Can we genetically modify animals to procure organs for humans?

Why the need to use animal organs for human transplants? Is there even such a need? No, rather it's a technological solution proposed for an urgent but non-scientific supply and demand problem, namely, shortage of organs. More people die on waiting lists than receive transplants. This fait accompli is apparently all that's necessary to breathe life into the need for Xenotransplantation - Wikipedia, i.e., animal organ transplant into humans. However, accepting this fait accompli at face value is not only dangerous but also quite disingenuous for the following reasons.

Why Xenotransplantation Isn't An Appropriate Response To The Organ Crisis: It Doesn't Address The Underlying Issue

Transplant waiting lists keep growing. Not too few donors. Rather too many potential recipients. While donations and transplants remain steady, numbers waiting for transplants grow year-on-year (1) in developed countries. Scenario is palpably ghastlier in poorer countries, where forget transplants, even dialysis is usually beyond reach for many organ failure patients.

Why is the need for transplants increasing though? This is typically swept under the carpet as increasing morbidity rates. But why are morbidity rates increasing in the first place, especially in developed countries? Somehow this, the very crux of the matter, gets short shrift in both the biomedical literature and popular media.

~80% of those on waiting lists need kidneys due to ESRD (end-stage renal disease, Chronic kidney disease - Wikipedia). Increasing numbers of organ failure patients have ESLD (end-stage liver disease) (2). Most common predisposing factors are alcoholic liver cirrhosis (3), diabetes (4) and obesity (5). Clearly lifestyle issues drive need for more transplants. That is not to imply all transplants are for lifestyle-mediated chronic diseases but rather that much of the annual increase is driven by such preventable increases in morbidity.

Bad diets and sedentary lifestyles are apparently impossible to change as are the underlying socioeconomic structure and accompanying culture that increasingly make these the norm the world over. In other words, preventable, consumption-driven practices that predispose to transplant-requiring chronic health conditions have been allowed to seed and settle into society, no questions asked. Let's state the obvious. Where's the profit in prevention? Changing the culture, especially diet and lifestyle, is hard work, and even less appetizing for those habituated to feeding on the profits to be made from chronic diseases.

Thus, once such preventable diseases have taken root, capital intensive high-tech solutions to treat them including even xenotransplants become all the rage. Few mention that the organ crisis is nothing new, having existed since at least the 1980s (6). Evidently a case of the tail wagging the dog, the prevailing hegemony is thus to hardly ever allude in the first place to why need for organs is increasing and how to reduce it but rather to bemoan the organ crisis and contrive ever more creative and ethically challenging ways to increase the organ pool.

These creative though ethically challenging solutions started with expanding the definition of appropriate transplant sources. Originally, only deceased donations were allowed. Then definition of death expanded to include the legal fiction of two types of death, circulatory death (traditionally used) and brain death (7) so organs could be harvested from more bodies. Obviously brain death 'decriminalizes the harvesting of beating hearts' (8). Then donations from the living got the nod. Any surprise organ trafficking and global black market in organs followed suit (9), especially among the multitude too poor to feed themselves or their children (10, 11, 12)? After all their bodies are all they can offer the market.

Some European countries such as Greece and Spain have even taken the creative urge to extremes, embracing the currently fashionable Nudge theory - Wikipedia by introducing opt-out consent (13), where people are automatically presumed to have given consent to post-death organ donations unless they specifically take the trouble to opt-out while they're still alive. Supposed rationale is we humans are well-intentioned but lazy. Well-intentioned as in of course, we intend to choose to donate our organs after death but somehow we're too lazy to ever get around to giving the necessary legal heft, i.e., consent, to our good intentions.

And of course, desperation increasingly permeates the medico-legal culture which now explores using even infected (14) and mismatched kidney transplants (15). Meantime, the ongoing US drug overdose epidemic provides a ghastly book-end to the organ crisis by increasing organ availability (16).

Why Xenotransplantation Isn't A Solution To The Organ Crisis: Immunological Rejection & Infectious Disease Risk

And so we arrive at xenotransplantations, a path to unlimited supply of donors and their organs at least in theory. After all, what other purpose for this planet and its various denizens but to serve the human's needs. Unfortunately for the human, in this instance biology has turned out to be a more intractable partner.

• Immunological rejection remains a vexing issue decades into the project with little sign of improvement (17) but that's not the only concern.
• SARS (Severe acute respiratory syndrome - Wikipedia) in 2003, Bird flu (Influenza A virus subtype H5N1 - Wikipedia) in 2007, Swine flu (2009 flu pandemic - Wikipedia) in 2009, MERS (Middle East respiratory syndrome - Wikipedia) in 2012, Ebola virus disease - Wikipedia in 2014 and Zika fever - Wikipedia in 2015, these are major infectious disease outbreaks since just the mid-2000s, many of them Zoonosis - Wikipedia, jumps from animals to humans. Obviously then known and even as yet undiscovered viruses being transmitted from the animal donors to organ recipients remains an ever-present danger (18). Yes, a high-powered group led by Harvard geneticist George Church used CRISPR-cas9 (CRISPR - Wikipedia) to delete potentially harmful DNA sequences at 62 sites in pig cells (19) but that was just a preliminary proof of principle study. Do we really need to concoct yet another path for more pathogens to jump species and thrive in humans, which may well turn out to be the risk with Xenotransplantation?

