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10 unsolved riddles in chemistry / Philip Ball

Many of the most essential scientific questions and some of humanity's most burning problems are related to the science of atoms and molecules

Chemicals in glass bottles. From Wikipedia
Chemicals in glass bottles. From Wikipedia

1 How did life begin?

The moment when the first living thing emerged from the dead matter, almost four billion years ago, is still shrouded in mystery. How did the relatively simple molecules of the primordial soup manage to create increasingly complex compounds? And how did some of these compounds begin to process energy and reproduce (two of the characteristics of life)? At the molecular level, all these steps are of course chemical reactions, so the question of how life began is a chemical question.

The chemists can no longer be satisfied with the scenarios that are received but barely conceivable - and there are many such. Researchers hypothesized, for example, that certain minerals, such as clay, were used as catalysts for the creation of the first self-replicating polymers (polymers, such as DNA or proteins, are molecular chains of smaller units); Or that it was hydrothermal vents at the bottom of the sea that provided the energy that drove the formation of the chemical complexity. There are also speculations about the "RNA world", where RNA molecules, which are similar to DNA and also act as enzymes that catalyze chemical reactions like proteins do, were used as universal molecules that preceded DNA and proteins.

The challenge now is to find a way to test these ideas using reactions that will occur slowly in vitro. Researchers have demonstrated, for example, how some relatively simple chemicals can spontaneously react with each other to form more complicated building blocks of living systems. These building blocks, amino acids and nucleotides, are the basic units of DNA and RNA. In 2009, a team led by John Sutherland, currently working at the MRC Laboratory for Molecular Biology in Cambridge, England, was able to demonstrate the creation of nucleotides from molecules that were most likely present in the ancient soup.

Other researchers focused on the ability of certain RNA strands to act as enzymes in order to find evidence to support the RNA world hypothesis. Through such steps, scientists hope to gradually bridge the gap between inanimate matter and sustainable systems capable of replicating themselves.

Now that scientists are getting to know strange and perhaps even fertile environments in our solar system, such as the water currents that appear intermittently on Mars, the petrochemical lakes on Titan, a moon of Saturn, and the salty oceans that are probably hidden beneath the ice that covers the moons of Jupiter, Europa, and Ganymede, a question of origin arises. Life on Earth is just one of a wider set of questions: under what circumstances can life arise? And how broad can the chemical basis of life be? In the last 16 years, more than 500 planets orbiting other suns outside our solar system have been discovered, worlds with a stunning variety, and discoveries enrich this research topic.

These discoveries pushed chemists to sail their imaginations beyond the single chemistry of life. The American space agency NASA, for example, believed for years that liquid water is a prerequisite for life. Now there are scientists who are no longer sure of this. What about liquid ammonia, or formamide, or an oily solvent like liquid methane, or liquid hydrogen in Jupiter's supercritical conditions? And why would life limit itself to DNA, RNA and proteins? After all, scientists have already created some artificial chemical systems that exhibit a form of replication through their constituent parts without relying on nucleic acids. It seems that all that is needed for this is a chemical system capable of being used as a template to create a copy and then detach.

From observing life on Earth, "we cannot decide whether the similarities [such as the use of DNA and proteins] between living things reflect a common origin or the universal needs of life," says chemist Stephen Benner of the Institute for Applied Molecular Evolution in Gainesville, Florida. But if we entrench ourselves in the position that we should stick only to what is sold, "it won't be fun."

Credit: Kate Francis, Brown Bird Design

Molecular bonds are a fundamental topic in chemistry, but surprisingly, their nature is not fully understood. However, computer simulations have become powerful enough to provide reasonably accurate predictions. For example, researchers discovered with this method, and later confirmed it experimentally, that two bucky balls can behave a bit like giant atoms and form bonds between them by sharing electrons similar to two hydrogen atoms.


How are molecules formed?

Molecular structures may be the mainstay of high school science classes, but the familiar image of balls and sticks representing the atoms and the bonds connecting them is mostly a common fabric story. The problem is that there is no agreement among scientists what should be the more accurate representation of molecules.

