Scientists are working on eye transplants for vision loss. Who will sign up?
Awash in a fluid finely calibrated to keep it alive, a human eye rests inside a transparent cubic device. This ECaBox, or Eyes in a Care Box, is a one-of-a-kind system built by scientists at Barcelona’s Centre for Genomic Regulation (CRG). Their goal is to preserve human eyes for transplantation and related research.
In recent years, scientists have learned to transplant delicate organs such as the liver, lungs or pancreas, but eyes are another story. Even when preserved at the average transplant temperature of 4 Centigrade, they last for 48 hours max. That's one explanation for why transplanting the whole eye isn’t possible—only the cornea, the dome-shaped, outer layer of the eye, can withstand the procedure. The retina, the layer at the back of the eyeball that turns light into electrical signals, which the brain converts into images, is extremely difficult to transplant because it's packed with nerve tissue and blood vessels.
These challenges also make it tough to research transplantation. “This greatly limits their use for experiments, particularly when it comes to the effectiveness of new drugs and treatments,” said Maria Pia Cosma, a biologist at Barcelona’s Centre for Genomic Regulation (CRG), whose team is working on the ECaBox.
Eye transplants are desperately needed, but they're nowhere in sight. About 12.7 million people worldwide need a corneal transplant, which means that only one in 70 people who require them, get them. The gaps are international. Eye banks in the United Kingdom are around 20 percent below the level needed to supply hospitals, while Indian eye banks, which need at least 250,000 corneas per year, collect only around 45 to 50 thousand donor corneas (and of those 60 to 70 percent are successfully transplanted).
As for retinas, it's impossible currently to put one into the eye of another person. Artificial devices can be implanted to restore the sight of patients suffering from severe retinal diseases, but the number of people around the world with such “bionic eyes” is less than 600, while in America alone 11 million people have some type of retinal disease leading to severe vision loss. Add to this an increasingly aging population, commonly facing various vision impairments, and you have a recipe for heavy burdens on individuals, the economy and society. In the U.S. alone, the total annual economic impact of vision problems was $51.4 billion in 2017.
Even if you try growing tissues in the petri dish route into organoids mimicking the function of the human eye, you will not get the physiological complexity of the structure and metabolism of the real thing, according to Cosma. She is a member of a scientific consortium that includes researchers from major institutions from Spain, the U.K., Portugal, Italy and Israel. The consortium has received about $3.8 million from the European Union to pursue innovative eye research. Her team’s goal is to give hope to at least 2.2 billion people across the world afflicted with a vision impairment and 33 million who go through life with avoidable blindness.
Their method? Resuscitating cadaveric eyes for at least a month.
If we succeed, it will be the first intact human model of the eye capable of exploring and analyzing regenerative processes ex vivo. -- Maria Pia Cosma.
“We proposed to resuscitate eyes, that is to restore the global physiology and function of human explanted tissues,” Cosma said, referring to living tissues extracted from the eye and placed in a medium for culture. Their ECaBox is an ex vivo biological system, in which eyes taken from dead donors are placed in an artificial environment, designed to preserve the eye’s temperature and pH levels, deter blood clots, and remove the metabolic waste and toxins that would otherwise spell their demise.
Scientists work on resuscitating eyes in the lab of Maria Pia Cosma.
Courtesy of Maria Pia Cosma.
“One of the great challenges is the passage of the blood in the capillary branches of the eye, what we call long-term perfusion,” Cosma said. Capillaries are an intricate network of very thin blood vessels that transport blood, nutrients and oxygen to cells in the body’s organs and systems. To maintain the garland-shaped structure of this network, sufficient amounts of oxygen and nutrients must be provided through the eye circulation and microcirculation. “Our ambition is to combine perfusion of the vessels with artificial blood," along with using a synthetic form of vitreous, or the gel-like fluid that lets in light and supports the the eye's round shape, Cosma said.
The scientists use this novel setup with the eye submersed in its medium to keep the organ viable, so they can test retinal function. “If we succeed, we will ensure full functionality of a human organ ex vivo. It will be the first intact human model of the eye capable of exploring and analyzing regenerative processes ex vivo,” Cosma added.
A rapidly developing field of regenerative medicine aims to stimulate the body's natural healing processes and restore or replace damaged tissues and organs. But for people with retinal diseases, regenerative medicine progress has been painfully slow. “Experiments on rodents show progress, but the risks for humans are unacceptable,” Cosma said.
The ECaBox could boost progress with regenerative medicine for people with retinal diseases, which has been painfully slow because human experiments involving their eyes are too risky. “We will test emerging treatments while reducing animal research, and greatly accelerate the discovery and preclinical research phase of new possible treatments for vision loss at significantly reduced costs,” Cosma explained. Much less time and money would be wasted during the drug discovery process. Their work may even make it possible to transplant the entire eyeball for those who need it.
