The most important man we’ve ever interviewed

Recently, we gave you exclusive complementary access to some first-class Frontier Tech Investor content. That publication is Exponential Investor’s “big brother”. Normally, it’s strictly for paying subscribers only. This week, I’ve wangled one more interview from Frontier Tech Investor – and it’s a biggie.

Today, we are again going to hand over to Eoin, as he interviews George Church – who’s professor of genetics, at Harvard Medical School. That’s reason enough to interview him. But beyond this, he’s actually one of the most important people we’ve ever been able to feature in Exponential Investor. That’s because he’s partially responsible for developing CRISPR – the novel method of gene editing, which is ushering in a radical new era of biotechnology.

For the first time ever, we can perform ultra-precise editing of genes, meaning that a wide range of genetic diseases can potentially be treated or cured. What’s more, it allows us to perform germline genetic engineering – on everything from food crops, to our own children. These changes will persist down the generations – leaving our mark on life, for all time.

Now, it’s over to Eoin – and George.

Despite this win, I’ve still had to hold back the best bits of Frontier Tech Investor – because we can’t give Eoin Treacy’s hot stock tips away. That’s strictly for paying subscribers. You can take out a trial here if you’d’ like all the details on the stocks he’s tipping.

Q: You are one of the chief developers of the CRISPR-Cas9 gene editing technology. Can you describe the technology and say how it was developed?

A: In nature, it works to kill bacterial invading viruses by remembering previous invasions. It does that by keeping a little piece of the DNA from the [invading] virus, and then that makes it super-easy for it to reprogram a cutting machine, the CRISPR nuclease. That’s what it does in nature.

Slowly, people adapted it. As a technology, it became editing: changing from killing viruses to editing DNA very precisely – not just making a mess, as you might with killing, with cutting, but replacing DNA. That was announced in January 2013 by two groups, mine and one of my ex-post-docs, Feng Zhang, who was by that time an independent investigator at the Broad Institute.

Soon thereafter, it became evident that, unlike some technologies which are hard, this one was easy. There is no way you could have predicted that. It’s easy to adapt to other organisms once you solve how to adapt it to humans, which is what we did first.

Q: Can you explain the implications and potential uses of this technology, now and in the future?

A: Any method of gene editing has some similarity to previous genetic engineering tools in what it can be applied to. Those applications include agriculture – plants and animals and to some extent microorganisms like fungi. It can be used for curing genetic diseases. It can be used for fighting infections, just like its original use for cutting viruses. It already is in use for fighting leukaemia and HIV/Aids. I’m being broad here, talking about genome editing – not just CRISPR.

It can be used for xenotransplantations – moving organs from pigs to humans – and making those pigs virus-resistant, or making a variety of things virus-resistant.

Finally, it can be used for gene drives, where you can engineer wild populations at low cost and high precision to fight diseases like malaria, dengue, Lyme disease and so on.

Q: You talk about the application of gene editing technology to cancer and HIV. Any other areas in human therapy where there could be breakthroughs?

A: Gene therapy is a big category that includes classically and typically inserting new genes. Then you can use more precise gene editing to both remove and insert, and that’s where CRISPR comes in.

There are 2,000 gene therapies in clinical trials, and many of those are already curing people. It doesn’t mean they’ve been approved for general use. They’re in the process of doing the gene therapy trials to get a fair number of people cured of, for example, blindness. There are some genetic causes of blindness that are curable by gene therapies. In most cases, you have to do it very early in life, like in young children – or else they’ll be able to cure them to the point where they can see light but they can’t interpret the light or stasis because their brains have developed too far.

There are other infectious agents like hepatitis viruses, blood diseases that cause hemolytic anemia – the list is long. There are thousands of genes that are so well understood that some of them can be addressed by genetic counselling. But once you have a child that has the disease, then you need to have some kind of cure or prevention for the development of downstream technologies.

Q: There are also potential risks and drawbacks. Can you talk about the risks related to CRISPR – for example, the risk of editing errors?

A: Almost every therapy has off-target effects, where it will affect something in addition to its target. Small molecule drugs do, protein drugs do, and CRISPR does.

The difference is that there are computer programs that help you design wherever CRISPR is targeting. If you use those well, then you can find something where there really is no off-target. Furthermore, there are ways in which you can change the CRISPR enzyme that makes it much more specific. When you put all these together, you end up with, essentially, off-targets that are undetectable.

Now, that doesn’t mean they’re undetectable in any reasonable laboratory experiment. It doesn’t mean they’ll be undetectable if you started treating a billion people with it, or a billion animals or plants. But our bodies are constantly mutating due to radiation and other chemicals, chemotherapies and so forth. So CRISPR is way, way below the spontaneous rate of mutation.  Also, you can direct it. So it’s a fairly hypothetical risk.

I think the bigger risk than off-target mutation is the systems risk: that it does what it’s supposed to do, but what it’s supposed to do has ramifications. It’s the reason all new drugs are tested by FDA-approved chemical trials. You see whether all your theories and all your simple tests on animals play out in humans accurately in terms of safety and efficacy.

