Medicine and Long Life

Why do we have medicine?

The answer is obvious that a child can answer. It is to help people. To help them live long and healthy lives.

 

But does medicine help us live long?

Some medicines do, like some vaccines, and most interventions help people live slightly longer.

 

But people still die. In the last hundred years, we have only improved life expectancy at older age by 6 years. The great improvement in medicine has been in helping children survive childhood. And this was not just medicine it was because of public health. We made great progress in getting clean fresh water to communities and an efficient sewage system. Laws that protect the air we breathe, the hours worked, and age restrictions. It is these factors that have improved life the most rather than medicine.

 

For older people medicine performs invasive treatment like heart operations, setting bone fractures, and through medication like controlling blood pressure, cholesterol, and diabetes. These help some older people live slightly longer and in better health. But only slightly.

 

Two researchers examined what happens if we completely cure some chronic diseases.

Like a magician with their magic wand, they eliminate all diseases. This can only be done statistically. Kenneth Manton eliminated one disease at a time. By eliminating all of these killer diseases at 87 years of age, people live an additional 5.7 years for males and 6.5 years for females.

 

Another researcher eliminated one disease at a time and saw the effect this had on people’s lives. Again, they did this using statistics. Douglas G. Manuel reported that by eliminating cancer they predicted that one fifth of the years of life gained would be spent in poor health—and increased cost. This is because living longer results in these people getting dementia or other chronic disease such as atherosclerosis. On the other hand, eliminating musculoskeletal conditions would result in a year of good health for women and under half a year for men.

 

Many diseases are waiting for us in older age. The healthiest people on earth, like the Blue Zone people, one of which is in Okinawa, tend to live a long life. They only get sick for a few days before they die. There is no long period of sickness. In the end, it is best to be healthy as death comes quickly and our bodies seem to know how to shut down effectively when we are healthy.

 

We need to understand why our bodies are designed to shut down. We need to study aging not just specific diseases.

 

Then I return the question. Does medicine help people live long and healthy lives?

 

The answer might be that medicine allows us to believe we can change our nature. But as yet we do not understand “aging” enough to be able to change very much, but we all take what we can get right now.

 

Don’t Blame the Chickens or the Foxes

I have been teaching a university course on programs for older people for ten years. Every year I get some of my bright students come back to tell me that the program does not run as it was intended. The program that they interned in (clinical experience) operated differently from how it should have operated. Most reduced their services to make a larger profit. At first, I thought that this was an anomaly, infrequent events. But it happened with many of my students across a broad range of services. At one time one of my students, an ex-military intelligence in his previous life, wrote a critique of hospice services. I thought it was intriguing so I followed up and did my own research. What I found was that not only was he right, but there were other ways that he missed that hospices use to increase their profit and unfortunately reduce their care to older adults that are dying. How can this be?

I then decided to research all services to older adults. The results were devastating but informative. In the United States, every service that is provided for older adults is designed to increase profit generation. Every single one and it did not matter if they were “for-profit”, or “not-for-profit.” There are only two ways to increase your profit, you either increase prices for your services, reduce the number of services, and/or reduce their costs. What I found is that across a broad range of services, the preferred method was to reduce services. This had the direct effect of causing harm to the older client. It is predictable institutional abuse at a level that is difficult to comprehend in a developed and rich country. But my task was not simply to document these abuses, but to find a solution. That is when I came up with a parable.

A farmer has a brood of hens, he sells their eggs. Next to the farm there were a couple of foxes with their own small family to feed. They often got into the chicken coop and helped themselves to some of the chickens. This continued to happen year after year. I ask my students, who is at fault? Are the chickens at fault as they remain defenseless? Are the foxes at fault since they attempt to feed themselves and their families? Or is it the farmer who is incompetent at protecting the chickens? You cannot blame the chickens or the foxes which is what the media does. They blame people for not doing their homework and checking up on nursing homes, or hospices when they are at their most vulnerable stage in their life. Others blame the medical and pharmaceutical companies for their greedy behavior as they need to make a profit to survive. No one seems to blame the farmer, the government. We have regulatory agencies that are designed to safeguard our citizens, but they are not doing their job. Like the farmer they are incompetent, but unlike the farmer who loses the sale of his eggs, these administrators still get a hefty paycheck every month. When I figured that the solution was to enhance and strengthen government regulatory agencies, I formulated a theory that explains all of this and predicts that these abuses will continue to increase unless we enhance oversight. The book was published as Critical Age Theory on Kindle an Amazon company. It was generating some interest, but not a blockbuster, but then one day my account on Kindle was deleted. No explanation was given and no apology for deleting more than 12 books I had online.

