"Here's a question for you," I say to our dinner guests, dodging a knowing glance from my wife. "Imagine a future in which you could surgically replace your legs with robotic substitutes that had all the functionality and sensation of their biological counterparts. Let's say these new legs would allow you to run all day at 20 miles per hour without getting tired. Would you have the surgery?"
Why are we so married to the arbitrary distinction between rehabilitating and augmenting?
Like most people I pose this question to, our guests respond with some variation on the theme of "no way"; the idea of undergoing a surgical procedure with the sole purpose of augmenting performance beyond traditional human limits borders on the unthinkable.
"Would your answer change if you had arthritis in your knees?" This is where things get interesting. People think differently about intervention when injury or illness is involved. The idea of a major surgery becomes more tractable to us in the setting of rehabilitation.
Consider the simplistic example of human walking speed. The average human walks at a baseline three miles per hour. If someone is only able to walk at one mile per hour, we do everything we can to increase their walking ability. However, to take a person who is already able to walk at three miles per hour and surgically alter their body so that they can walk twice as fast seems, to us, unreasonable.
What fascinates me about this is that the three-mile-per-hour baseline is set by arbitrary limitations of the healthy human body. If we ignore this reference point altogether, and consider that each case simply offers an improvement in walking ability, the line between augmentation and rehabilitation all but disappears. Why, then, are we so married to this arbitrary distinction between rehabilitating and augmenting? What makes us hold so tightly to baseline human function?
Where We Stand Now
As the functionality of advanced prosthetic devices continues to increase at an astounding rate, questions like these are becoming more relevant. Experimental prostheses, intended for the rehabilitation of people with amputation, are now able to replicate the motions of biological limbs with high fidelity. Neural interfacing technologies enable a person with amputation to control these devices with their brain and nervous system. Before long, synthetic body parts will outperform biological ones.
Our approach allows people to not only control a prosthesis with their brain, but also to feel its movements as if it were their own limb.
Against this backdrop, my colleagues and I developed a methodology to improve the connection between the biological body and a synthetic limb. Our approach, known as the agonist-antagonist myoneural interface ("AMI" for short), enables us to reflect joint movement sensations from a prosthetic limb onto the human nervous system. In other words, the AMI allows people to not only control a prosthesis with their brain, but also to feel its movements as if it were their own limb. The AMI involves a reimagining of the amputation surgery, so that the resultant residual limb is better suited to interact with a neurally-controlled prosthesis. In addition to increasing functionality, the AMI was designed with the primary goal of enabling adoption of a prosthetic limb as part of a patient's physical identity (known as "embodiment").
Early results have been remarkable. Patients with below-knee AMI amputation are better able to control an experimental prosthetic leg, compared to people who had their legs amputated in the traditional way. In addition, the AMI patients show increased evidence of embodiment. They identify with the device, and describe feeling as though it is part of them, part of self.
Where We're Going
True embodiment of robotic devices has the potential to fundamentally alter humankind's relationship with the built world. Throughout history, humans have excelled as tool builders. We innovate in ways that allow us to design and augment the world around us. However, tools for augmentation are typically external to our body identity; there is a clean line drawn between smart phone and self. As we advance our ability to integrate synthetic systems with physical identity, humanity will have the capacity to sculpt that very identity, rather than just the world in which it exists.
For this potential to be realized, we will need to let go of our reservations about surgery for augmentation. In reality, this shift has already begun. Consider the approximately 17.5 million surgical and minimally invasive cosmetic procedures performed in the United States in 2017 alone. Many of these represent patients with no demonstrated medical need, who have opted to undergo a surgical procedure for the sole purpose of synthetically enhancing their body. The ethical basis for such a procedure is built on the individual perception that the benefits of that procedure outweigh its costs.
At present, it seems absurd that amputation would ever reach this point. However, as robotic technology improves and becomes more integrated with self, the balance of cost and benefit will shift, lending a new perspective on what now seems like an unfathomable decision to electively amputate a healthy limb. When this barrier is crossed, we will collide head-on with the question of whether it is acceptable for a person to "upgrade" such an essential part of their body.
