Theory of Intelligent Design, the best explanation of Origins

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Open questions in biology, biochemistry, and evolution

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Open questions in biology, biochemistry, and evolution

When methodological naturalism is applied, the only explanation for the origin of life is abiogenesis, and of biodiversity, Darwins Theory of evolution. Proponents repeat like a mantra : Evolution is a fact. If that were the case, there would exist far more convincing , clear scientific answers to  almost all relevant scientific questions and issues. This is far from being the case. Based on scientific papers, quite a different picture arises. Instead of compelling answers, questionmarks and lack of understanding, generalized ignorance in regard of almost all relevant issues,  and conceptual problems are the most common. Since the information is widely sparse and scattered amongst thousands of scientific papers, its not so evident that this is the factual state of matter. The general public is duped by effect slogans, that give the false impression of certainty of naturalism. The standard answer, when proponents of naturalism are confronted with this situation, is: "We are working on it". Or: "We don't know yet".

As if naturalism would be the answer in the future, no matter what. Aren't these not a prima facie of  " evolution of the gaps" arguments ? The question is: If a certain line of reasoning  is not persuasive or convincing, or only leads to dead ends, then why do proponents of materialism not change their mind because of it? The more scientific papers are published, the less likely the scenario of evolution  and abiogenesis and cosmic evolution becomes. The gaps are NOT being closed. They widen more and more. Some evolutionary predictions have even been falsified. We should consider the fact that modern biology may have reached its limits on several key issues and subjects. All discussions on principal theories and experiments in the field either end in vague suppositions and guesswork, statements of blind faith, made up scenarios,  or in a confession of ignorance.  Fact is  there remains a huge gulf in our understanding… This lack of understanding is not just ignorance about some secondary details; it is a big conceptual gap.  The reach of the end of the road is evident in the matter of almost all major questions.

The major questions of evolutionary novelties and abiogenesis  are very far from being clearly formulated, even understood,  and nowhere near being solved, and for most, there is no solution at all at sight. But proponents of evolution firmly believe, one day a solution will be found. It doesn't take a couple of month, and a new scientific paper with wild speculations about abiogenesis is published, and eagerly swallowed by the anxious public, that finally wants its preferred world view being confirmed.  We don't know yet, therefore evolution and abiogenesis ? That way, the design hypothesis remains out of the equation in the beginning, and out at the end, and never receives a serious and honest consideration. If the scientific evidence does not provide satisfactory explanations through naturalism, why should we not change your minds and look somewhere else ?  I see only one reason : there is a emotional commitment to naturalism. Reason is not on the side of the materialist. The believer in creation IMHO has good reasons to hold his world view. Reason is on his side. The evidence points massive in that direction. There is certainly the opponent just right on the corner, eagerly waiting to claim " argument of ignorance ". Because evolution is not true, intelligent design is ?! I suggest to read the answer here :

If naturalistic explanations of the origin of life are not convincing, why not look somewhere else ?

If a certain line of reasoning  is not persuasive or convincing, then why do atheists not change their mind because of it? The more evolution papers are published, the less likely the scenario becomes. Some assertions have even been falsified. We should consider the fact that modern biology may have reached its limits on several  subjects of biology. All discussions on principal theories and experiments in the field either end in vague suppositions and guesswork, statements of blind faith, made up scenarios,  or in a confession of ignorance.  Fact is  there remains a huge gulf in our understanding… This lack of understanding is not just ignorance about some technical details; it is a big conceptual gap.  The reach of the end of the road is evident in the matter of almost all major questions. The major questions of macro change and abiogenesis  are very far from being clearly formulated, even understood,  and nowhere near being solved, and for most, there is no solution at all at sight. But proponents of evolution firmly believe, one day a solution will be on sight. Isn't that a prima facie of a " evolution of the gap" argument ? We don't know yet, therefore evolution and abiogenesis ? That way, the God hypothesis remains out of the equation in the beginning, and out at the end, and never receives a serious and honest consideration. If the scientific evidence does not provide satisfactory explanations through naturalism, why should we not change your minds and look somewhere else ?

Following a list of open questions and unanswered problems:

Origin and evolution of the genetic code: the universal enigma 1
In our opinion, despite extensive and, in many cases, elaborate attempts to model code optimization, ingenious theorizing along the lines of the coevolution theory, and considerable experimentation, very little definitive progress has been made. Summarizing the state of the art in the study of the code evolution, we cannot escape considerable skepticism. It seems that the two-pronged fundamental question: “why is the genetic code the way it is and how did it come to be?”, that was asked over 50 years ago, at the dawn of molecular biology, might remain pertinent even in another 50 years. Our consolation is that we cannot think of a more fundamental problem in biology.

Modern cells possess a sophisticated metabolic network, but its origins remain largely unknown. 2

Some of the remaining questions associated with it appear, however, to be the most crucial ones. First, how did early biomolecules, supposedly nucleotides, sugars, amino acids and fatty acids, form and reach life compatible concentrations? In this context, one needs to consider how the first forms of geochemical carbon fixation could have taken place [3,4]. Moreover, as life is unlikely to have started in an extreme dilute solution, this suggests that it was, from the beginning, bound by some sort of compartmentalization [5,6]. 32

Cells use sophisticated regulation to transform static genomic information into flexible function. We are still far from understanding how such regulation evolves. 3

Experimental evolution of an alternating uni- and multicellular life cycle in Chlamydomonas reinhardtii
The transition to multicellularity enabled the evolution of large, complex organisms, but early steps in this transition remain poorly understood. 4

Spinach, Or The Search For The Secret Of Life As We Know It
Deep in the heart of this nest of proteins lies the manganese cluster, whose precise arrangement of atoms remains one of biology's outstanding problems. 5

