Curated by UCL

Unlocking the Genetic Code of Human Hibernation

Conventional science fiction concepts of human hibernation conjure up romanticized notions of glossy hibernation pods harboring humans in “hypersleep,” thanks to the works of films such as the 1979 classic Alien.  But how far-reaching are these films? Is it an achievable feat to induce a hibernation-like state in humans? The dream of science fiction storywriters may soon become a reality as researchers now work to uncover the mysteries of hibernation hidden deep within the genetic code. Hibernation is one of the most extreme examples of survival tactics that mammals living in seasonal environments exploit when resource limitation poses a threat to survival.[1] Hibernation, a radical deviation from mammalian homeostasis, involves a complex host of physiological changes; for example: heart rate is lowered to 2-3 beats per minute, body temperature plummets to ambient levels, and brain activity nearly ceases.[2][3][4] The remarkable physiology exhibited by hibernating species would normally be detrimental, even fatal, to non-hibernators; however, hibernators exhibit these drastic responses without ill effect.

breifing_imageScientists now believe that these drastic alterations from normal mammalian physiology are governed by underlying changes in gene expression.[5][2] Regulation of gene expression originates from either environmental or internal signals and manifests as the constellation of physiological changes that defines hibernation. In the early 1990’s, scientists investigating biochemical changes during hibernation in ground squirrels—a model laboratory hibernating species—documented the first gene exhibiting differences in expression levels between ground squirrels’ active state and when the animals were deep in hibernation. This gene, alpha-2-Macroglobulin (A2M), which functions to inhibit blood clotting, displays higher levels of expression when an animal is hibernating relative to its active state.[6] This is especially important for survival during hibernation as circulation is nearly arrested due to a reduction in heart rate, increasing the potential risk for fatal blood clots to form during venous stasis.

As core body temperature is lowered to a few degrees above ambient during hibernation, it follows that fundamental physiological and cellular processes would be reduced due to enzymatic temperature effects alone. However, the discovery that specific genes, like A2M, are up-regulated during hibernation instead of being decreased as expected, indicates that these molecules are functionally important for the maintenance of hibernation.[6][7][8] These differentially expressed transcripts could provide vital clues to metabolic functions that are imperative for survival during hibernation—and that is exactly where scientists are digging for answers.

With the advent of next-generation high-throughput sequencing techniques, it has become technologically possible to take a systematic look at how differentially expressed genes function in concert to regulate complex behaviors, like hibernation, without the need for previously known genetic information.[9][10][11] Typically, these studies explore how genetic regulation may be correlated with hibernation by sampling a variety of tissues, such as the brain or liver, at different phases of the annual cycle–for example, when an animal is active versus when it is hibernating.[8][12] Gene expression profiles are identified and compared between time points, allowing researchers to pinpoint those differentially expressed genes that may be crucial players in the hibernation response.

Up until now, much of this work has been done in model mammalian hibernating species such as ground squirrels. Scientists working with these species have identified key genes that show differential expression between hibernation and active states that are similar to genes also found in the human genome.[8][12] This discovery has guided some to suggest that all mammals, including humans, may carry the genes necessary for hibernation but that the hibernation response is only activated through a unique pattern of gene expression.[6][2] This, then, begs the question: Is it really possible that humans may possess the genetic machinery required for hibernation?

Although this query remains unanswered and highly contentious, a hibernating primate model may provide some insights. The discovery that a genus of lemur is capable of natural hibernation created waves in the world of hibernation research when its unique metabolic profiles were documented for the first time by a team of German researchers in 2004.[13] These primates, found only on the island of Madagascar, belong to a group of lemurs collectively known as dwarf lemurs and can hibernate for up to eight months in certain geographic regions. They are significant given the fact that they are the closest genetic relatives to humans that exhibit long-term, natural hibernation. Using next-generation sequencing approaches to delve deeper into the genetic mechanisms that control hibernation in dwarf lemurs may provide some unique clues to how a hypometabolic state might be regulated within these exceptional primates and, by extension, offer hints to how human hibernation might someday be possible.

The use of human hibernation for interstellar space travel may still exist only in the minds of science fiction writers; however, further investigations using animal models that can survive extreme physiological changes during hibernation may lead to breakthrough medical treatments to improve the human condition. For example, understanding the mechanisms of how peripheral tissues withstand insufficient blood flow during hibernation might lead to better technologies for neuroprotection during stroke or brain trauma; elucidating the ways in which hibernating animals avoid atrophy following muscle disuse during 8-month inertia bouts might better the lives of immobilized or bed-ridden humans; and ascertaining how animals in hibernation can rely solely on stored fat as fuel will indeed have immediate benefits for understanding obesity and other metabolic disorders. By exploiting new innovations in molecular biology, such as next generation sequencing technologies, scientists will certainly accelerate the application of hibernation-induction strategies to the clinic. Is the key to human hibernation truly hidden within our own genetic code? Scientists might someday have the answer.

References

  1. Boyer, BB and Barnes, BM, Molecular and metabolic aspects of mammalian hibernation, Bioscience 49, pp. 713–72, 1999.
  2. Carey, HV and Andrews, MT and Martin, SL, Mammalian hibernation: Cellular and molecular responses to depressed metabolism and low temperature, Physiological Reviews 83, pp. 1153–1181, 2003.
  3. Morin, Pier and Storey, Kenneth B, Mammalian hibernation: differential gene expression and novel application of epigenetic controls, The International Journal of Developmental Biology 53, pp. 433–44, 2009.
  4. Geiser, Fritz, Metabolic rate and body temperature reduction during hibernation and daily torpor, Annual review of physiology 66, pp. 239–274, 2004.
  5. Andrews, Matthew T, Advances in molecular biology of hibernation in mammals, BioEssays 29, pp. 431–440, 2007.
  6. Srere, HK and Wang, LCH and Martin, SL, Central role for differential gene expression in mammalian hibernation, Proceedings Of The National Academy Of Sciences Of The United States Of America 89, pp. 7119–7123, 1992.
  7. O'Hara, B F and Watson, F L and Srere, H K and Kumar, H and Wiler, S W and Welch, S K and Bitting, L and Heller, H C and Kilduff, T S, Gene expression in the brain across the hibernation cycle, The journal of neuroscience 19, pp. 3781–3790, 1999.
  8. Hampton, Marshall and Melvin, Richard G and Kendall, Anne H and Kirkpatrick, Brian R and Peterson, Nichole and Andrews, Matthew T, Deep sequencing the transcriptome reveals seasonal adaptive mechanisms in a hibernating mammal, PLoS ONE 6, p. e27021, 2011.
  9. Collins, L J, An approach to transcriptome analysis of non-model organisms using short-read sequences, pp. 1–12, 2008.
  10. Gayral, Phillipe and Weiner, Lucy and Chiari, Ylenia and Tsagkogeorga, Georgia and Ballenghien, Marion and Galtier, Nicholas, Next-generation sequencing of transcriptomes: a guide to RNA isolation in non-model animals, Molecular Ecology Resources 11, pp. 650–661, 2011.
  11. Metzker, Michael L, Sequencing technologies--the next generation, Nature Reviews Genetics 11, pp. 31–46, 2009.
  12. Schwartz, Christine and Hampton, Marshall and Andrews, Matthew T, Seasonal and regional differences in gene expression in the brain of a hibernating mammal, PLoS ONE 8, p. e58427, 2013.
  13. Dausmann, KH and Glos, J and Ganzhorn, JU and Heldmaier, G, Hibernation in a tropical primate, Nature 429, pp. 825–826, 2004.

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