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.
Blood Money: Paying for Convalescent Plasma to Treat COVID-19
Convalescent plasma – first used to treat diphtheria in 1890 – has been dusted off the shelf to treat COVID-19. Does it work? Should we rely strictly on the altruism of donors or should people be paid for it?
The biologic theory is that a person who has recovered from a disease has chemicals in their blood, most likely antibodies, that contributed to their recovery, and transferring those to a person who is sick might aid their recovery. Whole blood won't work because there are too few antibodies in a single unit of blood and the body can hold only so much of it.
Plasma comprises about 55 percent of whole blood and is what's left once you take out the red blood cells that carry oxygen and the white blood cells of the immune system. Most of it is water but the rest is a complex mix of fats, salts, signaling molecules and proteins produced by the immune system, including antibodies.
A process called apheresis circulates the donors' blood through a machine that separates out the desired parts of blood and returns the rest to the donor. It takes several times the length of a regular whole blood donation to cycle through enough blood for the process. The end product is a yellowish concentration called convalescent plasma.
Recent History
It was used extensively during the great influenza epidemic off 1918 but fell out of favor with the development of antibiotics. Still, whenever a new disease emerges – SARS, MERS, Ebola, even antibiotic-resistant bacteria – doctors turn to convalescent plasma, often as a stopgap until more effective antibiotic and antiviral drugs are developed. The process is certainly safe when standard procedures for handling blood products are followed, and historically it does seem to be beneficial in at least some patients if administered early enough in the disease.
With few good treatment options for COVID-19, doctors have given convalescent plasma to more than a hundred thousand Americans and tens of thousand of people elsewhere, to mixed results. Placebo-controlled trials could give a clearer picture of plasma's value but it is difficult to enroll patients facing possible death when the flip of a coin will determine who will receive a saline solution or plasma.
And the plasma itself isn't some uniform pill stamped out in a factory, it's a natural product that is shaped by the immune history of the donor's body and its encounter not just with SARS-CoV-2 but a lifetime of exposure to different pathogens.
Researchers believe antibodies in plasma are a key factor in directly fighting the virus. But the variety and quantity of antibodies vary from donor to donor, and even over time from the same donor because once the immune system has cleared the virus from the body, it stops putting out antibodies to fight the virus. Often the quality and quantity of antibodies being given to a patient are not measured, making it somewhat hit or miss, which is why several companies have recently developed monoclonal antibodies, a single type of antibody found in blood that is effective against SARS-CoV-2 and that is multiplied in the lab for use as therapy.
Plasma may also contain other unknown factors that contribute to fighting disease, say perhaps signaling molecules that affect gene expression, which might affect the movement of immune cells, their production of antiviral molecules, or the regulation of inflammation. The complexity and lack of standardization makes it difficult to evaluate what might be working or not with a convalescent plasma treatment. Thus researchers are left with few clues about how to make it more effective.
Industrializing Plasma
Many Americans living along the border with Mexico regularly head south to purchase prescription drugs at a significant discount. Less known is the medical traffic the other way, Mexicans who regularly head north to be paid for plasma donations, which are prohibited in their country; the U.S. allows payment for plasma donations but not whole blood. A typical payment is about $35 for a donation but the sudden demand for convalescent plasma from people who have recovered from COVID-19 commands a premium price, sometimes as high as $200. These donors are part of a fast-growing plasma industry that surpassed $25 billion in 2018. The U.S. supplies about three-quarters of the world's needs for plasma.
Payment for whole blood donation in the U.S. is prohibited, and while payment for plasma is allowed, there is a stigma attached to payment and much plasma is donated for free.
The pharmaceutical industry has shied away from natural products they cannot patent but they have identified simpler components from plasma, such as clotting factors and immunoglobulins, that have been turned into useful drugs from this raw material of plasma. While some companies have retooled to provide convalescent plasma to treat COVID-19, often paying those donors who have recovered a premium of several times the normal rate, most convalescent plasma has come as donations through traditional blood centers.
In April the Mayo Clinic, in cooperation with the FDA, created an expanded access program for convalescent plasma to treat COVID-19. It was meant to reduce the paperwork associated with gaining access to a treatment not yet approved by the FDA for that disease. Initially it was supposed to be for 5000 units but it quickly grew to more than twenty times that size. Michael Joyner, the head of the program, discussed that experience in an extended interview in September.