Light-driven oxygen production from superoxide by Mn-binding bacterial reaction centers
One of the outstanding questions concerning the early Earth is how ancient phototrophs made the evolutionary transition from anoxygenic to oxygenic photosynthesis, which resulted in a substantial increase in the amount of oxygen in the atmosphere. 6

Perhaps the most widely discussed yet poorly understood event in the evolution of photosynthesis is the invention of the ability to use water as an electron donor, producing O2 as a waste product and giving rise to what is now called oxygenic photosynthesis. 7

Complex evolution of photosynthesis
The evolutionary path of type I and type II reaction center apoproteins is still unresolved owing to the fact that a unified evolutionary tree cannot be generated for these divergent reaction center subunits 8

The Continuing Puzzle of the Great Oxidation Event
While the rise of oxygen has been the subject of considerable attention by Earth scientists, several important aspects of this problem remain unresolved.  The emergence of oxygen-producing (oxygenic) photosynthesis fundamentally transformed our planet; however, the processes that led to the evolution of biological water splitting have remained largely unknown. 9

Non‐enzymatic glycolysis and pentose phosphate pathway‐like reactions in a plausible Archean ocean
The reaction sequences of central metabolism, glycolysis and the pentose phosphate pathway provide essential precursors for nucleic acids, amino acids and lipids. However, their evolutionary origins are not yet understood. 10

Origin and evolution of metabolic pathway
How the major metabolic pathways actually originated is still an open question, but several different theories have been suggested to account for the establishment of metabolic routes All these ideas are based on gene duplication. 11

The Evolution of Electron-Transport Chains
How did the crucial individual components—ATP synthase, redox-driven H+ pumps, and photosystems—first arise? Hypotheses about events occurring on an evolutionary time scale are difficult to test. 12

Early Fixation of an Optimal Genetic Code
The evolutionary forces that produced the canonical genetic code before the last universal ancestor remain obscure. 13

Non‐enzymatic glycolysis and pentose phosphate pathway‐like reactions in a plausible Archean ocean
The reaction sequences of central metabolism, glycolysis and the pentose phosphate pathway provide essential precursors for nucleic acids, amino acids and lipids. However, their evolutionary origins are not yet understood. 14

Basic functional states in the evolution of light-driven cyclic electron transport
It's a difficult problem for evolutionary theory, to say the least. How, within the available time, and by known mechanisms, did the necessary bacterial proteins arise? "From the data presented," concluded Scherer, "the evolution of cyclic photosynthetic electron transport is an unsolved problem in theoretical biology. On the basis of present understanding, no solution can be expected." 15

Evolutionary Theories On Gender And Sexual Reproduction
Proponents of evolution since have freely admitted that the origin of gender and sexual reproduction still remains one of the most difficult problems in biology 17

Evolutionary Origin of Recombination during Meiosis
The origin of meiosis, and in particular meiotic recombina-tion, is an unresolved mystery in biology

Evolution of Human Language Still a Mystery
“This kind of straightforward connection is just not the way organisms are put together,” he says. When it comes to something as complex as language, “one would be hard-pressed to come up with an example less amenable to evolutionary study.” And the specific Foxp2 connection is based on a whole chain of events, each of which is speculative, so there’s little chance of the whole story being right. 18

"The Integration Hypothesis of Human Language Evolution and Its Implications for the Study of Contemporary Languages"
How human language arose is a great mystery in the evolution of Homo sapiens. 19

Locomotion: The Case for a Designer
Why did vertebrates evolve two additional muscle types? Do we have animals or fossils that demonstrate this transition? The evolutionary theory is unable to answer these questions. 20

Centrosomal RNA correlates with intron-poor nuclear genes in Spisula oocytes
The evolutionary origin of centriole/kinetosomes, centrosomes, and other microtubule organizing centers (MTOCs), whether by direct filiation or symbiogenesis, has been controversial for >50 years. 21

On the Origin of the Canonical Nucleobases: An Assessment of Selection Pressures across Chemical and Early Biological Evolution
The native bases of RNA and DNA are prominent examples of the narrow selection of organic molecules upon which life is based. How did nature “decide” upon these specific heterocycles? Evidence suggests that many types of heterocycles could have been present on the early Earth. The prebiotic formation of polymeric nucleic acids employing the native bases remains, however, a challenging problem to reconcile.   22

Genome-wide analysis reveals origin of transfer RNA genes from tRNA halves.
Transfer RNAs (tRNAs) play an important role linking mitochondrial RNA and amino acids during protein biogenesis. Four types of tRNA genes have been identified in living organisms. However, the evolutionary origin of tRNAs remains largely unknown 23

Evolution of the Lyrebird
Although there is evidence that females choose the males with the most complexity and accuracy in their voice, it remains unclear why these traits would be appealing as evolutionary selection.

Absurd Creature of the Week: This Fish Swims Up a Sea Cucumber’s Butt and Eats Its Gonads
And it’s important to consider that the fish in fact benefits from the evisceration, because by using the sea cucumber as a home, it necessarily adopts its host’s predators. Its survival depends on the sea cucumber’s ability to defend itself, which is quite intriguing from an evolutionary perspective. 24

Absurd Creature of the Week: This Shrew Can Survive You Standing on It (Maybe. Please Don’t Try)
According to Stanley, its spine is, relative to body size, four times more robust than that of any other vertebrate, which poses quite the evolutionary conundrum: This is a singular species whose backbone is miles away from its shrew cousins. There’s a more typical shrew at one extreme and then the hero shrew at the other, with no species in between. This might suggest that the evolution of the robust spine was supremely rapid and dramatic, an evolutionary principle known as punctuated equilibrium, because there are no intermediate forms between the two to indicate a more gradual development. 25

How did teeth evolve in our earliest ancestors?

