Top 10 breakthroughs of the year
Version of the journal Science
A neutrino source, a crater hidden under the ice, a new genetic way to search for criminals, a liquid "glue" made of protein... What Science magazine considers the main discoveries of the outgoing year.
Trio for one
Since the time of Hippocrates, scientists have been shocked by how a cell can turn into an adult organism with several organs and billions of cells. Today, many years later, we know that it is DNA that controls the processes by which cells multiply and grow into certain cells, with their functions. And DNA has its own "musical score": just as strings, wind instruments, percussion and other instruments enter into a piece of music, genes are turned on in individual cells, calling on cells to play their specialized parts. This feature of the work of genes was revealed using a combination of several technologies, which opened new doors for scientists: now it has become possible to track the development of organisms and organs in detail, cell by cell, at a certain point in time. The journal Science recognizes this combination of technologies and its potential for further fundamental research in medicine as the breakthrough of the year in 2018.
This achievement is based on three methods: isolation of thousands of intact cells from living organisms, efficient sequencing of the expressed genetic material in each cell, and the use of a computer or cell labeling in order to reproduce their relationships in space and time. This technological "trio" will significantly influence future research in the next decade, scientists believe. Only this year, several works have already appeared that tell in detail how organs and appendages began to be created in flatworms, fish, frogs and other organisms. And research groups around the world are using these methods to study how human cells mature during life, how they change in case of illness and how tissues are restored.
Previously, it was possible to "spy" on the work of cells using "classical" RNA sequencing, but this method did not allow you to see how this work takes place in a single cell. Thanks to new methods, scientists can track which RNA is produced in each cell at a particular time. And since the RNA sequences are specific to the genes that produced them, researchers can see which genes are active – and from this it is possible to determine what the cell is doing.
The technology of single-cell RNA sequencing has been developing over the past few years. But the turning point came last year when two groups of researchers showed that it could be done on a large enough scale to track the early development of organisms. One group measured the activity of genes in 8000 cells extracted at one point in time from drosophila embryos. Around the same time, another team studied the gene activity in 50,000 cells of nematode larvae (roundworm) Caenorhabditis elegans. The data showed which proteins, called transcription factors, determined the "professional orientation" of cells. This year, these scientists and other researchers conducted an even more extensive analysis of vertebrate embryos. For example, one study showed how 25 cell types are formed in a fertilized egg of a danio rerio fish; in another study, it was possible to study the development of a frog in the early stages of organ formation and determine that some cells begin to specialize earlier than previously thought.
Since cells must be removed from the body for RNA sequencing, this technique alone is not enough to show how these cells interact with their neighbors, or to identify the "descendants" of cells. But thanks to genetic engineering tools, researchers can now track the work of cells and the development of their offspring in living organisms. So, some scientists add elements to early embryonic cells that carry genes of fluorescent labels of different colors, which randomly settle in the cells, giving different colors to each cell "line". Others use the gene editing technique – CRISPR - to mark the genomes of individual cells with unique identifiers-"strokes", which are then passed on to all their descendants. The gene editor can create new mutations in offspring cells while preserving the original mutations, which allows scientists to track how new cell types are formed.
By combining these techniques with single-cell RNA sequencing, researchers can monitor the behavior of individual cells and see how they fit into the unfolding architecture of the organism. Using this approach, scientists have determined the relationships of more than 100 cell types in the brains of danio-rerio fish. They used CRISPR to label early embryonic cells, then extracted and sequenced 60,000 cells at different points in time to track gene activity as fish embryos developed.
These technologies cannot yet be used to study human embryonic cells, but with their help, researchers are already studying gene activity, for example, in tissue and organ cells. Already one project has identified most, if not all, types of kidney cells, including those that tend to become malignant.
The revolution in this area has just begun. Scientists hope to combine the method of RNA sequencing of a single cell with new microscopy methods to see where in each cell its special molecular activity manifests itself and how neighboring cells affect this activity.
