Chimerism; A Possible Solution To The Ongoing Organs Availability Problems?

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It's been a busy week. I've been struggling with works and my personal project at the same time and let me tell you something, juggling things professionally and personally at the same time can be a pain in the bottom sometimes. I wish I had more than 24 hours a day to settle things, or maybe require fewer sleeping hours. I think I have mentioned somewhere in my previous article that someday, I'm going to take Master in Paediatric to become a Paediatrician, right? Well, yesterday, I was given an opportunity to visit a few establishments from Paediatric care in Kuala Lumpur and I must say, it looks promising. I mean, you knew sciences are advancing each and every day, but nothing beat the joy of seeing it with your own eyes. One of the things that I realised throughout the visit is there are a lot of kids, who are really sick waiting for organs so that they can keep on going as their original organs can't sustain them any longer.

Organ transplantation can be regarded as one of the greatest achievement in the field of medicine in the 21st century, right beside antibiotics and vaccinations. Like any other "things", the availability of organs will depend on several factors such as types of organ, the original donors and consent. Some organs can be contributed by a living donor while others need to be procured from someone who's dead e.g. heart and lungs. There is a lot of news, be it fake or the truth, I knew nothing about it, regarding brain transplant which has been carried out successfully in a few patients across the globe. If I'm a layman, I would believe it without doing any research on it but I'm a medical man and also someone who believes in evidence-based sciences, so until a valid paper is to be published, then I will consider it as null.

Up to 2015, there are more than 120,000 organ transplants which have been conducted in all of the 96 countries which are being surveyed by the World Health Organisation (WHO) for statistic purposes (Source). Even though organ transplant can be a potentially life-saving modality, not everyone is suitable to be a candidate and they were screened first for some possibility of organ rejection, in which (if ignored), can lead to a few fatal complications and a waste of resources. There were a few problems with the current implementation of organ transplants which will be emphasized more in this article. I would also touch on chimerism and how growing human organs inside an animal can be a life-saver and at the same time, raises a few issues with Animal's Right; without further ado, let's get on it.

Organs' Shortage

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Even though organ transplantation can be considered as an alternative for certain situations in order to provide a better clinical condition to patients, it is carried out selectively to ensure people at the top of priority would receive attention. There were fewer numbers of donors compared to people who are requesting organ transplantation and no matter how advanced our technologies are, there are by far no other methods of getting organs other than getting it from people, be it alive or dead. Let's put the theory into some numbers, in 2009, the number of people in America who were recorded by the Scientific Registry Of Transplant Recipients who desperately need a new kidney is 83,000. Do you want to guess how many people received it? The answer, 17,000. Not even reaching 20,000 and that's only accounted for 20% of people who need kidney transplants. Considering the number of people who need kidney transplants increase every year coupled with a reduction in the number of organs' donors, resorting to organ transplants as a treatment can be thought as the last possible solution.

There are a lot of reasons why this thing happened. Even though every year, the number of people who registered as organ donors increases, several factors could hinder organs procurement from the donors especially, if they were dead or diagnosed with brain death. When the decision whether to donate organs fall to the hand of grieving next of kins, depending on cultural and religious factors, most of them would disagree with organ donation and would like to bury their beloved the way they are; it is a decision that we, as clinicians, need to respect. Some hospitals or medical facilities don't have the necessary equipment or specialities to harvest organs so naturally if they want to do it, they need to send the donor to any capable institution; the problem is, some organs only have a specific amount of time before they were damaged and considered non-viable as the body turns acidotic. Even if the number of donors with respect to recipients is 1:5, in actuality, it could be lesser than that.

