BrainEx Archives - Prindle Institute

August 19, 2022December 14, 2022

The Animal Ethics of OrganEx

photograph of pig head poking around barn door

As Benjamin Franklin famously wrote in his 1789 letter to physicist Jean-Baptiste Le Roy, “in this world nothing can be said to be certain, except death and taxes.” While it seems nothing can be done about the latter, science has been progressively fighting the former for centuries. Or, at least, challenging when death’s inevitability befalls us.

In a recent paper published in Nature, a team from Yale University claim to have developed a system – dubbed OrganEx – capable of reversing some of death’s effects over an hour after cardiac arrest. If we’re to believe the findings (and there seems to be a good reason to do so), then this team has pushed the boundary separating life from death. Before going further, however, it should be pointed out that the experiment was carried out on pigs and the restored features of life were nothing as grand as consciousness and the capacity for independent living; they were cellular.

Nevertheless, the study’s results may have profound implications for medical practice, especially in end-of-life matters like organ transplantation and donation, palliative care, and assisted dying.

In short, OrganEx was developed from an already existing experimental system called BrainEx. Developed in 2019, BrainEx showed the capacity to preserve the structure and function of cells within a pig’s brain hours after decapitation. OrganEx takes the same principles and applies them to the entire body. It consists of two essential parts. The first is an infusion device attached to the body via the femoral artery and vein. The second part is a complex chemical cocktail that the infusion device circulates through the body, mixed with the recipient’s blood. This concoction consists of amino acids, vitamins, an artificial oxygen carrier, and neurological inhibiting compounds, among other things. An hour after researchers stopped the pig’s heart and withheld medical assistance, the OrganEx system started pumping the perfusate around the pig’s body. After six hours of circulation, tests showed that oxygen had begun reaching multiple bodily tissues and that the pig’s heart had demonstrated limited electricity activity. Additionally, some expected cellular degradation appeared absent. In fact, some cells were metabolizing glucose and building proteins.

In other words, compared to the experiment’s control groups, OrganEx began repairing damaged organs hours after death.

The study’s results are remarkable, and the paper has received significant media attention (many making references to the idea of Zombie Pigs). However, an unease sits at this study’s core and, unfortunately, at the core of many biomedical studies – the use of animals in experiments.

Unlike the BrainEx study, in which researchers acquired the pig’s head from a slaughterhouse, the pigs used in the OrganEx study were slaughtered deliberately for the study’s purposes. Is this ethical? Can we justify the use of these pigs in the OrganEx experiment? I believe a perfectly suitable alternative was overlooked, an alternative that would have meant that the pigs used in the experiment could have continued their lives without being slaughtered – human cadavers.

Within research ethics, there is a widely employed framework known as the 3Rs. Proposed by Russel and Burch in their 1959 book, The Principles of Humane Experimental Technique, these Rs stand for Replacement, Reduction, and Refinement, and researchers should consider each of these principles in order. Replacement refers to substituting animals in research with technological alternatives or simply nothing at all. If it isn’t possible to replace animals, researchers move on to the reduction principle, using as few animals as possible to minimize potential suffering. Finally, if replacement and reduction aren’t possible, researchers should seek to refine their husbandry and experimental methods to reduce suffering and improve welfare. The OrganEx’s study designers seemed to consider such principles, and Yale’s Institutional Animal Care and Use Committee gave comparable advice: “we sought to minimize the animal number and any potential discomfort and suffering.”

I believe, however, that the use of pigs in this experiment breached the first of these principles. The appropriate number of pigs would have been zero, as freshly deceased people would have provided equally effective test subjects.

This might strike some as an odd claim to make. After all, researchers use non-human animals in the preclinical research phase as a buffer before human testing. Bypassing such a precaution and going straight to human research goes against the typical wisdom of research ethics and protocol. However, it is essential to remember that the subject needs to be dead for the OrganEx experiment’s purposes (or at least “dead” according to our current conception of death). That is the experiment’s point, to explore the technology’s posthumous application. As such, research participants cannot be harmed as we typically envision (i.e., allergic reactions, unforeseen side effects, etc.) because they’re already dead.

Death is not an unusual event. It happens to countless people every day. My proposal is that the researchers could have taken advantage of this naturally occurring, potentially suitable research populace but chose to use pigs instead; pigs that they slaughtered deliberately.

So, the question becomes which potential subject is more ethically justifiable: live pigs needing slaughtering to satisfy the experiment’s participation requirements or the bodies of humans who had recently died from natural causes?

All other things being equal, this seems to be a fairly straightforward choice. Living beings deserve more moral consideration than dead ones because the living can experience harm, have a greater claim to dignity, and possess complex internal worlds (pigs especially). The dead lack these things, and while we may attach morally valuable attributes to the deceased, such qualities pale compared to the living. This is true for comparing intra-species (dead human vs. live human) and inter-species (dead human vs. live pig). In short, living pigs deserve more moral consideration than dead humans, and in a research context, if you can use an already dead human instead of slaughtering a live pig, and you subscribe to the principle of reduction, then you should use the human cadaver.