In 1920, the physicists Walter Hitler and Fritz London showed that it is possible to describe the chemical bond using the equations of quantum theory, a theory that was then in its infancy. The great American chemist Linus Pauling proposed the idea that bonds are formed when electronic orbitals of different atoms overlap each other in space. A competing theory by Robert Millikan and Friedrich Hund proposed that bonds are formed as a result of the fusion of atomic orbitals to form "molecular orbitals" that span more than one atom. It seemed that theoretical chemistry was about to become a branch of physics.

Almost 100 years later, the picture of molecular orbitals has been obtained almost completely, but still not all chemists are convinced that in all cases this is the best way to describe molecules. The reason for this is that this model of the molecules and similar ones are based on simplifying assumptions and are therefore only approximate and partial descriptions. In reality, a molecule is a bundle of atomic nuclei surrounded by a cloud of electrons within which "tug-of-war competitions" between opposing electrical forces and between the movement and reorganization of its components take place continuously. Current models of the molecule, which generally attempt to freeze this dynamic entity into a static entity, capture perhaps some of its salient features, but neglect others.

Quantum theory is unable to provide an unequivocal definition of chemical bonds that is consistent with the intuition of chemists whose bread and butter is to build and break these bonds. There are now many ways to describe molecules as atoms linked together by bonds. According to quantum chemist Dominique Marks of the Ruhr University in Bochum, Germany, most of these descriptions "are useful in some cases, but fail in others."

Computer simulations are now able to calculate with great precision the structure and properties of molecules from basic quantum principles - as long as the number of electrons is small enough. "By means of computational chemistry it is possible to reach very high degrees of realism and complexity," says Marks. As a result, one can see the computer calculations as a kind of virtual experiment through which one can predict the course of a chemical reaction. But once the simulation involves a reaction involving more than a few dozen electrons, the amount of calculations soon begins to overwhelm even the most powerful supercomputers. The challenge today is therefore to see if it is possible to extend these simulations and apply them, for example, to complicated biomolecular processes in the cell or to the structure of sophisticated materials.


How does the environment affect our genes?

The old idea of ​​biology was: our nature is determined by our genes. Today it is clear that an equally important question is which genes we use. And as in everything in biology, at the heart of this question is chemistry.

Cells from an early stage embryo can develop into any type of tissue. But as the embryo grows, these cells, called pluripotent stem cells, undergo differentiation and acquire specific functions (such as blood, muscle or nerve cells), functions that remain constant in their offspring. The formation of the human body is therefore a process in which the chromosomes in the stem cells undergo a chemical change that activates or deactivates entire sets of genes.

However, one of the most revolutionary discoveries in the study of cloning and stem cells was that these changes are reversible and influenced by the events that the body experiences. During differentiation the cells do not permanently disable genes and they only keep in standby the genes they need. Instead, the genes that have been turned off maintain a dormant capacity, meaning they retain their ability to produce the proteins they code for, and they may be reactivated, for example following exposure to certain chemicals from the environment.

The thing that excites and challenges chemists is that this gene control is probably related to chemical events on a larger scale than that of atoms and molecules, in an intermediate field (mesoscale), where large molecular structures and large groups of molecules operate. Chromatin, the substance that makes up the chromosomes from DNA and proteins, is built in a hierarchical structure. The double helix of DNA is wrapped around cylindrical particles composed of proteins called histones. This chain of beads is also packed in structures of a higher order that we rarely understand [see illustration on the opposite page]. In the cells there is a tight control over this case. How and where a particular gene is packaged within the chromatin may determine whether the gene is active or not.

Dedicated enzymes work in the cells that determine the changing shape of the chromatin. These enzymes play a central role in the cell's differentiation process. Chromatin in embryonic stem cells appears to have a looser and more open structure. When certain genes are silenced, the chromatin becomes more lumpy and organized. "The chromatin seems to fix and preserve, or stabilize the cells," says pathologist Bradley Bernstein of Massachusetts General Hospital.

Moreover, the design of the chromatin involves chemical changes of the DNA and the histones. Small molecules are attached to them and used as labels. They signal the cellular machinery to silence certain genes, or on the contrary, to release them into action. This marking is called "epigenetics" because it does not change the information that the genes themselves carry.

It seems that the answer to the question of how far it is possible to return mature cells to a pluripotent state, that is, whether it is possible to return them to a state where they will act like real stem cells, which is a crucial issue regarding the possibility of using them for regenerative medicine - depends mainly on the question of how far the epigenetic chemical marking can be eliminated .

Today it is clear that beyond the genetic code that dictates many of the important operating instructions of the cell, the cells also converse in a completely separate genetic chemical language - the language of epigenetics. "People may be predisposed to many diseases, including cancer, but environmental factors are often the ones that will determine whether or not it will break out, through these epigenetic pathways," says geneticist Brian Turner of the University of Birmingham in England.


How does the brain think and create memories?

The brain is a chemical computer. The mutual reactions between the nerve cells that make up its circuits are mediated by molecules called neurotransmitters. These messengers cross the synapses, the points of contact where nerve cells connect to each other. Perhaps the most impressive demonstration of the chemistry of thought is in the activation of memory, a process in which abstract principles and ideas, such as a telephone number or an emotional association, are embedded in certain states of the neural network through persistent chemical signals. How does chemistry create a memory that is both constant and dynamic and makes it possible to remember it, to change it, and to forget it?

We know parts of the answer. A cascade of biochemical processes, which lead to a change in the amount of nerve messenger molecules in the synapse, triggers the learning of the reflexes of the leg. But even this simple aspect of learning has short-term and long-term phases. In contrast, more complex memory processes called declarative memory (such as memory of people, places, etc.) occur through a different mechanism elsewhere in the brain. These processes involve the activation of a protein called the NMDA receptor found on certain nerve cells. Blocking this receptor with drugs prevents the retention of many types of declarative memories.

Our day-to-day declarative memories are often encoded through a process called long-term potentiation, which involves NMDA receptors and is accompanied by an expansion of the neuronal area of ​​a synapse. As the synapse grows, the connection with neighboring cells "strengthens", that is, the electrical voltage that induces nerve signals that reach the synaptic junction increases. The biochemistry of this process has become clear in recent years. The process involves the formation of fibers inside the nerve cell built from the protein actin, the substance that also participates in building the basic skeleton of the cell and determines its size and shape. But if biochemical factors prevent the stabilization of the new fibers, the process will stop and the fibers will disintegrate.

Once a long-term memory is encoded, in both simple and complex learning processes, it is actively maintained through the activation of genes that cause the appearance of certain proteins. At the moment it seems that a molecule called prion may be involved in this process. Prions are proteins that are able to oscillate between two different spatial forms. One form is soluble in water and the other is insoluble. The insoluble form acts as a catalyst that causes molecules similar to it to become insoluble as well and aggregate into a clump. Prions were first discovered due to their role in neurodegenerative diseases such as mad cow disease, but it is now clear that the mechanisms of action of prions also have a beneficial role: their accumulation marks a certain synapse in order to preserve a memory.

There are still large gaps in the story of memory operations, many of which are waiting to be closed by elucidating the chemical details. For example, how is the memory retrieved after it has been stored? "This is a deep problem that we are just beginning to analyze," says neurobiologist and Nobel laureate Eric Kandel of Columbia University.

A deeper understanding of the chemistry of memory presents us with the controversial temptation of improving memory through drugs. Already today we know several substances that stimulate memory, including sex hormones and synthetic chemicals, which act on receptors of nicotine, glutamine, serotonin and other neurotransmitters. In fact, the complex sequence of steps that leads to learning and long-term memory is littered with many possible targets for such memory drugs, says neurobiologist Gary Lynch of the University of California, Irvine.

Credit: Kate Francis, Brown Bird Design

Beyond the genes, there is another set of instructions that determine which genes will be activated in each cell. The information in this epigenetic code is transmitted through chemicals that attach to DNA or to histones, the proteins around which DNA is wrapped in chromosomes. This chemical marking determines whether the gene will be hidden in a compressed region of the chromosomes or displayed in a location accessible for transcription.