I remember a friend of mine Allen Smith, a Professor of Economics at Eastern Illinois University, who published about similar institutional abuse this time on social security. He published The Alleged Budget Surplus, Social Security, and Voodoo Economics and in 2000, The Looting of Social Security. All of these books were critical of what the government was doing. Strangely, the last of these books was stopped from being published. Someone bought the rights and stopped printing it. At the end of his life Professor Smith bought the rights back and made it public again. I distribute it free to my students.

Basically, he is saying the same thing, don’t blame the chickens or the foxes.

We must hold our government to a higher standard as their only job, their sole reason for existing, is to better the lives of its constituents, the chickens. If they are not doing that then they have relinquished their right to govern. Most radical governments now, the populists, want to overthrow all our institutions and start again. But that is wrong; these institutions developed for a reason. Just because they are not functioning properly does not mean that they cannot be fixed. Look at the motive for their inception and you will find the answer of how to fix them. Perhaps we can regain a system of care that promotes health and dignity in our last stages of life.

Many Dementias

My mother, of 86 years of age, has dementia. But we do not really know what that means. At first, she was slow and fragile; her short-term memory was shot. The doctors found high calcium in her blood and diagnosed a benign tumor in the hyperthyroid. They operated and she came back energetic, hyperactive, and hallucinating and talking with her dead mother and sister. Then she stopped eating and only drank when directed. She shrank in weight and became nearly catatonic. I met with the family as I predicted a quick death. I made the family take uncomfortable decisions.  We admitted her to a nursing home, and when my sister visited her four hours later and saw how anxious she was, mum came back home. She had an infection, ended up in hospital, and came back with a bloody nose. This abuse further solidified the primary caregiver, my younger brother's determination to protect mum by keeping her home. Then she started independently eating and drinking and while still looking for her dead relatives, she was getting more exercise than anyone else. She was physically getting stronger. She is in constant motion and repeats nonsensical words as though she is praying. From the moment she wakes up to the last breath at night she is in motion and vocal.

It seems there are layers of diseases, one waiting for the other to emerge and take priority, or both acting at the same time. Our categorization of diseases is not designed for older people with multiple diseases. Especially in psychiatric nosology, the idea of identifying specific diseases as distinct and independent diseases is nonsensical. As we get older the body ages across the board. A weaker heart, lung, muscles, skeleton, joints,  everything is diminished, some more than others. An emerging disease is not independent but can be an expression of all of these small deteriorations. My mother had a hyperthyroid tumor that created a calcium imbalance that slowed her cognition and body down, and she also had Lewy Bodies Dementia that created the hallucinations, and ontop of these she also must have Vascular dementia or Alzheimer’s disease that destroyed her memory. All of these were acting upon her at the same time. Then there are other neurological diseases that we still have not identified. Her improved eating habits cannot be explained by the dementia diagnosis alone. There are other changes that are hidden from us. Among 90-year-olds half of the cause of their dementia is unknown as there are so many other biological changes happening. When there are neurological deficits you can be certain that other diseases will emerge at the same time. Aging might be the most obvious factor, but that does not inform us on how to prevent or delay dementias as we cannot stop aging, but we can improve how we age.  Psychiatric nosology will eventually be dragged kicking and screaming through this terrain of older patients’ maladies until we finally admit that unless we start looking at the whole person, studying aging and not just diseases, we will never get a handle on dementia.

 

 

The Sixth Scientific Revolution Transforming Humans as Context Bound

All scientific discoveries contribute towards a better understanding of the universe that we live in. All of this knowledge reinforces our belief that the universe is orderly and that we are at the center. In contrast, there are some scientific revolutions that change how we think about ourselves, as humans. There are some discoveries that shake up our complacency about our importance in the grand scheme of the universe. Such scientific revolutions deserve special merit since by removing our self-centered bias, we get closer to a more universal truth about us and the universe we inhabit. Since our bias for self-centeredness is strong, so are these scientific revolutions. This paper examined five such scientific revolutions and postulates a sixth one that is emerging.

