Siddhartha Mukherjee on the Ethics of Gene Editing

CHRISTIANE AMANPOUR: Now, in our darkest times, it can be difficult to find hope whether personally or through a loved one. Most of us have experienced cancer. The good news, though, is that significant numbers survive the disease today. And our next guest, Dr. Siddhartha Mukherjee, is a Pulitzer-Prize winning author and an oncologist. He joined our Walter Isaacson to discuss the complicated landscape of cancer care.

WALTER ISAACSON: Sid, welcome to the show.

SIDDHARTHA MUKHERJEE, ONCOLOGIST: Thank you for having me.

ISAACSON: You have a great piece in the “New Yorker” and a more scientific piece in the proceedings of the National Academy of Science recently talking about modifying our white blood cells, our immune system so that they can hunt down cancer more correctly. Is this a big new way of looking at cancer?

MUKHERJEE: It’s a profound new way of looking at cancer. And the basis for this really dates back almost a century. So the centerpiece of all this is that for a long time, we’ve been focused on the cancer cell. What is wrong with the cancer cell? What genes are wrong with the cancer cell? Why does the cancer cell proliferate? Why does it divide? Et cetera. Et cetera. But over a century ago, a second group of scientists, a group of researchers, a group of doctors began to wonder why not just worry about the cancer cell, what about also worry about the environment, the home that the cancer cell is —

ISAACSON: In other words about the patient, the person.

MUKHERJEE: The person, but, in fact, the tissue of the person because cancer — what is interesting about cancer, I mean there’s some very basic questions. Why do some cancers only metastasize to some organs and not to other organs? Why does the breast cancer or lung cancer have a propensity to go to the bone? Why does myeloma, which could live anywhere love to live inside the bone and the bone marrow? Why does leukemia live in the bone and the bone marrow? So there are reasons and the reason has to do with interactions between the cancer and its microenvironment. The tissue or the home that the cancer builds around itself.

ISAACSON: So what you’re saying is you take our own immune system.

MUKHERJEE: That’s right.

ISAACSON: It’s called immunotherapy sometimes but now it’s going beyond that because your gene adapting our immune system to actually hunt down the exact right cancer.

MUKHERJEE: Exactly. So our work and other people’s work involves using gene editing to change the microenvironment of the host. Either to activate the immune system and thereby kill the cancer, or to change the immune system of the host or the blood system of the host such as the cancer becomes visible to the immune system. So all of these fall under a large family of ideas, which has to do with use whatever technology, gene editing, anti-bodies, et cetera but concentrate not just on the cancer cell but on the home that it builds around itself, on the tissues that it occupies, and ask the question what is it about the host? What is it about the patient that is allowing the cancer to flourish?

ISAACSON: You just talked about gene editing. And there are really two types of gene editing. Those that edit early stage, embryo, so it’s an inherited change in the gene and those that just try to do it in the body of the patient and a particular tissue. Which ones are you using now?

MUKHERJEE: So we are using exclusively gene editing in cells that will never be transmitted to the next generation.

ISAACSON: So it’s safer?

MUKHERJEE: So it’s — well, not only it’s safer. It’s actually ethically permissible. We’re working on an international framework to figure out whether or not to and to what extent to make changes in sperm and egg cells and in embryos. It’s called germline cells, cells that will transmit the information not just into you but into generations to come.

ISAACSON: You say that’s ethically problematic. Why is it ethically problematic to change our genes so that our children will be healthier?

MUKHERJEE: Well, the question is — that is really the biggest question. Can you change genes? Under what circumstances can you change genes so that your children will be healthier? Well, one idea which has become very clear is that there has to be a disease of extraordinary suffering involved. But these arguments are going on right now. There are other ways you can decide to treat some children. So there are other alternatives. The question of extraordinary suffering is very important. And perhaps the most important is that we don’t know all the side effects of changing genes in the germline. We don’t know exactly how accurate it is. It seems to be pretty accurate and pretty safe, but we need a lot of experiments. We need a kind of international agreement to figure out whether this is going to be permissible or not permissible and what should be in next case.

ISAACSON: In China, you have one doctor doing it last November.

MUKHERJEE: That’s right.

ISAACSON: In Russia right now —

MUKHERJEE: Correct.

ISAACSON: — you have a doctor about to do three different cases, just to cure congenital deafness in the germline. Why are you talking about creating this whole consensus when doctors are just going to go ahead and do it in some places?

MUKHERJEE: Well, doctors are not going to do it in some places. They would do it in ways that are not technically safe often and that will set back the field. I’ll remind you of what happened with gene therapy. So in the 1990s, there was an attempt to do a gene therapy on a young boy named Jesse Gelsinger.

ISAACSON: Yes, in Philadelphia.

MUKHERJEE: In Philadelphia, right. So this seemed — the experiment seemed relatively technically feasible. It was moved through various boards and authorities to make sure that it was safe. In fact, what turned out was that the child died as a consequence of gene therapy. But it set the whole field back by about 10 years.

