AN ICE AGE. PREDATION. PANDEMICS. Our plight as Homo sapiens has been harrowing; however, in nature, only the species is relevant. After passing on our genes, evolutionary forces weaken, leading to illness, aging and eventually death. We became fixated on transcending mortality, as evidenced by our mythology and beliefs, with medicine as a contemporary continuity. However, H. sapiens are relatively young and not so sapient, speciating about 300,000 years ago, with biomedicine even more insipient. Fortunately, humans share the planet with up to a trillion extant species. Many of these lifeforms have had quite a head start on us and experimented thoroughly, coming up with ingenious ways to elude the causes of mortality that dog humans. If there really is a secret to immortality, perhaps we ought to look to the natural world to unlock it.
STEM CELL POTENTIAL
We have all once grown the many components that compose our physiology, so why can’t we do it again? Though we have a natural capacity to heal and replace fingertips and portions of liver, entire limbs or organs are out of the question. Only embryonic stem cells have the capacity to generate and differentiate into every cell in the body, a characteristic known as pluripotency.
The ability to maintain stemness happens to be the specialty of planarians. These species of oceanic and freshwater flatworms were observed as “immortal under the edge of the knife” as early as 1814. Under experimental conditions, these worms are capable of complete regeneration within two weeks from fragments as little as 1/279th of the original organism. We are not talking about bacterial division or yeast budding – planarians are animals with digestive and nervous systems. In the centuries since their discovery, biologists learned that this ability stems from planarian neoblasts. These are pluripotent cells that persist into adulthood and are located throughout the parenchyma/functional tissue of the animal. Suffice it to say, neoblasts have no human equivalent. Neoblasts owe their abilities to the expression of genes whose human counterparts act in adult skeletal muscle stem cells, pluripotency, or determining sex during gestation.
In the field of regenerative medicine, Schmidtea mediterranea are a model organism of choice, being a diploid planarian species with a sequenced genome. One group has identified 240 different genes necessary for regeneration in these animals, 38 of which are homologues of known human disease genes. However, planarians may only represent a slice of similarly gifted organisms; hydras, tentacled freshwater animals, are equally capable of such heroic feats of regeneration.
SENESCENCE
In resource-abundant countries, human life expectancy has reached historically uncharted territory. This is largely attributed to having unraveled the nature of immunity and infectious disease. But though we’ve fortified ourselves against extrinsic causes of death, we currently cannot reverse the unidirectionality and deterioration of aging, known as biological senescence.
Setting aside stemness and environment for a moment, an intrinsic cause of senescence is termed the “Hayflick Limit.” Prior to Dr. Leonard Hayflick’s demonstration in 1961 that human fetal cells would cease to divide after 50 divisions, the prevailing hypothesis was that cells could divide indefinitely. It is now posited that cells eventually reach the end of the line, that line being the telomeres at the ends of our chromosomes. These are non-coding cushions of DNA that cap and protect our chromosomes, but that shrink with each subsequent cell division. One outcome of the eventual cellular arrest that occurs is thymus shrinking in vertebrates, which arises before puberty in humans. Later in life, this senescence becomes consequential for immunity, especially with other vital organs and systems following suit.
We know that an enzyme called telomerase, which lengthens telomeres, is active between conception and birth in humans but loses its function in somatic cells (with some exceptions such as lymphocytes). In general, telomere length is therefore inversely correlated with age. However, this is not universally true in the animal kingdom; birds such as the maritime Leach’s storm-petrel have telomeres that lengthen over time, allowing them to live for over 20 years. Their solution is to constitutively express telomerase, a technique also used by lobsters that allows for lifelong growth and fertility. Unfortunately, this strategy is not adaptive for everyone. On a clinical level, the aberrant expression of telomerase is one of the mutations that allows some human cancers to proliferate indefinitely, whereas tumours are rare in lobsters, with no correlation to the size or age of the animal.