“It is a very exciting project,” said Sanjay Sharma, a professor of ophthalmology and epidemiology at Queen's University, in Kingston, Canada. “The ability to explore and monitor regenerative interventions will increasingly be of importance as we develop therapies that can regenerate ocular tissues, including the retina.”
Seemingly, there's no sacred religious text or a holy book prohibiting the practice of eye donation.
But is the world ready for eye transplants? “People are a bit weird or very emotional about donating their eyes as compared to other organs,” Cosma said. And much can be said about the problem of eye donor shortage. Concerns include disfigurement and healthcare professionals’ fear that the conversation about eye donation will upset the departed person’s relatives because of cultural or religious considerations. As just one example, Sharma noted the paucity of eye donations in his home country, Canada.
Yet, experts like Sharma stress the importance of these donations for both the recipients and their family members. “It allows them some psychological benefit in a very difficult time,” he said. So why are global eye banks suffering? Is it because the eyes are the windows to the soul?
Seemingly, there's no sacred religious text or a holy book prohibiting the practice of eye donation. In fact, most major religions of the world permit and support organ transplantation and donation, and by extension eye donation, because they unequivocally see it as an “act of neighborly love and charity.” In Hinduism, the concept of eye donation aligns with the Hindu principle of daan or selfless giving, where individuals donate their organs or body after death to benefit others and contribute to society. In Islam, eye donation is a form of sadaqah jariyah, a perpetual charity, as it can continue to benefit others even after the donor's death.
Meanwhile, Buddhist masters teach that donating an organ gives another person the chance to live longer and practice dharma, the universal law and order, more meaningfully; they also dismiss misunderstandings of the type “if you donate an eye, you’ll be born without an eye in the next birth.” And Christian teachings emphasize the values of love, compassion, and selflessness, all compatible with organ donation, eye donation notwithstanding; besides, those that will have a house in heaven, will get a whole new body without imperfections and limitations.
The explanation for people’s resistance may lie in what Deepak Sarma, a professor of Indian religions and philosophy at Case Western Reserve University in Cleveland, calls “street interpretation” of religious or spiritual dogmas. Consider the mechanism of karma, which is about the causal relation between previous and current actions. “Maybe some Hindus believe there is karma in the eyes and, if the eye gets transplanted into another person, they will have to have that karmic card from now on,” Sarma said. “Even if there is peculiar karma due to an untimely death–which might be interpreted by some as bad karma–then you have the karma of the recipient, which is tremendously good karma, because they have access to these body parts, a tremendous gift,” Sarma said. The overall accumulation is that of good karma: “It’s a beautiful kind of balance,” Sarma said.
For the Jews, Christians, and Muslims who believe in the physical resurrection of the body that will be made new in an afterlife, the already existing body is sacred since it will be the basis of a new refashioned body in an afterlife.---Omar Sultan Haque.
With that said, Sarma believes it is a fallacy to personify or anthropomorphize the eye, which doesn’t have a soul, and stresses that the karma attaches itself to the soul and not the body parts. But for scholars like Omar Sultan Haque—a psychiatrist and social scientist at Harvard Medical School, investigating questions across global health, anthropology, social psychology, and bioethics—the hierarchy of sacredness of body parts is entrenched in human psychology. You cannot equate the pinky toe with the face, he explained.
“The eyes are the window to the soul,” Haque said. “People have a hierarchy of body parts that are considered more sacred or essential to the self or soul, such as the eyes, face, and brain.” In his view, the techno-utopian transhumanist communities (especially those in Silicon Valley) have reduced the totality of a person to a mere material object, a “wet robot” that knows no sacredness or hierarchy of human body parts. “But for the Jews, Christians, and Muslims who believe in the physical resurrection of the body that will be made new in an afterlife, the [already existing] body is sacred since it will be the basis of a new refashioned body in an afterlife,” Haque said. “You cannot treat the body like any old material artifact, or old chair or ragged cloth, just because materialistic, secular ideologies want so,” he continued.
For Cosma and her peers, however, the very definition of what is alive or not is a bit semantic. “As soon as we die, the electrophysiological activity in the eye stops,” she said. “The goal of the project is to restore this activity as soon as possible before the highly complex tissue of the eye starts degrading.” Cosma’s group doesn’t yet know when they will be able to keep the eyes alive and well in the ECaBox, but the consensus is that the sooner the better. Hopefully, the taboos and fears around the eye donations will dissipate around the same time.
Drugs That Trick Older People’s Bodies to Behave Younger Might Boost the Effectiveness of a COVID-19 Vaccine
In our April 23rd editorial for this magazine, we argued that addressing the COVID-19 pandemic requires that we both fight the SARS-CoV-2 virus and fortify the human hosts who are most vulnerable to it.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults.