Q: There’s also a risk that parents in the future are going to want designer babies, and pick and choose their future children’s traits. How do you rate that risk?

A: Again, that’s a risk of all new technologies. If you want your child to have computers and cars and education and so on, all of these could backfire, and they provide the parent with an awful lot of decision-making dilemmas and power. This would be no exception. It’s not clear to me that it’s more powerful than these other things, because the genetics takes a long time to arrive. It takes 20 years to arrive – while giving the child a very powerful toy could cause damage right away.

With all these things, you have feedback where you see the impact on society. Usually the things that are hardest to reverse are things that are attractive to society, or some section of society. If we want to prepare ourselves for them, we need to have discussions like the one that we’re having right now. It shouldn’t be limited to a particular technology, but all ways in which parents can influence their children.

Q: You don’t sound terribly concerned about this designer baby prospect.

A: Let’s be clear about that: I am terribly concerned about all new technologies. I’ve seen ways that you can get feedback and do safety testing on all new technologies, and I think that has to be a top priority.

But there are many other technologies that we should be worrying about. And we have standards. We have the EPA [Environmental Protection Agency] and the Food and Drug Adminstration [FDA] and their equivalents worldwide that require testing of everything. So I’m very far from unconcerned. And I want everybody else to be concerned – but to apply their concern to everything that can go wrong.

Q: Gene editing is seen, overall, as a benefit for humanity. But a line is being drawn at germline editing. Your colleague Eric Lander said at a recent conference that germline editing would only be used in rare cases, and that caution should be exercised to making permanent changes to the gene pool. Do you agree?

A: I think that what one person thinks is rare may turn out to be quite common. Calling it rare makes us less cautious, makes us more complacent. As I said, I’m very concerned about this, and if you say that it’s rare, then you don’t recognise the market forces that might be in place.

For example, right now there are many, many genetic diseases that cause very severe effects in life, like Tay-Sachs. There are individuals affected by it, and in larger numbers, their parents are carriers for it. This is not rare: there are many of them. The way it’s currently handled is, two parents know that they’re unaffected carriers. For each pregnancy, they will do a prenatal test, and about a quarter of those tests will result in them having to decide on abortion or not – termination. That’s a growing industry, if you will. At least half of the people are not comfortable with that outcome, whether it’s in their own home or other people’s homes, and they feel that all embryos are precious.

An alternative would be to engineer the sperm of the father so that no embryo would ever have to be aborted. In fact, you could even reduce the number of spontaneous abortions, which are more natural in some sense. That particular task might be more desirable to a larger number of people, and addresses a medical need as well as a societal need to reduce the number of embryo deaths.

If you edit the male sperm, then half of the children will be born carriers – so the gene will still be there – and half of them will be non-carriers. And both the carriers and non-carriers will be normal. But the genes will still be there.

Q: When Eric Lander says we should exercise caution before making permanent changes to the gene pool, what are your views?

A: My view is that we should always exercise caution, period, on everything. We don’t want to have false complacency into thinking that if we just weighed up the gene pool, then we’re all set, because there are many ways in which we can affect society that do not affect the gene pool. We can eliminate a particular disease or trait, or engineer a trait, without changing the total frequency of the DNA variant. So, for example, it makes no difference if you have two copies or one. You can have a huge impact on what the population looks like without changing the number of people that have one copy of the genetic variant.

It’s not cautious enough, is what I’m saying. We need to be cautious. He’s saying we just need to worry about things that affect the gene pool. I say we need to worry about things that happen much sooner than that.

Affecting the gene pool can take centuries, but we could, in just years, affect the trait pool – that is to say, what you’re actually expressing as traits. There are all kinds of educational and corporate pressures to have all the children in a classroom behave themselves. Without affecting their gene pool, you could have a huge impact on the behaviour of children in schools, much as in a variety of other ways. So I would say that caution is not nearly enough.

Q: So we have to be very careful every step of the way.

A: Right. And it’s not just germline, it’s somatic. In fact, I would be more concerned about somatic – meaning in the way we normally practice medicine. Because let’s say you developed a gene therapy to reduce cognitive decline in Alzheimer’s. This sounds very reasonable – we have a growing ageing population, and this will be very attractive. But there are various ways of doing that.

Some people like Eric will dismiss any drug involving intelligence, because we don’t understand it. The fact is, we do understand certain ways of proving cognitive tasks in mice, and if those are tested in humans, specifically under the umbrella of cognitive decline in later years, we can make progress. And if we can make progress, it can be tried out on people that don’t yet have any symptoms.

And then it can be tried on people who make money with their intellect, and just want to have higher intellect.

This is all done without germline, but it can spread so much faster than germline. Germline would take 20 years per generation to spread. This could spread in one year. That’s the difference between cultural inheritance and DNA inheritance. Cultural inheritance is much scarier and needs caution.

We’ll continue this epic interview tomorrow – but if you can’t wait to give feedback, the address is


Andrew Lockley
Exponential Investor

Category: Genetics and Biotechnology

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