In 2018, Chinese researcher He Jiankui was imprisoned for editing a human embryo — a procedure which resulted in the birth of the world’s first genetically modified twins.
Called “a profound leap of science and ethics” by the Associated Press, Jiankui’s announcement shocked the world of bioethics and opened new avenues of debate for researchers, medical professionals, ethicists, policy analysts and the public.
Germline gene editing — like Jiankui performed — alters the genetic code of not just an individual, but of every child, grandchild and great-grandchild the individual has. While somatic gene editing, which is currently used to treat conditions like sickle-cell anemia, only affects the diseased individual, germline editing alters an entire lineage. It’s illegal in the United States as well as many other countries.
For Janet Mertz, a researcher with the University of Wisconsin’s School of Medicine’s Carbone Cancer Center, the ethical debate behind gene editing is nothing new. Back in the 1970s, Mertz worked in Nobel prize-winning biochemist Paul Berg’s lab studying recombinant DNA — DNA made by inserting a gene from one organism into another.
Success with recombinant DNA opened the door to bigger possibilities in the realm of genetic engineering, Mertz said, but those successes also posed new ethical questions.
“This is the first time people said ‘are there experiments that we might be able to do that we shouldn’t do?’” Mertz said. “Are there experiments we can potentially do that might be too hazardous or unethical for other reasons that we shouldn’t do them?”
In 1993, Spanish researcher Francisco Mojica described what became known as a “CRISPR locus.” According to the Massachusetts Institute of Technology and Harvard University’s The Broad Institute, the CRISPR locus is a sequence of genes found in the immune systems of certain microbes. It allows scientists to edit the genetic code of an organism at a specific, targeted gene, and the technology has already begun to revolutionize medicine, agriculture, veterinary science and a plethora of other fields.
Now, labs all across the UW campus use CRISPR and CRISPR-modified animal models to conduct research.
Director of the Genome Editing and Animal Models Center Dustin Rubenstein said “it’s really hard to overstate how much it’s changed our ability to do research.”
But, as in the case of the Chinese researcher, there’s always a limit — if not technological, then ethical.
John Evans is a sociologist at the University of California, San Diego who studies controversial scientific debates. He spoke to UW students and faculty in February as a part of the weekly Life Sciences Communication Colloquium, where he described gene editing as a slippery slope. Allowing one slightly controversial action makes it easier, as a society, to favor more ethically ambiguous stances on issues like germline editing, Evans said.
“A lot of these debates are about the limits that we should put on scientific action,” Evans said. “You have to draw your line on the slope here somewhere.”
CRISPR on campus
Kathy Krentz co-directs GEAM at UW with Rubenstein. Krentz has worked in biotechnology on campus for over 25 years, and at GEAM, she helps create gene-edited animal models for researchers to study both on campus and nationwide.
Krentz said researchers can use CRISPR in a wide variety of ways, from knocking out or changing genes to inserting new ones.
“We can use CRISPR in many different ways,” she said. “We can create [a] break in the DNA within the genome, and in our lab that’s called creating a knockout animal where we knock out a reset or delete a region. And that’s been something that we’ve done, rather easily and routinely. And what’s been more complicated is to change the genome, where we go in and we create a cut in the genome but then we put in a piece of DNA, or we change some of the base pairs.”
At GEAM, Krentz and her team use germline editing techniques to create lineages of genetically engineered animal models.
Biochemist Melissa Harrison works with CRISPR in the reproductive cells of fruit flies. Her lab studies what happens to these cells and the proteins they make when different genes are modified. They can then apply their discoveries to other species.
“For us, genome editing is largely a tool,” Harrison said. “It’s really opened up a lot of ways that we can start to ask very mechanistic questions.”
One of Harrison’s colleagues, biochemist Jill Wildonger, also works with fruit flies. Her lab studies brain cells and how different proteins within them allow them to function differently.
Wildonger said CRISPR makes it easier for them to target and modify genes without having to insert foreign, lab-made DNA.
“What CRISPR does is it enables us to directly target the genes that are present within cells,” Wildonger said. “Previously, we would have to make DNA constructs that we would then have to get into the cells. And in some cases that has drawbacks, because you’re working with DNA that you’ve made in the lab. It might not be expressed at normal levels, it might not make it to the right position within the cell.”
And while Wildonger said CRISPR has revolutionized genetic research, it’s not perfect. For one, it’s only useful in models where the researcher knows the genomic sequence, otherwise, they have no idea what to target. Many organisms have reference sequences available, but the reference sequences cannot account for individual genetic variations.
One of the biggest challenges when applying CRISPR is minimizing off-target effects, said GEAM Research Specialist Brent Lehman.
“Turns out as much as I try to paint the rosy picture that this genome editing is perfect and precise, there are these off target effects,” Lehman said. “And all that means is while you were performing the genome editing at the site that you want in the genome, something else in the genome got altered.”
Off-target effects happen when editing a gene, called the target gene, that cause something else to change in a different gene. Sometimes they’re completely harmless, but they can also be dangerous.