Every jawed vertebrate needs teeth to function and feed. But exactly how teeth evolved is poorly understood, because it is difficult to interpret different stages of tooth development from fossils.Lead researcher Professor Moya Meredith Smith, Dental Institute at King’s, said: ‘We still don’t have a clear understanding of how dentitions are built. 26

Bioenergetics and Life's Origins
A plausible energy source for polymerization remains an open question. Condensation reactions driven by cycles of anhydrous conditions and hydration would seem to be one obvious possibility, but seem limited by the lack of specificity of the chemical bonds that are formed.  27

I would have thought a bigger question was what drives the relationship between brain evolution and body evolution. I would not expect a single genetic mutation to affect both the brain and what causes a sequence of mutations to converge in such a manner that the brain evolves to match the body functionality and vice versa. Surely for every permanent genetic change there have to be TWO mutations at a time ( one for body, one for brain ) in a long succession of such mutations. How, for example, does a primitive bird's brain know that the creature has developed wings ? 28

Evolution of sex and recombination: data
In summary, much of our work points to coevolutionary interactions with parasites as a mechanism selecting for sexual reproduction over parthenogenesis. There, nonetheless, remain important theoretical (link to theory) and empirical difficulties. For example, critical details regarding the genetic basis of infection have yet to be worked out. 29

How did sex start?
The areas discussed below pose the most profound challenges to evolutionary science. Despite years of research and discussion (and, in some cases, promising directions), there are still no answers. Origin of Sex. Why is sexuality so widespread in nature? How did this maleness and femaleness arise? If it is necessary to maintain genetic variability, why can many microorganisms do without it? How can one account for such phenomena as parthenogenesis: frog eggs, for instance, can produce tadpoles if they are pricked by pins or stimulated by electric current, without having been fertilized by male sperm. 30

Most of the single-celled organisms in the world, like bacteria, reproduce asexually by making copies of themselves. So how did sex come to rule the animal kingdom? Scientists have been trying to figure out the origin of sex for hundreds of years, without much luck.

Asexual reproduction is more convenient and requires less effort: there’s no search for a partner and you get to pass all your genes along, from the U.K.’s National History Museum:
In many ways asexual reproduction is the better evolutionary strategy: only one parent is needed and all of their genes are passed on to the next generation. All bacteria, most plants and even some animals reproduce asexually at least some of the time.
Sex is less efficient. Finding a mate can take time and energy, and any gametes that aren’t fertilised go to waste. Plus, each parent only passes half of its genes to the offspring.

Origin of Life. How did living matter originate out of nonliving matter? Was it a process that happened once or many times? Can it still happen today under natural or artificial conditions? Did it evolve out of the kind of growth and replication processes we see in crystals or on an entirely different basis?
Origin of Sex. Why is sexuality so widespread in nature? How did this maleness and femaleness arise? If it is necessary to maintain genetic variability, why can many microorganisms do without it? How can one account for such phenomena as parthenogenesis: frog eggs, for instance, can produce tadpoles if they are pricked by pins or stimulated by electric current, without having been fertilized by male sperm.
Origin of Language. How did human speech originate? We see no examples of primitive languages on Earth today; all mankind’s languages are evolved and complex. Can the answer be sought in the structure of the brain, experiments on teaching apes, animal communication systems or is there no way to ever find out?
Origin of Phyla. What is the evolutionary relationship between existing phyla and those of the past? There is still no agreement on how many there are today, how many we know from the fossil past and which may have come out of which. Transitional forms between phyla are almost unknown.
Cause of Mass Extinctions. Asteroids are currently in vogue, but far from proven as a cause of world-wide extinctions. And though punctuated equilibrium theory helps account for the so-called sudden appearance of new groups, and long persistence of others, it has raised many new questions about stability and extinction of species.
Relationship between DNA and Pheno­type. Can small steady changes (micromuta­tions) account for evolution, or must there be periodic larger jumps (macromutations)? Is DNA a complete blueprint for the individual, or is it subject to various influences and constraints in its expression? Are there any circumstances under which environment or behavior can work “backwards,” influencing changes in DNA?
How Much Can Natural Selection Explain? Darwin never claimed natural selection is the only mechanism of evolution. Although he considered it a major explanation, he continued to search for others, and the search continues.

Early Evolution of Photosynthesis 31
Evolutionary origins of oxygen evolution center and linked photosystems are important unsolved problems.
To understand the origin and early evolution of photosynthesis, we need to consider mechanisms and evolution of all these subsystems and processes:
Pigments ( Chls , carotenoids, bilins )
Reaction centers (including O2  Evolution Center)
Antenna complexes
Electron transfer pathways
Carbon fixation pathways
Photoprotection mechanisms
Integration into cellular metabolism
No single branching diagram can represent the complex path of evolution of photosynthesis. 
The evolution of PS2 proteins has been partially by gene recruitment and partially by gene duplication, but most of the proteins are orphans, with no known source.
Origin and Evolution of Photosynthesis- Remaining Challenges
Nature of the earliest PS systems not known
Significance of gene duplications in RC evolution not understood
Evolutionary origin of the oxygen evolving complex not known
No good understanding of how two photosystems were linked in series

Theoretical physicist and mathematician Freeman Dyson, “How We Know,” New York Review of Books, March 10, 2011.