At a societal level, the potential benefits of physical augmentation are far-reaching. The world of robotic limb augmentation will be a world of experienced surgeons whose hands are perfectly steady, firefighters whose legs allow them to kick through walls, and athletes who never again have to worry about injury. It will be a world in which a teenage boy and his grandmother embark together on a four-hour sprint through the woods, for the sheer joy of it. It will be a world in which the human experience is fundamentally enriched, because our bodies, which play such a defining role in that experience, are truly malleable.
This is not to say that such societal benefits stand without potential costs. One justifiable concern is the misuse of augmentative technologies. We are all quite familiar with the proverbial supervillain whose nervous system has been fused to that of an all-powerful robot.
The world of robotic limb augmentation will be a world of experienced surgeons whose hands are perfectly steady.
In reality, misuse is likely to be both subtler and more insidious than this. As with all new technology, careful legislation will be necessary to work against those who would hijack physical augmentations for violent or oppressive purposes. It will also be important to ensure broad access to these technologies, to protect against further socioeconomic stratification. This particular issue is helped by the tendency of the cost of a technology to scale inversely with market size. It is my hope that when robotic augmentations are as ubiquitous as cell phones, the technology will serve to equalize, rather than to stratify.
In our future bodies, when we as a society decide that the benefits of augmentation outweigh the costs, it will no longer matter whether the base materials that make us up are biological or synthetic. When our AMI patients are connected to their experimental prosthesis, it is irrelevant to them that the leg is made of metal and carbon fiber; to them, it is simply their leg. After our first patient wore the experimental prosthesis for the first time, he sent me an email that provides a look at the immense possibility the future holds:
What transpired is still slowly sinking in. I keep trying to describe the sensation to people. Then this morning my daughter asked me if I felt like a cyborg. The answer was, "No, I felt like I had a foot."
In November 2020, messenger RNA catapulted into the public consciousness when the first COVID-19 vaccines were authorized for emergency use. Around the same time, an equally groundbreaking yet relatively unheralded application of mRNA technology was taking place at a London hospital.
Over the past two decades, there's been increasing interest in harnessing mRNA — molecules present in all of our cells that act like digital tape recorders, copying instructions from DNA in the cell nucleus and carrying them to the protein-making structures — to create a whole new class of therapeutics.
Scientists realized that artificial mRNA, designed in the lab, could be used to instruct our cells to produce certain antibodies, turning our bodies into vaccine-making factories, or to recognize and attack tumors. More recently, researchers recognized that mRNA could also be used to make another groundbreaking technology far more accessible to more patients: gene editing. The gene-editing tool CRISPR has generated plenty of hype for its potential to cure inherited diseases. But delivering CRISPR to the body is complicated and costly.
"Most gene editing involves taking cells out of the patient, treating them and then giving them back, which is an extremely expensive process," explains Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the COVID-19 vaccines.
But last November, a Massachusetts-based biotech company called Intellia Therapeutics showed it was possible to use mRNA to make the CRISPR system inside the body, eliminating the need to extract cells out of the body and edit them in a lab. Just as mRNA can instruct our cells to produce antibodies against a viral infection, it can also teach them to produce the two molecular components that make up CRISPR — a guide molecule and a cutting protein — to snip out a problem gene.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies."
In Intellia's London-based clinical trial, the company applied this for the first time in a patient with a rare inherited liver disease known as hereditary transthyretin amyloidosis with polyneuropathy. The disease causes a toxic protein to build up in a person's organs and is typically fatal. In a company press release, Intellia's president and CEO John Leonard swiftly declared that its mRNA-based CRISPR therapy could usher in a "new era of potential genome editing cures."
Weissman predicts that turning CRISPR into an affordable therapy will become the next major frontier for mRNA over the coming decade. His lab is currently working on an mRNA-based CRISPR treatment for sickle cell disease. More than 300,000 babies are born with sickle cell every year, mainly in lower income nations.
"There is a FDA-approved cure, but it involves taking the bone marrow out of the person, and then giving it back which is prohibitively expensive," he says. It also requires a patient to have a matched bone marrow done. "We give an intravenous injection of mRNA lipid nanoparticles that target CRISPR to the bone marrow stem cells in the patient, which is easy, and much less expensive."
Meanwhile, the overwhelming success of the COVID-19 vaccines has focused attention on other ways of using mRNA to bolster the immune system against threats ranging from other infectious diseases to cancer.