How many chemical elements are there?

The periodic tables that adorn the walls of the classrooms need regular updating because the number of elements continues to increase. Scientists use particle accelerators to create collisions between atomic nuclei and create new "super-heavy" elements, whose nuclei have more protons and neutrons than the 92 elements found in nature. These swollen nuclei are not stable at all and decay by radioactive decay, sometimes within a fraction of a second. But as long as these synthetic elements exist, such as cyborgium (atomic number 106) and hasium (108), they are elements of everything, and have distinct chemical properties. Through amazing experiments, scientists seek to explore some of these properties using a small handful of cyborgium atoms and the elusive end in the brief moments before they disintegrate.

The studies do not only examine the physical limits of the periodic table, but also its principle limits: do the super-heavy elements continue to present the trends and periodic chemical behavior that characterized the table from the beginning? The answer is that some of them continue to do so, and some do not. And in particular, these nuclei, which have a large mass, attract the electrons closest to the nucleus with such force that the electrons move at speeds close to the speed of light. Under these conditions, the mass of the electrons increases, according to the special theory of relativity, and this may completely disrupt the set of quantum energy levels on which their chemical behavior depends - and also the very periodicity of the table.

Atomic nuclei with certain "magic numbers" of protons and neutrons are considered more stable. Some researchers therefore hope to find the region in the periodic table, a region known as the "instability". This region is located a bit after the artificial elements that the technology we have is capable of creating, where the super-heavy nuclei will exist for a longer time. And yet, is there a principled limit to their size? A simple calculation implies that the theory of relativity prevents the existence of nuclei with more than 137 protons. But more complex calculations challenge this limit. "The periodic table will not end at 137, in fact, it will never end," insists nuclear physicist Walter Greiner of Johann Wolfgang Goethe University in Frankfurt, Germany. The experimental test for this claim is still very far away.


Is it possible to build computers from carbon?

Computer chips made of graphene, a network of carbon atoms, will probably be faster and more powerful than silicon-based computers. The graphene explorers did win the Nobel Prize in Physics in 2010, but the success of nanotechnology based on graphene, or other types of carbon, ultimately depends on chemists' ability to create structures with atomic precision.

In 1985, they discovered Bucky balls, hollow, cage-like molecules made only of carbon atoms. This was the starting point for something much bigger. Six years later, carbon tubes appeared whose constituent atoms are arranged in a hexagonal network, similar to the network of chicken coops, just as they are arranged in the carbon layers in graphite. Because these carbon nanotubes are hollow, incredibly strong, rigid, and electrically conductive, they have promised a variety of applications, from high-strength carbon-based composites, to tiny electrical wires and electronic devices, to tiny molecular capsules and membranes for water filtration.

But despite the promise, carbon nanotubes have not yielded many commercial applications. For example, the researchers were unable to solve the problem of connecting the tubes to complicated electronic circuits. Recently, graphite took center stage after a way was found to separate the layers that make it up into single layers, similar to a cage network, and called graphene. This material may serve as a basis for very tiny, cheap and rigid electrical circuits. The hope is that the computer industry will be able to use graphene's narrow films and networks, cut to the right dimensions and with atomic precision, to build chips that will perform better than those based on silicon.

"Graphene can be designed in such a way that it overcomes the problems of connecting the carbon nanotubes and their location," says carbon expert Walt DeHeer from the Georgia Institute of Technology. But he adds that methods [currently accepted in the computer industry], such as chemical etching, are too crude methods for designing graphene circuits with single-atom precision. DeHeer therefore fears that graphene technology today owes its position to "ratings" and less to rigorous science. The key to such precise engineering on an atomic scale may be the use of organic chemistry methods: the construction of graphene circles from the bottom up, that is, the joining together of polyaromatic molecules, which contain several hexagonal carbon rings, which look like small parts of a graphene surface. Such methods could open the gate to the future of graphene-based electronics.


How can we utilize more solar energy?

