Beating God
Alexander Panchin, "Popular Mechanics" No. 3, 2017
The article has been published
on the "Elements" website
Synthetic biologists and their games of creating artificial genomes have led to the appearance of organisms that do not exist in nature, whose DNA contains only the minimum necessary set of genes. The perfect code. Without a single extra line.
Participants
George Church, professor at Harvard University and the Massachusetts Institute of Technology. He developed several revolutionary methods of DNA sequencing, made a great contribution to the creation of GM technologies using CRISPR/Cas9. In 2015, he successfully transplanted the genes of woolly mammoths into the DNA of modern elephants.
Craig Venter, president of his own Institute of Genetics. Led an independent project to read human DNA. In 2010, he demonstrated a living cell with an artificial genome: its DNA was not collected from fragments isolated from other cells, but synthesized in the laboratory.
The goal of the game
Cells are the basis of life. They contain hereditary information in the form of DNA molecules, the totality of which is called the genome. The genome determines which molecules a cell will produce, how it will divide, and what chemical reactions to carry out. Some of these functions are universal: Almost any cell needs the ability to double its DNA and synthesize proteins, divide, absorb substances from the environment and form a membrane.
Other tasks are specialized and often involve adaptation to specific living conditions. For example, bacteria may have genes that provide protection against antibiotics, or they may not if they do not need it. The cells of multicellular organisms contain instructions in the genome that allow them to cooperate and interact, organize in space and specialize, forming complex tissues and organs. The DNA regions regulating these processes are often not needed by individual cells, but are necessary for the functioning of the whole organism.
In 2016, independently of each other, Church and Venter presented projects for creating organisms with a "minimal" genome. Their approaches are different, their methods are different, but the final goals are almost the same
The task that our players solve is to establish the minimum set of genes required by the cell. Such an organism should contain a complete set of instructions that allow it to maintain its existence and share – but nothing beyond that. Only the most necessary.
Solving this problem is important for three reasons. First, we will be able to better understand how cells work. Secondly, we will get a convenient model for studying genes and their functions. Thirdly, the "minimal" organism can be adapted for the synthesis of some medicine, biofuel or other necessary compound. Deprived of extra genes, the body will not waste time and resources on their work and copying, becoming a more efficient producer.
Playing field
The size of the genome can be very different, and they are not directly related to the complexity of the organism itself. The DNA of Caenorhabditis elegans roundworms includes 97 million nucleotides and approximately 20,000 genes. The human genome is much more bulky – 3 billion nucleotides, but we have a little more protein-coding genes than a nematode, only 20-25 thousand. But there are organisms with even more "bloated" genomes. For example, in the lungfish Protopterus aethiopicus, it is 40 times larger than in humans. This variation in size is largely due to the fact that in addition to important genes, DNA accumulates a lot of unnecessary and unnecessary. Back in 2004, mice were obtained from whose genome very extensive "empty" DNA fragments were cut out – in 1.5 and 0.8 million nucleotides. Such animals were no different from their ordinary relatives, developed normally and left healthy offspring.
Viruses, bacteria and archaea can boast of the most "economical" genomes. Among the latter, those living in hot springs remain the record holder Nanoarchaeum equitans, whose DNA consists of only 490,000 nucleotides and contains exactly 5408 genes. One of the most compact genomes of bacteria belongs to parasitic Mycoplasma genitalium: 580,000 nucleotides and a ridiculous 475 protein-coding genes. It is a pity that these microbes multiply too slowly and are not too convenient for research. However, they have close and fast-growing relatives Mycoplasma mycoides with about twice the genome and number of genes. The DNA of this particular bacterium was chosen by Craig Venter for further "optimization".
Venter 's Move
In 2010, Venter's team obtained a synthetic copy of the M. mycoides genome. The scientists transferred it to a cell from which their own DNA had been removed beforehand; the resulting mycoplasma divided normally and functioned. It is this work that the staff of the American magazine Newsweek has been dubbed the "God Game." But if it was a game, then in 2016 Venter "outplayed" the Creator, reducing the original mycoplasma genome by about half – and again getting completely viable cells.
