Do New Tools Need New Ethics?
Symbols of countries on a chessboard.
Scarcely a week goes by without the announcement of another breakthrough owing to advancing biotechnology. Recent examples include the use of gene editing tools to successfully alter human embryos or clone monkeys; new immunotherapy-based treatments offering longer lives or even potential cures for previously deadly cancers; and the creation of genetically altered mosquitos using "gene drives" to quickly introduce changes into the population in an ecosystem and alter the capacity to carry disease.
The environment for conducting science is dramatically different today than it was in the 1970s, 80s, or even the early 2000s.
Each of these examples puts pressure on current policy guidelines and approaches, some existing since the late 1970s, which were created to help guide the introduction of controversial new life sciences technologies. But do the policies that made sense decades ago continue to make sense today, or do the tools created during different eras in science demand new ethics guidelines and policies?
Advances in biotechnology aren't new of course, and in fact have been the hallmark of science since the creation of the modern U.S. National Institutes of Health in the 1940s and similar government agencies elsewhere. Funding agencies focused on health sciences research with the hope of creating breakthroughs in human health, and along the way, basic science discoveries led to the creation of new scientific tools that offered the ability to approach life, death, and disease in fundamentally new ways.
For example, take the discovery in the 1970s of the "chemical scissors" in living cells called restriction enzymes, which could be controlled and used to introduce cuts at predictable locations in a strand of DNA. This led to the creation of tools that for the first time allowed for genetic modification of any organism with DNA, which meant bacteria, plants, animals, and even humans could in theory have harmful mutations repaired, but also that changes could be made to alter or even add genetic traits, with potentially ominous implications.
The scientists involved in that early research convened a small conference to discuss not only the science, but how to responsibly control its potential uses and their implications. The meeting became known as the Asilomar Conference for the meeting center where it was held, and is often noted as the prime example of the scientific community policing itself. While the Asilomar recommendations were not sufficient from a policy standpoint, they offered a blueprint on which policies could be based and presented a model of the scientific community setting responsible controls for itself.
But the environment for conducting science changed over the succeeding decades and it is dramatically different today than it was in the 1970s, 80s, or even the early 2000s. The regime for oversight and regulation that has provided controls for the introduction of so-called "gene therapy" in humans starting in the mid-1970s is beginning to show signs of fraying. The vast majority of such research was performed in the U.S., U.K., and Europe, where policies were largely harmonized. But as the tools for manipulating humans at the molecular level advanced, they also became more reliable and more precise, as well as cheaper and easier to use—think CRISPR—and therefore more accessible to more people in many more countries, many without clear oversight or policies laying out responsible controls.
There is no precedent for global-scale science policy, though that is exactly what this moment seems to demand.
As if to make the point through news headlines, scientists in China announced in 2017 that they had attempted to perform gene editing on in vitro human embryos to repair an inherited mutation for beta thalassemia--research that would not be permitted in the U.S. and most European countries and at the time was also banned in the U.K. Similarly, specialists from a reproductive medicine clinic in the U.S. announced in 2016 that they had performed a highly controversial reproductive technology by which DNA from two women is combined (so-called "three parent babies"), in a satellite clinic they had opened in Mexico to avoid existing prohibitions on the technique passed by the U.S. Congress in 2015.
In both cases, genetic changes were introduced into human embryos that if successful would lead to the birth of a child with genetically modified germline cells—the sperm in boys or eggs in girls—with those genetic changes passed on to all future generations of related offspring. Those are just two very recent examples, and it doesn't require much imagination to predict the list of controversial possible applications of advancing biotechnologies: attempts at genetic augmentation or even cloning in humans, and alterations of the natural environment with genetically engineered mosquitoes or other insects in areas with endemic disease. In fact, as soon as this month, scientists in Africa may release genetically modified mosquitoes for the first time.
The technical barriers are falling at a dramatic pace, but policy hasn't kept up, both in terms of what controls make sense and how to address what is an increasingly global challenge. There is no precedent for global-scale science policy, though that is exactly what this moment seems to demand. Mechanisms for policy at global scale are limited–-think UN declarations, signatory countries, and sometimes international treaties, but all are slow, cumbersome and have limited track records of success.
But not all the news is bad. There are ongoing efforts at international discussion, such as an international summit on human genome editing convened in 2015 by the National Academies of Sciences and Medicine (U.S.), Royal Academy (U.K.), and Chinese Academy of Sciences (China), a follow-on international consensus committee whose report was issued in 2017, and an upcoming 2nd international summit in Hong Kong in November this year.
These efforts need to continue to focus less on common regulatory policies, which will be elusive if not impossible to create and implement, but on common ground for the principles that ought to guide country-level rules. Such principles might include those from the list proposed by the international consensus committee, including transparency, due care, responsible science adhering to professional norms, promoting wellbeing of those affected, and transnational cooperation. Work to create a set of shared norms is ongoing and worth continued effort as the relevant stakeholders attempt to navigate what can only be called a brave new world.
Gene Transfer Leads to Longer Life and Healthspan
In August, a study provided the first proof-of-principle that genetic material transferred from one species to another can increase both longevity and healthspan in the recipient animal.
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman