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This article lists notableunsolved problems inbiology.

• Origin of life. Exactly how, where, and when did life onEarth originate? Which, if any, of the many hypotheses is correct? What were the metabolic pathways used by the earliest life forms? How did genetic code originate? What was the molecular mechanism that allows the association of the amino acids with their triplet codons?^[1] What were the biochemical paths from individual bio-building blocks like amino acids or nucleic acids to functional polymers such as proteins and DNA?^[2]
• Origin of sexual reproduction. What were the fundamental selective forces responsible for the origin of sexual reproduction?
• Maintenance of sexual reproduction. What are the fundamental selective forces maintaining sexual reproduction?
• Origins of viruses. Exactly how and when did different groups of viruses originate?
• Morphology problem. How are neural tissues formed in specific ways in different species? The formation of neural tissues in a certain way is necessary for the formation of certain goal-directed behavior for certain species.Developmental psychobiology posed this question since the lack of knowledge about the precise coordination of all cells, even those not related anatomically, in space and time during the embryonic period does not allow us to understand what forces at the cellular level coordinate four very general classes of tissue deformation, namely: tissue folding and invagination, tissue flow and extension, tissue hollowing, and, finally, tissue branching.^[3][4]
• Development andevolution of thebrain. How and why did the brain evolve? What are themolecular determinants of individual brain development?
• Origin ofEukaryotes (Symbiogenesis). How and why did cells combine to form the eukaryotic cell? Did one or more random events lead to the first eukaryotic cells, or can the formation of eukaryotic cells be explained by physical and biological principles? How did the mitochondria's mitosis cycle come in sync with its host cell? Did the mitochondria or the nucleus develop first in eukaryotes?
• Last universal common ancestor. What were the characteristics of the Last Universal Common Ancestor of Archaea and Bacteria?
• Thelipid divide: How didarchaea end up using membraneglycerophospholipids of the opposite chirality compared to bacteria?^[5] Why do eukaryotes have bacteria-type membrane lipids?^[6]

• Biologicalhomochirality. What is the origin of homochirality in living organisms? In biological organisms, amino acids appear almost exclusively in the left-handed form and sugars in the right-handed form. Homochirality is an obvious characteristic of life on Earth, yet extraterrestrial samples contain largelyracemic compounds.^[7] It is not known whether homochirality existed before life, whether the building blocks of life must have this particular chirality, or whether life must be homochiral at all.^[8][9]
• What do all the unknown proteins do? Two decades since the first eukaryotes were sequenced, the "biological role" of around 20% of proteins are stillunknown.^[10] Many of these proteins are conserved across most eukaryotic species and some are conserved in bacteria, indicating a role fundamental for life.^[10][11][12]
• Determinants ofcell size. How do cells determine what size to grow to before dividing?
• Golgi apparatus. Incell theory, what is the exacttransport mechanism by which proteins travel through theGolgi apparatus?
• Mechanism of action of drugs. The mechanisms of action of many drugs includinglithium,thalidomide andketamine^[13] are not completely understood.
• Protein folding. What is the folding code? What is the folding mechanism? Can the native structure of a protein be predicted from its amino acid sequence? Is it possible to predict the secondary, tertiary and quaternary structure of apolypeptide sequence based solely on the sequence and environmental information?^[14][15]
  • Prediction of native structure has turned out to be the easiest of the questions, as the variety of known structures have allowed the development of prediction methods such asRosetta (since 1998) and theAlphaFold neural network of 2020. AlphaFold is capable of predicting a protein's final shape based solely on its amino-acid chain with an accuracy of around 90% on a test sample of proteins used by the team.^[16] Accurate prediction of quaternary structure was achieved by AlphaFold3 in 2024.^[17]
  • Inverse protein-folding problem (protein design): Is it possible to design a polypeptide sequence which will adopt a given structure under certain environmental conditions? This turned out to be tractable given a good structual prediction method, starting with the success of the small globular proteinTop7 from the Rosetta team in 2002.^[18] The use of structure-prediction neural networks afforded even more complex designs.^[19]Large language models trained on protein sequences seem to learn a "grammar"; they represent yet another approach to the protein-design problem.^[20]
  • The success of prediction and design methods still skip overhow proteins end up in the final shape (folding mechanism and kinetics;protein dynamics).Wet lab methods of the 2020s allow for microsecond-level changes to be observed and quantified. 2020smolecular dynamics techniques can be used to simulate the folding behavior at the atomic level to this same timescale, though a specialized computer is needed for the simulation to finish in a reasonable amount of time.^[21] See alsoFolding@home.
  • The study ofintrinsically disordered proteins is also not as advanced as the study of globular proteins: some sequences do not fold into a fixed shape yet still have a function.
• Enzyme kinetics: Why do someenzymes exhibit faster-than-diffusion kinetics?^[22]
• RNA folding problem: Is it possible to accurately predict the secondary, tertiary and quaternary structure of a polyribonucleic acid sequence based on its sequence and environment?
• Protein design: Is it possible to design highly active enzymesde novo for any desired reaction?^[23]
• Biosynthesis: Can desired molecules, natural products or otherwise, be produced in high yield through biosynthetic pathway manipulation?^[24]
• What is themechanism of allosteric transitions of proteins? Theconcerted andsequential models have been hypothesised but neither has been verified.
• What are theendogenousligands oforphan receptors?
• What substance isendothelium-derived hyperpolarizing factor?
• Mechanism ofGolgi's method: Why does this specific method stain nerve tissues? Why does it only color a random portion of the cells?

