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.
Taboo topics occupy a difficult place in the history of medicine. Society has long been reticent about confronting stigmatized conditions, forcing many patients to suffer in silence and isolation, often with poorer care.
"Classically, doctors don't purposely kill people. That is really the core of the resistance."
AIDS activists recognized this in the 1980s when they coined the phrase Silence = Death to generate public debate and action over a growing epidemic that until then had existed largely in the shadows. The slogan and the activists behind it were remarkably successful at changing the public discourse.
It is not a lone example. Post-World War II medicine is better because it came to deal more forthrightly with a broad range of medical conditions from conception/abortion, to cancer, to sexually transmitted infections. The most recent issue to face such scrutiny is physician-assisted dying (PAD).
"Classically, doctors don't purposely kill people…that is really the core of the resistance" to PAD from the provider perspective, says Neil Wenger, an internist and ethicist at the University of California Los Angeles who focuses on end-of-life issues.
But from the patient perspective, the option of PAD "provides important psychological benefits ... because it gives the terminally ill autonomy, control, and choice," argued the American Public Health Association in support of Oregon's death with dignity legislation.
Jack Kervorkian, "Dr. Death," was one of the first to broach the subject when few in polite society were willing to do so. The modern era truly began twenty years ago when the citizens of Oregon embraced the option of death with dignity in a public referendum, over the objections of their political leaders.
Expansion of the legal option in North America was incremental until 2016 when the Supreme Court in Canada and legislators in California decided that control over one's body extended to death, at least under certain explicit conditions.
An estimated 18 percent of Americans now live in jurisdictions that provide the legal option of assisted death, but exercising that right can be difficult. Only a fraction of one percent of deaths are by PAD, even in Oregon.
Stakeholder Roles
Few organizations of healthcare professionals in the U.S. support PAD; some actively oppose it, others have switched to a position of neutrality while they study the issue.
One doctor wanted to organize a discussion of physician-assisted dying at his hospital, but administrators forbade it.
But once a jurisdiction makes the political/legal decision that patients have a right to physician-assisted death, what are the roles and responsibilities of medical stakeholders? Can they simply opt out in a vow of silence? Or do organizations bear some sort of obligation to ensure access to that right, no matter their own position, particularly when they are both regulated by and receive operating funds from public sources?
The law in California and other U.S. jurisdictions reflects ambivalence about PAD by treating it differently from other medical practices, says David Magnus, an ethicist at Stanford University School of Medicine. It is allowed but "it's intentionally a very, very burdensome process."
Medical decisions, including withdrawing life support or a do not resuscitate [DNR] order, are between a physician and the patient or guardian. But PAD requires outside consultation and documentation that is quite rigorous, even burdensome, Magnus explains. He recalls one phone consult with a physician who had to re-have a conversation with a patient at home in order to meet the regulatory requirements for a request for assistance in dying. "So it is not surprising that it is utilized so infrequently."
The federal government has erected its own series of barriers. Roused by the experience in Oregon, opponents tried to ban PAD at the national level. They failed but did the next best thing; they prohibited use of federal funds to pay for or even discuss PAD. That includes Medicare, Medicaid, and the large health delivery systems run by the Pentagon and Veterans Affairs. The restrictions parallel those on federal funding for access to abortion and medical marijuana.
Even physicians who support and perform PAD are reluctant to talk about it. They are unwilling to initiate the discussion with patients, says Mara Buchbinder, a bioethicist at the University of North Carolina at Chapel Hill who has interviewed physicians, patients, and families about their experience with assisted dying in Vermont.
"There is a stigma for health care workers to talk about this; they feel that they are not supported," says Buchbinder. She relates how one doctor wanted to organize a discussion of PAD at his hospital, but administrators forbade it. And when the drug used to carry out the procedure became prohibitively expensive, other physicians were not aware of alternatives.
"This just points to large inadequacies in medical preparation around end-of-life conversations," says Buchbinder, a view endorsed by many experts interviewed for this article.
These inadequacies are reinforced when groups like the Coalition to Transform Advanced Care (C-TAC), a 140-member organizational alliance that champions improved end-of-life care, dodges the issue. A spokesman said simply, PAD "is not within the scope of our work."
The American Medical Association has had a policy in place opposing PAD since 1993. Two years ago, its House of Delegates voted to reevaluate their position in light of evolving circumstances. Earlier this year the Council of Ethical and Judicial Affairs recommended continued opposition, but in June, the House of Delegates rejected that recommendation (56 to 44 percent) and directed the Council to keep studying the issue.
Only those with the economic and social capital and network of advocates will succeed in exercising this option.
Kaiser Permanente has provided assisted dying to its members in multiple states beginning with Oregon and has done "a wonderful job" according to supporters of PAD. But it has declined to discuss those activities publicly despite a strenuous effort to get them to do so.
Rather than drawing upon formal structures for leadership and guidance, doctors who are interested in learning more about PAD are turning to the ad hoc wisdom of providers from Oregon and Washington who have prior experience. Magnus compares it with what usually happens when a new intervention or technology comes down the pike: "People who have done it, have mastered it, pass that knowledge on to other people so they know how to do it."