"Messengers" from a distant galaxy
Another key discovery of this year, according to the journal Science, is the discovery of a source of ultrahigh–energy neutrinos. To catch these tiny "ghost particles", it took a cubic kilometer of ice, which is located deep underground at the South Pole. It was "decorated" with light detectors to detect a weak flash initiated by neutrinos. Known as IceCube, the massive detector has already detected many neutrinos, some of which were outside the Milky Way, but their source has never been determined. Until September 22, 2017. Then the neutrino collided with the nucleus in the ice, and the sensors accurately determined the direction from which the particle came.
As the researchers reported in July, NASA's Fermi gamma-ray space telescope detected a bright light source right where the neutrino seemed to come from. It was a blazar, one of the most extreme objects in the universe. This active galactic core is a powerful source of electromagnetic radiation. It is believed that the blazar is associated with a supermassive black hole, whose gravity heats the gas circulating around it, causing the material to glow brightly and throw jets of particles (relativistic jets) out of the whirlpool.
Researchers are almost certain that the blazar that erupted during the detection is the source of neutrinos – that is, this is the first time that a neutrino telescope has detected an extragalactic source of an elusive particle. The IceCube team is waiting for other extragalactic "messengers". Having greeted the first "visitor", scientists have already begun to prepare a new detector, the volume of which is 10 times larger than the current one.
It has become faster and easier to look inside the molecule
In October, two research groups described a new method that will help "decipher" the structure of a previously unknown molecule. And in a matter of minutes, not in a few days, weeks or months, which are required for traditional decryption methods.
For decades, X-ray crystallography has been such a "golden" method. Millions of copies of molecules, organized in a certain order, are embedded in the crystal. Then scientists track how the X–rays are reflected from the crystal - this allows you to determine the location of the atoms. It is necessary to know the structure of molecules in order to understand how biological molecules behave and how drugs interact with them. But this technique has a big disadvantage: it is very difficult to grow a crystal the size of at least a grain of sand – and some substances require this. It is possible to grow two–dimensional "sheets" instead of bulk crystals - and irradiate them with a stream of electrons. But if the crystal thickness is more than one molecule, the method with electrons will not work, and the sample will be too small for X-ray crystallography.
A new technique allows you to solve this problem. Two groups of scientists – one from the USA, the other from Germany and Switzerland – proposed replacing X-rays with an electron beam. They placed three-dimensional crystals on a rotating stand, which is irradiated by a stream of electrons. Then they compared the images of the irradiated crystal obtained from different angles of view. At the same time, the whole process took only a few minutes, not a few days or even weeks. The new method is great for deciphering the structure of small molecules – for example, like hormones.
Deep wounds of unearthly origin
A meteorite crashed into northwest Greenland as if a nuclear bomb had exploded. The impact left a large scar – Hiawatha crater (Hiawatha) 31 kilometers wide. Scientists reported the startling discovery in November, after the plane's radar detected a crater hiding under a kilometer-thick layer of ice.
Hiawatha Crater is one of the 25 largest on Earth. Although the most catastrophic phenomenon among meteorite impacts was the Chicxulub impact, which put an end to the era of dinosaurs and "cut out" a crater 200 kilometers wide in Mexico 66 million years ago, Hiawatha's impact could also have a powerful impact on the planet. Namely, its climate. Meltwater from the impact, pouring into the northern part of the Atlantic Ocean, could cause a decrease in temperature, stopping the "conveyor" with flows that bring heat to northwestern Europe.
The radar images show that Hiawatha is very young: the crater is only 100,000 years old. This fact has led scientists to confusion: in the glaciers of Greenland, there is no evidence of the fall of a meteorite – fragments or debris – during this period. Further – more: some disturbances in the ice structure in the depths of the crater even hint that the meteorite could have collided with the Earth just 13,000 years ago. If this is the case, then the fall of the meteorite will be able to explain the millennial global cooling in the late Dryas, which abruptly replaced the Alleredian warming that began 14,000 years ago. Only the study of tiny mineral crystals recovered from under the ice will be able to give an accurate answer.
#MeToo
One of the most unexpected achievements that got into the top 10 of Science magazine is the movement against sexual harassment. This problem exists in the academic environment, but its scale has been underestimated and ignored. Until June of this year, when the report of the Academies of Sciences, Engineering and Medicine of the USA was published.
