Portland Magazine
February 21, 2022
For the span of her career Ami Ahern-Rindell has been working to understand—and eventually contribute to a cure for—a particular fatal genetic disease. Advances in science and technology are bringing her research closer to her goal. But the technology—CRISPR gene editing, specifically—raises a whole host of ethical questions. With the support of an applied ethics grant from the Dundon-Berchtold Institute, she is raising awareness and encouraging the campus to examine the issues.
Story by Jessica Murphy Moo
Photos by Adam Guggenheim
Illustrations by Violet Reed
BIOLOGY PROFESSOR AMI-AHERN-RINDELL REMEMBERS THE phone calls to the lab during her postdoc years. Parents were calling to ask if she could help, to see if her research was ready to be applied in a clinical setting for their child. She was working in a molecular genetics lab, working to get to the bottom of the cause of a particular genetic condition called GM1 Gangliosidosis. The condition is fatal. Life expectancy for infants born with this condition is between two to four years. As you might imagine, those phone calls from parents of children who had been diagnosed with GM1 were heart-wrenching.
“For them you couldn’t find a therapy, a cure, quick enough,” Ahern-Rindell says. “They would hear that we were doing research and trying to figure out what was going on in GM1. They would ask us, ‘How far along are you? Can you find a treatment for my child?’ … These people wanted a cure, and you couldn’t give it to them. That was difficult. But at the same time, it was a very strong motivator, and it meant that we were going to work as hard as we could to learn as much as we could as quickly as we could in order to eventually help people.”
Thirty-five years later, Ahern-Rindell is still working to unlock the genetic secrets of this condition and to find a therapy and, she hopes, a cure.
“We still don’t have a treatment for GM1,” she says, “but I think we’re much closer.”
THE CELLS THAT AHERN-RINDELL USES in her genetic research have been frozen in liquid nitrogen since 1985. They are sheep cells (not human cells), and they are—she likes to point out—significantly older than her undergraduate students. She also points out that after 35 years of exposure to liquid nitrogen her fingertips can sometimes get a little numb.
In their frozen state, these sheep cells have traveled—from graduate work at Washington State University to her postdoc work at the Center for Molecular Genetics at the University of California, San Diego and on to her 25-year career at University of Portland.
During this time period, the cells themselves haven’t changed. Indeed, they have been frozen in time. Only when they are thawed in a warm water bath and placed in the right culture conditions do they again begin to divide and multiply. They are then ready for microscopic examination and for use in experiments that might elicit information.
Ahern-Rindell acquired these cells—they are cells from the tail skin of sheep—because a rancher came to the WSU Veterinary School to say that some of his sheep were having trouble keeping up with the rest of the flock. After running many different types of tests, they suspected that the sheep had GM1 Gangliosidosis, a fatal genetic condition that severely affects the nervous system. (In addition to humans and sheep, GM1 also presents in cats, dogs, cattle, black bears, and emus.)
To give you a sense of the challenge of narrowing down the potential locations of genetic mutations: In the 3 billion genetic base pairs in the human genome, the source of one mutation can be a change to just one base pair in the gene. In GM1, the gene that has been altered is called GLB1, which has been found to possess more than 100 different mutations, some of which don’t cause any disease. The odds are decidedly against the scientists, and yet they have made progress.
IN THE SHEEP MODEL OF GM1, Ahern-Rindell and her students have identified one base difference in this GLB1 gene when they compare the gene in the cells of healthy sheep and the gene in the cells of sheep presenting with the condition. Ahern-Rindell is working to determine if this mutation is what causes GM1 in the affected sheep. Verification could be a game-changer for finding a treatment/cure for sheep and possibly (eventually) for humans.
The research is slow, slower than any parent on the other end of those decades-ago phone calls could have ever wanted. But Ahern-Rindell maintains hope—especially now, given the scientific and technological advances during the 35 years that those sheep cells have been dormant in that liquid nitrogen. Because of these advances, Ahern-Rindell and her student researchers are able to unlock more of the cell’s molecular secrets than she ever could during the decades that she’s been looking at them through a microscope. As she says, “we’re closer.”
It’s somewhat easy for us to take a step back and think about the massive technological advances that have occurred over the past three-plus decades. Think about how we were writing papers, conducting and sharing research, or making phones calls 35 years ago. Enormous changes.