Because people over 70 account for more than 80 percent of reported COVID-19 deaths globally, this means we must do everything possible to protect our elders.
A range of recent studies have suggested that systemic knobs might metaphorically be turned to slow the cellular aging process, making us better able to fight off the many diseases correlated with aging. These types of systemic changes might be used to stem the specific decline in immunity caused by aging and to increases the biological capacity of elderly people to effectively fight viral infection.
But while helping make older people more resilient in the face of a viral infection is critical, that's not the only way geroscience can help in our fight against this deadly pandemic.
As we move toward hopefully developing one or more COVID-19 vaccines, researchers must more fully appreciate the ways in which traditional vaccines can be less effective in older people than in younger ones.
Repeated studies have shown that the flu vaccine, for example, has lower efficacy in older people than in younger ones. Older people tend to develop fewer antibodies after being vaccinated because a subset of their white blood cells, called T cells, have become less responsive over time. Some inflammatory peptides that increase with aging are also preventing the action of those T cells.
This is why there's a distinct possibility that a future COVD-19 vaccine, particularly one utilizing the traditional attenuated virus approach, could be less effective in older people than in younger ones.
Given the extreme urgency of developing vaccines that work well for everyone, we need to make sure that researchers are exploring all of the ways our elders can be best protected. While generating a vaccine that works equally well for people of all ages would be ideal, we can't count on that.
One way to bridge this gap might be to trick the bodies of older people into behaving as if they are younger just at the moment what a vaccine is delivered by giving them pre-immunization boosters.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults. Use of the drug for a short time period before flu shot immunization increased the antibody production for the flu and resulted in a 52 percent decrease in the occurrence of severe diseases needing medical help or hospitalization. This short-term pre-immunization intervention can also decrease the severity of serious respiratory tract infections, the deadliest manifestations of COVID-19, by similar magnitude. These patients also had almost half the incidence of the non-COVID-19 coronaviruses associated with the common cold.
The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
An inexpensive generic drug called metformin similarly targets the decline in immunity and inflammation (and extends health span and lifespan) in animals and has been used for decades to protect against the flu. A recent paper from a hospital in Wuhan, China showed that mortality of elderly COVID-19 diabetic patients on metformin was 25 percent less than that of patients with diabetes but not on metformin.
Another study from the U.S. showed that COVID-19 patients on metformin had a 20 percent decrease in mortality and lower inflammation. The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
We don't yet know whether rapalogues or metformin could be used as COVID-19 immunization boosters, not least because we don't have those vaccines. But we can and should make sure that all vaccine trials including older subjects also consider offering a subset of those subjects appropriate doses of rapalogues or metformin to explore whether doing so can boost the efficacy of a given vaccine.
If we weren't in the middle of the worst pandemic in a century, we would have more time to test our vaccines slowly and sequentially. In the context of the current crisis, however, testing whether immunization boosters might increase the efficacy of potential COVID-19 vaccines for older adults is at the very least a hypothesis worth exploring.
How We Can Return to Normal Life in the COVID-19 Era
I was asked recently when life might return to normal. The question is simple but the answer is complex, with many knowns, lots of known unknowns, and some unknown unknowns. But I'll give it my best shot.
To get the fatality rate down to flu-like levels would require that we cut Covid-19 fatalities down by a factor of 5.
Since I'm human (and thus want my life back), I might be biased toward optimism.
Here's one way to think about it: Is there another infection that causes sickness and death at levels that we tolerate? The answer, of course, is 'yes': influenza.
According to the Centers for Disease Control, from 2010 to 2019, an average of 30 million Americans had the flu each year, leading to an annual average of 37,000 deaths. This works out to an infection-fatality rate, or IFR, of 0.12 percent. We've tolerated that level of illness death from influenza for a century.
Before going on, let's get one thing out of the way: Back in March, Covid-19 wasn't, as some maintained, "like the flu," and it still isn't. Since then, the U.S. has had 3.9 million confirmed Covid-19 cases and 140,000 deaths, for an IFR of 3.6 percent. Taking all the cases — including asymptomatic patients and those with minimal symptoms who were never tested for Covid-19 — into account, the real IFR is probably 0.6 percent, or roughly 5 times that of the flu.
Nonetheless, even a partly effective vaccine, combined with moderately effective medications, could bring Covid-19 numbers down to a tolerable, flu-like, threshold. It's a goal that seems within our reach.
Chronic mask-wearing and physical distancing are not my idea of normal, nor, I would venture to guess, would most other Americans consider these desirable states in which to live. We need both now to achieve some semblance of normalcy, but they're decidedly not normal life. My notion of normal: daily life with no or minimal mask wearing, open restaurants and bars, ballparks with fans, and theaters with audiences.
My projection for when we might get there: perhaps a year from now.