According to the report, more than 50% of female teachers and staff, and from 20% to 50% of students (the percentage depends on the field of study), have been subjected to sexual harassment and humiliation – in most cases on the basis of sexist prejudices (because of them, a woman may not be hired).
The report caused a large wave of official complaints from female students and employees of scientific institutions, and was widely publicized in the media. Some institutions began to dismiss those scientists who, according to the results of investigations, turned out to be guilty. But in most cases, nevertheless, great merits to science "crossed out" all the accusations. The pace of change is still very slow.
BethAnn McLaughlin, a neurologist at Vanderbilt University (USA), who founded the human rights group #metooSTEM this year, notes, for example, that the National Institutes of Health (NIH) does not require universities to somehow punish grantees for sexual harassment: neither to send them under investigation, nor to impose disciplinary responsibility. McLaughlin begins each of his public appearances with a 46-second silence: a second for every year when the National Institutes of Health gave money to scientists and doctors for their research, without even asking if they violated Title IX – the 1972 U.S. law prohibiting sexual harassment of students.
The daughter of a Neanderthal and a Denisovan
A fragment of the bone of a woman who lived more than 50,000 years ago has been found, pointing to a striking connection between two extinct groups of ancient people. DNA extracted from a bone found in a cave in Siberia in 2012 showed that the woman's mother was a Neanderthal and her father was a Denisovan, one of a mysterious group of ancient people whose remains were discovered in the same cave in 2011.
Scientists knew before that during the Ice Age in Europe and Asia, representatives of Denisovans, Neanderthals and modern humans could sometimes overlap. This is evidenced by the discovered genes of both types of archaic people in the DNA of modern inhabitants of Europe and Asia. Fossils found in the Siberian cave have already confirmed that members of all three groups lived there at different times. But the new find was evidence of intimacy between representatives of Denisovans and Neanderthals.
Researchers from the Max Planck Society Institute for Evolutionary Anthropology in Leipzig (Germany) sequenced bone DNA and found that the skeleton fragment belongs to a woman and that her genome is equally the same as the genome of Denisovans and Neanderthals. This could be due to her parents' mixed ancestry. But the pairs of chromosomes of almost half of her genes contained different heterozygous alleles, which suggests that the maternal and paternal chromosomes came from different lines of the genus Homo. Her mitochondrial DNA, which is almost completely inherited from her mother, was Neanderthal, so the researchers concluded that the ancient woman was a "half-breed" of the first generation of Denisovian men and Neanderthals. Upon closer examination of the genome, it can be assumed that her father could also be a carrier of Neanderthal genes.
DNA surveillance
The police have a new tool to track down a criminal – DNA genealogy. This method allows you to find a criminal through the family tree of his relatives by downloading his DNA "profile".
to the DNA genealogical database. With this method, the US police were able to solve the already "cold" case and find a maniac who committed a series of rapes and murders in the state of California in the 1970s and 1980s.
Today there are private companies, such as Ancestry and 23andMe, which help to find a person's relatives by pieces of common DNA. The police can also access these "databases" to find the perpetrator. In the Golden State Killer case, authorities turned to the publicly available online database GEDmatch, which was launched by two amateur genealogists from Texas and Florida. With her help, 73-year-old criminal Joseph James De Angelo was discovered.
This fall, geneticists reported that 60% of Americans of European descent (who make up the majority of ancestral site users) will be able to find a second cousin or a closer relative in a database with one million samples.
"Molecular windows" to primordial worlds
This year, scientists have discovered molecular traces of creatures that lived more than half a billion years ago – "signatures" of fat molecules in some of the strangest fossils known, mysterious life forms called ediacaras, and molecular evidence of the existence of sponges long before they appeared in fossils.
For more than 70 years, scientists have been puzzling over the amazing forms of Ediacaran fossils. Some resemble the leaves of a fern. Were they plants from the bottom of the ancient ocean, or animals, or some completely separate form of life that could not survive?
