Here we have proposed a new biological definition of life based on the function and reproduction of existing genes and creation of new ones, which is applicable to both unicellular and multicellular organisms. First, we coined a new term “genetic information metabolism” comprising functioning, reproduction, and creation of genes and their distribution among living and non-living carriers of genetic information. Encompassing this concept, life is defined as organized matter that provides genetic information metabolism. Additionally, we have articulated the general biological function of life as Tetz biological law: “General biological function of life is to provide genetic information metabolism” and formulated novel definition of life: “Life is an organized matter that provides genetic information metabolism”. New definition of life and Tetz biological law allow to distinguish in a new way living and non-living objects on Earth and other planets based on providing genetic information metabolism.
In the last few decades, there has intensive development in molecular biology and its pervasion into various fields of biology and medicine. In this milieu, it is important to have a biological law that can unify the functions of all living unicellular and multicellular organisms, as well as non-living carriers of genetic information, into a single system of biological definition of life. The formulation of such a law based on the definitions of life and the general biological functions of life will allow the identification of new avenues for drug development and prediction of the results of genetic interventions.
Defining life is important to understand the development and maintenance of living organisms and to answer questions on the origin of life. Several definitions of the term “life” have been proposed (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Although many of them are highly controversial, they are predominantly based on important biological properties of living organisms such as reproduction, metabolism, growth, adaptation, stimulus responsiveness, genetic information inheritance, evolution, and Darwinian approach (1, 2, 3, 4, 5, 15).
As suggested by the Nobel Prize-winning physicist, Erwin Schrödinger, in his influential essay What Is Life ?, the purpose of life relies on creating an entropy, and therefore defined living things as not just a “self-reproducing” entity as living cells involve more than just replication of DNA (10). Some authors have proposed the definition of life predominantly based on the fact of reproduction, such as “Life is metabolizing material informational system with ability of self-reproduction with variations” proposed by Trifonov (14). This definition is close but is a much more minimalistic determination of life compared with the definition of Macklem and Seely - selfcontained, self-regulating, self-organizing, selfreproducing, interconnected, open thermodynamic network of component parts which performs work, existing in a complex regime which combines stability and adaptability in the phase transition between order and chaos, as a plant, animal, fungus, or microbe” (3).
On the contrary, all definitions based on reproduction are limited to events that happen on the Earth, but they should be applicable to other possible forms of life in the universe (3).
Combining various characteristics of living objects, Ruiz-Mirazo et al. defined living entities as “autonomous systems with open-ended evolution capacities, and that all such systems must have a semi-permeable active boundary (membrane), an energy transduction apparatus (set of energy currencies) and, at least, two types of functionally interdependent macromolecular components (catalysts and records)” (13).
Furthermore, for over 200 years, the most influential biologists have discussed the definition and origin of life without precise definitions, with only phenomenological descriptions and explanations (16).
The problems and inaccuracies with the existing definitions of “life” arise due to the appearance of new categories such as artificial life (a-life, synthetic life) and life engineered by redesigning of biological components that is studied in the field of synthetic biology (17, 18, 19). Furthermore, the definition of life must be universal, for both unicellular and multicellular organisms (1, 20). The current definitions of life correspond to the phenomenon of life; but in our opinion, they do not reflect the connection of the three-domain system of Archaea, Bacteria, and Eukarya proposed by Woese in the united network of the essence of life and do not reflect interactions with nonliving objects (21).
Here, we propose a new definition of life, “Life is an organized matter that provides genetic information metabolism”. We defined “genetic information metabolism” as the process responsible for, and involved in, DNA and RNA replication, methylation, repair, mutation, transcription, recombination, survival, and their spreading in both unicellular and multicellular organisms. Based on the above, we have articulated the general biological functions of life as the Tetz biological law “General biological function of life is to provide genetic information metabolism”.