In the world of genetics, those leaps in knowledge and technology have been just as great, if not greater. The Human Genome Project, initiated in 1990, set about working to decipher the 3 billion base pairs that make up the human genome. Our scientific understanding of DNA (deoxyribonucleic acid) has grown astronomically during this time.
Thirty-five years ago, we knew even less about RNA (ribonucleic acid), its structure, and the many roles it plays. Advances in our understanding of RNA have led to a new kind of technology—called CRISPR gene editing—which is a versatile molecular editing technique with potentially countless applications. It is also the next step in Ahern-Rindell’s research with the GM1-affected sheep cells (more on CRISPR technology in a moment).
AHERN-RINDEL HAD A FORMATIVE EXPERIENCE when she was a teenager that helped her to decide to become a geneticist and molecular biologist. In her early teens, she was a regular babysitter for three young girls who had the genetic condition Cystic Fibrosis (CF). The second youngest of five siblings, Ahern-Rindell found she was suited to the chaos that sometimes is babysitting. The girls were able to do everyday kid activities—play with dolls, do puzzles, go outside—but she was always aware that they had to be careful. If the children got too physical, too worked up, they would cough. She tried to avoid that. She remembers putting them to bed in special tents that she zipped up to help with their breathing at night.
Initially, she thought she might want to be a doctor, perhaps a pediatrician who treated patients with conditions like CF. At that time there was no such thing as genetic counseling or much in the way of therapies for the condition. She grew in her understanding of genetic diseases. She understood that the girls had CF because a copy of the recessive gene had come from their mother and a copy of the recessive gene had come from their father. Then, tragically, the children passed away, and their deaths—and the reality that medical care does not always involve a cure—raised big questions for her. She started to wonder what was actually going on with this (or other) genetic conditions. She started to wonder if she might be better suited to lab work and trying to find a cure for genetic diseases like CF.
After an opportunity to do research as an undergraduate, Ahern-Rindell ultimately decided to pursue a career in a research lab and in teaching. She wanted to get to the molecular root of things, though she didn’t end up working on CF. She ended up in a lab working to unlock the secrets of GM1, first in cats and later in dogs and sheep. (I admit I find it fascinating how a scientist’s career has a good deal to do with interest, curiosity, and intuition, but it also has something to do with chance, i.e., which graduate school or lab has an opening or perhaps you happen to be working in a lab near a ranch with sheep who present with GM1.)
Those children that Ahern-Rindell babysat for did something else for this budding scientist. They made her think long and hard about the contribution she wanted to make to society, and how science and her role as a researcher and teacher of young people could be a part of making that contribution. She also began to think about the ethics involved in doing the work of science, both generally and specifically when it comes to research on the human genome. Bioethics eventually became an ongoing part of her career. In large part due to her efforts and one of her research students, and through funding from the Dundon-Berchtold Institute for Moral Formation and Applied Ethics, every student, faculty, and staff member at UP who is involved in any type of research now takes a tutorial in ethical research practices, how to handle confidential data, how to accurately give credit to others for their previous work, etc.
AHERN-RINDELL AND HER CURRENT RESEARCH student, senior biology major Christina Buselli, are using CRISPR technology to try to verify that the base change they are seeing in the GLB1 gene of GM1-affected sheep is actually the mutation that causes the condition in the sheep model. The base change should cause an enzyme deficiency (this enzyme deficiency is what ultimately leads to the deterioration of the nervous system).
How are they aiming to prove this? First they are taking healthy sheep cells and using CRISPR technology to target and “edit out” the healthy GLB1 gene and replace it with the altered version of the gene. If the healthy sheep cells start to express the enzyme deficiency, the science will be another step closer to showing that this base change in the GLB1 gene is the condition-causing mutation.
The next step would be to conduct the experiment in the other direction: start with a gene that exhibits the mutation that leads to GM1, then use CRISPR technology to “cut” or “edit” that mutated gene out and replace it with a healthy, functioning gene, thereby removing the condition-causing mutation. This would alter the sheep’s genome, and it would also cure them of GM1.
Rightly, all manner of ethical questions arise at the prospect of editing a being’s genome—microorganism, animal, plant, or human.