Researchers at the Australian National University wondered if they could extract chemical clues from some exceptional fossils that still retain a film resembling organic material. These fossils were taken from a rock on the shore of the White Sea in northwestern Russia, where the samples escaped heat and pressure – conditions under which molecular traces can be erased.
The researchers tested this method for the first time on a collection of small round Ediacaran fossils called Beltanelliformis. They removed the film from the stone, dissolved it, and used gas chromatography and mass spectrometry techniques to search for preserved organic molecules. They were able to detect a high level of gopans – molecules that were presumably colonies of cyanobacteria. After the first successful tests, scientists decided to try this technique on the fossils of a creature named Dickinsonia, one of the most famous Ediacaran species: oval in shape, about half a meter long (it resembles a bath mat). The result was not long in coming. The Dickinsonia fossil contained traces of cholesterol-like molecules, which is a sign of animal life. This is consistent with other evidence suggesting that at least some Ediacarans were among the earliest animals on Earth.
A little later, another team found traces of molecules that are produced only by sponges today in layers of rock between 660 million and 635 million years old. The discovery means that sponges, another animal life form, may have evolved 100 million years earlier than their oldest recognizable fossils.
Gene Silencer approved
The drug, based on a gene suppression mechanism called RNA interference (RNAi), received approval this year. Now the doors will be able to open for a new class of drugs targeting genes that cause diseases.
Twenty years ago, two geneticists from the United States discovered that short RNA molecules can disrupt gene translation by attaching to informational RNA, which transmits the "message" of the gene to the mechanism of protein creation in the cell. This is how the RNA interference method was discovered, which causes genes not to produce protein by blocking informational RNA. The discovery earned scientists the Nobel Prize, but attempts to make new drugs based on it immediately ran into obstacles. Scientists have struggled to keep intact the fragile RNA molecules that are supposed to create interference, and direct them to the right tissue.
Ten years later, in 2008, researchers from Alnylam Pharmaceuticals in Cambridge (USA, Massachusetts) proposed their solution to the problem: to create a shell of lipid nanoparticles for the RNA that makes the gene "silent", which would protect the RNA and deliver it to the liver. Such a drug would help in the treatment of a rare disease – hereditary transtiretinic amyloidosis – by blocking the production of improperly folding protein that accumulates and damages the heart and nerves.
Liquid "glue" from protein
How do the molecules inside the cell assemble in the right place and at the right time to perform their functions? Perhaps the answer can be given by liquid drops – from protein. Unnoticed until recently, they appear everywhere in the cells, organizing (and sometimes gluing) its elements.
Tens of thousands of proteins and other molecules fill the cytoplasm, the thick liquid that surrounds the cell nucleus, often pushing each other and interacting to perform vital tasks: from the destruction of nutrients to the release of energy and waste disposal. The researchers found that many proteins split or condense into individual droplets with concentrated contents, especially when the cell reacts to stress. This phase separation of the liquid, similar to the "stirring" of oil and vinegar in a vinaigrette dressing, is currently one of the hottest topics in cell biology. There is growing evidence that such separation contributes to critical biochemical reactions and, apparently, is the basic principle of cell organization.
Two 2017 articles in the journal Nature described the behavior of liquid protein droplets in the cell nucleus. In 2018, three articles in Science pointed to an even greater role of phase separation. Proteins that control the transmission of the genetic code from DNA to RNA can condense into droplets that attach to DNA. The details are yet to be clarified, but these studies show the role of phase separation in one of the fundamental mysteries of life, selective gene expression.
Biophysicists are now trying to figure out how these droplets are formed. Certain classes of proteins follow spaghetti-like "tails" that interact to cause condensation. But when the process goes wrong, the liquid can turn into a gel, and the gel can harden, forming aggregates observed in neurodegenerative diseases such as amyotrophic lateral sclerosis. A March scientific paper showed that this happens when such proteins are improperly excluded from the cell nucleus. In April, as many as four articles in Cell talked about how toxic aggregates can be dissolved, and currently several laboratories are trying to use this knowledge to find drugs that will help in the treatment of neurodegenerative diseases.
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