We also describe the general biological functions of life as the Tetz biological law based on the Pangenome concept (22, 23). The Pangenome concept is the collective genetic system of all living organisms and comprises the organic molecules and their complexes (DNA- and RNA-containing viruses, plasmids, transposons, and insertion sequences) that are involved in the storage and transmission of genetic information (24, 25, 26, 27). The Pangenome concept has been proposed as a common platform uniting both living and non-living parts of nature, and it focuses on the properties of all objects carrying genetic information. The Pangenome is hypothesized to respond to environmental changes as a whole, independently from any individual species, through the development, maintenance, and distribution of modified genes for use by multiple organisms, including unrelated ones. Building on the Pangenome concept, we divided all the carriers of genetic information included in the Pangenome into the categories of “living” and “non-living”. Living carriers include all unicellular and multicellular organisms, while non-living objects that contain genetic information including viruses, plasmids, transposons, and extracellular DNA and RNA. Here, we have collectively termed all of these non-living objects as “non-living genetic elements” (NLGEs).
The definition of viruses as non-living entities is consistent with that of many authors; however, their definitions are based on other characteristics such as lack of cell metabolism and the fact that viruses do not reproduce by themselves (28). As viruses evolve, certain characteristic of living organisms, as suggested by some authors, can be transferred into viruses, making them living organisms, considering that all biological entities that actively participate in the process of life are living (29, 30).
According to our definition of life, viruses are considered non-living as they do not provide “genetic information metabolism”, which distinguishes them from living objects.
Living organisms depend on NLGEs for the distribution and spreading of their genetic information during horizontal gene transfer (HGT; also known as lateral gene transfer) (31, 32). One of the most common mechanisms of acquiring antibiotic resistance is due to HGT implemented with plasmids, bacteriophages, cell-free DNA, and other NLGEs (33, 34). Recent studies have also demonstrated gene transfer between phylogenetically distinct organisms, such as between eukaryotic cells and bacteria, and vice versa (35, 36, 37). It has been demonstrated that bacteria have even acquired genetic material from the human genome (38). Moreover, some bacteriophages have been found to harbor eukaryotic genes (39). The primary goal of NLGEs in the maintenance of living organisms is highlighted by their global distribution. The total number of NLGEs in the environment exceeds the number of unicellular and multicellular organisms by many times. Indeed, it is estimated that there are >1031 phage particles in the ocean, the adult human contains >1015 bacteriophages, and marine sediments are believed to contain >0.45 gigatons of cell-free DNA and extracellular DNA (eDNA) (40, 41). eDNA and eRNA are released and are present in most terrestrial and aquatic environments, in bacterial and fungal biofilms, and in animal and human blood, where they play an important role in the distribution of genes and are frequently acquired by other organisms (42, 43, 44, 45, 46). We believe that generation and propagation of modified genes occur in the cells of living carriers, while their distribution among the microbiome involves the active participation of NLGEs. Indeed, the formation of new genes is possible only in living organisms as a result of various changes in the genome. Both living and non-living organisms containing genetic information are involved in the distribution of modified genes.
In the context of the Pangenome concept, as articulated above, the specific functions of living organisms must include the following four processes (also shown in Figure 1):
(1) Supporting the functioning of existing genes; (2) Enabling the modification of existing genes and the formation of new genes; (3) Increasing the copy numbers of modified and new genes; and (4) Distributing modified and new genes within the Pangenome, which is necessary for its improvement.
The functioning of existing genes needed to maintain the organism’s life includes a variety of processes related to replication, modification, reparation, transcription, and translation.
The formation of modified and new genes in the Pangenome refers to the formation of modified and new genes in any unicellular or multicellular organisms.
Increasing the copy number of modified or new genes is an important process in introducing new phenotypic traits into the microbiome. It is assumed that modified genes are often propagated, while new genes have a high rate of extinction, which explains why the total number of genes in the Pangenome remains relatively constant (47).
However, it has been demonstrated that the new genes can sometimes be retained and propagated, which increases the probability of their widespread distribution in the Pangenome (48).