Buchbinder says it becomes an issue of social justice when providers are not adequately trained, and when patients are not ordinarily offered the option of a medical service in jurisdictions where it is their right.
Legalization of PAD "does not guarantee practical access, and well-intentioned policies designed to protect vulnerable groups may at times reinforce or exacerbate health care inequalities," she says. Only those with the economic and social capital and network of advocates will succeed in exercising this option.
O Canada
Canada provides a case study of how one might address PAD. They largely settled on the term medical aid in dying – often shortened to MAID – as the more neutral phrase for their law and civil discourse.
The Canadian Medical Association (CMA) decided early on to thread the needle; to not take a position on the core issue of morality but to proactively foster public discussion of those issues as the legal challenge to the ban on assisted dying headed to that country's Supreme Court.
"We just felt that it was too important for the profession to sit on the sidelines and not be part of the discussion," says Jeff Blackmer, CMA's vice president for medical professionalism.
It began by shifting the focus of discussion from a yes/no on the morality of MAID to the questions of, "If the court rules that the current laws are unconstitutional, and they allow assisted dying, how should the profession react and how should we respond? And how does the public think that the profession should respond?"
"I had to wear a flack jacket, a bulletproof vest, and there were plainclothes police officers with guns in the audience because it is really really very controversial."
The CMA teamed up with Maclean's magazine to host a series of five town hall meetings throughout the country. Assisted dying was discussed in a context of palliative care, advanced care planning, and other end-of-life issues.
There was fear that MAID might raise passions and even violence that has been seen in recent controversies over abortion. "I had to wear a flack jacket, a bulletproof vest, and there were plainclothes police officers with guns in the audience because it is really really very controversial," Blackmer recalls. Thankfully there were no major incidents.
The CMA also passed a resolution at its annual meeting supporting the right of its members to opt out of participating in MAID, within the confines of whatever law might emerge.
Once legislation and regulations began taking shape, the CMA created training materials on the ethical, legal, and practical consideration that doctors and patients might face. It ordinarily does not get involved with clinical education and training.
Stefanie Green is president of Canadian Association of MAID Assessors & Providers, a professional medical association that supports those working in the area of assisted dying, educates the public and health care community, and provides leadership on setting medical standards. Green acknowledges the internal pressures the CMA faced, and says, "I do understand their stance is as positive as it gets for medical associations."
Back in the USofA
Prohibitionism – the just say no approach – does not work when a substantial number of people want something, as demonstrated with alcohol, marijuana, opioids for pain relief, and reproductive control. Reason suggests a harm reduction strategy is the more viable approach.
"Right now we're stuck in the worst of all worlds because we've made [PAD] sort of part of medicine, but sort of illicit and sort of shameful. And we sort of allow it, but we sort of don't, we make it hard," says Stanford's Magnus. "And that's a no man's land where we are stuck."
Imagine this scenario: A couple is involved in a heated custody dispute over their only child. As part of the effort to make the case of being a better guardian, one parent goes on a "genetic fishing expedition": this parent obtains a DNA sample from the other parent with the hope that such data will identify some genetic predisposition to a psychiatric condition (e.g., schizophrenia) and tilt the judge's custody decision in his or her favor.
As knowledge of psychiatric genetics is growing, it is likely to be introduced in civil cases, such as child custody disputes and education-related cases, raising a tangle of ethical and legal questions.
This is an example of how "behavioral genetic evidence" -- an umbrella term for information gathered from family history and genetic testing about pathological behaviors, including psychiatric conditions—may in the future be brought by litigants in court proceedings. Such evidence has been discussed primarily when criminal defendants sought to introduce it to make the claim that they are not responsible for their behavior or to justify their request for reduced sentencing and more lenient punishment.
However, civil cases are an emerging frontier for behavioral genetic evidence. It has already been introduced in tort litigation, such as personal injury claims, and as knowledge of psychiatric genetics is growing, it is further likely to be introduced in other civil cases, such as child custody disputes and education-related cases. But the introduction of such evidence raises a tangle of ethical and legal questions that civil courts will need to address. For example: how should such data be obtained? Who should get to present it and under what circumstances? And does the use of such evidence fit with the purposes of administering justice?
How Did We Get Here?
That behavioral genetic evidence is entering courts is unsurprising. Scientific evidence is a common feature of judicial proceedings, and genetic information may reveal relevant findings. For example, genetic evidence may elucidate whether a child's medical condition is due to genetic causes or medical malpractice, and it has been routinely used to identify alleged offenders or putative fathers. But behavioral genetic evidence is different from such other genetic data – it is shades of gray, instead of black and white.
Although efforts to understand the nature and origins of human behavior are ongoing, existing and likely future knowledge about behavioral genetics is limited. Behavioral disorders are highly complex and diverse. They commonly involve not one but multiple genes, each with a relatively small effect. They are impacted by many, yet unknown, interactions between genes, familial, and environmental factors such as poverty and childhood adversity.