It is easy to define the first of such revolutionary thinking. Thales of Miletus 6th century BCE argued that we should observe physical events without assigning the cause to "god." He argued that there is an underlying process that causes the world to behave the way it does and that we need to work out these hidden processes rather than simply call it the will of god. This revolutionary thinking caused the birth of science. 

The second scientific revolution was by the 16th  century Nicolaus Copernicus., who in astronomy, removed the earth from the center of the universe and placed it among other planets revolving around the sun. By doing this Copernicus also moved humankind, and not just Earth, from being at the center of the universe and we attained a more peripheral place in the universe.

The third revolution that continued to move humans away from being the center of the universe was by the 19th century Charles Darwin. By publishing his The Origin of Species, Darwin pushed humans off the throne of superior beings and back into our mammalian lineage. The theory asserts that like all other beings, we evolved and share lineage with lower primates and other living things. Like all other animals, we are a work in progress. 

The 20th century brought the fourth revolution with Sigmund Freud who emphasized the concept of an unconscious mind. The notion of the unconscious can be traced back to ancient civilizations when dreams were considered to be messages from the gods. Even early philosophers like Plato and Aristotle explored the idea of unconscious mental processes. At the turn of the century, scientists such as Franz Anton Mesmer, Pierre Janet, Alfred Adler, and Carl Jung all worked on this unconscious mind that hid thoughts and decisions from consciousness and therefore from us. But it was Freud that took this concept further and developed a theory of the mind that argued that the unconscious mind is the primary motivator for behavior. The theory put forward the interpretation that we are not in conscious control of our actions.

The later part of the 20th century brought us the fifth revolution with Albert Einstein and his colleagues who developed the idea that the matter is relative. This theory of relativity postulated that gravity and acceleration are indistinguishable, that mass and energy cause gravity and time to curve, and that the acceleration of massive objects causes ripples in spacetime. All of this makes our natural world less rigid, and our reality is determined by context by the locality of the event. 

These theories have one thing in common, what we believe about who we are, as humans on Earth, is not true. That we are part of a larger universe, that we evolved from other life forms, and that how we see the world is relative to our position in the universe. There is a locality in our reality. Where we are is important. The sixth revolution takes all these concepts of moving humankind away from being to the center of the universe as it argues that even our body is part of such a locality. That the biological and chemical context that we reside in determines how we function and behave. This environmental physiology, where the environment changes our physiology proposes that although we see ourselves as sovereign entities we are in reality a conglomerate of different processes that are influenced by the world we live in. As such, under this environmental physiology, there is no “us” and “them”, no “me” and the “environment”, as both converge. Environmental physiology highlights the malleability of our physiology. Richard Rorty said this beautifully: “…had physiology been more obvious psychology would never have arisen…if the body had been easier to understand, nobody would have thought that we had a mind.” (p 239). 

Most of the developments in environmental physiology highlight human intervention in modifying the body. However, equally impressive, and more instructive, is the evidence showing how nature itself manipulates our bodies. By observing how nature manipulates and modifies our bodies, scientists have learned new techniques that emulate nature. Despite the impressive nature of these technological advances, the underlying theme is how nature has such a powerful force on us by constantly changing and modifying our bodies. 

Technological advancements include: 

Genetic Engineering and Recombinant DNA technology led to the creation of genetically modified organisms (GMOs); 

Polymerase Chain Reaction (PCR) amplified specific DNA segments, making it possible to study and analyze genes and their functions more easily;

Gene Sequencing has led to insights into genetic variations, disease mechanisms, and personalized medicine; Stem Cell Research that promoted regenerative medicine, and tissue engineering; 

CRISPR-Cas9 Gene Editing technology allows precise modification of DNA sequences, making gene editing faster, and more accessible; 

Synthetic Biology of new biological components, systems, and even entire organisms, with varied applications; 

Omics Technologies advancements in how molecules interact within living organisms resulting in contributions to genomics, proteomics, and metabolomics; 

Human Embryonic Stem Cells that repair specific damaged organs; 