Increases in the copy numbers of modified and new genes occur by cell division and gene amplification both within the cell genome structure and as mediated by NLGEs. After capturing a gene during integrative infection, NLGEs can propagate it via their subsequent genomic replication cycles.
The fourth process of living organisms, as outlined above, is the distribution of modified or new genes among other organisms and/ or NLGEs. The dissemination of genes includes their transfer to various related and unrelated eukaryotic and prokaryotic organisms, including those that are geographically remote and located in different ecological niches. There are various methods of gene transfer, such as via migration of the animals, distribution of the plants and seeds, flow of water, and air. Genes can be transported within the genome of living organisms or as molecules of DNA and RNA within NLGEs. Among the methods of gene transfer between organisms, food chains play a vital role by facilitating direct contact among macrobiota and microbiota in the roles of predator and prey. The available data suggest that microbiota can not only send genes to and receive genes from other microorganisms but can also acquire genes of its host and other microbiota ingested by its host as food.
It is possible that genes can be disseminated between multicellular organisms via their distribution among the unicellular microbiota of one multicellular host, followed by gene transfer to the microbiota of a second host and then to the second host itself. It is known that horizontal gene transfer has played an important role in prokaryotic and eukaryotic genome evolution (49). It is believed that most, but not all, of the functionally significant HGT to eukaryotes is mediated by bacteria, in part due to chance, but probably also because bacteria have a great metabolic diversity (50, 51).
In this case, the behavior of consuming excrement that is widespread among animals can be considered as a fast way of distributing genetic information among the microbiotas of genetically related and unrelated multicellular organisms. The existence of such a HGT pathway is proven by data demonstrating the transfer of genes in different directions between fungi, bacteria, animal cells, and human cells, which plays an important role in increasing variability and adaptation (50, 52, 53, 54, 55, 56) The transportation of genes directly into cells occurs by transformation, transduction, and conjugation (57).
As stated above, genetic information metabolism includes the replication of genetic information, modification of gene functions by methylation, repair of DNA and RNA, alteration of DNA by mutation and recombination, transcription, saving of DNA in living objects and NLGEs, and spreading of DNA and RNA by transformation, transduction, conjugation, type 6 secretion, and membrane vesicles (58, 59, 60, 61). We suggest that, by this definition, living organisms can be distinguished from non-living objects (including those carrying genetic information), by their role and participation in all the processes of genetic information metabolism. Living organisms differ from non-living carriers of genetic information in that they proceed with all processes of genetic information metabolism, whereas NLGEs participate only in the recombination, mutation and spreading of genetic material (35, 54, 61, 62, 63, 64).
Therefore, the general biological function is identical for both uni- and multi-cellular organisms and links living organisms with NLGEs, which are essential for a certain stages of genetic information metabolism. Such an identification of the general biological functions of life will allow the re-estimation of traditional approaches of the cross-talk of living objects with non-living genetic elements.
Here, the novel definition of life and the Tetz biological law were considered a part of the first theoretical framework that unites the functions of all living unicellular and multicellular organisms, as well as non-living carriers of genetic information, into a single system, based on the “genetic information metabolism.”
We suggest that “genetic information metabolism” could also reflect the purpose of existence of life from a biological perspective. The processes that are a part of genetic information metabolism overlap and are key biological events that combine many well-established purposes of life in both unicellualar and multicellular organisms suggested by different authors, such as perpetuate life, reproduction, reproduction of genes, and evolution (including genome evolution) (65).
It should be noted that NLGEs are not classified as living organisms by any existing definition, and they are often not adequately considered within the theories and models of biology, evolutionary science, and other life sciences. At the same time, according to Tetz biological law, it is obvious that NLGEs play an important role in maintaining life within the Pangenome by participating in the implementation of the general biological functions of life, including the distribution of newly created genetic elements between different organisms.
In conclusion, the proposed definition of life reflects the phenomenon of life based on its completeness of genetic information metabolism. While on one hand, the definition distinguishes between living entities and inanimate objects in a sharp manner, on the other hand, it includes them in the linked network based on their role in genetic information.