And a specific gene variant may be associated with more than one behavioral disorder and be manifested with significantly different symptoms. Thus, biomarkers about "predispositions" for behavioral disorders cannot generally provide a diagnosis or an accurate estimate of whether, when, and at what severity a behavioral disorder will occur. And, unlike genetic testing that can confirm litigants' identity with 99.99% probability, behavioral genetic evidence is far more speculative.
Genetic theft raises questions about whose behavioral data are being obtained, by whom, and with what authority.
Whether judges, jurors, and other experts understand the nuances of behavioral genetics is unclear. Many people over-estimate the deterministic nature of genetics, and under-estimate the role of environments, especially with regards to mental health status. The U.S. individualistic culture of self-reliance and independence may further tilt the judicial scales because litigants in civil courts may be unjustly blamed for their "bad genes" while structural and societal determinants that lead to poor behavioral outcomes are ignored.
These concerns were recently captured in the Netflix series "13 Reasons Why," depicting a negligence lawsuit against a school brought by parents of a high-school student there (Hannah) who committed suicide. The legal tides shifted from the school's negligence in tolerating a culture of bullying to parental responsibility once cross-examination of Hannah's mother revealed a family history of anxiety, and the possibility that Hannah had a predisposition for mental illness, which (arguably) required therapy even in the absence of clear symptoms.
Where Is This Going?
The concerns are exacerbated given the ways in which behavioral genetic evidence may come to court in the future. One way is through "genetic theft," where genetic evidence is obtained from deserted property, such as soft-drink cans. This method is often used for identification purposes such as criminal and paternity proceedings, and it will likely expand to behavioral genetic data once available through "home kits" that are offered by direct-to-consumer companies.
Genetic theft raises questions about whose behavioral data are being obtained, by whom, and with what authority. In the scenario of child-custody dispute, for example, the sequencing of the other parent's DNA will necessarily intrude on the privacy of that parent, even as the scientific value of such information is limited. A parent on a "genetic fishing expedition" can also secretly sequence their child for psychiatric genetic predispositions, arguably, in order to take preventative measures to reduce the child's risk for developing a behavioral disorder. But should a parent be allowed to sequence the child without the other parent's consent, or regardless of whether the results will provide medical benefits to the child?
Similarly, although schools are required, and may be held accountable for failing to identify children with behavioral disabilities and to evaluate their educational needs, some parents may decline their child's evaluation by mental health professionals. Should schools secretly obtain a sample and sequence children for behavioral disorders, regardless of parental consent? My study of parents found that the overwhelming majority opposed imposed genetic testing by school authorities. But should parental preference or the child's best interests be the determinative factor? Alternatively, could schools use secretly obtained genetic data as a defense that they are fulfilling the child-find requirement under the law?
The stigma associated with behavioral disorders may intimidate some people enough that they back down from just claims.
In general, samples obtained through genetic theft may not meet the legal requirements for admissible evidence, and as these examples suggest, they also involve privacy infringement that may be unjustified in civil litigation. But their introduction in courts may influence judicial proceedings. It is hard to disregard such evidence even if decision-makers are told to ignore it.
The costs associated with genetic testing may further intensify power differences among litigants. Because not everyone can pay for DNA sequencing, there is a risk that those with more resources will be "better off" in court proceedings. Simultaneously, the stigma associated with behavioral disorders may intimidate some people enough that they back down from just claims. For example, a good parent may give up a custody claim to avoid disclosure of his or her genetic predispositions for psychiatric conditions. Regulating this area of law is necessary to prevent misuses of scientific technologies and to ensure that powerful actors do not have an unfair advantage over weaker litigants.
Behavioral genetic evidence may also enter the courts through subpoena of data obtained in clinical, research or other commercial genomic settings such as ancestry testing (similar to the genealogy database recently used to identify the Golden State Killer). Although court orders to testify or present evidence are common, their use for obtaining behavioral genetic evidence raises concerns.
One worry is that it may be over-intrusive. Because behavioral genetics are heritable, such data may reveal information not only about the individual litigant but also about other family members who may subsequently be stigmatized as well. And, even if we assume that many people may be willing for their data in genomic databases to be used to identify relatives who committed crimes (e.g., a rapist or a murderer), we can't assume the same for civil litigation, where the public interest in disclosure is far weaker.
Another worry is that it may deter people from participating in activities that society has an interest in advancing, including medical treatment involving genetic testing and genomic research. To address this concern, existing policy provides expanded privacy protections for NIH-funded genomic research by automatically issuing a Certificate of Confidentiality that prohibits disclosure of identifiable information in any Federal, State, or local civil, criminal, and other legal proceedings.
But this policy has limitations. It applies only to specific research settings and does not cover non-NIH funded research or clinical testing. The Certificate's protections can also be waived under certain circumstances. People who volunteer to participate in non-NIH-funded genomic research for the public good may thus find themselves worse-off if embroiled in legal proceedings.
Consider the following: if a parent in a child custody dispute had participated in a genetic study on schizophrenia years earlier, should the genetic results be subpoenaed by the court – and weaponized by the other parent? Public policy should aim to reduce the risks for such individuals. The end of obtaining behavioral genetic evidence cannot, and should not, always justify the means.