Synopsis: Scientists have developed the technology to edit single genes, which could eventually eliminate some inherited diseases. If the technology is used on embryos or egg and sperm cells, it could eliminate some diseases from succeeding generations. However, doctors don’t know how such “germline editing” or errors in execution of it would affect other genes for generations to come, calling the practice into question.

Host: Reed Pence. Guests: Dr. Debra Mathews, Assistant Director for Science Programs, Johns Hopkins Berman Institute of Bioethics and Associate Professor of Pediatrics, Johns Hopkins School of Medicine; Alta Charo, Warren P. Knowles Professor of Law and Bioethics, Law and Medical Schools, University of Wisconsin-Madison

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Gene Editing

Reed Pence: Cindy and Jason desperately want a child. But tragically, their first-born died just five days after birth due to complications from a rare inherited disease. Understandably, the couple is wary of trying to get pregnant again. But what if doctors had the know-how and the technology to alter the mutant gene present in Cindy’s egg or Jason’s sperm? Or what if they could remove the gene from the embryo after in vitro fertilization? What if that rare disease could be eliminated from Cindy and Jason’s line for generations to come?

Debra Mathews:  We have been talking for decades – we, the scientific ethics communities, have been talking for decades about the possibility of human germline genetic modification. That is, making changes to our DNA that is heritable to the next generation. So not just changing my DNA as an individual patient, but changing the DNA of the cells that would go on to make my children and their children and their children, etc.

Pence: That’s Dr. Debra Mathews, assistant director for science programs in the Johns Hopkins Berman Institute of Bioethics and an associate professor of pediatrics at the Johns Hopkins School of Medicine.

Mathews:  So we have been discussing this for decades and the possibility of it, but we have never had a technology that was anywhere close to safe and effective for these purposes. So, we have always been able to say, we could never do this safely in humans, so we’re not going to do it.

Pence: However, now things are changing. In the beginning of 2012, a group of researchers introduced a much more specific and efficient technology for genome editing.

Mathews:  Namely CRISPR CAS 9, which you can really just think of as a much more specific pair of scissors with which you can cut DNA and potentially paste in as you would in a computer program, cutting and pasting. So, we now have this technology that is relatively inexpensive, relative to all the technologies we’ve had in the past, specific, and because it’s specific, meaning we can make the changes we want to make and not changes we don’t want to make, that still happens, but it’s much, much less common with this technology, we actually have to now have a conversation not about can we do it, but should we do it.

Pence: Now, it’s important to reiterate the difference between gene editing and germline editing. Gene editing, or somatic editing, refers to changing a localized gene in one individual patient, for example a person with leukemia. Those changes can’t be inherited by future generations. Germline editing refers to altering genes in an egg, sperm or embryo of just a few cells, which would result in heritable changes for generations to come.

Mathews:  There have been two cases published in very recent history of somatic gene editing. So, gene therapy using this technology. One was in HIV and the other was a case that was published in the newspaper not too long ago of a baby girl whose cancer was cured using this technology. The idea in these cases is you modify a gene to prevent or cure disease, and that is the idea with this technology for its use in humans. The idea is that you could cure disease either through gene therapy in the person in front of you, or potentially in an entire family going forward by eliminating a disease causing mutation entirely through germline genome editing.

Pence: However, researchers don’t know what will occur for generations to come when a gene is altered or removed from the germline. Or when the genetic scissors aren’t quite precise enough, and take out an unintended gene along with the intended one.

Mathews:  Genes interact with each other. The gene that you’re interested in makes some product, a protein for example, that has a role to play in your cells, but it has to interact in a system. It’s not acting on its own, so by changing that individual gene, and therefore the product it makes, you’re having an effect on the genome, not just that particular gene.

Pence: Mathews says researchers usually take great pains to avoid DNA changes in sperm and eggs. But only certain countries have strict oversight and regulatory processes in place to govern the use of these gene-editing technologies. Researchers from countries that do have oversight met this past fall at the International Summit on Human Gene Editing in Washington, D.C. One of their goals was to draft a consensus document on gene therapy and germline modification. Unfortunately, we’ve already gotten a sad lesson about the lack of rules for other new high tech procedures. It’s created chaos.

Mathews:  One of the big motivators is that in the stem field over the last ten years we have seen many, many “clinics” turn up all over the world offering injections of stem cell something for hundreds, thousands of dollars to sick people. And there is no science backing up what folks are doing, and there’s no transparency about what it is they are doing. But people are crowd sourcing fundraising on line to take their very sick children or family member overseas to be injected with who knows what? And people in the field are very worried that because this technology is relatively specific and inexpensive and very broadly available that the same kind of situation is going to happen here.

