BIG QUESTION OF THE MONTH: Should we use CRISPR, the new technique that enables precise DNA editing, to change the genes of human embryos to eradicate disease – or even to enhance desirable traits? LeapsMag invited three leading experts to weigh in.
Over the last few decades, the international community has issued several bioethical guidelines and legally binding documents, ranging from UN Declarations to regional charters to national legislation, about editing the human germline--the DNA that is passed down to future generations. There was a broad consensus that modifications should be prohibited. But now that CRISPR-cas9 and related methods of gene editing are taking the world by storm, that stance is softening--and so far, no thorough public discussion has emerged.
There is broad agreement in the scientific and ethics community that germline gene editing must not be clinically applied unless safety concerns are resolved. Predicting that safety issues will indeed be minimized, the National Academy of Sciences issued a report this past February that sets up several procedural norms. These may serve as guidelines for future implementation of human embryo editing, among them that there are no "reasonable alternatives," a condition that is left deliberately vague.
I regard the conditional embrace of germline gene editing as a grave mistake: It is a dramatic break with the previous idea of a ban, departing also from the moratorium that the UNESCO International Bioethics Committee had recommended in 2015. But in a startling move, the Academy already set the next post, recommending "that genome editing for purposes other than treatment or prevention of disease and disability should not proceed at this time" (my emphasis). It recommended public discussions, but without spelling out its own role in facilitating them.
"The international community should explicitly ban embryo gene editing as a method of human reproduction."
To proceed ethically, I argue that the international community, through the United Nations and in line with the ban on human reproductive cloning, should explicitly ban embryo gene editing as a method of human reproduction. Together with guidelines adjusted for non-reproductive and non-human applications, a prohibition would ensure two important results: First, that non-reproductive human embryo research could be pursued in a responsible way in those countries that allow for it, and second, that individual scientists, public research institutes, and private companies would know the moral limit of possible research.
Basic human embryo research is required, scientists argue, to better understand genetic diseases and early human development. I do not question this, and I am convinced that existing guidelines can be adjusted to meet the moral requirements in this area. Millions of people may benefit from different non-reproductive pathways of gene editing. Germline gene editing, in contrast, does not offer any resolutions to global or local health problems – and that alone raises many concerns about the current state of scientific research.
I support a ban because germline gene editing for reproductive purposes concerns more than safety. The genetic modification of a human being is irreversible and unpredictable in its epigenetic, personal, and social effects. It concerns the rights of children; it exposes persons with disabilities to social stigmatization; it contradicts the global justice agenda with respect to healthcare; and it infringes upon the rights to freedom and well-being of future persons.
"Reproductive germline gene editing directly violates the rights of individual future person."
Apart from questions of justice, reproductive germline gene editing may well increase the stigmatization of persons with disabilities. I want to emphasize here, however, that it directly violates the rights of individual future persons, namely a future child's right to genetic integrity, to freedom, and potentially to well-being, all guaranteed in different UN Declarations of Human Rights. For all these reasons, it is an unacceptable path forward.
The way the discussion has been framed so far is very different from my perspective that situates germline gene editing in the broader framework of human rights and responsibilities. In short, many others never questioned the goal but instead focused on the unintentional side-effects of an otherwise beneficial technique for human reproduction. Some scientists see germline gene editing as an alternative to embryo selection via Preimplantation Genetic Diagnosis (PGD), a procedure in which multiple embryos are tested to find out which ones carry disease-causing mutations. Others see it as the first step to human enhancement.
Some physicians argue that in the field of assisted reproduction, not every couple is comfortable with embryo selection via PGD, because potentially, unchosen embryos are discarded. Germline gene editing offers them an alternative. It is rarely mentioned, however, that germline gene editing would most likely still require PGD as a control of the procedure (though without the purpose of selection), and that prenatal genetic diagnosis would also be highly recommended. In other words, germline gene editing would not replace existing protocols but rather change their purpose, and it would also not necessarily reduce the number of embryos needed for assisted reproduction.
In some (rare) cases, PGD is not an option, because in the couples' condition, all embryos will be affected. One current option to avoid transmitting genetic traits is to use a donor sperm or egg, though the resulting child would not be genetically related to one parent. If these parents had an obligation, as some proponents argue, to secure the health of their offspring (an argument that I do not follow), then procreation with sperm or egg donation would even be morally required, as this is the safest procedure to erase a given genetic trait.