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In search of the original flapper... new theory on evolution of flight
"If they were tree dwellers they would naturally hold their forelimbs out symmetrically, as they jumped from branch to branch or from ground to branch," Dr Nudds says. "However, if they were ground dwellers, which fossil studies suggest is more likely, holding the forelimbs out symmetrically would impede progress while running or moving along the ground. So there must have been another reason for this posture to appear."

In his 2001 book, Evolution: The Triumph of an Idea, Carl Zimmer admitted:
Sex is not only unnecessary, but it ought to be a recipe for evolutionary disaster. For one thing, it is an inefficient way to reproduce…. And sex carries other costs as well…. By all rights, any group of animals that evolves sexual reproduction should be promptly outcompeted by nonsexual ones. And yet sex reigns. 2

The Evolution Of Sexual Reproduction
"Sex is the queen of problems in evolutionary biology. Perhaps no other natural phenomenon has aroused so much interest;  certainly none has sowed so much confusion." - Graham Bell, 1982

Solving the Sex Problem in Evolution
Explaining the evolution of sex has been a problem for a very long time. Most ideas have focused on the advantages to populations. For example, sex causes a genetic mixing which is good for a species' survival in a changing environment. Unfortunately evolution can't work on populations - it has to have advantages for the individual as well. This is especially true for sex given its high cost to the individual (the existence of males, sexually transmitted diseases, etc.). 3

A Bioenergetic Basis for Membrane Divergence in Archaea and Bacteria
The archaea and bacteria are the deepest branches of the tree of life. The two groups are similar in morphology and share some fundamental biochemistry, including the genetic code, but the differences between them are stark, and rank among the great unsolved problems in biology.  The composition of cell membranes and walls is utterly different in the two groups, while the mechanism of DNA replication seems unrelated. 4

An Origin-of-Life Reactor to Simulate Alkaline Hydrothermal Vents
Chemiosmotic coupling is universal: practically all cells harness electrochemical proton gradients across membranes to drive ATP synthesis, powering biochemistry. Autotrophic cells, including phototrophs and chemolithotrophs, also use proton gradients to power carbon fixation directly. The universality of chemiosmotic coupling suggests that it arose very early in evolution, but its origins are obscure.The precise mechanisms by which natural proton gradients, H2, CO2 and metal sulphides could have driven organic synthesis are uncertain, and theoretical ideas lack empirical support. de Duve (2005) has asked how biological catalysts, whether enzymes or ribozymes, might have first arisen, to which his “only scientifically plausible explanation” was “by selection”Selection therefore imposes a link between protometabolism and metabolism, providing good grounds for seeking just such a link. This argument is at least parsimonious, and advocates that we should look to life itself for clues to how life arose (Martin et al. 2014). 5

Evolution of vacuolar proton pyrophosphatase domains and volutin granules: clues into the early evolutionary origin of the acidocalcisome
Although the endosymbiotic origin of plastids is well established [4,5], the events that drove the evolution of other sophisticated membrane-bound cellular compartments remain unclear. 6

Post-translational modifications of tubulin
In spite of their extraordinary level of structural conservation, microtubules fulfill a vast range of different functions in cells. How this functional diversity is achieved remains an open question 7

The phylogenetic analysis of tetraspanins projects the evolution of cell–cell interactions from unicellular to multicellular organisms
In animals, the tetraspanins are a large superfamily of membrane proteins that play important roles in organizing various cell–cell and matrix–cell interactions and signal pathways based on such interactions. However, their origin and evolution largely remain elusive and most of the family's members are functionally unknown or less known due to difficulties of study, such as functional redundancy. 8

Evolution of DNA polymerases: an inactivated polymerase-exonuclease module in Pol epsilon and a chimeric origin of eukaryotic polymerases from two classes of archaeal ancestors.
Evolution of DNA polymerases, the key enzymes of DNA replication and repair, is central to any reconstruction of the history of cellular life. However, the details of the evolutionary relationships between DNA polymerases of archaea and eukaryotes remain unresolved. 9

Evolution of Two-Component Signal Transduction
Two-component signal transduction (TCST) systems are the principal means for coordinating responses to environmental changes in bacteria as well as some plants, fungi, protozoa, and archaea. These systems typically consist of a receptor histidine kinase, which reacts to an extracellular signal by phosphorylating a cytoplasmic response regulator, causing a change in cellular behavior. Although several model systems, including sporulation and chemotaxis, have been extensively studied, the evolutionary relationships between specific TCST systems are not well understood, and the ancestry of the signal transduction components is unclear. 10

The evolutionary origins of chordate hematopoiesis and vertebrate endothelia.
The vertebrate circulatory system is the most complex vascular system among those of metazoans, with key innovations including a multi-chambered heart and highly specialized blood cells. Invertebrate vessels, on the other hand, consist of hemal spaces between the basal laminae of epithelia. How the evolutionary transition from an invertebrate-type system to the complex vertebrate one occurred is, however, poorly understood.  11

The Mystery of Human Blood Types
Humans and all other apes share this trait, inheriting these blood types from a common ancestor at least 20 million years ago and maybe even earlier, claims a new study published online today in Proceedings of the National Academy of Sciences. But why humans and apes have these blood types is still a scientific mystery. 12

The invention of platelets
So here we have a complete and unusual system for creating platelets without an obvious evolutionary path toward its accomplishment. Where is there an intermediate between the thrombocytes found in reptiles and birds and the platelets in mammals? What selective advantage do platelets provide and what brought the selective pressure to bear to create this complex system? It is a mystery of punctuated evolution. Readers of Scientia are invited to speculate. 13

The evolutionary origins of chordate hematopoiesis and vertebrate endothelia.
The vertebrate circulatory system is the most complex vascular system among those of metazoans, with key innovations including a multi-chambered heart and highly specialized blood cells. Invertebrate vessels, on the other hand, consist of hemal spaces between the basal laminae of epithelia. How the evolutionary transition from an invertebrate-type system to the complex vertebrate one occurred is, however, poorly understood. 14