That said, there might be good reasons why the researchers chose to use pigs instead of humans. They do indicate that the BrainEx study focused on a pig brain, and some consistency with that existing work would make sense. I’m unconvinced, however, that this is a compelling enough reason to decide to use pigs in this subsequent study. This is certainly true given that, presumably, the OrganEx’s anticipated application isn’t on pigs but on humans. It would seemingly make sense to align the experiment closely to the anticipated application as early as possible and skip unnecessary research steps.

Ultimately, there are good arguments to use animals for research if doing so helps prevent downstream harmful outcomes (although I don’t necessarily buy them). Nevertheless, if those outcomes can be avoided without using animals, then there is an ethical duty to do so. Preventable harm, including death, should be avoided where possible, which applies to animals as much as it does to humans.

July 31, 2019December 14, 2022

The Ethics of Cell Cultured Brains

Earlier this month, the New York Times reported that Yale neuroscientist Nenad Sestan and his team successfully produced active brain cells through a process of culturing the inactive brain matter of deceased creatures. The cells were active for more than mere moments—some of them survived for weeks at a time. These results may lead to important discoveries about the way the brain works, and could, in the long term, be an important step to understanding and/or curing brain diseases and disorders.

Sestan is interested in generating activity beyond individual cells to entire slices of brain matter. Doing so would allow him to study what neuroscientists call the “connectome”—essentially, the wiring of the brain and its synapses. The New York Times piece focused on Sestan’s work in particular, but he was eager to point out that other scientists are doing similar work. In fact, some scientists have cell cultured “mini-brains” that demonstrate the kind of neural activity that one might expect to see in fetuses at 25-29 weeks after conception.

In Sestan’s work, and in other work like it, brain matter is obtained from the bodies of deceased humans who, while living, consented to donate their bodies to assist in scientific research. Because the cells and, potentially, organs being cultured here are brain cells and organs, these processes are philosophical and ethical quagmires. There is much potential for discovery concerning the answers to fascinating questions, but there is also the potential for some pretty significant ethical violations.

One concern has to do with whether the individuals who donated their bodies to science actually consented to the creation of beings that can think. As long as humans have understood that brains are responsible for thought, we’ve been obsessed with the notion of a “brain in a vat.” It pops up relentlessly in pop culture, and even in academic philosophy. Noteworthy examples include the 1962 sci-fi/horror classic The Brain That Wouldn’t Die and the 1983 Steve Martin comedy The Man with Two Brains. Whenever the concept arises in popular culture, one thing is clear—we attribute personhood to the brain. That is, we think of the brain as a someone rather than a something. If this is true, though, the consent needed from the donor is not the consent required to simply use that donor’s body for testing. It is the consent that might be required if one were to clone that donor or to create a child from that donor’s reproductive material. One might think that the consent conditions for that might be very different, and might well be consent that the donor did not provide.

Some concern has been raised over whether this kind of experimentation could lead to the creation of suffering—if active brain cells or a series of connected cells have the potential to give rise to thoughts or experiences of some kind, they might give rise to negative experiences. Some neuroscientists view this possibility as remote, but, nevertheless, Christof Koch, the president and chief scientist at the Allen Institute for Brain Science, claims, “it would be best if this tissue were anesthetized.”

The existence of active brain states in a network gives rise to the possibility of the existence of mental states. One important question, then, becomes: what kinds of mental states are morally relevant? Is there something inherently valuable about thoughts or about sensory experiences? (Are there such things as sensory experiences in the absence of sense organs and an entire central nervous system?) If there is something valuable about such states, is it always a good thing to bring them about? In that case, every time a scientist creates a cell or system of cells capable of having a thought or experience, that scientist has done something that increases the overall level of value in the world. On the other hand, we have no way of knowing what kinds of experiences are being produced. If the sole experience produced in the creation of a cell or a system of cells is a negative experience, then the scientist has arguably done something wrong by generating that cell or system of cells.

Some philosophers think that it isn’t merely the presence of thoughts, but the presence of thoughts of a particular kind that make a being a person. Personhood, according to many moral theories, is a characteristic a being must possess in order to be a member of the moral community. According to philosopher Harry Frankfurt, a being is a person if and only if their first order desires are guided by their second order desires. So, a person might have a first-order desire to eat a slice of cake. They might have a second order desire to refrain from eating the cake, say, because they are on a diet. Persons, and only persons, can use their second order desires to guide their first order desires. Through the process of having thoughts about one’s own thoughts and desires about one’s own desires, a being starts to develop an identity.