1 Chodasewicz K. Evolution, reproduction and definition of life. Theory in Biosciences. 2013;133:39-45. Search in Google Scholar
2 Koshland Jr D. Special Essay: The Seven Pillars of Life. Science. 2002;295:2215-2216. Search in Google Scholar
3 Macklem PT, Seely A. Towards a Definition of Life. Perspectives in Biology and Medicine. 2010;53:330-340. Search in Google Scholar
4 Tirard S, Morange M, Lazcano A. The Definition of Life: A Brief History of an Elusive Scientific Endeavor. Astrobiology. 2010;10:1003-1009. Search in Google Scholar
5 Neuman Y. The Definition of Life and the Life of a Definition. Journal of Biomolecular Structure and Dynamics. 2012;29:643-646. Search in Google Scholar
6 Szathmáry E, Smith J. The major evolutionary transitions. Nature. 1995;374:227-232. Search in Google Scholar
7 Muller HJ. The gene material as the initiator and the organizing basis of life. The American Naturalist. 1966;100:493-517. Search in Google Scholar
8 Korzeniewski B. Cybernetic formulation of the definition of life. Journal of Theoretical Biology. 2001;209:275-286. Search in Google Scholar
9 Weber BH. What is life? Defining life in the context of emergent complexity. Orig Life Evol Biosph. 2001;40:221-229. Search in Google Scholar
10 Schrodinger E. What is Life? The Physical Aspect of the Living Cell. The American Naturalist 1945;79:554-555. Search in Google Scholar
11 Davies P. The Demon in the Machine. How Hidden Webs of Information Are Finally Solving the Mystery of Life. London: Allen Lane 2019:. Search in Google Scholar
12 Forterre P. To be or not to be alive: How recent discoveries challenge the traditional definitions of viruses and life. Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 2016;59:100-108. Search in Google Scholar
13 Ruiz-Mirazo K, Peretó J, Moreno A. A Universal Definition of Life: Autonomy and Open-Ended Evolution. Origins of Life and Evolution of the Biosphere 2004;34:323-346. Search in Google Scholar
14 Trifonov E. Vocabulary of Definitions of Life Suggests a Definition. Journal of Biomolecular Structure and Dynamics 2011;29:259-266. Search in Google Scholar
15 Bedau M, Church G, Rasmussen S, Caplan A, Benner S, Fussenegger M, et al. Life after the synthetic cell. Nature. 2010;465:422-424. Search in Google Scholar
16 Tirard S. Origin of Life and Definition of Life, from Buffon to Oparin. Origins of Life and Evolution of Biospheres 2010;40:215-220. Search in Google Scholar
17 Witze A. Light in the dark: Factory of life: Synthetic biologists reinvent nature with parts, circuits. Science news. 2013;183:22-28. Search in Google Scholar
18 Bedau MA, McCaskill JS, Packard NH, Rasmussen S, Adami C, Green DG, et al. Open problems in artificial life. Artificial life. 2000;6:363-376. Search in Google Scholar
19 Farmer JD. Belin A. Artificial life: the coming evolution. See Langton et al. 1992, 815-840. Search in Google Scholar
20 Dupré J, O’Malley MA. Varieties of living things: life at the intersection of lineage and metabolism. Philosophy & Theory in Biology. 2009:1. Search in Google Scholar
21 Woese CR, Fox GE. Phylogenetic structure of the prokaryotic domain: the primary kingdoms. Proceedings of the National Academy of Sciences. 1977;74:5088-5090. Search in Google Scholar
22 Tetz G, Tetz V. Tetz’s theory and law of longevity. Theory in Biosciences. 2018:1-10. Search in Google Scholar
23 Tetz VV. The Pangenome concept: a unifying view of genetic information. Med Sci Monit. 2005;11:HY24-29 Search in Google Scholar
24 Andersson JO. Lateral gene transfer in eukaryotes. CMLS. 2005;62:1182-1197. Search in Google Scholar