Evolutionary Transition of Promoter and Gene Body DNA Methylation across Invertebrate-Vertebrate Boundary
The evolutionary steps leading to the differentiation of invertebrate and vertebrate genomic DNA methylation remain unresolved. 15

The RNA world and the origin of metabolic enzymes
We are far from understanding the origin of life, as several of the problems associated with it are yet unsolved [1,2]. Some of the remaining questions associated with it appear, however, to be the most crucial ones. First, how did early biomolecules, supposedly nucleotides, sugars, amino acids and fatty acids, form and reach life compatible concentrations? 16

2) ...Why is sex a success, despite all its disadvantages? (pp. 230,231, emp. added).

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3 So Much More to Know … on Tue Feb 09, 2016 5:01 pm


So Much More to Know …

From the nature of the cosmos to the nature of societies, the following 100 questions span the sciences. Some are pieces of questions discussed above; others are big questions in their own right. Some will drive scientific inquiry for the next century; others may soon be answered. Many will undoubtedly spawn new questions.

Is ours the only universe?
A number of quantum theorists and cosmologists are trying to figure out whether our universe is part of a bigger “multiverse.” But others suspect that this hard-to-test idea may be a question for philosophers.

What drove cosmic inflation?
In the first moments after the big bang, the universe blew up at an incredible rate. But what did the blowing? Measurements of the cosmic microwave background and other astrophysical observations are narrowing the possibilities.

When and how did the first stars and galaxies form?
The broad brush strokes are visible, but the fine details aren't. Data from satellites and ground-based telescopes may soon help pinpoint, among other particulars, when the first generation of stars burned off the hydrogen “fog” that filled the universe.

Where do ultrahigh-energy cosmic rays come from?
Above a certain energy, cosmic rays don't travel very far before being destroyed. So why are cosmic-ray hunters spotting such rays with no obvious source within our galaxy?

What powers quasars?
The mightiest energy fountains in the universe probably get their power from matter plunging into whirling supermassive black holes. But the details of what drives their jets remain anybody's guess.

What is the nature of black holes?
Relativistic mass crammed into a quantum-sized object? It's a recipe for disaster—and scientists are still trying to figure out the ingredients.

Why is there more matter than antimatter?
To a particle physicist, matter and antimatter are almost the same. Some subtle difference must explain why matter is common and antimatter rare.

Does the proton decay?
In a theory of everything, quarks (which make up protons) should somehow be convertible to leptons (such as electrons)—so catching a proton decaying into something else might reveal new laws of particle physics.

What is the nature of gravity?
It clashes with quantum theory. It doesn't fit in the Standard Model. Nobody has spotted the particle that is responsible for it. Newton's apple contained a whole can of worms.

Why is time different from other dimensions?
It took millennia for scientists to realize that time is a dimension, like the three spatial dimensions, and that time and space are inextricably linked. The equations make sense, but they don't satisfy those who ask why we perceive a “now” or why time seems to flow the way it does.

Are there smaller building blocks than quarks?
Atoms were “uncuttable.” Then scientists discovered protons, neutrons, and other subatomic particles—which were, in turn, shown to be made up of quarks and gluons. Is there something more fundamental still?

Are neutrinos their own antiparticles?
Nobody knows this basic fact about neutrinos, although a number of underground experiments are under way. Answering this question may be a crucial step to understanding the origin of matter in the universe.

Is there a unified theory explaining all correlated electron systems?
High-temperature superconductors and materials with giant and colossal magnetoresistance are all governed by the collective rather than individual behavior of electrons. There is currently no common framework for understanding them.

What is the most powerful laser researchers can build?
Theorists say an intense enough laser field would rip photons into electron-positron pairs, dousing the beam. But no one knows whether it's possible to reach that point.

Can researchers make a perfect optical lens?
They've done it with microwaves but never with visible light.

Is it possible to create magnetic semiconductors that work at room temperature?
Such devices have been demonstrated at low temperatures but not yet in a range warm enough for spintronics applications.

What is the pairing mechanism behind high-temperature superconductivity?
Electrons in superconductors surf together in pairs. After 2 decades of intense study, no one knows what holds them together in the complex, high-temperature materials.

Can we develop a general theory of the dynamics of turbulent flows and the motion of granular materials?
So far, such “nonequilibrium systems” defy the tool kit of statistical mechanics, and the failure leaves a gaping hole in physics.

Are there stable high-atomic-number elements?
A superheavy element with 184 neutrons and 114 protons should be relatively stable, if physicists can create it.

Is superfluidity possible in a solid? If so, how?
Despite hints in solid helium, nobody is sure whether a crystalline material can flow without resistance. If new types of experiments show that such outlandish behavior is possible, theorists would have to explain how.

What is the structure of water?
Researchers continue to tussle over how many bonds each H2O molecule makes with its nearest neighbors.

What is the nature of the glassy state?
Molecules in a glass are arranged much like those in liquids but are more tightly packed. Where and why does liquid end and glass begin?

Are there limits to rational chemical synthesis?
The larger synthetic molecules get, the harder it is to control their shapes and make enough copies of them to be useful. Chemists will need new tools to keep their creations growing.

What is the ultimate efficiency of photovoltaic cells?
Conventional solar cells top out at converting 32% of the energy in sunlight to electricity. Can researchers break through the barrier?

Will fusion always be the energy source of the future?
It's been 35 years away for about 50 years, and unless the international community gets its act together, it'll be 35 years away for many decades to come.