ISAACSON: You say it should only be used in cases of extraordinary suffering. Meaning editing of our genes from our children and children’s children. Why? Why not do it so that you could be taller or blond or whatever you might want to be, blue-eyed?

MUKHERJEE: I think the question of enhancement, first of all, it’s not technically easy. It’s a vast technical problem. People underestimate it. It’s not if I can insert or take a gene away or edit a gene to allow you to grow wings or even enhance your height. We now know for most normal human beings, height is controlled probably by a hundred-odd gene or maybe more, thousands of genes. Our most complicated — complex features we have, skin color and height and other things, are controlled by hundreds if not thousands of genes. We don’t have the technology to edit thousands of genes at a time. But leave aside the technical question that the specter of handing this technology to potentially people who are wealthy and powerful and leaving behind people who are not wealthy and powerful and cannot afford or access these technologies creates the possibility of a genetic rift in society, which I think most reasonable people would think is it divides human beings rather than unites human beings. And I think that’s where a lot of the ethical conundrums come, too. Do we really want to genetically divide the society? That’s a big deal. That’s a human species altering itself. That’s the prospect of — as John Sulston, the biologist said, that’s where the machine begins to change its own manual. We, I think, are not ready to be the machine that changes its own manual. We’re not ethically ready. We’re not technically ready. We’re not scientifically ready. We’re not prepared as a culture, as a — if it’s the right word to use, as a species. We’re not ready to start changing our own manual.

ISAACSON: You’re an expert in blood cancers.

MUKHERJEE: Uh-huh.

ISAACSON: Suppose we knew that a child had a predisposition to leukemia —

MUKHERJEE: Yes.

ISAACSON: — some form of leukemia. What do you do?

MUKHERJEE: Well, we are now beginning to understand what to do with someone with such a predisposition. We are now finally beginning to figure out how to monitor them. And whether that monitoring actually will end up saving their lives. So there are many, many children where we now know that there are genes that will predispose them to leukemia. We’ve identified some of these genes. It’s not an easy answer because you don’t want to over-treat patients before they have the disease. There’s clearly an environmental and a chance component to the disease so you don’t want to treat a person who doesn’t have a disease. But you also don’t want to ignore the fact that they have a propensity, which is increasing, perhaps every year to have the disease. So now there are — now that we have those information, there are, I would tell you literally, tens and dozens, perhaps hundreds of clinical studies trying to figure out exactly what to do with people with the predispositions for the disease but you don’t have the disease itself.

ISAACSON: If you saw somebody with a predisposition to such a disease, could you genetically engineer, say, the bone marrow in that body? Take it out of the body, genetically engineer it, reinsert it back in so it would be less likely to get a cancer?

MUKHERJEE: In principle, you can do that. Especially if it’s a single gene. In principle, you can do absolutely that. Again, it can be technically challenging. It depends on the exact gene. It depends on whether it will be amenable to doing things like editing or not. But in principle, you could do exactly that. You could — and especially for blood diseases. Blood diseases are important because they have this unique capacity, which is not true for most diseases that you can take the bone marrow out, you can then re- engineer it in the laboratory, and then insert it back in. I’ll give you some examples of what is happening in this area. Take a disease like sickle cell anemia. So not a leukemia but a terrifying form of anemia. We now have technologies to take blood from an individual, take it out, modify them genetically, either introduce the correct gene or correct the gene that’s already a problem, and then put it back into a patient’s body. These trials are ongoing. It will be — there’s no doubt in my mind whatsoever that in the next 10 years this will be the practice for disease like sickle cell anemia. Again, single gene-disease.

ISAACSON: You talk about gene therapies that are done in the body like changing the bone marrow, our immune system, or white blood cells. And you speak of it as a drug. Yet these treatments now cost more than a million dollars. Are you worried that these will bankrupt our entire health system? Or how do we even approve them as “drugs” when they’re not like drugs where you just manufacture it in New Jersey and package it up and a people buy it at the pharmacy?

MUKHERJEE: That’s right. So this is a conundrum and it’s the center of the conundrum of this piece that I just wrote in “The New Yorker.” So we used to be able, in the past, to be able to divide the world of medicine into procedures and drugs. What is amazing about these cellular therapies, including genetic therapies, is that they live in between. They’re in this in-between land. On one hand, they’re procedures because you have to take cells out of the body, manipulate them in the laboratory, grow them up, and then inject them back into the body. And it requires a lot of artisanal work, a lot of manual work, handwork, quality control. So the blurring of these boundaries is happening right now. The problem, one of the central conundrums, is that these procedures, drugs, these drugs/procedures, costs around $400,000 if you take in all the hospital costs involved. The fact that you would be in the hospital, you have complications, et cetera, et cetera. And if we were to start having these — and some of them are curative. So if we were to start using them, it would soon start amounting to several billion dollars. And it’s hard to say that they’re useless because they’re not. They’re useful things we’re doing. We’re actually helping patients. So the conundrum of how to price these properly, how to understand these properly, and how to bill for them properly without bankrupting Medicare is a huge conundrum.