And it’s difficult to predict them, Lehman said. Some computer algorithms can help model where they might pop up, and researchers have discovered techniques to limit them, but even in the perfect experiment there’s still a small chance.
One new discovery in the field that might make this easier, however, is a technique called prime editing, which edits the genome with more precision. Lehman said he’s excited to try it out in the lab.
Harrison said though CRISPR is far more advanced than the technology they used to have, it isn’t 100% efficient. Sometimes other tools prove better alternatives for an experiment — but since CRISPR is new and exciting, there’s pressure to use it for everything.
“Because we can now do [CRISPR], when you don’t do it, other scientists and reviewers are like ‘why didn’t you do this?’” Harrison said. “Keeping up with the technology is a challenge because it’s really fast paced and moving quickly. We just need to read more and do more.”
A Slippery Slope
Since the widespread popularization of CRISPR techniques, Evans said bioethicists have begun to shift their attitudes towards these technologies. That being said, Evans added, they still mark that distinct barrier between somatic and germline editing.
While somatic cell gene editing only affects the individual seeking treatment, germline alters all their offspring — and it’s this distinction that means a whole new realm of ethical issues.
For one, Rubenstein said, the new babies born from germline-edited embryos cannot give their informed consent.
“A mom might decide that they want this disease cured in their embryo,” Rubenstein said. “But that child doesn’t really get decide, and that’s going to pass down to their children and their children’s children. One of the pillars of medical bioethics is informed consent, right? So, it gets a little tricky when there is this permanent change that’s handed down for all of the generations where no informed consent can possibly be given.”
Beyond the question of consent, there’s a question of this technology’s application, Mertz said.
Mertz said CRISPR has advanced enough that germline editing for solely the purpose of enhancement is possible — which is why, as detailed in a Nature article, many countries have placed moratoriums, or bans, on the technology.
“The future is here now,” she said. “We have the technology to be able to genetically [engineer] humans and make ‘designer’ human beings.”
Evans said the idea of “designer” human beings isn’t a new one — functionally, it has the same outcome as eugenics, one of the ideologies behind the Nazi party in World War II. And Evans said even though germline editing for enhancement falls way at the bottom of this slippery slope, it’s the little shifts in morality that push society slowly farther to that point.
Evans said while the slope has barriers, these barriers can break down. While many researchers, like Lehman and Rubenstein, oppose germline editing in humans, the National Academies of Science released a statement in 2017 stating germline gene editing could one day be permitted for serious conditions. This excludes editing for enhancement.
Evans said germline editing technology tempts some — like Jiankui, the jailed researcher — because of its immense potential.
“The very first thing people tried to modify was a human embryo,” Evans said. “And so this sort of eugenic impulse rears its head like, ‘gosh, we can finally modify it.’”
Chair of the Life Sciences Communications Department at UW Dominique Brossard is an expert on public opinions of science. Brossard also has firsthand experience working with gene editing — she received her masters degree in plant biotechnology.
Brossard said while scientists make the distinction between germline gene editing and somatic gene editing when assessing the ethical implications of the technologies, the public tends to make a different distinction — one between editing for therapeutic purposes and enhancement purposes.
Essentially, this boils down to the distinction between gene editing to fix a medical condition and gene editing for personal enhancement.
Brossard and several of her colleagues recently published some of their work about public perceptions of gene editing in Science magazine. They used data from the National Academy of Science consensus report to argue greater integration of public opinion into gene editing policy.
“We need to actually have broad public participation to discuss this,” Brossard said. “This is something that’s going to affect everyone, so the public engagement needs to be taken seriously, to make sure that we know ahead of time how to regulate. Because there’s no right or wrong answer. This is a policy. This is a political question, it’s not a scientific one. So that means that scientists themselves cannot just answer that.”
Brossard said instead of going into the purely technical aspect of CRISPR and educating the public about the science, what’s more important is to start a discussion about the kind of values they hold as a society, and what the best way to apply the technology might be.
Brossard said since people tend to use mental shortcuts when thinking about difficult topics, institutions should foster deep discussions that go beyond partisan or religious boundaries about these issues.
“It’s about what kind of society we want to be,” Brossard said. “Obviously you want to be able to understand what the technology can do or what the technology cannot do or how the technology can go wrong, but the decision to go forward or whatever, that’s really a policy decision.”
Wildonger said communicating CRISPR is important to her and her lab because the technology isn’t too difficult to learn about, and it can help people who don’t have a science background get interested in and excited about research.
When it comes to applying the technology, Wildonger said it’s important to foster open communication between experts and the public. Plus, she said making sure students receive a sound science education helps, because when students learn about these new technologies, they’re likely to be more discretous towards — rather than scared of — future technological advances.
“We want to [have a] dialogue,” Brossard said. “We want to get to a point where scientists from genetics, or social scientists for that matter, or religious groups or a representation of a consumer group, or parents and family of those who have the genetic disease can actually decide on the pros and cons, all together to reach a compromise.”