What drives the solar magnetic cycle?
Scientists believe differing rates of rotation from place to place on the sun underlie its 22-year sunspot cycle. They just can't make it work in their simulations. Either a detail is askew, or it's back to the drawing board.

How do planets form?
How bits of dust and ice and gobs of gas came together to form the planets without the sun devouring them all is still unclear. Planetary systems around other stars should provide clues.

What causes ice ages?
Something about the way the planet tilts, wobbles, and careens around the sun presumably brings on ice ages every 100,000 years or so, but reams of climate records haven't explained exactly how.

What causes reversals in Earth's magnetic field?
Computer models and laboratory experiments are generating new data on how Earth's magnetic poles might flip-flop. The trick will be matching simulations to enough aspects of the magnetic field beyond the inaccessible core to build a convincing case.

Are there earthquake precursors that can lead to useful predictions?
Prospects for finding signs of an imminent quake have been waning since the 1970s. Understanding faults will progress, but routine prediction would require an as-yet-unimagined breakthrough.

Is there—or was there—life elsewhere in the solar system?
The search for life—past or present—on other planetary bodies now drives NASA's planetary exploration program, which focuses on Mars, where water abounded when life might have first arisen.

What is the origin of homochirality in nature?
Most biomolecules can be synthesized in mirror-image shapes. Yet in organisms, amino acids are always left-handed, and sugars are always right-handed. The origins of this preference remain a mystery.

Can we predict how proteins will fold?
Out of a near infinitude of possible ways to fold, a protein picks one in just tens of microseconds. The same task takes 30 years of computer time.

How many proteins are there in humans?
It has been hard enough counting genes. Proteins can be spliced in different ways and decorated with numerous functional groups, all of which makes counting their numbers impossible for now.

How do proteins find their partners?
Protein-protein interactions are at the heart of life. To understand how partners come together in precise orientations in seconds, researchers need to know more about the cell's biochemistry and structural organization.

How many forms of cell death are there?
In the 1970s, apoptosis was finally recognized as distinct from necrosis. Some biologists now argue that the cell death story is even more complicated. Identifying new ways cells die could lead to better treatments for cancer and degenerative diseases.

What keeps intracellular traffic running smoothly?
Membranes inside cells transport key nutrients around, and through, various cell compartments without sticking to each other or losing their way. Insights into how membranes stay on track could help conquer diseases, such as cystic fibrosis.

What enables cellular components to copy themselves independent of DNA?
Centrosomes, which help pull apart paired chromosomes, and other organelles replicate on their own time, without DNA's guidance. This independence still defies explanation.

What roles do different forms of RNA play in genome function?
RNA is turning out to play a dizzying assortment of roles, from potentially passing genetic information to offspring to muting gene expression. Scientists are scrambling to decipher this versatile molecule.

What role do telomeres and centromeres play in genome function?
These chromosome features will remain mysteries until new technologies can sequence them.

Why are some genomes really big and others quite compact?
The puffer fish genome is 400 million bases; one lungfish's is 133 billion bases long. Repetitive and duplicated DNA don't explain why this and other size differences exist.

What is all that “junk” doing in our genomes?
DNA between genes is proving important for genome function and the evolution of new species. Comparative sequencing, microarray studies, and lab work are helping genomicists find a multitude of genetic gems amid the junk.

How much will new technologies lower the cost of sequencing?
New tools and conceptual breakthroughs are driving the cost of DNA sequencing down by orders of magnitude. The reductions are enabling research from personalized medicine to evolutionary biology to thrive.

How do organs and whole organisms know when to stop growing?
A person's right and left legs almost always end up the same length, and the hearts of mice and elephants each fit the proper rib cage. How genes set limits on cell size and number continues to mystify.

How can genome changes other than mutations be inherited?
Researchers are finding ever more examples of this process, called epigenetics, but they can't explain what causes and preserves the changes.

How is asymmetry determined in the embryo?
Whirling cilia help an embryo tell its left from its right, but scientists are still looking for the first factors that give a relatively uniform ball of cells a head, tail, front, and back.

How do limbs, fins, and faces develop and evolve?
The genes that determine the length of a nose or the breadth of a wing are subject to natural and sexual selection. Understanding how selection works could lead to new ideas about the mechanics of evolution with respect to development.

What triggers puberty?
Nutrition—including that received in utero—seems to help set this mysterious biological clock, but no one knows exactly what forces childhood to end.

Are stem cells at the heart of all cancers?
The most aggressive cancer cells look a lot like stem cells. If cancers are caused by stem cells gone awry, studies of a cell's “stemness” may lead to tools that could catch tumors sooner and destroy them more effectively.

Is cancer susceptible to immune control?
Although our immune responses can suppress tumor growth, tumor cells can combat those responses with counter-measures. This defense can stymie researchers hoping to develop immune therapies against cancer.

Can cancers be controlled rather than cured?
Drugs that cut off a tumor's fuel supplies—say, by stopping blood-vessel growth—can safely check or even reverse tumor growth. But how long the drugs remain effective is still unknown.

Is inflammation a major factor in all chronic diseases?
It's a driver of arthritis, but cancer and heart disease? More and more, the answer seems to be yes, and the question remains why and how.

How do prion diseases work?
Even if one accepts that prions are just misfolded proteins, many mysteries remain. How can they go from the gut to the brain, and how do they kill cells once there, for example.

How much do vertebrates depend on the innate immune system to fight infection?
This system predates the vertebrate adaptive immune response. Its relative importance is unclear, but immunologists are working to find out.

Does immunologic memory require chronic exposure to antigens?
Yes, say a few prominent thinkers, but experiments with mice now challenge the theory. Putting the debate to rest would require proving that something is not there, so the question likely will not go away.