The Centers for Medicare and Medicaid Services (CMS) also created associated reimbursement codes, which became permanent in August.
Mayo published an analysis of the first 35,000 patients as a preprint in August. It concluded, "The relationships between mortality and both time to plasma transfusion, and antibody levels provide a signature that is consistent with efficacy for the use of convalescent plasma in the treatment of hospitalized COVID-19 patients."
It seemed to work best when given early in infection and in larger doses; a similar pattern has been seen in studies of monoclonal antibodies. A revised version will soon be published in a major medical journal. Some criticized the findings as not being from a randomized clinical trial.
Convalescent plasma is not the only intervention that seems to work better when used earlier in the course of disease. Recently the pharmaceutical company Eli Lilly stopped a clinical trial of a monoclonal antibody in hospitalized COVID-19 patients when it became apparent it wasn't helping. It is continuing trials for patients who are less sick and begin treatment earlier, as well as in persons who have been exposed to the virus but not yet diagnosed as infected, to see if it might prevent infection. In November the FDA eased access to this drug outside of clinical trials, though it is not yet approved for sale.
Show Me the Money
The antibodies that seem to give plasma its curative powers are fragile proteins that the body produces to fight the virus. Production shuts down once the virus is cleared and the remaining antibodies survive only for a few weeks before the levels fade. [Vaccines are used to train immune cells to produce antibodies and other defenses to respond to exposure to future pathogens.] So they can be usefully harvested from a recovered patient for only a few short weeks or months before they decline precipitously. The question becomes, how does one mobilize this resource in that short window of opportunity?
The program run by the Mayo Clinic explains the process and criteria for donating convalescent plasma for COVID-19, as well as links to local blood centers equipped to handle those free donations. Commercial plasma centers also are advertising and paying for donations.
A majority of countries prohibit paying donors for blood or blood products, including India. But an investigation by India Today touted a black market of people willing to donate convalescent plasma for the equivalent of several hundred dollars. Officials vowed to prosecute, saying donations should be selfless.
But that enforcement threat seemed to be undercut when the health minister of the state of Assam declared "plasma donors will get preference in several government schemes including the government job interview." It appeared to be a form of compensation that far surpassed simple cash.
The small city of Rexburg, Idaho, with a population a bit over 50,000, overwhelmingly Mormon and home to a campus of Brigham Young University, at one point had one of the highest per capita rates of COVID-19 in the current wave of infection. Rumors circulated that some students were intentionally trying to become infected so they could later sell their plasma for top dollar, potentially as much as $200 a visit.
Troubled university officials investigated the allegations but could come up with nothing definitive; how does one prove intentionality with such an omnipresent yet elusive virus? They chalked it up to idle chatter, perhaps an urban legend, which might be associated with alcohol use on some other campus.
Doctors, hospitals, and drug companies are all rightly praised for their altruism in the fight against COVID-19, but they also get paid. Payment for whole blood donation in the U.S. is prohibited, and while payment for plasma is allowed, there is a stigma attached to payment and much plasma is donated for free. "Why do we expect the donors [of convalescent plasma] to be the only uncompensated people in the process? It really makes no sense," argues Mark Yarborough, an ethicist at the UC Davis School of Medicine in Sacramento.
"When I was in grad school, two of my closest friends, at least once a week they went and gave plasma. That was their weekend spending money," Yarborough recalls. He says upper and middle-income people may have the luxury of donating blood products but prohibiting people from selling their plasma is a bit paternalistic and doesn't do anything to improve the economic status of poor people.
"Asking people to dedicate two hours a week for an entire year in exchange for cookies and milk is demonstrably asking too much," says Peter Jaworski, an ethicist who teaches at Georgetown University.
He notes that companies that pay plasma donors have much lower total costs than do operations that rely solely on uncompensated donations. The companies have to spend less to recruit and retain donors because they increase payments to encourage regular repeat donations. They are able to more rationally schedule visits to maximize use of expensive apheresis equipment and medical personnel used for the collection.
It seems that COVID-19 has been with us forever, but in reality it is less than a year. We have learned much over that short time, can now better manage the disease, and have lower mortality rates to prove it. Just how much convalescent plasma may have contributed to that remains an open question. Access to vaccines is months away for many people, and even then some people will continue to get sick. Given the lack of proven treatments, it makes sense to keep plasma as part of the mix, and not close the door to any legitimate means to obtain it.