There are no therapeutic scenarios that exclusively require reproductive gene editing even if one accepts the right to reproductive autonomy. The fact is that couples who rightly wish to secure and protect the health of their future children can be offered medical alternatives in all cases. However, this requires considering sperm or egg donation as the safest and most reasonable option – the condition the NAS Report has set.
Scientists in favor of germline gene editing argue against this: the desire for genetic kinship, they say, is a legitimate expression of a couple's reproductive freedom, and germline gene editing offers them an alternative to have a healthy child. In the future, proponents say, these (very few) couples who wish for genetically related offspring will be faced with the dilemma of either accepting the transmission of a genetic health risk to their children or weighing the benefits and risks of gene editing.
But here is a blind spot in the whole discussion.
Many scientists and some bioethicists think that reproductive freedom includes the right to a genetically related child. But even if we were to presuppose such a right, it is not absolute in the context of assisted reproduction. Although sperm or egg donation may be undesirable for some couples, the moral question of responsibility does not disappear with their reproductive rights. At a minimum, the future child's rights must be considered, and these rights go further than their health rights.
It is puzzling that in claiming their own reproductive freedom, couples would need to ignore their children's and possibly grandchildren's future freedom – including the constraints resulting from being monitored over the course of their lives and the indirect constraints of the children's own right to reproductive freedom. From a medical standpoint, it would be highly recommended for them, too, to have children through assisted reproduction. This distinguishes germline gene editing from any other procedure of assisted reproduction: we need the data from the second and third generations to see whether the method is safe and efficacious. Whose reproductive freedom should count, the parents' or the future children's?
But for now, the question of parental rights may well divert the discussion from the question of responsible gene editing research; its conditions and structures require urgent evaluation and adjustment to guide international research groups. I am concerned that we are in the process of developing a new technology that has tremendous potential and ramifications – but without having considered the ethical framework for a responsible path forward.
Glioblastoma is an aggressive and deadly brain cancer, causing more than 10,000 deaths in the US per year. In the last 30 years there has only been limited improvement in the survival rate despite advances in radiation therapy and chemotherapy. Today the typical survival rate is just 14 months and that extra time is spent suffering from the adverse and often brutal effects of radiation and chemotherapy.
Scientists are trying to design more effective treatments for glioblastoma with fewer side effects. Now, a team at the Department of Neurosurgery at Houston Methodist Hospital has created a magnetic helmet-based treatment called oncomagnetic therapy: a promising non-invasive treatment for shrinking cancerous tumors. In the first patient tried, the device was able to reduce the tumor of a glioblastoma patient by 31%. The researchers caution, however, that much more research is needed to determine its safety and effectiveness.
How It Works
“The whole idea originally came from a conversation I had with General Norman Schwarzkopf, a supposedly brilliant military strategist,” says Dr David Baskin, professor of neurosurgery and leader of the effort at Houston Methodist. “I asked him what is the secret to your success and he said, ‘Energy. Take out the power grid and the enemy can't communicate.’ So I thought about what supplies [energy to] cancer, especially brain cancer.”
Baskin came up with the idea of targeting the mitochondria, which process and produce energy for cancer cells.
This is the most exciting thing in glioblastoma treatment I've seen since I've been a neurosurgeon but it is very preliminary.”
The magnetic helmet creates a powerful oscillating magnetic field. At a set range of frequencies and timings, it disrupts the flow of electrons in the mitochondria of cancer cells. This leads to a release of certain chemicals called ROS (Reactive Oxygen Species). In normal cells, this excess ROS is much lower, and is neutralized by other chemicals called antioxidants.
However, cancer cells already have more ROS: they grow rapidly and uncontrollably so their mitochondria need to produce more energy which in turn generates more ROS. By using the powerful magnetic field, levels of ROS get so high that the malignant cells are torn apart.
The biggest challenge was working out the specific range of frequencies and timing parameters they needed to use to kill cancer cells. It took skill, intuition, luck and lots of experiments. The helmet could theoretically be used to treat all types of glioblastoma.