25 Boto L. Horizontal gene transfer in evolution: facts and challenges. Proc R Soc Lond B Biol Sci. 2010;277:819-827. Search in Google Scholar
26 Robinson KM, Sieber KB, Hotopp JCD. A review of bacteria-animal lateral gene transfer may inform our understanding of diseases like cancer. PLoS Genet, 2013;9:e1003877. Search in Google Scholar
27 Yue J Hu X, Sun H, Yang Y, Huang J. Widespread impact of horizontal gene transfer on plant colonization of land. Nat Commun. 2012;3:1152. Search in Google Scholar
28 Moreira D, López-García P. Ten reasons to exclude viruses from the tree of life. Nature Reviews Microbiology. 2009;7(4):306. Search in Google Scholar
29 Forterre P. To be or not to be alive: How recent discoveries challenge the traditional definitions of viruses and life. Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 2016;59:100-108. Search in Google Scholar
30 Hegde N, Maddur M, Kaveri S, Bayry J. Reasons to include viruses in the tree of life. Nature Reviews Microbiology 2009;7:615-615. Search in Google Scholar
31 Dröge M, Pühler A, Selbitschka W. Horizontal gene transfer as a biosafety issue: A natural phenomenon of public concern. Journal of Biotechnology 1998;64:75-90. Search in Google Scholar
32 Canchaya C, Fournous G, Chibani-Chennoufi S, Dillmann ML, Brüssow H. Phage as agents of lateral gene transfer. Current opinion in microbiology. 2003;6:417-424. Search in Google Scholar
33 Normark BH, Normark S. Evolution and spread of antibiotic resistance. Journal of internal medicine. 2002;252:91-106. Search in Google Scholar
34 Gay PB, Gillespie S. H. Antibiotic resistance markers in genetically modified plants: a risk to human health? The Lancet infectious diseases. 2005;5:637-646. Search in Google Scholar
35 Lacroix B, Citovsky V. Transfer of DNA from Bacteria to Eukaryotes. MBio. 2016;7:e00863-16. Search in Google Scholar
36 Gay PB, Gillespie SH. Antibiotic resistance markers in genetically modified plants: a risk to human health? The Lancet infectious diseases. 2005;5:637-646. Search in Google Scholar
37 Hotopp JCD, Clark ME, Oliveira DC, Foster JM, Fischer P, Torres MCM, et al. Widespread lateral gene transfer from intracellular bacteria to multicellular eukaryotes. Science. 2007;317:1753-1756. Search in Google Scholar
38 Salzberg SL, White O, Peterson J, Eisen JA. Microbial genes in the human genome: lateral transfer or gene loss? Science. 2001;292:1903-1906. Search in Google Scholar
39 Anderson MT, Seifert HS. Opportunity and means: horizontal gene transfer from the human host to a bacterial pathogen. MBio, 2011;2:e00005-11. Search in Google Scholar
40 Bordenstein SR, Bordenstein SR. Eukaryotic association module in phage WO genomes from Wolbachia. Nature communications. 2016;7. Search in Google Scholar
41 Dell’Anno A, Danovaro R. Extracellular DNA plays a key role in deep-sea ecosystem functioning. Science, 2005;309:2179-2179. Search in Google Scholar
42 Tetz G, Tetz V. Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model. Gut Pathogens. 2016;8:33. Search in Google Scholar
43 Butt AN, Swaminathan R. Overview of circulating nucleic acids in plasma/serum. Annals of the New York Academy of Sciences. 2008;1137:236-242. Search in Google Scholar
44 Mao D, Luo Y, Mathieu J, Wang Q, Feng L, Mu Q, et al. Persistence of Extracellular DNA in River Sediment Facilitates Antibiotic Resistance Gene Propagation. Environmental Science & Technology. 2013;48:71-78. Search in Google Scholar