To get the fatality rate down to flu-like levels would require that we cut Covid-19 fatalities down by a factor of 5, via some combination of fewer symptomatic cases and a lower chance that a symptomatic patient will go on to die. How might that happen?
First, we have to make some impact on young people – getting them to follow the public health directives at higher rates than they are currently. The main reason we need to push younger people to stay safe is that they can spread Covid-19 to vulnerable people (those who are older, with underlying health problems). But, once the most vulnerable are protected (through the deployment of some combination of effective medications and a vaccine), the fact that some young people aren't acting safely – or maybe won't take a vaccine themselves – wouldn't cause so much concern. The key is whether the people at highest risk for bad outcomes are protected.
Then there's the vaccine. The first principle: We don't need a 100 percent-effective vaccine injected into 320 million deltoid muscles (in the U.S. alone). Thank God, since it's fanciful to believe that we can have a vaccine that's 100 percent effective, universally available by next summer, and that each and every American agrees to be vaccinated.
How are we doing in our vaccine journey? We've been having some banner days lately, with recent optimistic reports from several of the vaccine companies. In one report, the leading candidate vaccine, the one effort being led by Oxford University, led to both antibodies and a cellular immune response, a very helpful belt-and-suspenders approach that increases the probability of long-lasting immunity. This good news comes on the heels of the positive news regarding the American vaccine being made by Moderna earlier in July.
While every article about vaccines sounds the obligatory cautionary notes, to date we've checked every box on the path to a safe and effective vaccine. We might not get there, but most experts are now predicting an FDA-approvable vaccine (more than 50 percent effective with no show-stopping side effects) by early 2021.
It is true that we don't know how long immunity will last, but that can be a problem to solve later. In this area, time is our friend. If we can get to an effective vaccine that lasts for a year or two, over time we should be able to discover strategies (more vaccine boosters, new and better medications) to address the possibility of waning immunity.
All things considered, I'm going to put my nickel down on the following optimistic scenario: we'll have one, and likely several, vaccines that have been proven to be more than 50 percent effective and safe by January, 2021.
If only that were the finish line.
Once we vaccinate a large fraction of high-risk patients, having a moderate number of unvaccinated people running around won't pose as much threat.
The investments in manufacturing and distribution should pay off, but it's still inconceivable that we'll be able to get vaccines to 300 million people in three to six months. For the 2009 Swine Flu, we managed to vaccinate about 1 in 4 Americans over six months.
So we'll need to prioritize. First in line will likely be the 55 million Americans over 65, and the six to eight million patient-facing healthcare workers. (How to sort priorities among people under 65 with "chronic diseases" will be a toughie.) Vaccinating 80-100 million vulnerable people, plus clinicians, might be achievable by mid-21.
If we can protect vulnerable people with an effective vaccine (with the less vulnerable waiting their turn over a subsequent 6-12 month period), that may be enough to do the trick. (Of course, vulnerable people may also be least likely to develop immunity in response to a vaccine. That could be an Achilles' heel – time will tell.)
Why might that be enough? Once we vaccinate a large fraction of high-risk patients, having a moderate number of unvaccinated people running around won't pose as much threat. Since they're at lower risk, they have a lower chance of getting sick and dying than those who received the vaccine first.
We're likely to have better meds by then, too. Since March, we've discovered two moderately effective medications for Covid-19 — remdesivir and dexamethasone. It seems likely that we'll find others by next summer, perhaps even a treatment that prevents patients from getting ill in the first place. There are many such therapies, ranging from zinc to convalescent plasma, currently being studied.
Moreover, we know that hospitals that are not overrun with Covid-19 have lower mortality rates. If we've gotten a fairly effective vaccine into most high-risk people, the hospitals are unlikely to be overwhelmed – another factor that may help lower the mortality rate to flu-like levels.
All of these factors – vaccination of most vulnerable people, one or two additional effective medications, hospitals and ICU's that aren't overwhelmed – could easily combine to bring the toll of Covid-19 down to something that resembles that of the flu. Then, we should be able to return to normal life.
Whatever the reason, if enough people refuse the vaccine, all bets are off.
What do I worry about? There's the growing anti-vaxxer movement, for one. On top of that, it seems that many Americans worry that a vaccine discovered in record speed won't be safe, or that the FDA approval process will have been corrupted by political influences. Whatever the reason, if enough people refuse the vaccine, all bets are off.
Assuming only high-risk people do get vaccinated, there will still be cases of Covid-19, maybe even mini-outbreaks, well into 2021 and likely 2022. Obviously, that's not ideal, and we should hope for a vaccine that results in the complete eradication of Covid-19. But the point is that, even with flu-like levels of illness and death, we should still be able to achieve "normal."
Hope is not a strategy, as the saying goes. But it is hope, which is more than we've had for a while.