Paving the way for regenerative medicine

Plants, Salamanders, and Humans

Almost every class of life on earth has some member who can regenerate a lost limb, tail, or appendage. Some Salamanders can regrow their limbs after amputation, some Lizards can regrow their tails, Zebrafish can regrow lost fins, etc. This incredible regenerative ability has been the subject of both intensive medical research and science fiction for the last century.

Even more impressive than regrowing an amputated limb is the fact that almost all plants have the capacity to regrow severed leaves. Some plants even have the incredible regenerative ability to have one of their severed leaves grow roots and even into an entire separate plant.

The ability to regenerate lost body parts can be observed all throughout the plant and animal kingdom with one exception: mammals.

Lets investigate what makes mammals atypical in this aspect.

Temperature and Metabolism

Thermometers make great tools to measure the internal temperature of something. In the context of a biological system we can use internal temperature as an indicator of how high someones metabolic rate is. Stick a thermometer in a human being and it will usually give a reading around 100 degrees (Fahrenheit, obviously). Stick a thermometer in a salamander, and it will give you a reading significantly less than that. If you stick a thermometer in a plant (depending on the location), you will get a temperature reading less than the salamander.

This observation aligns well with our current understanding of metabolism in warm blooded mammals, cold blooded salamanders, and non-blooded plants.

(Note: some pedantic biology nerd will arguably get angry with me for my loose application of the words “cold blooded” and for saying that plants would have a lower internal temperature than a salamander, even though I have explicitly pointed to the context. If the salamander can move, the sum total kinetic energy of every particle in his body is greater than a plant that does not move, in which case his internal temperature would be greater. As for my use of the words “cold blooded” I say “whats in a name?”)

Humans, like all mammals are a walking furnace constantly burning calories to supply our muscles, heart, and allegedly advanced central nervous system with the energy they need to perform their functions. Specifically us humans have sacrificed a lot in terms of our evolutionary biology to have the brains that we have, so it is worth emphasizing just how much we have lost biologically in order to obtain our higher level cognition which allows us to watch YouTube and comment on Instagram posts for hours every day.

Unlike reptiles or plants, humans needed to produce massively larger quantities of ATP(energy) to keep our brains running. A key component to accomplishing this task was to become energy efficient enough for our cells to perform their biological function without consuming too much energy. In order to reach this optimum point of energy efficiency, more compartmentalization and more precise signaling was required to allow for better division of labor among our cells. There were major biological consequences of doing this.

The demand for metabolic efficiency meant we had less energy to devote to maintenance and repair. Division of labor, and by extension more precise signaling made us more prone to diseases both genetic and infectious.

For instance, humans (unlike plants or reptiles) have imprinted regions on some of their chromosomes. Imprinting means that for some chromosome pairs (chromosome 15 for example) each chromosome out of that pair is chemically unique and provides essential information in the development of that organism.

Normally, having chromosomes in pairs provides us with a backup system: if one gene becomes defective the other spare copy can still perform the necessary function (for example, women tend not to display Duchenne muscular dystrophy even if one of their chromosomes contains the defective gene because they inherit two copies of the associated gene, one on each X chromosome). In imprinting, mammals are sacrificing this backup system in exchange for more precise signaling. This gave us the means to divide our labor and increase the energy production in our metabolism. But also lead to increased susceptibility to genetic diseases. Prader Willi and Angelman Syndrome (PWS and AS for short) are both genetic diseases where the effected individual can have perfectly normal chromosomes (no translocation, extra copies, or anything like that) but still have severe cognitive, metabolic, and developmental problems. One cause of PWS or AS is a rare occurrence whereby the child inherits 2 copies of chromosome 15 by one parent only. A phenomenon known as uniparental disomy. Normally we receive two copies of each chromosome from our parents: one from our mom and one from dad. Since imprinting makes each chromosome chemically unique we need to have one copy of chromosome 15 from our mom and one copy from our dad in order to avoid developing either PWS or AS.

(Note: yes there are other ways in which patients can get PWS or AS, im not writing a blog about genetic pathologies, just trying to emphasize the sacrifices we made with genomic imprinting)

Keeping a constant internal body temperature of around 100 degrees gives humans a relatively high metabolism. While this did provide us the energy we needed to keep our brains working, it made us more prone to infections relative to our cold blooded cousins. If you have ever gotten a fever you know that having your body temperature fluctuate by even a few degrees can cause you to start feeling terrible and maybe even hallucinate. This is your body’s own means of trying to fight off an infection by disrupting homeostasis and making your internal environment less stable. This in turn makes it harder for bacteria or some other pathogen to set up shop inside of you.

In the case of salamanders, or other cold blooded animals, their internal temperature fluctuates drastically along with the temperature of their environment. Salamanders dont generate their own internal heat, they rely on the environment to act as the heat source to run their metabolism. Since outside temperatures rise and fall with the times of day, pathogens have a very hard time multiplying and staying alive inside of these incredible animals. This is why infections are far less common among cold blooded animals such as salamanders as opposed to warm blooded mammals like humans.

Since plants and salamanders never had to acquire conscious thought during their evolution, they didn’t have to sacrifice so much to increase their energy production, and as such have more than enough stem cells to regrow and repair lost limbs.

Only through division of labor were we able to become energetically efficient enough to have the necessary fuel to run our brains. One of the ways in which we were able to divide our labor efficiently was by developing many hyperspecialized cell types that fully differentiate into mature cells. By fully differentiating into the various cell types, our tissues were able to devote certain specific tasks to certain cells which enabled our bodies to spend less energy on signaling and multi-task performance. This increased our energy yield, but in doing so we had to sacrifice much of our stem cell population as well as investment in the biochemistry of repair mechanisms. This lowered stem cell population and repair energy in turn, cost us much of our regenerative capacity.

The liver provides a great example of this: the more tasks assigned to that organ or cell type the less efficient it is metabolically but the more regenerative (plastic) it is. This is why your liver is one of the only mammalian organs that can regenerate.

The graph above is merely of concept: As metabolic rate (internal temperature) goes up, regenerative capacity goes down. (The actual relationship is probably not linear).

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