Induced Pluripotent Stem Cells (iPSCs) takes adult cells and reprogram them to an embryonic stem cell-like state; Immunotherapy such as immune checkpoint inhibitors and CAR-T cell therapy, harness the immune system to target and eliminate cancer cells; 

Microbiome Research that evaluates the bacterial makeup of the stomach enabling the development of probiotics; 

Nanobiotechnology that promotes targeted drug delivery, biosensors, and imaging technologies; 

Neuroscience and Brain Imaging such as functional MRI (fMRI), provide insights into the brain's structure and function; and 

Artificial Intelligence and Machine Learning in Biology accelerate data analysis, drug repurposing, protein folding predictions, and diagnostics.

Such advancements, impressive as they may seem, are just a small insight into the way that nature itself behaves. Scientists have used this limited knowledge about what we know about how the environment influences our bodies to experiment with coming up with technologies in a short span of time. But it would express a special kind of hubris if we forget to add how nature itself manipulates “us.” There is a vast number of unknown-unknowns, but what we have learned provides enough substantiating evidence to affirm that our context, our environment, changes us. This knowledge has taught us that we are more malleable and receptive than we believe. Nature manipulates our bodies on a daily basis. The sixth revolution in science is knowledge about how nature influences and changes our genes, how genes are expressed, how our body processes food, how we uptake nutrients, how we age, how we think, and how we behave.

Natural influences on the body include: 

Epigenetic modifications that determine the expression of specific genes, subdue some and excite others without altering the underlying genetic sequence. Environmental factors, such as diet, stress, and exposure to toxins, can lead to epigenetic modifications, influencing health outcomes; 

Plasmids, are small, circular DNA molecules in humans that come from bacteria and archaea and become inserted in human cells. They often carry genes that provide selective advantages, such as antibiotic resistance, leading to the spread of antibiotic resistance genes; 

Horizontal Gene Transfer (HGT) is the transfer of genetic material between different organisms, typically bacteria can exchange genetic material-- share beneficial genes, such as antibiotic resistance genes--through processes like conjugation, transformation, and transduction; 

Jumping Genes (Transposons) are segments of DNA capable of moving within a genome. They can "jump" from one location to another, potentially affecting gene regulation and function, playing a significant role in shaping the human genome's evolution and diversity; 

Retroviruses are individual strands of RNA viruses that can multiply into human cell DNA by integrating their genetic material into the host genome; 

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in our ancestors' germ cells; MicroRNAs (miRNAs) play a crucial role in post-transcriptional gene regulation by binding to messenger RNAs (mRNAs) and either degrade them or inhibit their translation into proteins;

Dysregulation of miRNAs has also been linked to the progression of diseases, such as cancer and neurodegenerative disorders; 

Prions are misfolded proteins that can induce the misfolding of other normal proteins, leading to a chain reaction that can propagate disease in the brain and nervous system, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy (mad cow disease) in cattle; 

Endocrine Disruptors such as Bisphenol A (BPA) are chemicals that can interfere with the endocrine system, disrupting hormonal regulation reproductive and developmental abnormalities; 

Gut bacteria break down complex carbohydrates, producing essential vitamins, and regulating immune responses affecting weight, inflammatory bowel disease, and allergies. which can influence our metabolism, immune system, and overall health; 

RNA editing such as Adenosine-to-inosine (A-to-I),  is a process that alters the nucleotide sequence of RNA after transcription. It is modified by enzymes called ADARs (adenosine deaminases acting on RNA and can impact gene expression, particularly in the nervous system, and is essential for normal brain function;

Genetic recombination is the process of exchanging genetic material between two DNA molecules during meiosis (cell division), homologous chromosomes exchange genetic material through crossing over. It occurs during sexual reproduction and contributes to genetic diversity; 

DNA Repair Mechanisms correct errors that arise during replication or as a result of external factors. For example,  Nucleotide excision repair (NER) is a DNA repair pathway that removes and replaces damaged nucleotides caused by exposure to ultraviolet radiation;

Hormesis where exposure to low or moderate levels of a stressor or toxin can result in a beneficial or stimulatory response, leading to improved health, resilience, or longevity. In other words, "What doesn't kill you makes you stronger." Hormesis can occur in various biological contexts such as Radiation Hormesis, Exercise Hormesis, Caloric Restriction Hormesis, and Phytochemical Hormesis.

