In this series of interviews. I ask scientists, engineers, and ethicists how technology might change our future. We had these conversations during the research for my book, Welcome to the Future (Quarto, 2021).
Interview 2 – Kiran Musunuru
Dr. Kiran Musunuru is a doctor who specializes in cardiology and genetics at the University of Pennsylvania Perelman School of Medicine. He is also an expert in gene editing and the author of The CRISPR Generation: The Story of the World’s First Gene-Edited Babies. I spoke with him in October 2019.
How do you hope genetic engineering will impact human lives in the future?
[I hope we will lead] healthier lives that are free of disease. If you have a mutation that causes disease, [a doctor] could correct or address the mutation. This could also be true for diseases like heart disease, which is partly genetic, partly lifestyle, partly bad luck. Some of those factors you control, some you don’t. Gene editing and genetic engineering have the potential to treat or prevent heart disease or reduce lifetime risk. Treatment and prevention of other common disorders could be possible as well.
What about the future of genetic engineering makes you afraid or uncomfortable?
Any technology has the potential to be used for what could be considered good and what could be considered bad. I don’t like the term “designer babies,” but that’s certainly something I would worry about. This is the idea that if it becomes very easy, straightforward, and safe to edit multiple genes very effectively in human embryos or germ cells like sperm or egg, you could design babies [with certain traits or features]. This is not going to happen any time soon. But what’s going to happen 25 or 50 years from now as we get a better understanding of genes or traits? I can easily imagine parents wanting to make changes they feel are beneficial for their babies, things you might consider enhancements. This could be frivolous things, such as hair color or eye color, or it could be intelligence or athletic ability. In 2019, we’re nowhere close to being able to do that, but who knows.
Why aren’t we anywhere close to being able to genetically edit these traits?
Intelligence and athletic ability are very complicated traits that reflect that influence of hundreds of genes, maybe thousands of genes. It’s oversimplifying the situation to imagine you can make a single change and all of a sudden have a smarter kid. Right now we struggle to make just one change. We also don’t understand the genetic basis of intelligence or athletic ability. We don’t know which genes we would want to change.
Also, changing genes is pretty risky with today’s technology. Let’s talk about what happened when the researcher He Jiankui edited the genes of human embryos and then implanted them back in their mother. Twin girls with edited genes were born in 2018. Jiankui wound up in jail for what he did. Why do you think he did it?
This was an excuse to make history more than anything else. His excuse was that he wanted to make the kids resistant to disease, but in fact they were never at any great risk of getting the disease [HIV], and the disease is very treatable with medications and very preventable. If it was some terrible disease for which there’s no treatment it might be more acceptable, but there was no need for it. If the kids had not had the edits, they would have been fine, healthy kids. They would have had as much a chance as any other average kid of having a long, healthy life. He quite possibly made their situation much worse than if he had nothing to do with them at all.
What problems did his edits cause?
Frankly, it was a disaster. The tool he used, called CRISPR, I think of it like fire. If you control fire, you can cook food or keep warm. But if you don’t have good control, it can do very bad things. It can burn down the house or cause a wildfire that burns down a whole town. There’s a potential for good and potential for bad. With CRISPR technology, there’s a potential for damage and hurting people rather than helping them even if you start out with the best of intentions. What’s clear from the data that he generated on the twins is that he didn’t have much control. The editing was wild and uncontrolled.
Both of the embryos that gave rise to Lulu and Nana – it blows my mind that we’re talking about living, breathing human beings – both showed mosaicism. It’s hard to know if this will hurt the health of the babies, but it’s definitely possible. He broke every single medical ethics principle there was in the textbook. He violated every single one.
What’s mosaicism?
It means that not all cells were edited. In the body, some cells have the intended edit, some cells have a different edit, perhaps not what was intended, and some cells got no edits at all. From his data it was clear there was one place in the genome where there was an off target edit. And Lulu’s embryo was mosaic for that unintended edit. Since this mosaic edit may be in some cells and not others, it may not be easy to detect. If you did a blood test to look at the genome, you might not pick it up. But it could still cause a problem. We worry about unintended edits increasing the risk of cancer. Even if a few cells in the heart have a mutation, that can cause life threatening heart disease.
Even worse than that, let’s say some cells have the unintended edit, but not enough to cause a problem for Lulu or Nana. They could pass that harmful edit on to the next generation. That kid wouldn’t be mosaic because every cell in the body is going to pick up the mutation. So you could actually see the health consequence being much worse in Lulu or Nana’s kids if they get to the point where they grow up and want to have children.
That’s so sad. Some of the hype about CRISPR makes it seem like it allows us to edit life however we want. Why is it not that easy?
I think most adults have the impression it’s this magical word processing tool that allows you to do search and replace, or erase a letter and fill it in. The metaphor I like to use, is to think of the human genome like a book. It has 6.4 billion letters in it. Each chromosome is a chapter, each paragraph is a gene. And when you’re talking about gene editing, the most common or easiest thing to do is to turn off a gene or break a gene. Let’s say there’s a paragraph in this book that you want to disrupt. Basically what you are doing is making a tear through that paragraph. And then what the cell does when it senses a tear or a break in its DNA, it tries to repair it by putting it together. With this metaphor, that means taping it back up and fixing it to its original state. If the tear is very rough, then when you try to tape it back up, it doesn’t quite match up, and then the paragraph is no longer readable. That is the most common form of gene editing. If you just want to turn off a gene, it can work very well. If there’s a gene that’s causing disease and you can turn it off, obviously that’s a beneficial thing. But it’s crude. Some people have called it genetic vandalism.
Now if you want to do a search and replace, that’s not so easy. Using standard gene editing tools like CRISPR. Let’s say there’s a typo on a page and you want to fix that typo. You might think, oh that’s easy I’m just going to erase that letter and put in the right letter. Unfortunately CRISPR doesn’t work that way. With CRISPR you have to tear out the whole page, you have to print out a whole new page with the correction on it – then you have to tape that page back into the book. It’s a lot more involved and a lot more complicated. You need not just CRISPR, but that whole new page. What that means in the real world is you have to make that new page as a synthetic DNA molecule and put that into the cell along with CRISPR. CRISPR has to take that DNA and incorporate it into the genome after it has broken the genome at the site you’re trying to target. It’s hard to do.
There are newer forms of CRISPR technology that make it more like a search and replace, where you can find a letter and change that one letter. I do think if we’re talking 25 or 50 years from now, CRISPR or something like it will get to the point where it is much more capable than it is now. Maybe kids and adults might go in and change a lot of genes and do it all safely. I suspect it will come to pass. Things move very fast.
Having a more precise tool won’t solve everything, though. We still need a better understanding of the genetic code, too. We need to understand all the consequences of an edit.
The CCR5 gene [which He Jiankui edited to attempt to provide resistance to HIV] is a great example of this. Having the gene turned off does seem to prevent HIV infection. But there’s pretty solid evidence that it increases vulnerability to West Nile Virus and increases the likelihood of having a bad outcome if you get the flu. Genetics is complicated.
Any last thoughts?
My personal view is that to begin with, it’s better to do gene editing in cases where disease and suffering are already in the picture. If they’re sick and they’re suffering, you’re willing to take some risks to relieve that suffering. If you’re doing more cosmetic things, it doesn’t make a lot of sense.