Vaccines Without Vaccinations Won’t End the Pandemic
COVID-19 vaccine development has advanced at a record-setting pace, thanks to our nation's longstanding support for basic vaccine science coupled with massive public and private sector investments.
Yet, policymakers aren't according anywhere near the same level of priority to investments in the social, behavioral, and data science needed to better understand who and what influences vaccination decision-making. "If we want to be sure vaccines become vaccinations, this is exactly the kind of work that's urgently needed," says Dr. Bruce Gellin, President of Global Immunization at the Sabin Vaccine Institute.
Simply put: it's possible vaccines will remain in refrigerators and not be delivered to the arms of rolled-up sleeves if we don't quickly ramp up vaccine confidence research and broadly disseminate the findings.
According to the most recent Gallup poll, the share of U.S. adults who say they would get a COVID-19 vaccine rose to 58 percent this month from 50 percent in September, with non-white Americans and those ages 45-65 even less willing to be vaccinated. While there is still much we don't understand about COVID-19, we do know that without high levels of immunity in the population, a return to some semblance of normalcy is wishful thinking.
Research from prior vaccination campaigns such as H1N1, HPV, and the annual flu points us in the right direction. Key components of successful vaccination efforts require 1) Identifying the concerns of particular segments of the population; 2) Tailoring messages and incentives to address those concerns, and 3) Reaching out through trusted sources – health care providers, public health departments, and others in the community.
Research during the H1N1 flu found preparing people for some uncertainty actually improved trust, according to Dr. Sandra Crouse Quinn, professor and chair, Family Science, University of Maryland. Dr. Crouse Quinn's research during that period also underscored the need to address the specific vaccine concerns of racial and ethnic groups.
The stunning scientific achievement of COVID-19 vaccines anticipated to be ready in record time needs to be backed up by an equally ambitious and evidence-based effort to build the public's confidence in the vaccines.
Data science has provided crucial insight about the social media universe. Dr. Neil Johnson, a scientist at George Washington University, found that despite having fewer followers, anti-vaccination pages are more numerous and growing faster than pro-vaccination pages. They are more often linked to in discussions on other Facebook pages – such as school parent associations – where people are undecided about vaccination.
We've learned about building vaccine confidence from earlier campaigns. Now, however, we are faced with a unique and challenging set of obstacles to unpack quickly: How do we communicate the importance of eventual COVID-19 vaccines to Americans in light of the muddled-to-poor messaging from political leaders, the weaponizing of relatively simple public health recommendations, the enormous disproportionate toll on people of color, and the torrent of online misinformation? We urgently need data reflective of today's circumstances along with the policy to ensure it is quickly and effectively disseminated to the public health and clinical workforce.
Last year prompted in part by the measles outbreaks, Reps. Michael C. Burgess (R-TX) and Kim Shrier (D-WA), both physicians, introduced the bipartisan Vaccines Act to develop a national surveillance system to monitor vaccination rates and conduct a national campaign to increase awareness of the importance of vaccines. Unfortunately, that legislation wasn't passed. In response to COVID-19, Senate HELP Committee Ranking member Patty Murray (D-WA) has sought funds to strengthen vaccine confidence and combat misinformation with federally supported communication, research, and outreach efforts. Leading experts outside of Congress have called for this type of research, including the Sabin-Aspen Vaccine Science Policy Institute. Most recently, the National Academy of Sciences, in its report regarding the equitable distribution of the COVID-19 vaccine, included as one of its recommendations the need for "a rapid-response program to advance the science behind vaccine confidence."
Addressing trust in vaccination has never been as challenging nor as consequential. The stunning scientific achievement of COVID-19 vaccines anticipated to be ready in record time needs to be backed up by an equally ambitious and evidence-based effort to build the public's confidence in the vaccines. In its remaining days, the Trump Administration should invest in building vaccine confidence with current resources, targeting efforts to ensure COVID vaccines reduce rather than exacerbate racial and ethnic health disparities. Congress must also act to provide the additional research and outreach resources needed as well as pass the Vaccines Act so we are better prepared in the future.
If we don't succeed, COVID-19 will continue wreaking havoc on our health, our society, and our economy. We will also permanently jeopardize public trust in vaccines – one of the most successful medical interventions in human history.