NEURODEGENERATION
The most active known site of neurogenesis in humans, the hippocampus, only sees a 1.75% renewal annually, whereas the epidermis undergoes a complete turnover in about 1.5 months. This lack of proliferation contrasts with an imposed limit on the number of cellular divisions, but both the existence of said limit and its subversion can be explained in part by pleiotropy – the fact that genes multitask. For example, in cats, there is an association between iris pigmentation and hearing – seemingly innocuous blue eyes are strongly associated with deafness. In the human central nervous system and elsewhere, the pleiotropy at work is antagonistic: genes that inhibit division may also inhibit cancer. However, enabling cell division is not just about shutting down mechanisms that suppress cancer; our friend the planarian requires the tumour suppressors PTEN and P53 for healing, illustrating that neoblasts are not runaway stem cells.
Insight into our distant relatives suggests that a common vertebrate ancestor may have had a greater capacity for neurogenesis. Both zebrafish and the sea lamprey spectacularly recover from complete spinal cord transection that would paralyze any human. We know that myelin sheath, an axon insulator, inhibits neuron growth in humans, and lamprey axons are not myelinated. However, adult zebrafish can also regenerate, despite requiring myelin for neural function. Both animals can help us understand how it is that they are genetically similar to humans, sharing Alzheimer’s and Parkinson’s susceptibility genes for instance, yet retain ability for neural recovery. Some researchers, such as Dr. Bret Pearson from the Hospital for Sick Children (Toronto, Ontario), may also model adult neurogenesis using the planarian. Additionally, planarians even exhibit powers of recall. Others have observed that regenerated daughter organisms more rapidly reach food within environments that the parent was familiarized with. The study of memory in planarians may have implications for dementia, where memories – on top of neurons – need to be restored.
GENETICS
Immunologist Sir Peter Medawar’s theory of Mutation Accumulation explains that cancer susceptibility genes act later in life, thus providing no reproductive disadvantage and accumulating. Thus, Charles Darwin’s Evolution by Natural Selection fulfills its promise of providing safe passage to reproductive age. Beyond that, gene-environment interactions weigh heavily on disease.
Genome editing can address not only congenital diseases but also cancer. Outside of germ cells and lymphocytes, we have no intrinsic mechanism to introduce new genetic information into adult somatic cells. In contrast, bacteria certainly do not need gene therapy. To make up for asexual reproduction, they routinely undergo horizontal gene transfer through conjugation, allowing rapid public dissemination of antibiotic resistance across disparate species. How’s that for free universal healthcare? Horizontal gene transfer even exists in eukaryotes. In an analysis of just 1% of the genome of freshwater Bdelloids, invertebrate animals, Arkhipova and colleagues identified genes of bacterial, fungal and plant origin.
Our DNA is also susceptible to environmental damage such as UV radiation, which can lead to melanoma. Tardigrades (moss piglets or water bears) can escape extreme radiation doses unscathed through unique DNA-protective proteins. Researchers have demonstrated partial transfer of this resistance to human cell lines. Additionally, entering a (viable) state of desiccation allows these micro-invertebrates to sidestep even the temperature, radiation and vacuum of space, no mini spacesuit and helmet required.
THERE IS GRANDEUR IN THIS VIEW OF LIFE
CLIMATE CHANGE. OVEREXPLOITATION. INDUSTRY. In the grand scheme of things, none of the exceptional organisms discussed can truly live forever. But one thing that does last forever is extinction. Through a selection most unnatural, at least 500 terrestrial animals have gone extinct in the past 500 years, with current extinction rates being 1,000 times over background. Metabolism and homeostasis remain intrinsic and necessary properties of life; by imperiling the very creatures and ecosystems we depend upon, we risk manufacturing our own extinction.
Darwin marveled at biodiversity and the ingenuity of life brought on by 3 billion years of fortuitous events. Maybe we need to rekindle this sense of wonder to restore both ourselves and the planet we inhabit. In the end, our decisions as a species will determine whether “endless forms most beautiful and most wonderful” can arise and persist.
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Justin Chan
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