It sounds like science fiction — and heavy on the fiction at that.
Take an impossibly small tool, a molecule of RNA — call it, say, CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, and pronounce it as if it were the drawer at the bottom of your refrigerator — make it function like shears, and have it snip out broken bits of genetic code and replace it with healthy DNA.
Use that technology for many things — it seems to work in all living things, down to the bacteria where it first was discovered. Use it to cure such fairly rare diseases as the Bubble Boy syndrome — more formally, Severe Combined Immunodeficiency, or SCID — and move on from there to more common and genetically complicated lymphomas and cancers, particularly the ones that attack and kill children.
But it’s real — CRISPR has been and scientists hope that it can be used to work what would look to non-scientists like miracles. One of those scientists, Dr. Ayal Hendel, a principal investigator (translation — he heads his own laboratory, a great responsibility and huge honor) at Bar Ilan University in Ramat Gan, Israel, talked about his work last week at a meeting in Englewood for American Friends of Bar Ilan University. (He was staying there with his cousin, Shelly Sokolow.)
Dr. Hendel’s lab studies genomic editing and genetic engineering. “We’re developing technology where we can actually correct broken genes,” he said. “We use what I call cut-and-paste technology to replace broken genes with whole genes.”
It is important to remember that although work on the CRISPR has been going on for a few years, it’s still new, and he is just beginning his work on finding a cure for SCID.
He shifted to another metaphor, this one even more physical than the virtual copy-and-paste. “Working with the CRISPR is pretty much like working with scissors,” he said. “All the DNA in our bodies is built from four different bases — A, T, G, and C. If there is one mistake, one typo in the code, it can lead to disorders, like bubble boy, or cancer. We use the CRISPR tool to cut out the broken gene and replace it with a synthetic normal gene.”
A synthetic gene? More science fiction? No, Dr. Hendel says.
“We can take blood — hematopoietic stem cells — from different sources,” he said. “We can take it from stem cord blood — some parents decide to collect and freeze it in case they need it. Another source is the bone marrow; you can go into the bone with a needle and take some out. And a third source is to give the patient a drug that mobilizes the cells from the bone marrow to the bloodstream.”
Where do the cells come from? Cautioning that this still is dream, not reality, Dr. Hendel said that they could come from the patient. “That is the beauty of this procedure. What happens when a kid has some kind of leukemia, or bubble boy disease? We can do what we call allogenic bone marrow transplant — we take the stem cells from somebody else — but many times we can’t find the right donor. The tissues aren’t the right match. In the technology we are developing, every patient can be his own donor. If you don’t have the stem cord, you can take it; you start to work on the collection process.
“All the options are valid,” he said.
He explained a little bit more about how a CRISPR works — and also said that because it’s such a hot topic now, a little bit of googling can add up to lots of information. But in short, “the CRISPR is built from a very small molecule of RNA and a very small molecule of a protein. The RNA part is what’s actually sending the scissor to the right address.” The RNA functions like a GPS, headed for the target; the protein is the goon behind it, cutting out and demolishing the broken gene as if it were a gambler welshing on its mob debts. And then the new, custom-made repair cell can be injected close to the hole created when the bad one was removed. “There is a very sophisticated machinery inside ourselves that knows how to repair the break by using this piece of normal DNA,” Dr. Hendel said.
“Nature is so beautiful,” he said. “This system came from bacteria.
“In order to protect itself against viruses — because when a virus attacks a bacteria, it injects its DNA into it — the bacteria can copy a small piece of the virus’s DNA and keep it in its memory. So the next time the same kind of virus attacks, the bacteria will have an image of the sequence of the DNA virus.” It will know what to attack — according to NPR’s RadioLab, which did a show on CRISPR, that image is basically a mug shot, a list of viruses that are the bacteria’s most wanted public enemies.
That bacteria defense is ancient, far older than human beings, but it was discovered in the 1980s. “Then we adapted the system from nature, and we use it in medicine to cure genetic disorders,” he said.
“Many people talk about personalized medicine for many different disorders,” he continued. “Different people have different mutations, so first you have to identify what went wrong, and you have to really get the right piece of DNA and the right correction. Different people could need different synthetic DNA for different disorders.
“Once you are able to do it, you want to be sure that you do it in a very specific and safe way. You don’t want to fix something over there, but at the same time break something over there.” Brand-new changes can have unintended consequences; no one wants to attempt to heal someone and to start the butterfly effect that leads to a jumble of disasters and eventual collapse. Caution is necessary.
“This amazing genome editing technology — I call it iPhone 1.0 — was developed for the first time in 2003,” he said. “But then it was expensive, slow, and very difficult to work with. Then came iPhone 2.0 — but it was the third generation, 3.0, that really changed the field, because suddenly scientists had a tool that was cheap, easy to make and design, and really meant that many scientists could start working in parallel ways.”