The truth is, we simply don’t know how this works—we don’t know what conditions need to be in place for either the existence of first order or of second order thought. We don’t know how brain matter works, and we don’t know exactly what “thoughts” consist of. We don’t know if or how mental states may be reducible to brain states. We don’t know what states of matter might give rise to second order beliefs and desires—we don’t know the conditions under which we might create a “brain in a vat” that is a person and has an identity. What’s more, the brain wouldn’t be capable of communicating that fact to us (unless, of course, the horror movies have it right and all such brains can communicate telepathically—but I wouldn’t bet on that.)

As technology progresses, we run into a familiar ethical issue over and over again: what steps are we morally justified in taking, given that we don’t really know what we’re doing or how our actions may ultimately affect other beings with interests that matter? When we know we’re potentially dealing with thinking beings, we must proceed with caution.

May 1, 2019December 14, 2022

Death and Consciousness: The Prospect of Brain Resuscitation

Recently published by Nature, Yale School of Medicine completed a study where they were able to revive disembodied pig brains several hours after death. In their study, they looked at 32 brains from pigs that had been dead for four hours. The brains were separated from the body and hooked up to a machine called BrainEx. On this system oxygen, nutrients, and protective chemicals were pumped into the organ for approx 6 hours. The study found that the brain tissue was largely intact and functional compared to those that did not receive the BrainEx treatment. The cells were alive, able to take up oxygen and produce carbon dioxide, but there was no further brain communication between the cells.

These findings are considered a breakthrough for the scientific community because they challenge the previously believed fact that brain cells are irreversibly damaged after a few minutes from being oxygen deprived. In general, when an organ is oxygen deprived for about 15 minutes, it should die. Nenad Stestan, a Yale neuroscientist explained during a press conference, “Previously, findings have shown that in basically minutes, the cells undergo a process of cell death. What we’re showing is that the process of cell death is a gradual step-wise process, and some of those processes can either be postponed, preserved, or even reversed.” BrainEx, a tool developed to study the living brain beyond the confines of the body, has allowed researchers a new way to look at brain cells. Previously, studies were limited to slices of the brain from dead animals, which explains our lack of knowledge on the complex organ. We now have the means to study the interrelational association between the many parts of the brain.

Bioethicists have been equally excited and alarmed with the new means of brain research. This kind of study in is uncharted territory. Technically, because the brain is taken from a dead animal, it doesn’t fall into the category of animal research. Animal research is protected through the ethical guidelines that animals should not be subjected to unnecessary harm. However, do we know enough about consciousness to truly know if the pig is experiencing harm in the process? If the pig were to feel harm during this experiment, would it make it an unethical practice?

The scientists took a measure of steps to be proactive in protecting the possibility of the pig gaining consciousness. A series of chemicals were pumped into the brain by the BrainEx machine, one of which was supposed to stop any possibility of neural interaction that would lead to consciousness. An electroencephalogram (EEG) monitored the brains throughout the whole study. Researchers said that if they had detected any levels of consciousness, they would shut down the experiment immediately. In addition, they were standing by with anesthesia to administer. Luckily, the only findings were that cell metabolism could be recovered and no consciousness was detected. With little well known about consciousness in general, can we even be sure that an EEG should be the only indicator of consciousness or perception? It is still unknown how many neurons are needed to be activated for the pig to have any feelings at all.

Weighing the cost of the unknown harm with the benefits is one step for researchers to consider with this project. Ultimately, we will gain expertise of the interactions of a mammalian brain. Understanding the internetwork of relations between the many parts of the brain can point scientists towards new cures for dementia, brain diseases, or injuries that were once considered irreversible. Future studies can include testing drugs, studying neural pathways, and furthering general knowledge of neuroanatomy.

What cannot be ignored with these studies are the implications for long-term changes in the medical community. These findings could challenge the definition of death as it is right now. According to MedicineNet, the current law standard for death is the following: “An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem is dead. A determination of death must be made in accordance with accepted medical standards.” This definition was approved and accepted by the American Medical Association in 1980. With the findings from the Yale study, it challenges the notion that all brain cells are irreversibly damaged. Could doctors continue with this assessment if these studies lead to a means to reverse the damage, and if so, how do we now declare when someone has died?

Another worry is related to organ transplant. According to the United Network for Organ Sharing, someone is added to the transplant waiting list every 10 minutes. In the US, 18 people die every day while waiting for a transplant. Described in a commentary by Stuart Youngner and Insoo Hun, is the worry that doctors would feel reluctant to harvest organs for donation. If people could become candidates for brain resuscitation rather than donation, when, where, and for who do doctors make this decision? There is already the struggle for when do doctors switch from saving someone’s life to saving their organs for the benefit of another person. The answers only come down to moral decision making and the possibility of brain resuscitation further complicates the answers.

The continuation of these studies have the potential to make a huge difference for our expertise of neural anatomy and the process of cell death. For now, researchers have weighed the perceived benefits to outweigh the possibility of harm to the research subject. With the means to learn more about the definitions of consciousness and death, it is necessary for after each study to reevaluate the process of BrainEx in order to continue the study in an ethical manner.