ISAACSON: So you have cured people of cancer but some of these procedures, $400,000 up to a million dollars, right?

MUKHERJEE: Yes.

ISAACSON: So who gets it? Only people who can afford it?

MUKHERJEE: Absolutely. I mean, you have to have — first of all, the person who is paying is ultimately insurance, if you are insured. But as you know, many many people in this country are not insured. So you won’t even have access to these medicines.

ISAACSON: What about Medicaid/Medicare? Should they cover it?

MUKHERJEE: Again, if it’s useful, then it’s valuable. Medicare and Medicaid should cover it.

ISAACSON: So how long would it take to bankrupt Medicaid and Medicare if you did it?

MUKHERJEE: It depends on how many of such drugs there are. Right now, most of these are for rare diseases but they’re actually rapidly moving.

ISAACSON: Leukemia, which is not all that rare.

MUKHERJEE: So the work that we do has to do with leukemia. It’s actually not that rare. In fact, there’s a pre-leukemia condition, before you have leukemia which we’re now attempting to do and it’s just as lethal by the way, very lethal condition. We’re trying to use that. So that would already expand the number of patients to about 20 or 30,000 patients a year.

ISAACSON: OK, I can’t do the math real well. But let’s say it’s a million dollars and there’s 30,000 patients.

MUKHERJEE: That would be a big, big blow.

ISAACSON: No, it would totally just end Medicare and Medicaid, if you did that.

MUKHERJEE: That’s right. So we have to find a new system. I mean, either we go bankrupt —

ISAACSON: Yes.

MUKHERJEE: — or we really innovate not just scientifically. The scientific innovation is on a fire hydrant now. But that said, the manufacturing cost will probably come down at least 5 to 10 fold. That’s the prediction for most people. I work in the field. We are making rapid engineering innovations. It’s not the kind of innovation that hits the front page of “The New York Times.” It’s things like how do you automate? How do you use robots? How do you use quality control? Small improvements, none of which make the cover of the “New York Times” or Science or Nature Magazine but, in fact, bring the cost down chip by chip by chip by chip so that you can get to a point of time when it’s affordable.

ISAACSON: When you say “we”, that we’re bringing the press in, you’re partly talking about yourself not only as a scientist but as somebody who has started drug companies, pharmaceutical companies yourself and you’re making money. When you write about this, when you write in “The New Yorker” about it, when you propose this, how do you resolve sort of the conflict of interest in a way between you having a drug company trying to do it and you trying to advocate that the FDA do different rules?

MUKHERJEE: So in my case, the companies emerged under the laboratory but they’re not drug companies yet. These are companies that are not selling any medicines. We’re making medicines. We’re in early clinical trials. We — so one of them is called Vor Biopharma. There’s another one called Fayette. These are not selling drugs. The minute these companies sell drugs to human beings, the conflicts of interest lines go up very strongly. These are not publicly traded companies. They’re companies that are completely privately — actually they’re running partly out of my own labor and money. So there are strong distinctions between conflicts of interest that happen when you are no longer an inventor but the seller of something. I’m an inventor. So I explicitly declare it in a piece like this. In a piece like this, I will tell people, you know, I’m doing this myself. I’m in the middle of doing this myself. And in the world of science, writing about things that you’re doing yourself, even if that has commercial value, is not a conflict of interest. The minute that drug becomes a pharmaceutical product, it’s going out into people and is being priced and charged, it becomes a conflict and that’s when a barrier will come up. And never again will that piece be written.

ISAACSON: So gene therapy, genetic editing, cancer research, what gives you the most hope in the next 10-year time frame?

MUKHERJEE: Well, I think what is happening is that these fields, immunotherapy, gene editing, cancer research, cancer epidemiology, and hopefully, hopefully, hopefully, cancer prevention will come together in ways that some ways that we’re predicting but in some ways that we’re anticipating. Just to give you one example, for breast cancer — and this is recent data. For breast cancer, we can now begin to predict for people who have familial breast cancer. People who we know there’s a family history of breast cancer, we can predict with a quite high level of accuracy your propensity to get breast cancer in the future. And now there are going to be in the next few years, dozens of studies to try to figure out how to stop this person from getting breast cancer. Do we give them a medicine? Do we monitor them extensively? Do we take a blood test and try to figure out the minute they get breast cancer? Do we treat them? So the whole idea of cancer prevention, meeting genetics, meeting early detection becoming a whole, meeting cancer epidemiology becoming a whole, that’s what gives me the most hope that we would create a new — based on science, we would create a new oncologist of trying to build up this pyramid again from prevention to early detection to treatment so that fewer people get treatment and less toxic treatment. Most people get prevented and some people get detected early enough so that we can actually treat the cancer in its earliest possible phases.

ISAACSON: Thanks for giving us hope, Sid.

MUKHERJEE: My pleasure.

ISAACSON: See you later.

MUKHERJEE: See you later.