Why doesn't a pregnant woman reject her fetus?
Recent evidence suggests that the mother's immune system doesn't “realize” that the fetus is foreign even though it gets half its genes from the father. Yet just as Nobelist Peter Medawar said when he first raised this question in 1952, “the verdict has yet to be returned.”

What synchronizes an organism's circadian clocks?
Circadian clock genes have popped up in all types of creatures and in many parts of the body. Now the challenge is figuring out how all the gears fit together and what keeps the clocks set to the same time.

How do migrating organisms find their way?
Birds, butterflies, and whales make annual journeys of thousands of kilometers. They rely on cues such as stars and magnetic fields, but the details remain unclear.

Why do we sleep?
A sound slumber may refresh muscles and organs or keep animals safe from dangers lurking in the dark. But the real secret of sleep probably resides in the brain, which is anything but still while we're snoring away.

Why do we dream?
Freud thought dreaming provides an outlet for our unconscious desires. Now, neuroscientists suspect that brain activity during REM sleep—when dreams occur—is crucial for learning. Is the experience of dreaming just a side effect?

Why are there critical periods for language learning?
Monitoring brain activity in young children—including infants—may shed light on why children pick up languages with ease while adults often struggle to learn train station basics in a foreign tongue.

Do pheromones influence human behavior?
Many animals use airborne chemicals to communicate, particularly when mating. Controversial studies have hinted that humans too use pheromones. Identifying them will be key to assessing their sway on our social lives.

How do general anesthetics work?
Scientists are chipping away at the drugs' effects on individual neurons, but understanding how they render us unconscious will be a tougher nut to crack.

What causes schizophrenia?
Researchers are trying to track down genes involved in this disorder. Clues may also come from research on traits schizophrenics share with normal people.

What causes autism?
Many genes probably contribute to this baffling disorder, as well as unknown environmental factors. A biomarker for early diagnosis would help improve existing therapy, but a cure is a distant hope.

To what extent can we stave off Alzheimer's?
A 5- to 10-year delay in this late-onset disease would improve old age for millions. Researchers are determining whether treatments with hormones or antioxidants, or mental and physical exercise, will help.

What is the biological basis of addiction?
Addiction involves the disruption of the brain's reward circuitry. But personality traits such as impulsivity and sensation-seeking also play a part in this complex behavior.

Is morality hardwired into the brain?
That question has long puzzled philosophers; now some neuroscientists think brain imaging will reveal circuits involved in reasoning.

What are the limits of learning by machines?
Computers can already beat the world's best chess players, and they have a wealth of information on the Web to draw on. But abstract reasoning is still beyond any machine.

How much of personality is genetic?
Aspects of personality are influenced by genes; environment modifies the genetic effects. The relative contributions remain under debate.

What is the biological root of sexual orientation?
Much of the “environmental” contribution to homosexuality may occur before birth in the form of prenatal hormones, so answering this question will require more than just the hunt for “gay genes.”

Will there ever be a tree of life that systematists can agree on?
Despite better morphological, molecular, and statistical methods, researchers' trees don't agree. Expect greater, but not complete, consensus.

How many species are there on Earth?
Count all the stars in the sky? Impossible. Count all the species on Earth? Ditto. But the biodiversity crisis demands that we try.

What is a species?
A “simple” concept that's been muddied by evolutionary data; a clear definition may be a long time in coming.

Why does lateral transfer occur in so many species and how?
Once considered rare, gene swapping, particularly among microbes, is proving quite common. But why and how genes are so mobile—and the effect on fitness—remains to be determined.

Who was LUCA (the last universal common ancestor)?
Ideas about the origin of the 1.5-billion-year-old “mother” of all complex organisms abound. The continued discovery of primitive microbes, along with comparative genomics, should help resolve life's deep past.

How did flowers evolve?
Darwin called this question an “abominable mystery.” Flowers arose in the cycads and conifers, but the details of their evolution remain obscure.

How do plants make cell walls?
Cellulose and pectin walls surround cells, keeping water in and supporting tall trees. The biochemistry holds the secrets to turning its biomass into fuel.

How is plant growth controlled?
Redwoods grow to be hundreds of meters tall, Arctic willows barely 10 centimeters. Understanding the difference could lead to higher-yielding crops.

Why aren't all plants immune to all diseases?
Plants can mount a general immune response, but they also maintain molecular snipers that take out specific pathogens. Plant pathologists are asking why different species, even closely related ones, have different sets of defenders. The answer could result in hardier crops.

What is the basis of variation in stress tolerance in plants?
We need crops that better withstand drought, cold, and other stresses. But there are so many genes involved, in complex interactions, that no one has yet figured out which ones work how.

What caused mass extinctions?
A huge impact did in the dinosaurs, but the search for other catastrophic triggers of extinction has had no luck so far. If more subtle or stealthy culprits are to blame, they will take considerably longer to find.

Can we prevent extinction?
Finding cost-effective and politically feasible ways to save many endangered species requires creative thinking.

Why were some dinosaurs so large?
Dinosaurs reached almost unimaginable sizes, some in less than 20 years. But how did the long-necked sauropods, for instance, eat enough to pack on up to 100 tons without denuding their world?

How will ecosystems respond to global warming?
To anticipate the effects of the intensifying greenhouse, climate modelers will have to focus on regional changes and ecologists on the right combination of environmental changes.

How many kinds of humans coexisted in the recent past, and how did they relate?
The new dwarf human species fossil from Indonesia suggests that at least four kinds of humans thrived in the past 100,000 years. Better dates and additional material will help confirm or revise this picture.