Developing the magnetic helmet was a collaborative process. Dr Santosh Helekar is a neuroscientist at Houston Methodist Research Institute and the director of oncomagnetics (magnetic cancer therapies) at the Peak Center in Houston Methodist Hospital. His previous invention with colleagues gave the team a starting point to build on. “About 7 years back I developed a portable brain magnetic stimulation device to conduct brain research,” Helekar says. “We [then] conducted a pilot clinical trial in stroke patients. The results were promising.”
Helekar presented his findings to neurosurgeons including Baskin. They decided to collaborate. With a team of scientists behind them, they modified the device to kill cancer cells.
The magnetic helmet studied for treatment of glioblastoma
Dr. David Baskin
After success in the lab, the team got FDA approval to conduct a compassionate trial in a 53-year-old man with end-stage glioblastoma. He had tried every other treatment available. But within 30 days of using the magnetic helmet his tumor shrank by 31%.
Sadly, 36 days into the treatment, the patient had an unrelated head injury due to a fall. The treatment was paused and he later died of the injury. Autopsy results of his brain highlighted the dramatic reduction in tumor cells.
Baskin says, “This is the most exciting thing in glioblastoma treatment I've seen since I've been a neurosurgeon but it is very preliminary.”
The helmet is part of a growing number of non-invasive cancer treatments. One device that is currently being used by glioblastoma patients is Optune. It uses electric fields called tumor treating fields to slow down cell division and has been through a successful phase 3 clinical trial.
The magnetic helmet has the promise to be another useful non-invasive treatment according to Professor Gabriel Zada, a neurosurgeon and director of the USC Brain Tumor Center. “We're learning that various electromagnetic fields and tumor treating fields appear to play a role in glioblastoma. So there is some precedent for this though the tumor treating fields work a little differently. I think there is major potential for it to be effective but of course it will require some trials.”
Professor Jonathan Sherman, a neurosurgeon and director of neuro-oncology at West Virginia University, reiterates the need for further testing. “It sounds interesting but it’s too early to tell what kind of long-term efficacy you get. We do not have enough data. Also if you’re disrupting [the magnetic field] you could negatively impact a patient. You could be affecting the normal conduction of electromagnetic activity in the brain.”
The team is currently extending their research. They are now testing the treatment in two other patients with end-stage glioblastoma. The immediate challenge is getting FDA approval for those at an earlier stage of the disease who are more likely to benefit.
Baskin and the team are designing a clinical trial in the U.S., .U.K. and Germany. After positive results in cell cultures, they’re in negotiations to collaborate with other researchers in using the technology for lung and breast cancer. With breast cancer, the soft tissue is easier to access so a magnetic device could be worn over the breast.
“My hope is to develop a treatment to treat and hopefully cure glioblastoma without radiation or chemotherapy,” Baskin says. “We're onto a strategy that could make a huge difference for patients with this disease and probably for patients with many other forms of cancer.”
Astronauts at the International Space Station today depend on pre-packaged, freeze-dried food, plus some fresh produce thanks to regular resupply missions. This supply chain, however, will not be available on trips further out, such as the moon or Mars. So what are astronauts on long missions going to eat?
Going by the options available now, says Christel Paille, an engineer at the European Space Agency, a lunar expedition is likely to have only dehydrated foods. “So no more fresh product, and a limited amount of already hydrated product in cans.”
For the Mars mission, the situation is a bit more complex, she says. Prepackaged food could still constitute most of their food, “but combined with [on site] production of certain food products…to get them fresh.” A Mars mission isn’t right around the corner, but scientists are currently working on solutions for how to feed those astronauts. A number of boundary-pushing efforts are now underway.
The logistics of growing plants in space, of course, are very different from Earth. There is no gravity, sunlight, or atmosphere. High levels of ionizing radiation stunt plant growth. Plus, plants take up a lot of space, something that is, ironically, at a premium up there. These and special nutritional requirements of spacefarers have given scientists some specific and challenging problems.
To study fresh food production systems, NASA runs the Vegetable Production System (Veggie) on the ISS. Deployed in 2014, Veggie has been growing salad-type plants on “plant pillows” filled with growth media, including a special clay and controlled-release fertilizer, and a passive wicking watering system. They have had some success growing leafy greens and even flowers.
"Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources."
A larger farming facility run by NASA on the ISS is the Advanced Plant Habitat to study how plants grow in space. This fully-automated, closed-loop system has an environmentally controlled growth chamber and is equipped with sensors that relay real-time information about temperature, oxygen content, and moisture levels back to the ground team at Kennedy Space Center in Florida. In December 2020, the ISS crew feasted on radishes grown in the APH.