In other words, technocracy encourages solutionism rather than trying to understand the fundamental crux of the problem, which in this case is spiraling rates of lifestyle-driven chronic diseases. Reducing them would automatically reduce the need for transplants in the first place (see below from 20, emphasis mine).

'Medical strategies to prevent end-stage organ failure

The prevention or delay of end-stage organ failure must be accomplished to reduce the need for organ transplantation and to achieve national self-sufficiency. This approach is especially relevant to low-income countries, where resources can be better used for other pressing medical needs. Thus, education programmes about organ donation for the public and the media should also address the maintenance of a healthy lifestyle. Early detection and prevention of diseases leading to end stage organ failure, such as diabetes, cardiovascular disease, and kidney disease, is necessary.'

Bibliography

1. Organ Procurement and Transplantation Network

2. Williams, Roger, et al. "Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis." The Lancet 384.9958 (2014): 1953-1997.

3. Williams, Roger, et al. "Implementation of the Lancet Standing Commission on Liver Disease in the UK." The Lancet 386.10008 (2015): 2098-2111. https://www.researchgate.net/pro...

4. Wild, Sarah H., et al. "Type 2 diabetes and risk of hospital admission or death for chronic liver diseases." Journal of hepatology 64.6 (2016): 1358-1364.

5. Williams, Bronwen, Michelle Clayton, and Joanne Bosanquet. "Obesity: a growing threat to liver health." Gastrointestinal Nursing 13.Sup10 (2015): S16-S19.

6. Miller, Melanie. "A proposed solution to the present organ donation crisis based on a hard look at the past." Circulation 75.1 (1987): 20-28. http://circ.ahajournals.org/cont...

7. Truog, Robert D., and Franklin G. Miller. "Changing the conversation about brain death." The American Journal of Bioethics 14.8 (2014): 9-14.

8. Epstein, Miran. "Constructing the Legal Concept of Death: The Counterhegemonic Option." The American Journal of Bioethics 14.8 (2014): 45-47.

9. Scroll, Sanjay Nagral, August 3, 2016. Better buy than die? The unfortunate enduring saga of organ sales in India

10. Epstein, Miran. "The ethics of poverty and the poverty of ethics: the case of Palestinian prisoners in Israel seeking to sell their kidneys in order to feed their children." Journal of medical ethics 33.8 (2007): 473-474. https://www.researchgate.net/pro...

11. Budiani‐Saberi, Debra A., and Francis L. Delmonico. "Organ trafficking and transplant tourism: a commentary on the global realities." American Journal of Transplantation 8.5 (2008): 925-929. https://www.researchgate.net/pro...

12. Danovitch, Gabriel M., et al. "Organ trafficking and transplant tourism: The role of global professional ethical standards—The 2008 Declaration of Istanbul." Transplantation 95.11 (2013): 1306-1312. https://www.researchgate.net/pro...

13. The Economist, Nov 20, 2008. Opting out of opting out

14. Stat, Elie Dolgin, March 18, 2016. Surgeons to test use of infected kidneys for transplants

15. Orandi, Babak J., et al. "Survival benefit with kidney transplants from HLA-incompatible live donors." New England Journal of Medicine 374.10 (2016): 940-950. http://www.nejm.org/doi/pdf/10.1...

16. The Guardian, Amanda Holpuch, May 1, 2016. Drug overdose epidemic has driven increase in organ donors, data shows

17. Tirumalai Kamala's answer to Is xenotransplantation remotely possible?

18. Tirumalai Kamala's answer to What would happen to humans if they were affected by endogenous retroviruses as a result of xenotransplantation?

19. Yang, Luhan, et al. "Genome-wide inactivation of porcine endogenous retroviruses (PERVs)." Science 350.6264 (2015): 1101-1104. http://arep.med.harvard.edu/pdf/...

20. Delmonico, Francis L., et al. "A call for government accountability to achieve national self-sufficiency in organ donation and transplantation." The Lancet 378.9800 (2011): 1414-1418. http://www.who.int/transplantati...

https://www.quora.com/Can-we-genetically-modify-animals-to-procure-organs-for-humans/answer/Tirumalai-Kamala

Does occasional use of anticholinergic drugs such as Benadryl have serious neurological risks?