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It is therefore important to note that, establishing a community which understands the importance of organ donation can be a vital step towards saving a lot of lives that can be saved with organ transplants. Cultural and religious factors often being two of the many reasons why organ donation programs in certain countries failed despite their great protocol which complies with the international standard of organ transplantation set up by the World Health Organisation. There were too many steps, procedures, rituals etc that must be carried out in certain cultures or religious beliefs after a person's death which make the organs non-viable at the end of the process. By the way, no offence, this is just my personal opinion. It's frustrating to see someone who originally intended to do good by signing up to the organ donation program end up with nothing to give. Nevertheless, even some organs which can be transferred from a living donor to someone who needs it are scarce; for example in Israel, 2010, there are 151 people who need liver transplants but only 46 of them were performed and the others need to remain in the waiting list.

Brain Death And Consent

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It's relatively easier to go ahead with harvesting organs from clinically dead people (people who have been confirmed to be dead) compared to people who are diagnosed as brain dead (I'm not sure whether brain dead is really a diagnosis but you get the gist). There are too many emotions and denial from the next of kins which can steer the deceased organ's condition from good to bad. I'm not saying it is bad for the family to grieve for getting the patient's brain dead diagnosis, it is a normal, healthy reaction from receiving a bad news (everyone who is mentally healthy will react the same way), but, it certainly wouldn't make things better for the organs that can soon fail (multi-organ failure). Even with all of the guides provided to clinicians to diagnose brain dead, it is a relatively difficult decision to be made. Afterall, we have heard several news and stories regarding people who suddenly woke up during a funeral service which often being mistakenly assumed as a medical miracle; it can be, but most of the times, it is due to a misdiagnosis. The doctor who announced the time of death would be in a real, deep trouble for committing such mistake.

Even though death was perceived differently in the majority of cultures and religions, I think we can all agree that a brain is an extremely important organ for humans to operate thus brain dead equals to death itself; it's like a central processing unit of a computer. There are 3 basic steps of confirming brain death:

• Loss of Brain Stem Reflexes
• Glasgow Coma Scale 3/15 (Deep coma)
• Loss of cardiorespiratory function (The patient can't breath when they were disconnected from the cardiorespiratory machine)

However, brain death is diagnosed differently, in different countries to not only comply with the clinical guideline provided to the clinician but also to respect the cultural and religious aspects of the community. In Israel, for example, the diagnosis of brain death is achieved through multiple objective tests which include transcranial Doppler, single photon emission computed tomography (SPECT) imaging and other available technology which can confirm that people are actually dead. There are a few exclusion criteria that should be examined before we can disconnect patients from life supports, checking whether they were organ donors, asking for consent from the deceased next of kin and finally, proceed with the organ harvesting and transplantation. However, in certain countries, each hospital may have different approaches in determining brain death.

Based on these contemporary medical practices and the situation in the country, the committee drew up the guidelines on brain death. Essentially, it is a clinical diagnosis, but brain death can only be certified when the diagnosis of irreversible brain damage is absolutely certain, and metabolic factors are not the cause of the state the patient is in. The patient must be apnoeic and properly ventilated, be totally unreceptive and unresponsive and the brain stem reflexes absent. The loss of the inherent ability to breathe is further ascertained by the apnoea test.

Guideline From The Malaysian Medical Council - Brain Death

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The need for a standardisation of the criteria to diagnose brain death for all of the hospitals across the globe has been proposed a few years back but the idea was met with a variety of reactions from all of the doctors around the world. The notion of having a standard of procedure for a critical issue such as this is understandable asiIt'll be much easier for both the doctors and the community to accept the brain death diagnosis as every hospital on this planet utilise the same principle of determining death. People who are in denial tend to seek for a second opinion and different approaches in determining brain death can lead to confusion and as a result, prolonging the diagnosis which can lead to multi-organ failures. However, it is difficult for professionals around the world to conform to different sets of cultures and beliefs in order to achieve a consensus. We are not only trying to seek a solution for the clinicians but also to provide a robust explanation and understanding to the one who seeks when they started to question the diagnosis which has been given based on our professional judgement. Yeah, I know, it's what we do. Something that we didn't like, but need to do it regardless.