“But salad doesn’t give you any calories,” says Erik Seedhouse, a researcher at the Applied Aviation Sciences Department at Embry-Riddle Aeronautical University in Florida. “It gives you some minerals, but it doesn’t give you a lot of carbohydrates.” Seedhouse also noted in his 2020 book Life Support Systems for Humans in Space: “Integrating the growing of plants into a life support system is a fiendishly difficult enterprise.” As a case point, he referred to the ESA’s Micro-Ecological Life Support System Alternative (MELiSSA) program that has been running since 1989 to integrate growing of plants in a closed life support system such as a spacecraft.
Paille, one of the scientists running MELiSSA, says that the system aims to recycle the metabolic waste produced by crew members back into the metabolic resources required by them: “The aim is…to come [up with] a closed, sustainable system which does not [need] any logistics resupply.” MELiSSA uses microorganisms to process human excretions in order to harvest carbon dioxide and nitrate to grow plants. “Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources,” Paille adds.
Microorganisms play a big role as “fuel” in food production in extreme places, including in space. Last year, researchers discovered Methylobacterium strains on the ISS, including some never-seen-before species. Kasthuri Venkateswaran of NASA’s Jet Propulsion Laboratory, one of the researchers involved in the study, says, “[The] isolation of novel microbes that help to promote the plant growth under stressful conditions is very essential… Certain bacteria can decompose complex matter into a simple nutrient [that] the plants can absorb.” These microbes, which have already adapted to space conditions—such as the absence of gravity and increased radiation—boost various plant growth processes and help withstand the harsh physical environment.
MELiSSA, says Paille, has demonstrated that it is possible to grow plants in space. “This is important information because…we didn’t know whether the space environment was affecting the biological cycle of the plant…[and of] cyanobacteria.” With the scientific and engineering aspects of a closed, self-sustaining life support system becoming clearer, she says, the next stage is to find out if it works in space. They plan to run tests recycling human urine into useful components, including those that promote plant growth.
The MELiSSA pilot plant uses rats currently, and needs to be translated for human subjects for further studies. “Demonstrating the process and well-being of a rat in terms of providing water, sufficient oxygen, and recycling sufficient carbon dioxide, in a non-stressful manner, is one thing,” Paille says, “but then, having a human in the loop [means] you also need to integrate user interfaces from the operational point of view.”
Growing food in space comes with an additional caveat that underscores its high stakes. Barbara Demmig-Adams from the Department of Ecology and Evolutionary Biology at the University of Colorado Boulder explains, “There are conditions that actually will hurt your health more than just living here on earth. And so the need for nutritious food and micronutrients is even greater for an astronaut than for [you and] me.”
Demmig-Adams, who has worked on increasing the nutritional quality of plants for long-duration spaceflight missions, also adds that there is no need to reinvent the wheel. Her work has focused on duckweed, a rather unappealingly named aquatic plant. “It is 100 percent edible, grows very fast, it’s very small, and like some other floating aquatic plants, also produces a lot of protein,” she says. “And here on Earth, studies have shown that the amount of protein you get from the same area of these floating aquatic plants is 20 times higher compared to soybeans.”
Aquatic plants also tend to grow well in microgravity: “Plants that float on water, they don’t respond to gravity, they just hug the water film… They don’t need to know what’s up and what’s down.” On top of that, she adds, “They also produce higher concentrations of really important micronutrients, antioxidants that humans need, especially under space radiation.” In fact, duckweed, when subjected to high amounts of radiation, makes nutrients called carotenoids that are crucial for fighting radiation damage. “We’ve looked at dozens and dozens of plants, and the duckweed makes more of this radiation fighter…than anything I’ve seen before.”
Despite all the scientific advances and promising leads, no one really knows what the conditions so far out in space will be and what new challenges they will bring. As Paille says, “There are known unknowns and unknown unknowns.”
One definite “known” for astronauts is that growing their food is the ideal scenario for space travel in the long term since “[taking] all your food along with you, for best part of two years, that’s a lot of space and a lot of weight,” as Seedhouse says. That said, once they land on Mars, they’d have to think about what to eat all over again. “Then you probably want to start building a greenhouse and growing food there [as well],” he adds.
And that is a whole different challenge altogether.