All of these processes, and many others that we still have not discovered, interact. For example, exposure to low or moderate stressors that trigger hormetic responses may lead to epigenetic modifications. A hormetic response could activate specific cellular pathways that, in turn, influence epigenetic modification that changes how some genes are expressed (Vaiserman, 2011). The relationship can also be reciprocal where epigenetic modifications can regulate genes involved in stress response pathways or cellular repair mechanisms. Specific epigenetic changes may enhance or dampen hormetic responses, affecting the magnitude of the beneficial effect elicited by the stressor. In some cases, epigenetic changes induced by hormetic responses may be heritable. Offspring could inherit the altered epigenetic marks from their parents, potentially passing on the beneficial effects of hormesis to subsequent generations (Xavier, et al, 2019). Both hormesis and epigenetics have been linked to aging and longevity (Vaiserman, 2011). Moderate stressors that induce hormetic responses are believed to contribute to lifespan extension in various organisms. Epigenetic changes, on the other hand, can influence the aging process by regulating genes involved in cellular senescence and age-related diseases.

The Sixth Revolution in science moves humans from a homo-centric view of the world to one that places humans as more malleable and porous, allowing for the context, and the environment, to influence and change us.

REFERENCES

Rorty, R. (1979). Transcendental arguments, self-reference, and pragmatism. Transcendental arguments and science: Essays in epistemology, 77-103.

Vaiserman, A. M. (2011). Hormesis and epigenetics: is there a link?. Ageing research reviews, 10(4), 413-421.

Xavier, M. J., Roman, S. D., Aitken, R. J., & Nixon, B. (2019). Transgenerational inheritance: how impacts to the epigenetic and genetic information of parents affect offspring health. Human reproduction update, 25(5), 519-541.

TECHNOLOGICAL INNOVATIONS

Genetic Engineering and Recombinant DNA Technology:

Watson, J. D., & Crick, F. H. (1953). Molecular structure of nucleic acids: A structure for deoxyribose nucleic acid. Nature, 171(4356), 737-738.

Cohen, S. N., Chang, A. C., Boyer, H. W., & Helling, R. B. (1973). Construction of biologically functional bacterial plasmids in vitro. Proceedings of the National Academy of Sciences, 70(11), 3240-3244.

Polymerase Chain Reaction (PCR):

Mullis, K. B. (1986). The unusual origin of the polymerase chain reaction. Scientific American, 262(4), 56-61.

Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., & Arnheim, N. (1985). Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science, 230(4732), 1350-1354.

Gene Sequencing:

Sanger, F., Nicklen, S., & Coulson, A. R. (1977). DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences, 74(12), 5463-5467.

Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., ... & Zhu, X. (2001). The sequence of the human genome. Science, 291(5507), 1304-1351.

Stem Cell Research:

Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819), 154-156.

Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663-676.

CRISPR-Cas9 Gene Editing:

Doudna, J. A., & Charpentier, E. (2014). Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science, 346(6213), 1258096.

Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096), 816-821.

Synthetic Biology:

Gibson, D. G., Glass, J. I., Lartigue, C., Noskov, V. N., Chuang, R. Y., Algire, M. A., ... & Venter, J. C. (2010). Creation of a bacterial cell controlled by a chemically synthesized genome. Science, 329(5987), 52-56.

Khalil, A. S., & Collins, J. J. (2010). Synthetic biology: applications come of age. Nature Reviews Genetics, 11(5), 367-379.

Omics Technologies:

Aebersold, R., & Mann, M. (2003). Mass spectrometry-based proteomics. Nature, 422(6928), 198-207.

Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., ... & Bouvrette, S. (2001). Initial sequencing and analysis of the human genome. Nature, 409(6822), 860-921.

Human Embryonic Stem Cell Research:

Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., & Jones, J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145-1147.

Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., ... & Thomson, J. A. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917-1920.

Immunotherapy:

Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., ... & Urba, W. J. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363(8), 711-723.

Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., ... & Wood, P. (2018). Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine, 378(5), 439-448.