For a layman, it is difficult to see the line between people who were in a deep coma or they have actually died. This kind of manifestation seems to affect the process of getting consent which can be seen as rude by the next of kins when they thought their beloved was still alive when in fact they are not. In 2010, it was found that out of 700 patients who experienced brain damage, only 122 people are declared brain dead, the rest were either unsure of brain death status, not consented by the family to be declared as brain death or they can't accept the fact that their beloved has died. Out of 122 people, only 52 organ donors contributed to organ donation. That's merely 7% out of 700 potential donors and for most of them, brain death diagnosis can't be determined due to several factors (Source). The number of people being added up into the waiting list grows longer and we have to deal with the fact that quite a number of them will suffer from their damaged organ for a very long period of time. It's rude and quite unethical to pray for a brain-dead patient to come and save someone but up to this point, what kind of words they can utter in their prayers?

Creating Human's Organs In Animals

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In 2017, the Salk Institute has published a study pioneered by a group of dedicated scientist which pointed out the possibility of creating human's organ inside a pig by mean of genome editing tools. I know, it is quite unethical for Animal Lovers especially, that we modify an animal DNA structure to find a solution for organs shortage but up to this point, every day, approximately 22 people on the waiting list died hoping for organs that they would never get and 6 new one would be added every hour, searching for organs as a solution to their own diseases. I can't really imagine the possibility of the United States government to authorise such experiment as they would get in trouble with people, so the experiment was funded by a private, anonymous group.

Do you still remember how happy the scientific community was when the first time James Thomson was able to discover the potential of a specific kind of cell to grow into anything which is called as the Human Embryonic Stem Cell? Well, the scientist at the Salk Institute found that, if certain mice genes that supposed to code for the formation of the pancreas were deleted and replaced with a set of genes which code for the pancreas of rats at the blastocyst level, all of the mice born would have rats' pancreases instead of their own. It's quite inspirational and without realising, we have possibly created a creature which we can call a chimaera. There were no symptoms of organs rejection and all of the mice grew up healthily. The problem with this model is all of the mice were born with rats organ so by that time, their pancreases can be considered as their own. They would be no issue with the immune system and nothing would happen even though the type of cells presented are quite different. What if they grew a rat and try to transplant the organ into a mouse, would it been possible?

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Regardless, they tried to do the same things with a pig but the experiment failed. This can be due to the fact that pigs and mouse might have a significant difference in terms of the organ's molecular computation that would allow it to be accepted. The experiment was then continued by using a portion of the gene from human's pancreas; guess what, it grows! Do you think we can use the organ and implant it inside humans? Well, there will be a few issues with that:

• First and foremost, the embryonic development of the pig which has been modified with human's gene was rather slow. They would need maybe twice or thrice from normal to grow.
• Even though the pancreas has human's cell, it doesn't change the fact that it is not 100% human's cell. A large portion of it would be composed of pig's cell and this can predispose to organ rejection.
• If for the sake of argument, we successfully create an organ which is 100% human's, then we have to slaughter quite a lot of pigs(or any other animals) to satisfy the demand of organs shortage. It would be unethical and impossible for them to proceed with testing a large sample.

It's rather difficult to provide for humans and if you think this is the end of it, well, it is not. In 1st August 2018, Joan E. Nichols has published a paper which entailed a lab-manufactured pig's lungs which have been transplanted into pigs without any signs and symptoms of organ rejection even without giving them immunosuppressant. Quite cool, huh? It's will be long before that experiment can be adopted into creating a lab-manufactured human's organ but it is a step in a right direction, I guess. At least for now. As for the chimerism, the experiment can be considered unethical, but what they have achieved is quite big. It can be a potential solution of providing organs which can be donated without killing the host, like kidney and stuff or they can modify it into some other procedures which can be considered less or non-invasive for the animals that they are going to use. Solving the problem of organs shortage is important to ensure the welfare of those who need it is taken care of.

Source

• Challenges in Organ Transplantation
• Human-Pig Hybrid Created in the Lab—Here Are the Facts
• Lab-grown pig lungs are great news for the future of organ transplantation
• Production and transplantation of bioengineered lung into a large-animal model
• The diagnosis of brain death

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