic thing that’s going on between universities. There are other companies that are providing tools, and there are companies that are providing transplantation, like eGenesis, and none of these seem to be particularly concerned about this little tempest in a teapot.

Q: So it’s really down to each university wanting the prestige?

A: No, I think that’s a misunderstanding. This is a formal procedure the patent office did. The universities are responding to the patent office.

It’s not universities or people suing each other. It’s the patent office saying, “Hey, I see an interference here where two things came in about the same time. One was a little bit ahead prophetically. The other one was ahead in terms of actually reducing it to practice. We’ve got to make some kind of decision…” Probably it will end up with each group getting some patents at the end of the day, some claims.

You get into these little disputes of who thought of it first. You can have somebody saying, “I thought of it but I didn’t do it.” Another one says, “I did it and it took a little extra finesse to get it to work.” So they both get a little credit.

Now it’s whoever filed first. And that’s the way it has been in the rest of the world for a number of years. The United States just caught up, around the time that this was happening.

Q: You’re saying that the financial benefits are going to be minimal to each group?

A: I think the industry will be an amazing industry. There’s going to be a lot of wealth created by these little companies in Cambridge. But I don’t think they’re currently interfering with each other. They’re not, as far as we know, working on the same topics.

The real point of patents is that you get a limited monopoly on whatever product you’re making. I don’t think they’re making the same product. Even if they create billions of dollars of wealth, if there are ten different products per each of the three companies and none of them overlap, then they won’t be suing each other, no matter how the patents turn out.

Q: What are some of the other projects you’re pursuing at the Church Lab? I believe one is lengthening human life?

A: Right – not lengthening so much as reversing ageing. The problem with getting FDA approval for lengthening life is – say you want your tool bottle to say extend life by 20 years: that’s a 20-year study. For ageing reversal, you can demonstrate on animals and then humans in principle in weeks – things like changing muscle strength, reaction time, cognition, etc.

There are lots of examples of ageing reversal in animal experiments that are quite convincing. There are probably even more. We’re taking the approach of using gene therapy, because it’s a much more cost-effective route from an idea to therapy – since you have an idea, you know the genes involved, and you could make a treatment. And so we have dozens of those currently in pre-clinical animal trials.

Q: You explain that human ageing is one of the primary causes of disease, and given that one of your main concerns is combating disease, reversing ageing is a way to go.

A: Right. I think that in industrialised nations, 90% of people die of a disease that does not afflict 20-year-olds.

In developing nations, you have a slightly different issue, where gene drives might be useful for malaria and other major diseases there. But putting aside the differences in different parts of the world, as the world as a whole becomes more and more industrialised, you have more and more people dying of these diseases of ageing. Before they die, they consume vast amounts of resources from post-retirement, and this could become a huge economic drain in a world population that’s becoming on average older.

Q: Any other projects at the Church Lab we should know about?

A: We’ve historically participated in another revolution, which is in reading DNA. What people sometimes forget is that all of these therapies – genetic and otherwise – are increasingly dependent on our ability to read our genomes.

That revolution was predicted to take somewhere between, optimistically, six decades and six centuries. It ended up being six years. So like CRISPR evolution, which is now three years in, the next-gen sequencing revolution has taken about six years to come down from $3 billion to, as my company just announced, $199 for a complete genome and genetic counselling – so not just raw data but interpretation.

That will probably continue to come down, and extend to knowing an environment and viruses and life organisms. We don’t know whether a particular cough or sneeze is highly pathogenic or completely non-pathogenic. That’s the revolution in analysis that could be as big or bigger than some of these therapeutic uses we’re talking about.

Q: There was an Economist article about you in 2014 headlined “Welcome to my genome” where you had made your genome public and allowed everyone to come and rummage through your DNA. How is that project going, and are you able to persuade many other people to do as you did?

A: Many of the projects we do are meant to provide a road map. It’s not so important who gets credit or who gets the money, it’s to show that it’s possible. Over the decade, we’ve been promoting this idea of sharing data – both sharing it back to the person who donated their time and medical records as a patient, and sharing it with everyone worldwide. If everybody in the world had their genome in a vault in their home, no one would benefit. The idea of sharing was bizarre ten years ago, but now it’s generally useful.

Whatever the status of the Personal Genome Project itself, which has now expanded worldwide to many countries including Canada, England, Korea, Austria and so forth, what’s more important is the impact it’s had on almost the entire field of medical research, where sharing is now the norm, where it used to be the exception. That’s extremely important, because that’s the way we’re going to make all these connections between genes, environments and traits that will help provide preventative medicine for everyone. Rather than reactive waiting until you get a metastasis, we’ll find increasing number of ways of completely avoiding cancer.

Most people don’t die of cancer. We’d like that to be all people never get it, rather than “we have something that will extend your life in a very painful way for the next two or three months for hundreds of thousands of dollars.” That is the way that most cancer research and most cancer dollars have gone. We need to be looking at correlations and causations in the population.

Q: You are the founder or co-founder of many companies. Can you talk a little about that?

A: There are about nine that are starting up this year. When you add them to the 12 – depends how well they do – that are in the incubation phase. We have a terrific incubator at Harvard called the Wyss Institute for Biologically Inspired Engineering. It helps them to get started without panicking about financial support. They can test out their ideas and then calmly launch. Some of the recent companies that are fully launched are things like Warp Drive Bio, which makes small molecule chemicals that have evolved in the wild, in the war between bacteria and fungae, but that can be used for various human diseases. Editas just had an IPO – it provides gene editing therapies for a variety of human diseases, infectious and inherited.

Q: Are you a cofounder of Editas as well?

A: Yes. Jennifer Doudna and I were looking into how to co-found a gene editing company. We recruited three more co-founders. And then I also worked with Jennifer on Caribou, which then co-founded Intelia, which is the second of the three companies in Cambridge.

Q: Do you have financial stakes in these companies?

A: Yes, in Intelia, Editas and Warp Drive Bio – and in fact in all the ones I founded. I’m very careful about listing all my conflicts of interest both on my website and in every talk that I give, or article.

Q: It sounds like gene-related technology is going to potentially be of great benefit to humanity. What I take from my conversation from you is that we should be embracing this technology, proceeding with caution – but that overall it’s a good thing.

A: Yes. I don’t think we should relax our protocols for testing safety and efficacy, but I agree with everything you said. Proceed with caution, as we always have, or almost always have, and focus on prevention whenever we can, because that’s really where we have the biggest impact.

I’d love to hear your opinions on this controversial subject. Genes make up much of your identity. Would you risk changing yours – or your children’s? Do keep writing in: andrew@southbankresearch.com.


Andrew Lockley
Exponential Investor

Category: Genetics and Biotechnology

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