45 Steinberger RE, Holden PA. Extracellular DNA in single-and multiple-species unsaturated biofilms. Applied and environmental microbiology, 2005;71:5404-5410. Search in Google Scholar
46 Tetz GV, Artemenko NK, Tetz VV. Effect of DNase and antibiotics on biofilm characteristics. Antimicrobial agents and chemotherapy. 2009;53:1204-1209. Search in Google Scholar
47 Schlotterer C. Genes from scratch–the evolutionary fate of de novo genes. TIG. 2015;31:215-219. Search in Google Scholar
48 Presgraves DC. Evolutionary genomics: new genes for new jobs. Cur Biol. 2005: 15, R52-R53. Search in Google Scholar
49 Keeling PJ, Palmer JD. Horizontal gene transfer in eukaryotic evolution. Nat Rev Genet. 2008;9:605-618. Search in Google Scholar
50 Gamieldien J, Ptitsyn A, Hide W. Eukaryotic genes in Mycobacterium tuberculosis could have a role in pathogenesis and immunomodulation. TIG;2002:18, 5-8. Search in Google Scholar
51 Keeling PJ. Functional and ecological impacts of horizontal gene transfer in eukaryotes. Curr Opin Genetics Dev. 2009;19:613-619. Search in Google Scholar
52 Acuña R, Padilla BE, Flórez-Ramos CP, Rubio JD, Herrera JC, Benavides P, et al. Adaptive horizontal transfer of a bacterial gene to an invasive insect pest of coffee. PNAS. 2012: 109,4197-4202. Search in Google Scholar
53 Boto L. Horizontal gene transfer in the acquisition of novel traits by metazoans. In Proc. R. Soc. B. 2014;1777:2450. Search in Google Scholar
54 Rogers MB, Watkins RF, Harper JT, Durnford DG, Gray MW, Keeling PJ. A complex and punctate distribution of three eukaryotic genes derived by lateral gene transfer. BMC Evolutionary Biology. 2007;7:1. Search in Google Scholar
55 Waters V. Conjugation between bacterial and mammalian cells. Nature Genetics. 2001;29:375-376. Search in Google Scholar
56 Wenzl P, Wong L, Kwang-won K, Jefferson RA. A functional screen identifies lateral transfer of β-glucuronidase (gus) from bacteria to fungi. Mol Biol Evol. 2005;22:308-316. Search in Google Scholar
57 O’Connell M. Genetic transfer in procaryotes: transformation , transduction, and conjugation. In: Puhler A, Timmis K , editors. Advance molecular genetics. Springer Verlag , Berlin, Germany. 1984;pp. 2-13. Search in Google Scholar
58 Christie PJ, Vogel JP. Bacterial type IV secretion: conjugation systems adapted to deliver effector molecules to host cells. Trends in microbiology. 2000;8:354-360. Search in Google Scholar
59 Ochman H, Lawrence JG, Groisman EA. Lateral gene transfer and the nature of bacterial innovation. Nature. 2000;405:299. Search in Google Scholar
60 Renelli M, Matias V, Lo RY, Beveridge TJ. DNA-containing membrane vesicles of Pseudomonas aeruginosa PAO1 and their genetic transformation potential. Microbiology. 2004;150:2161-2169. Search in Google Scholar
61 Canchaya C, Proux C, Fournous G, Bruttin A, Brüssow H. Prophage genomics. Microbiology and Molecular Biology Reviews. 2003;67(2) :238-276. Search in Google Scholar
62 Lorenz MG, Wackernagel W. Bacterial gene transfer by natural genetic transformation in the environment. Microbiological reviews. 1994: 58, 563-602. Search in Google Scholar
63 Nielsen KM, Johnsen PJ, Bensasson D, Daffonchio D. Release and persistence of extracellular DNA in the environment. Environmental biosafety research. 2007;6:37-53. Search in Google Scholar
64 Harrison E, Brockhurst MA. Plasmid-mediated horizontal gene transfer is a coevolutionary process. Trends in microbiology. 2012;20:262-267. Search in Google Scholar
65 Dawkins R. The Selfish Gene. Oxford, England: Oxford University Press; 1976; Life-Centered Ethics, And The Human Future In Space. Search in Google Scholar