Ahern-Rindell wants to use her research to lean into the ethics of CRISPR technology, and she wants the community to lean in too.
“With any advances you make in science,” Ahern-Rindell says, “you have to think about the potential consequences. You cannot just do your research and not think about ethical concerns. With any new piece of knowledge you acquire in biology, you have to stop and think about: What is that science telling you? How can you apply that science in a beneficial way? Are there negative consequences to that scientific knowledge and how are you going to determine how best to turn the scientific knowledge into applied knowledge?”
Let’s think through a few hypotheticals as they could relate to the sheep cells.
If the gene editing is for purposes of medical treatment with GM1—to cure a disease, prevent suffering in a sheep—is that an ethical thing to do?
If you could edit that gene out in the cells that make sperm and eggs, then you could theoretically prevent the sheep from handing that gene down to their offspring. How does that change the ethical considerations?
If, theoretically, you edit a sheep’s genes early enough (say, before cells have acquired diversified function), you might be able to remove that mutation so that it is never passed on in their family line ever again. How should we be thinking about that possibility?
Replace the sheep cells with human cells in the questions above and it’s not hard to think about how the application of gene editing—or CRISPR technology—to the human genome raises a whole host of serious concerns.
The scientific community has been thinking through the ethical concerns from the beginning. There is consensus among the global scientific community that doing gene editing on viable human embryos is not acceptable. Outside of the US, there is a scientist in prison for doing gene editing on two viable embryos, who are now young girls, in an attempt to prevent them from being infected by HIV and developing AIDS. This scientist crossed a line that was globally accepted in the scientific community (especially since there are established alternative treatments for AIDS).
And yet, before you get to that line, there are a lot of other uses of CRISPR that are important to think through.
AHERN-RINDELL AND BUSELLI WERE GIVEN funding to find out what the general student population understands about CRISPR gene-editing technology. Ahern-Rindell believes that society needs to be examining these questions, so they are starting with the corner of society that they know best: University of Portland.
It may seem simple to decide that if gene editing will save a child from a life-threatening disease, that this would be something good to explore.
But if changing a parent’s genetic code changes the genetic code in a family line forevermore, new questions arise. Who gets to make a decision about someone’s genetic line? If it means a child will avoid a fatal condition, or suffering, is it unethical not to make the change? What are the long-term evolutionary consequences of changing the human genome? Are the voices of those who live with disabilities being centered and heard in these discussions?
What happens if parents want to embark on a different kind of gene editing that doesn’t involve treatment for a fatal disease? What if people start wanting to make changes, or “enhancements,” in their offspring? Without regulations, what’s to stop a parent from saying they want, say, a child who has the necessary genes for becoming tall so she can play in the WNBA?
And who will have access to this technology? Who will pay for it? Will it (won’t it) exacerbate disparities in health care or in society as a whole? What kind of regulations need to be in place? And another caution, what if editing one disease-causing gene makes you more susceptible to another disease, like cancer? Is it ethical to make that decision for someone other than oneself?
Ahern-Rindell doesn’t come with prescriptive answers, but she does want students (and the general public) to be asking questions. If this technology is here to stay, how do we use it responsibly and for the greater good?
University of Portland, a liberal arts institution with an Institute that funds research in applied ethics, is well-positioned to have these conversations thoughtfully.
“We’re trying to involve citizens and engage the public,” Ahern-Rindell says. And she wants to find ways to educate and combat misinformation. She wants to think critically and carefully about how we can move basic scientific knowledge from the lab into society in a thoughtful and safe way.
THEY WILL FINISH OUT THE YEAR working on the sheep model. They will see how far they get in their search for answers. Buselli will present on their findings in a Founders’ Day presentation this spring. She feels a certain responsibility. “People in younger generations are going to be responsible for using this technology for clinical applications,” Buselli says, “so it’s important to understand both the science behind it and the ethics behind using this technology moving forward.”
Buselli’s words ring especially true knowing that Ahern-Rindell is due to retire this year. These questions will indeed become the responsibility of the next generation. Ahern-Rindell is looking for a lab to continue work on her sheep cells and build on the body of knowledge that she has amassed in hopes that a treatment/cure for GM1 Gangliosidosis will be possible soon.
JESSICA MURPHY MOO is the editor of this magazine.
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