That happened in 2013; “the technology was developed in parallel in Berkeley and MIT, and then once I was doing my training at Stanford, with Dr. Matthew Porteus, I thought okay, if I can apply it to hematopoietic stem cells, we can use it for disorders of the blood and the immune system, but when I tried to apply it to hematopoietic stem cells, it didn’t work. It was a problem and I had to solve it.
“I established a collaboration with a bio-tech company, Agilant Technologies, the science company that was spun off by Hewlett-Packard. They could chemically synthetize RNA, and I thought that if we could do that and use chemistry on the RNA at the end of the molecule, we can really make this system work.”
You need the synthetic RNA, he explained, because there are enzymes — “They are like small machines — I call them Pacmen — they degrade and attack the RNA. But if you can put a fancy chemical modification on the end of the RNA, we can really stabilize the RNA inside the cell and make the machine work.” He did experiments on this technique at Stanford, and it worked. “As a result of these achievements, I was able to apply for positions in academia in Israel,” Dr. Hendel said. “I really wanted to stay in academia, and I really wanted to go back to Israel.” He was given many offers and “I decided to take the offer from Bar Ilan, in the nanotechnology center,” he said.
Dr. Hendel is interested in diseases that affect children. He is focusing on SCID “because it is the result of just one typo in the DNA. It’s just one mutation, that means that these kids can’t develop functional immune systems.
“So I chose this disease because there is a higher chance of success. If we cure only one to ten percent of the stem cells and put them back into the body, that will be enough to cure the disease. The body will be able to generate enough immune cells.
“It would be more challenging with other diseases; we would have to correct from 80 to 100 percent of the genes.
“We have to have a success,” Dr. Hendel said. “I chose to focus on a disease where we have a high chance of being successful.” And of course the fact that the disease is so dramatic and terrifying makes the idea of being able to cure it all the more dramatic and joy-producing.
The work cannot be rushed, he added. There already have been clinical trials using CRISPR in China, but there has not been enough time to evaluate how safe these experiments are. He foresees his own process taking about four or five years; then, he hopes, he will “be able to start thinking about a clinical trial, maybe in collaboration with a big center in the United States or in Israel.
“I like to think about it like putting men on the moon in the 1960s,” he said. “Our mission is to make the DNA editor. During the 60s, it was to send somebody into space. We didn’t send them directly to Mars. Now, our mission is to build this DNA editor, so whenever there is a devastating mistake leading to childhood disorders, we can take the CRISPR and fix the origin of the problem.”
Robert Katz of Fair Lawn is senior vice president for development for the American Friends of Bar Ilan University. He filled in some of Dr. Hendel’s biography — Dr. Hendel admitted to being 42, having gotten his bachelor’s degree from the Hebrew University and his master’s and doctoral degrees from the Weizmann Institute, but he didn’t mention that he has some patents in his name. “He’s a humble, modest guy, and I feel like his proud mother,” Mr. Katz said.
Even more the proud mother, Mr. Katz said, he was sure that Dr. Hendel had omitted to mention that the institutional review board of the Helsinki Committee allowed Dr. Hendel to try experimental research on human subjects. Such approval is rarely given, and is a sign of great trust in a great scientist.
Still, he added, Dr. Hendel may be extraordinary, but he is not unique. There are many off-the-charts-gifted scientists in Israel. “There was a big brain drain, and many of Israel’s best scientists were attracted to the Stanfords, Yales, and MITS of the world,” Mr. Katz said. “We were losing our best and brightest. The problem was called out maybe 10 years ago, and within the last five years, Israel has done an amazing job at bringing these guys back.”
Why does Israel seem to grow so many gifted scientists? “I think that Israelis have an innate need to find a solution to problems,” Mr. Katz said. “They grow up living in the worst neighborhood in the world, so from birth they always are challenged with obstacles, and they have an innate need to overcome them.
“I met a young woman on a trip to Bar Ilan in December,” he continued. “She was an engineering student; her name was Michal. I wrote down her words. She was about to leave Israel; she was getting a Ph.D. at Bar Ilan and had accepted a post doc at Stanford. I asked her what motivated her to succeed beyond her mother or father’s wildest dreams, and she said, “I need to be competitive on an international level. I need to represent Israel, and to fulfill my potential, so that people will respect Israel on the world stage.”
Dr. Hendel certainly is competitive on an international level. If he can get anywhere near a cure for childhood cancers, he will represent his country extraordinarily well. (And, of course, he will have gotten near a cure for childhood cancers.)
There are some worries about CRISPR, too. Does it give people too much power? Make them too God-like? Are we overstepping our limits when we use a technology that can make irrevocable changes not only in our bodies, but in our descendants as well? Will we have considered all unexpected consequences — which is a hard thing to do, given that the consequences by definition are unexpected — before we allow revolutionary techniques to be used?
These are all important questions. But Dr. Hendel can use these techniques to try to end childhood cancer, and that is an outcome devoutly to be wished.