• Why doesbiological aging occur? There are a number of hypotheses as to why senescence occurs including those that it is programmed by gene expression changes and that it is the accumulative damage of biological structures, particularlydamage to DNA.^[25][26][27]
• How do organs grow to the correct shape and size?^[28] How are the final shape and size of organs so reliably formed? These processes are in part controlled by theHippo signaling pathway.
• Can developing biological systems tell the time?^[28] To an extent, this appears to be the case, as shown by theCLOCK gene.
• Star jelly. A complete explanation about its origins is still lacking.
• Forest rings. The origin of forest rings is not known, despite several mechanisms for their creation having been proposed. Such hypotheses include radially growing fungus, buriedkimberlite pipes, trapped gas pockets, and meteorite impact craters.

• Handedness: It is unclear how handedness develops, what purpose it serves, why right-handedness is far more common, and why left-handedness exists.
• Laughter: While it is generally accepted that laughing evolved as a form of social communication, the exact neurobiological process that leads humans to laugh is not well understood.
• Yawning: It is yet to be established what the biological or social purpose of yawning is.^[29]
• Heritable components ofhomosexuality: How to reconcile evolution with the heritable components of human homosexuality? Homosexuality is prevalent across human societies, past and present. These facts constitute an evolutionary puzzle.^{[30][non-primary source needed]}
• Decline in average human body temperature since the 19th century: Medical data suggests that the average body temperature has declined 0.6 °C since the 19th century. The cause is unclear although it has been suggested that it has some relation with reduced inflammation from reduced exposure to microorganisms.^[31]
• Why are thereblood types? It is unclear what the origin and purpose of having blood types is. It is thought that O blood may be an adaptation to malaria and that different blood types respond to different diseases but this hypothesis has yet to be proven. Why did these antigens develop in the first place? What accounts for the differences in blood type? How ancient are the differences in blood types? What accounts for the large number of rare non ABO blood types? What role do blood types have in fighting disease?^[32]
• Photic sneeze effect: What causes the photic sneeze effect? Why is it so common yet not universal?
• Human sex pheromones: There is contradictory evidence on the existence of human pheromones. Do they actually exist, and if so, how do they affect behavior?^[33]
• Existence of theGrafenberg spot (G-spot): Does the G-spot actually exist? If so is it present in all women? What exactly is it?^[34]
• Extinction ofarchaic humans: Why did archaic human species such asNeanderthals become extinct, leavingHomo sapiens the only surviving species of humans?^[35]
• Love: When didpair bonding evolve? Is pair bonding an antecedent toromantic love, or have there been other steps in the evolution of pair bonds in humans (e.g. a seasonal bond)? A theory exists that romantic love evolved byco-opting the systems for mother-infant bonding, but this does not explain when or why (under whatselection pressure) romantic love evolved.^[36]

Unsolved problems relating to the interactions between organisms and their distribution in the environment include:

• Paradox of the plankton. The highdiversity ofphytoplankton seems to violate thecompetitive exclusion principle.
• Ediacaran biota. How should Ediacaran biota be classified? Even what kingdom they belong to is unclear. Why were they so decisively displaced by Cambrian biota?
• Cambrian explosion. What is the cause of the apparent rapid diversification of multicellular animal life around the beginning of theCambrian, resulting in the emergence of almost all modern animalphyla?
• Darwin's abominable mystery ofbotany/plants. What is the exact evolutionary history offlowers and what is the cause of the apparently sudden appearance of nearly modern flowers in the fossil record?
• Adult form ofFacetotecta. The adult form of this animal has never been encountered in the water, and it remains a mystery what it grows into.
• Origin ofsnakes. Did snakes evolve from burrowing lizards or aquatic lizards? There is evidence for both hypotheses.
• Origin ofturtles. Did turtles evolve fromanapsids ordiapsids? There is evidence for both hypotheses.
• Paleodictyon: What is the origin of this trace fossil and its modern counterparts? Despite many theories proposed, no evidence has been found to confirm any of them.
• Francevillian biota: were they early multicellular organisms?
• Snowball Earth: what was the effect ofCryogenian glaciations on the origin and evolution of early animals?
• Eocyathispongia: is it an earlysponge? Did it havechoanocytes?
• Vernanimalcula guizhouena: is this fossil organism an earlybilaterian?
• Tullimonstrum: a taxonomic position of this fossil organism is unknown.
• Adult form ofPlanctosphaera pelagica, ahemichordate known, as of 2023, only by itstornarialarvae. Due to differences between larvae ofacorn worms and that ofPlanctosphaera pelagica,Planctosphaera is sometimes given its ownclass.
• Xenacoelomorpha: are theydeuterostomes, forming a cladeXenambulacraria together withechinoderms andhemichordates, or rather primitivebilaterians and a sister group toNephrozoa?
• Jennaria pulchra: the taxonomic position of this animal is unknown and more research is needed to establish it.^[39]
• Nervous system ofLobatocerebrida. Why do these simple unsegmentedannelids, which are unselective deposit feeders and lacksense organs, have a relatively complexbrain?^[40]
• Diurodrilus: is it an unusual annelid?^[41][42] What are the origins of morphological similarities betweenDiurodrilus andmicrognathozoanLimnognathia maerski?^[43]
• Taxonomic position ofpentastomids. Are they a sister group toArgulidae or an ancient lineage ofPanarthropoda?
• Taxonomic position ofTricholepidion gertschi: is it a member of the orderZygentoma (silverfishes) or an independent ancient lineage ofinsects?
• How will organisms respond to complex, novel environments? Climate change is of significant relevance.^[44]
• What is the relative importance ofvariability, across scales, and its mechanisms?^[44]
• Why does intragenotypic variability persist? Striking phenotypic differences exist even among individuals with identical genotypes, and environments.^[44]
• What determinespopulation density? There is disagreement over which regulatory mechanisms of population are density-dependent, or density-independent.^[44]
• Why are all leaves the size they are, and not an order of magnitude larger or smaller? How is the upper limit on leaf size set?^[44]
• Persistence paradox: why does the evolution of novel species almost never lead to the extinction of resident species?^[44]
• Is the ecosystem asuperorganism, or a collection of organisms? Couldthe Earth be a superorganism, or aunit of selection?^[44]
• Why doPogonomyrmex badius colonies cover the surface of their nests with a circular region of charcoal pieces?

Unsolved problems relating to the behaviour of animals include:

• Homing. A satisfactory explanation for the neurobiological mechanisms that allow homing in animals has yet to be found.
• Flocking (behavior). How flocks of birds and bats coordinate their movements so quickly is not fully understood. Nor is the purpose of large flocks like those of starlings which seem to invite predators rather than protect them.^[45]
• Butterfly migration. How do the descendants ofmonarch butterfly all over Canada and the US eventually, after migrating for several generations, manage to return to a few relatively small overwintering spots?
• Blue whale. There is not much data on the sexuality of the blue whale.^[46]
• Gall-inducing insects. At least seven groups of insects, in six orders, have independently evolved the gall-inducing habit. Several adaptation hypotheses have been proposed, but it is largely unknown why this habit evolved and how gall-inducing insects induce gall formation in plants; chemical, mechanical, and viral triggers have been discussed.

Unsolved problems relating to the structure and function of non-human organs, processes and biomolecules include:

• Korarchaeota (archaea). The metabolic processes of this phylum of archaea are so far unclear.
• Glycogen body. The function of this structure in the spinal cord of birds is not known.
• Arthropod head problem. A long-standing zoological dispute concerning the segmental composition of the heads of the various arthropod groups, and how they are evolutionarily related to each other.
• Ovaries ofbasking sharks. Only the right ovary in female basking sharks appears to function. The reason is unknown.^[47]
• Brightly colored bird eggs. It is unknown what evolutionary process would lead birds to having brightly colored eggs given the increased visibility to predators.^[48]
• Stegosaur osteoderms/scutes. There is a long-standing debate over whether the primary function of the osteoderms/scutes of stegosaurs is protection from predators, sexual display, species recognition, thermoregulation, or other functions.
• Function ofvanadocytes, a type ofblood cells found in sometunicates.Vacuoles ofvanadocytes are notable for high levels of the metalvanadium and their lowpH.
• Metabolism inHenneguya zschokkei, a species ofmyxozoan. This species ofcnidarian was found to lackmitochondria and, therefore, is incapable ofaerobic respiration.
• Mitochondria inloriciferans living inanoxic conditions. It is unknown whether members of the phylumLoricifera adapted to life in anoxic conditions in theL'Atalante basin, likeSpinoloricus cinziae, havemitochondria.

Unsolved problems inartificial life include:^[49][50]

• How does life arise from thenon-living?
• What are the potentials and limits of living systems?
• How is life related to mind, machines, and culture?

• Unsolved problems in medicine
• List of unsolved problems in neuroscience
• Biological dark matter

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• Lists of unsolved problems

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