Pence: That practice of traveling to a different country to receive stem cell treatment came to be known as stem cell tourism.

Alta Charo: Stem cell tourism is a phrase used to describe the phenomenon of patients going from country to country looking for what they believe will be treatments even if they are not approved as safe and effective in their own country. We see it with Americans going to other countries, but also Australians going abroad, some Europeans going abroad. It is not restricted to the U.S. Typically they go from a highly regulated country to a less regulated country in order to seek out these so-called treatments.

Pence: That’s Alta Charo, Warren P. Knowles professor of law and bioethics at the University of Wisconsin Law School and Medical School.

Charo: Typically, you’ll have on the web clinics that are advertising something that they call stem cell treatment. It’s often very unclear. It’s hard to be specific because the clinics vary in what they do and they are under no reporting requirements. So getting precise information is virtually impossible.

Pence: The lack of regulation also makes it nearly impossible to document problems, but Charo says people have been injured from such treatments. At least one death due to such treatments has been documented in Germany. Charo and others fear that something like gene editing tourism may occur as well.

Charo: The thing that really may happen first is that while patients in regulated environments like the U.S., the European Union, Japan, Australia, and such, while they’re waiting for their local regulatory authorities to confirm the safety and effectiveness of some of these techniques, they may go to less regulated environments. In the past we’ve seen that happen in Mexico, in the Ukraine, in Russia, for example. So, germline may not be the first thing you need to be thinking about. It could be claims that we can treat your cancer tumor, which will certainly touch on a much broader range of people, and does have, in theory, the same possibility for tourism that we’re now seeing with stem cells, and which we’ve seen in the past with other kinds of highly hyped technologies. Back in the ‘70s it was about apricot seeds to cure cancer that sent Americans across the boarder into Mexico.

Pence: You may be surprised to learn that anyone can go online and order CRISPR CAS 9 technology for under a thousand dollars. There are no buying restrictions and no screening applications. So, what’s to stop unscrupulous clinicians in an unregulated country from marketing gene-editing therapy that they claim will cure your cancer? Or perhaps germline editing that will eliminate sickle cell anemia, M.S., Parkinson’s or countless other inheritable diseases from a family line? Or perhaps, even more troubling, germline editing to create promising designer babies? Order your tall, intelligent, blue-eyed genius today.

Mathews:  That is certainly what people are worried about, because it is not absolutely – underscored, bold, exclamation point – not ready to be used in humans. I’m very concerned about the safety of the individuals who use this or have this done before it’s ready. I am worried that we just don’t know enough about the human genome to necessarily start making long-term changes in it. We just don’t know. We have just started sequencing lots and lots of genomes and what we’re primarily learning is that there’s a ton we don’t know and that’s about individual genes and the effects of individual genes. But then figuring out how this gene interacts with that gene, which interacts with that network – we have no clue.

Pence: However, despite those scary scenarios, both Mathews and Charo are less concerned with unregulated germline editing than they are with gene editing. The difference is in the numbers.

Mathews:  From my perspective, more about the safety of the individuals and not as much about affecting the gene pool, because the human population is enormous, and expanding. And even if this becomes widespread, it’s not going to be widespread enough that it actually affects the human genome writ large. But I’m very worried about the safety of individuals who would go through this when we are just not anywhere approaching ready to do it.

Charo: If one looks at the potential population of the patients who might be interested in gene editing, it’s going to be much larger when we talk about somatic cell applications because it applies to a much wider range of diseases, many of which are fatal, and in the area of reproductive options, we do have options now that allow people to screen for diseases either before they conceive, after they conceive, even after they are pregnant, so that we don’t have as large a population of people who lack other options.

Pence: However, Mathews and many other researchers are worried that if a clinic in an unregulated country were to use this technology reproductively in humans, then oversight regulators may shut down all legitimate research, even somatic uses of the technology that appear to be promising.

Mathews:  I do know that the decisions that we make now about how this technology should or shouldn’t move forward will have long-term effects both positive and negative, right? There are opportunity costs to not going down particular roads, but there are also absolutely areas that we shouldn’t touch. We need to make decisions about which category or some intermediate category this falls into, because science can tell you, we now have a relatively safe, effective technology. We can tell you that we can do it; we can tell you that it’s relatively safe. The scientific community cannot tell you whether we should or should not use it. That’s a societal decision.

Pence: The National Academy of Sciences and Medicine has formed a committee headed by Charo to solicit broad input from researchers, clinicians, policymakers, and the public. The committee’s meetings are public and any presentations will appear on its website. If you want to be heard, or merely stay abreast of developments concerning human gene editing, you can find a link on our website at radio health journal dot net.

Our writer/producer this week is Polly Hansen.

I’m Reed Pence.

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