What gave rise to modern human behavior?
Did Homo sapiens acquire abstract thought, language, and art gradually or in a cultural “big bang,” which in Europe occurred about 40,000 years ago? Data from Africa, where our species arose, may hold the key to the answer.

What are the roots of human culture?
No animal comes close to having humans' ability to build on previous discoveries and pass the improvements on. What determines those differences could help us understand how human culture evolved.

What are the evolutionary roots of language and music?
Neuroscientists exploring how we speak and make music are just beginning to find clues as to how these prized abilities arose.

What are human races, and how did they develop?
Anthropologists have long argued that race lacks biological reality. But our genetic makeup does vary with geographic origin and as such raises political and ethical as well as scientific questions.

Why do some countries grow and others stagnate?
From Norway to Nigeria, living standards across countries vary enormously, and they're not becoming more equal.

What impact do large government deficits have on a country's interest rates and economic growth rate?
The United States could provide a test case.

Are political and economic freedom closely tied?
China may provide one answer.

Why has poverty increased and life expectancy declined in sub-Saharan Africa?
Almost all efforts to reduce poverty in sub-Saharan Africa have failed. Figuring out what will work is crucial to alleviating massive human suffering.

The following six mathematics questions are drawn from a list of seven outstanding problems selected by the Clay Mathematics Institute. (The seventh problem is discussed on p.96.) For more details, go

Is there a simple test for determining whether an elliptic curve has an infinite number of rational solutions?
Equations of the form y2 = x3 + ax + b are powerful mathematical tools. The Birch and Swinnerton-Dyer conjecture tells how to determine how many solutions they have in the realm of rational numbers—information that could solve a host of problems, if the conjecture is true.

Can a Hodge cycle be written as a sum of algebraic cycles?
Two useful mathematical structures arose independently in geometry and in abstract algebra. The Hodge conjecture posits a surprising link between them, but the bridge remains to be built.

Will mathematicians unleash the power of the Navier-Stokes equations?
First written down in the 1840s, the equations hold the keys to understanding both smooth and turbulent flow. To harness them, though, theorists must find out exactly when they work and under what conditions they break down.

Does Poincaré's test identify spheres in four-dimensional space?
You can tie a string around a doughnut, but it will slide right off a sphere. The mathematical principle behind that observation can reliably spot every spherelike object in 3D space. Henri Poincaré conjectured that it should also work in the next dimension up, but no one has proved it yet.

Do mathematically interesting zero-value solutions of the Riemann zeta function all have the form a + bi?
Don't sweat the details. Since the mid-19th century, the “Riemann hypothesis” has been the monster catfish in mathematicians' pond. If true, it will give them a wealth of information about the distribution of prime numbers and other long-standing mysteries.

Does the Standard Model of particle physics rest on solid mathematical foundations?
For almost 50 years, the model has rested on “quantum Yang-Mills theory,” which links the behavior of particles to structures found in geometry. The theory is breathtakingly elegant and useful—but no one has proved that it's sound.

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List of unsolved problems in biology

AdaptationAt present there is no theoretical model for how adaptation occurs that is close to being complete. Mathematical models of evolution (e.g. within population genetics) describe how the process of natural selection influences the frequency of already-existing gene variants based on their relative fitnesses. Only a small amount of theory treats the problem of modelling the generation of new variants through mutation, in terms of either the fitnesses or phenotypic forms they confer.
AlkaloidsThe function of these substances in living organisms which produce them is not known1
Arthropod head problemA 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.
Basking sharkOnly the right ovary in this fish appears to function, the reason is unknown.
Biological agingThere are a number of hypotheses why senescence occurs including those that it is programmed by gene expression changes and that it is the accumulative damage of biological processes.
Blue WhaleThere is not much data on the sexuality of the biggest animal ever.2
Botany/PlantsWhat is the exact evolutionary history of flowers and theirblossoms?
Butterfly migrationHow do the descendants of Monarch butterfly all over Canada and the US eventually, after migrating for several generations, manage to return to a few relatively small overwintering spots?
Cambrian explosionWhat 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 animal phyla?
ConsciousnessWhat is the brain basis of subjective experience, cognition, wakefulness, alertness, arousal, and attention? Is there a "hard problem of consciousness"? If so, how is it solved? What, if any, is the function of consciousness?34
Evolution of sexWhat selective advantages drove the development of sexual reproduction, and how did it develop?5
Extraterrestrial lifeMight life which does not originate from planet Earth also have developed on other planets? Might this life be intelligent?
Fairy circle (Africa)There is intense debate about the formation process of the circles. Research has shown that some can be explained by the activities of the sand termite, Psammotermes allocerus but there is no theory explaining all fairy circles.
Gall waspIt is largely unknown how these insects induce gall formation in plants; chemical, mechanical, and viral triggers have been discussed.
Glycogen bodyThe function of this structure is not known.
Golgi apparatusIn cell theory, what is the exact transport mechanism by which proteins travel through the Golgi apparatus?
Hammerhead sharkThe reason for their distinctive and unusual head structure is not known.
Homing (biology)A satisfactory explanation for the neurobiological mechanisms that allow Homing, has yet to be found.
KorarchaeotaTheir metabolic processes are so far unclear.
Latitudinal diversity gradientWhy does biodiversity increase when going from the poles towards the equator?
LoriciferaThere are at least 100 species of this phylum that are yet to be described, but none of them is known to be present in the fossil record.
Origin of lifeExactly how and when did life on Earth originate? Which, if any, of the many hypotheses is correct?
Paradox of the planktonThe high diversity of phytoplankton seems to violate thecompetitive exclusion principle.

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Unsolved problems in biology—The state of current thinking

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