Every sunrise reminds us that we use only a pitiful fraction of this huge clean energy resource - the sun. The main problem is the cost: the price of ordinary photovoltaic panels, made of tin, still limits their use. But life on Earth, which is almost all driven, in the end, through photosynthesis by sunlight, proves to us that solar cells do not have to be very efficient, provided that, like leaves, it is possible to produce them in large quantities and at sufficiently low prices.

"One of the overarching goals of solar energy research is using sunlight to produce fuel," says Arizona State University's Devens Gast. The easiest way to produce fuel from solar energy is to break down water and create gaseous hydrogen and oxygen. Nathan S. Lewis and his colleagues at the California Institute of Technology (Caltech) are developing an artificial leaf that should do this using nanowires made of tin.

In early 2011, Daniel Nosera from the Massachusetts Institute of Technology (MIT) and his colleagues revealed the development of a crucible-based membrane containing a cobalt-based catalyst that breaks down water. Nosra estimates that less than 4 liters of water would be enough to provide enough fuel for one day for one house in developing countries. "Our goal is to turn every house into its own powerhouse," he says.

Catalytic water fracturing is still a difficult task. "Cobalt catalysts, like Nusra's, and other recently discovered catalysts, catalysts based on other common metals, hold promise," Gast says, but the ideal cheap catalyst has yet to be found. "We still don't know how the natural catalyst works in photosynthesis, which is based on four manganese atoms and one calcium atom," Gast adds.

Gast and his colleagues are looking for a way to build molecular mechanisms for artificial photosynthesis that will be more similar to the biological sources of inspiration. His team was able to synthesize several components that could be incorporated into such a mechanism. But a lot of work is still needed on this front. Organic molecules like the ones nature uses tend to break down quickly. Plants are constantly producing new proteins, replacing those that have broken down, but artificial leaves, on the other hand, are not (yet) equipped with a complete mechanism for chemical synthesis like the one that works in a living cell.


What is the best way to produce biofuels?

Instead of creating fuel materials by capturing the light rays from the sun, maybe we leave the job of storing the sun's energy to plants and then turn the plant material into fuel? Biofuels, such as ethanol, produced from corn, and biodiesel, produced from seeds, have already integrated into the energy markets. But they threaten to replace food crops, especially in developing countries where exporting biofuels may bring in more than food supplies for the population at home. And the numbers are scary: to meet today's fuel demand, it will be necessary to expropriate huge areas of fertile land.

Thus, turning food into energy may not be the best approach. One answer is to utilize other, less essential forms of biomass. The amount of residues that US agriculture and its forests produce every year is enough to provide about a third of the annual gasoline and diesel consumption for transportation.

In order to turn this lower quality biomass into fuel materials, very rigid molecules such as lignin and cellulose, the building blocks of plants, need to be broken down. Chemists already know how to do this, but current methods tend to be too expensive, inefficient, or difficult to scale up to meet the massive amounts of fuel the economy needs.

One of the challenges in breaking down lignin is in breaking the carbon-oxygen bonds bridging aromatic carbon rings, similar to benzene. John Hartwig and Alexei Sergeev from the University of Illinois recently succeeded in overcoming this challenge using a nickel-based catalyst. Hartwig says that if you want to use biomass as a substitute for the chemical raw materials and fuels that currently come from fossil fuels, chemists must extract aromatic substances from the biomass (molecules with a skeleton composed of aromatic rings). Lignin is the single largest potential source of aromatics in biomass.

From a practical point of view, such conversion of biomass will have to operate mainly on solid materials and turn them into liquid fuels that can be easily flowed through pipes. The drainage process will have to take place in the field, where the plants are collected. One of the difficulties in such a conversion using catalysts is the fact that the raw materials are very far from being pure. Classical synthetic chemistry does not usually deal with dirty materials like wood. "There is no consensus on how this will be done in the end," says Hartwig. The solution definitely rests on the shoulders of chemistry, especially finding the right catalysts. "Almost every large-scale industrial reaction involves some kind of catalyst," says Hartwig.


Can we find new ways to create drugs?

