Often called the window to the soul, the eyes are more sacred than other body parts, at least for some.
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.
Biochemist Longxing Cao is working with colleagues at the University of Washington on promising research to disable infectious coronavirus in a person's nose.
This may sounds like science fiction, but several research groups are already working on such trickster coronavirus drugs, with some candidates close to clinical trials and possibly even becoming available late this year. The teams began working on them when the pandemic arrived, and continued in lockdown.
When the pandemic first hit and the state of California issued a lockdown order on March 16, postdoctoral researchers Anum and Jeff Glasgow found themselves stuck at home with nothing to do. The two scientists who study bioengineering felt that they were well equipped to research molecular ways of disabling coronavirus's cell-penetrating spike protein, but they could no longer come to their labs at the University of California San Francisco.
"We were upset that no one put us in the game," says Anum Glasgow. "We have a lot of experience between us doing these types of projects so we wanted to contribute." But they still had computers so they began modeling the potential virus-disabling proteins in silico using Robetta, special software for designing and modeling protein structures, developed and maintained by University of Washington biochemist David Baker and his lab.
"We saw some imperfections in that lock and key and we created something better. We made a 10 times tighter adhesive."
The SARS-CoV-2 virus that causes Covid-19 uses its surface spike protein to bind on to a specific receptor on human cells called ACE2. Unfortunately for humans, the spike protein's molecular shape fits the ACE2 receptor like a well-cut key, making it very successful at breaking into our cells. But if one could design a molecular ACE2-mimic to "trick" the virus into latching onto it instead, the virus would no longer be able to enter cells. Scientists call such mimics receptor traps or inhibitors, or blockers. "It would block the adhesive part of the virus that binds to human cells," explains Jim Wells, professor of pharmaceutical chemistry at UCSF, whose lab took part in designing the ACE2-receptor mimic, working with the Glasgows and other colleagues.
The idea of disabling infectious or inflammatory agents by tricking them into binding to the targets' molecular look-alikes is something scientists have tried with other diseases. The anti-inflammatory drugs commonly used to treat autoimmune conditions, including rheumatoid arthritis, Crohn's disease and ulcerative colitis, rely on conceptually similar molecular mechanisms. Called TNF blockers, these drugs block the activity of the inflammatory cytokines, molecules that promote inflammation. "One of the biggest selling drugs in the world is a receptor trap," says Jeff Glasgow. "It acts as a receptor decoy. There's a TNF receptor that traps the cytokine."
In the recent past, scientists also pondered a similar look-alike approach to treating urinary tract infections, which are often caused by a pathogenic strain of Escherichia coli. An E. coli bacterium resembles a squid with protruding filaments equipped with proteins that can change their shape to form hooks, used to hang onto specific sugar molecules called ligands, which are present on the surface of the epithelial cells lining the urinary tract.
A recent study found that a sugar-like compound that's structurally similar to that ligand can play a similar trick on the E. Coli. When administered in in sufficient amounts, the compound hooks the bacteria on, which is then excreted out of the body with urine. The "trickster" method had been also tried against the HIV virus, but it wasn't very effective because HIV has a high mutation rate and multiple ways of entering human cells.
But the coronavirus spike protein's shape is more stable. And while it has a strong affinity for the ACE2 receptors, its natural binding to these receptors isn't perfect, which allowed the UCSF researchers to design a mimic with a better grip. "We saw some imperfections in that lock and key and we created something better," says Wells. "We made a 10 times tighter adhesive." The team demonstrated that their traps neutralized SARS-CoV-2 in lab experiments and published their study in the Proceedings of the National Academy of Sciences.
Baker, who is the director of the Institute for Protein Design at the University of Washington, was also devising ACE2 look-alikes with his team. Only unlike the UCSF team, they didn't perfect the virus-receptor lock and key combo, but instead designed their mimics from scratch. Using Robetta, they digitally modeled over two million proteins, zeroed-in on over 100,000 potential candidates and identified a handful with a strong promise of blocking SARS-CoV-2, testing them against the virus in human cells. Their design of the miniprotein inhibitors was published in the journal Science.
Biochemist David Baker, pictured in his lab at the University of Washington.
UW
The concept of the ACE2 receptor mimics is somewhat similar to the antibody plasma, but better, the teams explain. Antibodies don't always coat all of the virus's spike proteins and sometimes don't bind perfectly. By contrast, the ACE2 mimics directly compete with the virus's entry mechanism. ACE2 mimics are also easier and cheaper to make, researchers say.
Antibodies, which are long protein chains, must be grown inside mammalian cells, which is a slow and costly process. As drugs, antibody cocktails must be kept refrigerated. On the contrary, proteins that mimic ACE2 receptors are smaller and can be produced by bacteria easily and inexpensively. Designed to specs, these proteins don't need refrigeration and are easy to store. "We designed them to be very stable," says Baker. "Our computation design tries to come up with the stable proteins that have the desired functions."
That stability may allow the team to create an inhaler drug rather than an intravenous one, which would be another advantage over the antibody plasma, given via an IV. The team envisions people spraying the miniprotein solution into their nose, creating a protecting coating that would disable the inhaled virus. "The infection starts from your respiratory system, from your nose," explains Longxing Cao, the study's co-author—so a nasal spray would be a natural way to administer it. "So that you can have it like a layer, similar to a mask."
As the virus evolves, new variants are arising. But the teams think that their ACE2 protein mimics should work on the new variants too for several reasons. "Since the new SARS-CoV-2 variants still use ACE2 for their cell entry, they will likely still be susceptible to ACE2-based traps," Glasgow says.
Cao explains that their approach should work too because most of the mutations happen outside the ACE2 binding region. Plus, they are building multiple binders that can bind to an array of the coronavirus variants. "Our binder can still bind with most of the variants and we are trying to make one protein that could inhibit all the future escape variants," he says.
Baker and Cao hope that their miniproteins may be available to patients later this year. But besides getting the medicine out to patients, this approach will allow researchers to test the computer-modeled mimics end-to-end with an unprecedented speed. That would give humans a leg up in future pandemics or zoonotic disease outbreaks, which remain an increasingly pressing threat due to human activity and climate change.
"That's what we are focused on right now—understanding what we have learned from this pandemic to improve our design methods," says Baker. "So that we should be able to obtain binders like these very quickly when a new pandemic threat is identified."