Craig Venter: "Thanks to advances in genetic engineering and synthetic biology, we can manipulate DNA at an unprecedented level, editing it like lines of program code"
In theory, the approach to simplifying the genome is simple: it is enough to obtain mutant cells and analyze their DNA. If a cell remains alive, despite the fact that some gene in it is corrupted, we can assume that this gene is not so necessary for it, and remove it from the final set. In this way, Venter and his group studied tens of thousands of mutants, finding that there is almost nothing unnecessary in the mycoplasma genome. Discarding everything superfluous, the scientists obtained a functioning bacterium with a genome of 531,000 nucleotides: 438 protein genes, plus another 35 encoding functional RNA molecules. There are only 428 fewer genes than in the original Mycoplasma mycoides genome, from which the work began.
Discarding everything superfluous, the scientists obtained a functioning bacterium with a genome of 531,000 nucleotides
It cannot be said that the removal of "extra genes" affected the resulting cells somehow especially badly. One of the criteria for the fitness of a unicellular organism to the environment is the rate of its division. It takes about 180 minutes for the cells of a "simplified" bacterium to double their number. This is three times longer than for the original version of mycoplasma, but five times faster than its slow counterpart M. genitalium requires. However, the authors of the simplified genome themselves do not believe that the work is completed. Comparing the genomes of different unicellular organisms, scientists have identified about 250 ubiquitous "universal genes" – this is the ideal that Venter and his colleagues strive for. Meanwhile, George Church explores simplicity on the other hand, trying to minimize the DNA code itself.
Church 's Move
The genetic code is a set of rules by which genes encode proteins. Copies of DNA (genes) are read from DNA sections in the form of RNA molecules, which serve as instructions for the synthesis of proteins consisting of amino acids. Each amino acid is encoded by a triple of nucleotides of the original DNA chain. For example, in the HAGGCCGA sequence, the first three letters (GAA) correspond to glutamic acid, followed by glycine (GHZ) and arginine (CGA). At the same time, both DNA and RNA consist of only four types of nucleotides, which can add 64 different triples, but there are only 20 amino acids in proteins (with the rarest exceptions). Therefore, almost every amino acid is "attributed" to several such triples-codons – for example, glutamic acid is encoded by the sequences GAA and GAG. But it follows from this that if in all the genes of an organism the triples of GAA are replaced by GAG (or vice versa), then the proteins of this organism will not change, but we will simplify the genome itself by getting rid of excess nucleotide codons. George Church and his team are engaged in such work. In 2016, they published an article about obtaining the world's first organism, a modified E. coli with a genetic code consisting of only 57 codons instead of the standard 64. That is, with seven removed triples of nucleotides.
George Church: "Potentially synthetic genomics can repeat the path that evolution has taken – with the difference that our conscious will will guide its development"
The "simplification" of the genetic code can have an important effect – the incredible resistance of such organisms to viruses. In fact, these intracellular parasites themselves are unable to reproduce. They rely entirely on the capabilities of the "enslaved" cell, counting on the fact that their own genes will work in it the same way as always, as the genome of the bacterium itself works. But if she simply does not have an apparatus that can interpret unfamiliar bacteria codons in the viral genome, then the parasite simply will not be able to function.
New game
Today, George Church and his colleagues are seriously discussing the possibility of launching a project to synthesize the human genome – all 3 billion nucleotides organized into chromosomes. And let this task look obviously losing for now: once upon a time, the project of reading the human genome looked completely unaffordable. However, it stimulated such a leap in sequencing technologies that the cost of reading the genome has fallen thousands of times and today it is affordable for the most ordinary people. Perhaps a global project in the field of genome synthesis will make it possible to make a breakthrough in the methods of creating new DNA molecules. Make the process cheaper, faster, more efficient. In parallel, new ways of delivering DNA to cells that are so necessary in medicine may appear: already today, doctors are starting to use gene therapy to treat certain hereditary and oncological diseases. The approach and application of these methods to fight viruses, including HIV, and the success of promising new approaches depends on solving the problem of delivering genes to target cells.
It remains to be hoped that Church, Venter and everyone else will have the courage to bring the game to an end. Perhaps by this time reliable human cloning technologies will have arrived. Then we will be able to obtain not just a single cell with an artificially created genome, but a full-fledged human with synthetic, optimized chromosomes. From individual chemicals, "from clay" – almost from nothing.
Portal "Eternal youth" http://vechnayamolodost.ru 16.06.2017