The heart of chemistry is practical and creative: building molecules. This is the key to creating everything from new materials to antibiotic drugs to overcome the rise of resistant bacteria.

One of the hopes of the 90s was compound chemistry: building thousands of new molecules, using random combinations of building blocks, and scanning the products to identify the ones that perform the necessary task best. But today this field, which was announced at the time as the future of medicinal chemistry, is obsolete, because it brought almost no practical benefit.

But the syrupy chemistry might win a more successful second round. It may only work if we can produce a sufficiently wide range of products, find better ways to select the successful molecules and exhaust their tiny amounts. Biotechnology can be of help. For example, it is possible to link each molecule to a "bar-code" based on DNA that can identify the molecules and also help in optimization. In another approach, researchers can refine the library of candidate molecules through a process similar to Darwinian evolution in vitro. They can, for example, encode molecules of protein-based drugs in a suitable DNA sequence and reproduce it in an error-prone mechanism. Such replication will produce new versions of the most successful molecules, and thus improvements will be found in each cycle of replication and selection.

Other new methods are based on nature's skill in connecting molecular parts together in predetermined arrangements. Proteins, for example, have a precise arrangement of amino acids because this sequence is encoded in genes. Using such a model, future chemists will be able to program molecules to assemble themselves independently. The approach also has a "green" advantage because it reduces the amount of by-products typical of traditional chemical production processes and the waste of energy and raw materials that accompanies them.

David Liu of Harvard University and his colleagues operate in this approach. They programmed the structure of the desired molecule by connecting short DNA strands to its building blocks. They also created a molecule capable of moving on DNA, reading the code and connecting small molecules, according to the order, to the building blocks to create the desired molecule, a process parallel to protein synthesis in living cells. Liu's method may be useful in the construction of new drugs. "Many scientists dealing with life sciences at the molecular level believe that giant molecules will play a more central role, and perhaps even decisive, in the future of healing processes," says Liu.

Credit: Kate Francis, Brown Bird Design

To mimic plants, chemists are developing new catalysts and materials that capture the sun's energy and store it as hydrogen gas. In the picture before you, nanowires exposed to sunlight are used to break water molecules into hydrogen ions, oxygen atoms and electrons. The hydrogen ions and electrons cross a membrane. On the other side of the membrane, the nanowires catalyze the formation of hydrogen from the electrons and ions.


Can we continuously monitor our chemistry?

More and more chemists aspire not only to create molecules but also to communicate with them: to use chemistry as an information technology that will serve as an interface with everything, from living cells to ordinary computers and ending with fiber optic communication.

This vision is partly old ideas: chemical sensors that use chemical reactions to report blood glucose concentrations have been around since the 60s, though only recently have they become cheap, portable and common enough to be used as diabetes monitoring tools. But chemical sensing may have countless uses: identifying contaminants in food and water at very low concentrations, for example, or monitoring polluting or rare gases in the atmosphere. Faster, cheaper, more sensitive and more common chemical sensors will bring considerable progress in these areas.

But the field where these new chemical sensors will have the most dramatic impact is probably the field of biomedicine. Some of the products of cancer genes, for example, are widespread in the blood circulation long before the disease is detected in normal laboratory tests. Detecting these substances in early stages may lead to a more accurate diagnosis at the right stage. Rapid determination of a genetic profile will enable a personalized drug regimen, reduce the risk of side effects and allow the use of several drugs, a use that is currently delayed because these drugs are dangerous for a certain genetic minority.

Some chemists contract continuous and non-invasive monitoring of a variety of biochemical markers for health and disease. Surgeons may be able to use real-time information and automated systems will provide drugs. This future vision depends on the development of chemical methods to selectively sense certain substances and signal their presence even in very low concentrations.


And more on the subject


Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering. National Research Council. National Academies Press, 2003.

Beyond the Bond. Philip Ball in Nature, Vol. 469, pages 26-28; January 6, 2011.

Let's get practical. George M. Whitesides and John Deutch in Nature, Vol. 469, pages 21-22; January 6, 2011.

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