The practicality of mRNA vaccines – relatively small quantities are required to induce an antibody response – coupled with their adaptable design, mean companies like Moderna are now targeting pathogens like Zika, chikungunya and cytomegalovirus, or CMV, which previously considered commercially unviable for vaccine developers. This is because outbreaks have been relatively sporadic, and these viruses mainly affect people in low-income nations who can't afford to pay premium prices for a vaccine. But mRNA technology means that jabs could be produced on a flexible basis, when required, at relatively low cost.
Other scientists suggest that mRNA could even provide a means of developing a universal influenza vaccine, a goal that's long been the Holy Grail for vaccinologists around the world.
"The mRNA technology allows you to pick out bits of the virus that you want to induce immunity to," says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech that's developing mRNA-based vaccines for malaria and HIV, as well as various forms of cancer. "This means you can get the immune system primed to the bits of the virus that don't vary so much between strains. So you could actually have a single vaccine that protects against a whole raft of different variants of the same virus, offering more universal coverage."
Before mRNA became synonymous with vaccines, its biggest potential was for cancer treatments. BioNTech, the German biotech company that collaborated with Pfizer to develop the first authorized COVID-19 vaccine, was initially founded to utilize mRNA for personalized cancer treatments, and the company remains interested in cancers ranging from melanoma to breast cancer.
One of the major hurdles in treating cancer has been the fact that tumors can look very different from one person to the next. It's why conventional approaches, such as chemotherapy or radiation, don't work for every patient. But weaponizing mRNA against cancer primes the immune cells with the tumor's specific genetic sequence, training the patient's body to attack their own unique type of cancer.
"It means you're able to think about personalizing cancer treatments down to specific subgroups of patients," says Mulqueen. "For example, eTheRNA are developing a renal cell carcinoma treatment which will be targeted at around 20% of these patients, who have specific tumor types. We're hoping to take that to human trials next year, but the challenge is trying to identify the right patients for the treatment at an early stage."
Repairing Damaged mRNA
While hopes are high that mRNA could usher in new cancer treatments and make CRISPR more accessible, a growing number of companies are also exploring an alternative to gene editing, known as RNA editing.
In genetic disorders, the mRNA in certain cells is impaired due to a rogue gene defect, and so the body ceases to produce a particular vital protein. Instead of permanently deleting the problem gene with CRISPR, the idea behind RNA editing is to inject small pieces of synthetic mRNA to repair the existing mRNA. Scientists think this approach will allow normal protein production to resume.
Over the past few years, this approach has gathered momentum, as some researchers have recognized that it holds certain key advantages over CRISPR. Companies from Belgium to Japan are now looking at RNA editing to treat all kinds of disorders, from Huntingdon's disease, to amyotrophic lateral sclerosis, or ALS, and certain types of cancer.
"With RNA editing, you don't need to make any changes to the DNA," explains Daniel de Boer, CEO of Dutch biotech ProQR, which is looking to treat rare genetic disorders that cause blindness. "Changes to the DNA are permanent, so if something goes wrong, that may not be desirable. With RNA editing, it's a temporary change, so we dose patients with our drugs once or twice a year."
Last month, ProQR reported a landmark case study, in which a patient with a rare form of blindness called Leber congenital amaurosis, which affects the retina at the back of the eye, recovered vision after three months of treatment.
"We have seen that this RNA therapy restores vision in people that were completely blind for a year or so," says de Boer. "They were able to see again, to read again. We think there are a large number of other genetic diseases we could go after with this technology. There are thousands of different mutations that can lead to blindness, and we think this technology can target approximately 25% of them."
Ultimately, there's likely to be a role for both RNA editing and CRISPR, depending on the disease. "I think CRISPR is ideally suited for illnesses where you would like to permanently correct a genetic defect," says Joshua Rosenthal of the Marine Biology Laboratory in Chicago. "Whereas RNA editing could be used to treat things like pain, where you might want to reset a neural circuit temporarily over a shorter period of time."
Much of this research has been accelerated by the COVID-19 pandemic, which has played a major role in bringing mRNA to the forefront of people's minds as a therapeutic.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies," says Mulqueen. "In the future, I would not be surprised if many of the top pharma products are mRNA derived."
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.