Microbiome Research:

Turnbaugh, P. J., Ley, R. E., Hamady, M., Fraser-Liggett, C. M., Knight, R., & Gordon, J. I. (2007). The human microbiome project. Nature, 449(7164), 804-810.

Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., ... & Wang, J. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464(7285), 59-65.

Nanobiotechnology:

Farokhzad, O. C., & Langer, R. (2009). Impact of nanotechnology on drug delivery. ACS Nano, 3(1), 16-20.

Sweeney, S. M., & Wooley, K. L. (2005). Self-assembling polymers for gene delivery: from laboratory to clinical trial. Advanced Drug Delivery Reviews, 57(15), 2075-2087.

Neuroscience and Brain Imaging:

Ogawa, S., Lee, T. M., Nayak, A. S., & Glynn, P. (1990). Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magnetic Resonance in Medicine, 14(1), 68-78.

Kandel, E. R., Schwartz, J. H., & Jessell, T. M. (2000). Principles of neural science (Vol. 4). McGraw-Hill, Health Professions Division.

Artificial Intelligence and Machine Learning in Biology:

Alipanahi, B., Delong, A., Weirauch, M. T., & Frey, B. J. (2015). Predicting the sequence specificities of DNA- and RNA-binding proteins by deep learning. Nature Biotechnology, 33(8), 831-838.

Topol, E. J. (2019). High-performance medicine: the convergence of human and artificial intelligence. Nature Medicine, 25(1), 44-56.

NATURAL INFLUENCES

Epigenetics

Jirtle, R. L., & Skinner, M. K. (2007). Environmental epigenomics and disease susceptibility. Nature Reviews Genetics, 8(4), 253-262.

Plasmid 

Modi, S. R., Lee, H. H., Spina, C. S., & Collins, J. J. (2013). Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature, 499(7457), 219-222.

Horizontal Gene Transfer

Thomas, C. M., & Nielsen, K. M. (2005). Mechanisms of, and barriers to, horizontal gene transfer between bacteria. Nature Reviews Molecular Cell Biology, 6(9), 711-721.

Jumping Genes

Chuong, E. B., Elde, N. C., & Feschotte, C. (2017). Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science, 351(6277), 1083-1087.

Retroviruses

Grandi, N., & Tramontano, E. (2018). Human endogenous retroviruses are ancient acquired elements still shaping innate immune responses. Frontiers in Immunology, 9, 2039.

MicroRNAs

Bartel, D. P. (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136(2), 215-233.

Prions

Prusiner, S. B. (1998). Prions. Proceedings of the National Academy of Sciences, 95(23), 13363-13383.

Endocrine Disruptors

Diamanti-Kandarakis, E., Bourguignon, J. P., Giudice, L. C., Hauser, R., Prins, G. S., Soto, A. M., ... & Zoeller, R. T. (2009). Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocrine Reviews, 30(4), 293-342.

Gut Bacteria

Sender, R., Fuchs, S., & Milo, R. (2016). Revised estimates for the number of human and bacteria cells in the body. PLOS Biology, 14(8), e1002533.

RNA Editing

Nishikura, K. (2010). Functions and regulation of RNA editing by ADAR deaminases. Annual Review of Biochemistry, 79, 321-349.

Genetic Recombination

Hunter, N. (2015). Meiotic recombination: The essence of heredity. Cold Spring Harbor Perspectives in Biology, 7(12), a016618.

DNA Repair

Lehmann, A. R., & McGibbon, D. (2006). Xeroderma pigmentosum. Orphanet Journal of Rare Diseases, 1(1), 27.

Radiation Hormesis, 

Macklis, R. M., & Beresford, B. (1991). Radiation hormesis. Journal of Nuclear Medicine, 32(2), 350-359.

Exercise Hormesis, 

Ji, L. L., Kang, C., & Zhang, Y. (2016). Exercise-induced hormesis and skeletal muscle health. Free Radical Biology and Medicine, 98, 113-122.

Caloric Restriction Hormesis, 

Turturro, A., Hass, B. S., & Hart, R. W. (2000). Does caloric restriction induce hormesis?. Human & experimental toxicology, 19(6), 320-329. 

Phytochemical Hormesis

Son, T. G., Camandola, S., & Mattson, M. P. (2008). Hormetic dietary phytochemicals. Neuromolecular medicine, 10, 236-246.