It's important to keep in mind the following issues about the recent epidemiological study (1, 2) that examined the connection between cumulative anticholinergic drug use and incident dementia when considering the extent to which its results are generalizable.

• Though interesting, these results need to be confirmed by other independent studies on larger numbers of patients.
• This study was restricted to patients 65 years and older.
• Authors studied cumulative, not occasional, exposure to Anticholinergic drugs. As defined in this study, cumulative anticholinergic exposure was defined 'as the total standardized daily doses (TSDDs) dispensed in the past 10 years' (1, emphasis mine), is quite different from occasional use, which is presumably not daily use.
• The Anticholinergic drug Benadryl is a 1st generation Antihistamine, containing Diphenhydramine, a Histamine H1 receptor antagonist. In the case of diphenhydramine, the daily dose criterion used in this study was 50mg.
• Authors studied whether long-term cumulative intake of all sorts of combinations of antihistamines, antidepressants, antivertigo, antiparkinson, antipsychotics, bladder antimuscarinics, skeletal muscle relaxants, gastrointestinal antispasmodics and antiarrythmics predisposed those 65 years or older to incident dementia, i.e., newly diagnosed dementia. They did not study outcome of prolonged Benadryl intake alone.
• There is currently little biological basis in the scientific literature for linking cumulative anticholinergic use to outcomes like Alzheimer's disease. Even the authors of this study could make a plausible case only for people with Parkinson's disease, i.e., for people with pre-existing brain damage.

This answer therefore discusses the particulars of the question as asked, that is the effects of occasional, i.e., not daily, use of the anticholinergic Benadryl.

'Serious neurological risks' of occasional Benadryl use consist of strong albeit temporary dose-dependent effects on the central nervous system. It can sedate as well as profoundly impair psychomotor function, i.e., tasks, such as driving an automobile, that require both concentration as well as fine motor skills.

Antihistamines are typically used to treat allergy symptoms, specifically those associated with allergic rhinitis such as runny nose, sneezing, itching. A common symptom of allergic reactions, excess histamine is the consequence of Mast cell degranulation caused by their binding to complexes of Allergen bound to Immunoglobulin E, i.e., antigen-antibody complexes (see figure below from 3). When taken during allergy episodes, antihistamines bind histamine receptors, thereby preventing mast cell-derived histamine from doing so. This in turn prevents the full expression of allergy symptoms such as runny nose, sneezing and itching. So far so good.

Problem is action of 1st generation and even some 2nd generation antihistamines isn't limited to just inhibiting the excess histamine that's secreted when large numbers of mast cells degranulate during an allergy episode.

With its own source of histamine, the brain also widely expresses histamine receptors. The tuberomamillary nucleus, a cluster of neurons in the posterior hypothalamus, synthesizes histamine, and these neurons project into various regions of the brain as part of the histaminergic nervous system, and all four types of histamine receptors are abundantly expressed in the brain in distinct patterns (see figures below from 4, 5).

Since most 1st generation and even some 2nd generation antihistamines penetrate the Blood–brain barrier, they can have profound effects on brain function including Anticholinergic effects, sedation and effects on psychomotor function.

Temporary impairment of driving skills is a prominent example of diphenhydramine's effect on the brain. In 2004, the US National Highway Traffic Safety Administration reviewed antihistamine effect on driving-related skills by examining a total of 130 scientific papers published on the subject until 1998 (6). Among other findings, it concluded (6, emphasis mine),

'There is overwhelming evidence from the experimental literature that the 1st-generation antihistamines produce objective signs of skills performance impairment as well as subjective symptoms of sedation'

Obviously, 1st generation antihistamines include diphenhydramine, the one in Benadryl (see figures below from 6).

Bibliography

1. Gray, Shelly L., et al. "Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study." JAMA internal medicine 175.3 (2015): 401-407. https://www.researchgate.net/pro...

2. Harvard Health Publications, Beverly Merz, January 18, 2015. Common anticholinergic drugs like Benadryl linked to increased dementia risk - Harvard Health Blog

3. NIAID Researchers Identify Potential Drug Target for Allergies

4. Thurmond, Robin L., Erwin W. Gelfand, and Paul J. Dunford. "The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines." Nature Reviews Drug Discovery 7.1 (2008): 41-53.

5. Haas, Helmut, and Pertti Panula. "The role of histamine and the tuberomamillary nucleus in the nervous system." Nature Reviews Neuroscience 4.2 (2003): 121-130.

6. Moskowitz, Herbert, and Candace Jeavons Wilkinson. Antihistamines and driving-related behavior: A review of the evidence for impairment. No. HS-809 714,. 2004. http://ntl.bts.gov/lib/26000/260...

https://www.quora.com/Does-occasional-use-of-anticholinergic-drugs-such-as-Benadryl-have-serious-neurological-risks/answer/Tirumalai-Kamala