How to stop being afraid and love system biology
about the author
The author of the following note was born in 1981, which put the final cross on the secret eugenics program in the Ukrainian SSR, which gave the world so many of those about whom he did not ask at all. He was born in a dangerous proximity to the Dnieper Hydroelectric Power Station, which is why one of his favorite activities was to write the word "hydroelectric power station" on the blackboard with chalk. Another favorite pastime of the author was the launch of improvised missiles based on agricultural saltpeter, foil and newspapers. In view of the manic tendency to bring any matter to the end, the author continued to pursue his hobbies, first at the chemistry department of Moscow State University, and then at graduate school at the University of Michigan. After receiving a Ph.D. in organic chemistry, the author suddenly had the idea that a saltpeter rocket was not as interesting as the head that came up with it - or at least what was left of it.
Molecular biology at the moment is a typical frontier, the scientific equivalent of California during the Gold Rush (they still read Jack London, huh? No, not "To Adam", there are about programmers). But as we all learned from fiction, the Wild West is not only terrible diseases, scalps, indiscriminate shooting, unscrupulousness, animal cruelty, dirt, stench and lack of culture, but also the opportunity to earn a few coins for your life, show your unmatched courage , and generally have a good time. I hope this note will annoy you, and you too risk dipping a little gold coin.
The following text can be regarded as a short and frivolous sketch of the current state of affairs in systems biology.
Life frontier
The beginning of 2015 turned out to be fascinating for biologists, although somewhat discouraging. At first, we were informed that a change in the mRNA level, on the measurement of which the methods of gene expression are based, can very little correlate with changes in protein concentration . Then they said that mammals also have horizontal gene transfer, using cancer cells stealing mitochondrial DNA as an example . And for dessert, they told us about the Rqc2p protein, which can recruit tRNA without mRNA and ensure the growth of the polypeptide in the ribosome .
A: Mitochondrial DNA transfer between healthy cells and cancer cells
B: Rqc2p protein structure
American magazines and blogs writing about science for the general public are once again full of catchy headlines like "Time to throw textbooks in the trash!". The elderly billionaires and gerontocrats of all stripes had gone, and even John McCain and Dick Cheney stopped rubbing their cold hands in anticipation of immortality, and, as a result, of imminent world domination. Once again, they convincingly showed us how little we know about living cells.
“A couple more of these discoveries, Dick, and all your eggheads are going to visit Guantanamo.”
“I told them so right away!”
However, throwing away books is generally barbarism, which in the case of molecular biology is also dangerous for others (you can kill someone to death, you saw these bricks). Plus, such a treatment with textbooks is probably especially annoying for those who are trying to write them. This is a truly ungrateful affair, and, in contrast to writing ABCs for American universities, is quite poorly paid. Modern biology most of all resembles nuclear physics at the beginning of the 20th century, when the normal chain of science “to discover nothing new here” - “we are the lords of the Universe” - “we understand nothing at all” has been passed many times by the entire scientific community for a decade.
“Masha, remind me - who was the last to use the autoclave?”
The situation for workers in the industry today is compounded by the fact that new methods require increasingly serious computer skills, as well as knowledge of mathematics and statistics. Unfortunately for many, in modern biology it is no longer possible to "escape" from mathematics if it bothered you at school. For example, the questions of what constitutes a significant result occupy an increasingly important place in the interpretation of results, and have not been considered secondary for a long time. Analysis of sequencing results requires the ability to write small programs and handle gigantic files. In general, as expected a long time ago, biology is becoming an increasingly accurate science, and therefore - a more mathematical science. However, the speed of accumulation of information does not allow to stand standards
- Either they brought us new equipment, or it covered me, but, in any case, things are going well.
The revolution in sequencing
Highly efficient DNA sequencing has revolutionized molecular biology. First of all, the views on the structure of the genome, both of humans and tens of thousands of other organisms, including hundreds of animals, were radically revised. The development of RNA-Seq technology made it possible, on the one hand, to more accurately assess gene expression quantitatively, and on the other hand, to find thousands of previously uncharacterized RNAs, as well as characterize new types of RNAs. A successful combination of the previously known immunoprecipitation method with sequencing, known as ChIP-Seq, radically expanded ideas about epigenetic modifications of histones, and how transcription factors work. Bisulfite sequencing and DNase-Seq gave us information about DNA methylation and which DNA sections are the most open, and therefore the most active in a given tissue or under given conditions. The piquancy of the situation was added by the simply incredible (and already become a byword) sequencing price drop - over a certain period, it even significantly overtook Moore's law , which is an empirical rule that describes successful technological progress in any industry. At the moment, the cost of sequencing the human genome is estimated at about $ 1,000; Human Genome Project pilot budget, often not quite correctly compared with this price, amounted to about $ 3 billion.
The cost of human-equivalent genome sequencing, 2001-2012 The
hopes of new methods were the most daring and comprehensive. Nevertheless, the amount of data was growing at a supernatural rate, and our ability to extract information from experiments was increasingly lagging (and lagging) behind the rate of their accumulation. Quick solutions do not exist here - in fact, we are talking about the most serious methodological problems, which, with a high probability, will face many more sciences in the future. As in any other cases, you can try to learn from successful examples - what is called success stories in the American tradition. For example, one can recall the discovery of long non-coding RNAs, which can be considered a canonical example of a case where integrative analysis of computer data led to a great biological discovery.
The combination of two histone modifications and expression data allowed us to discover tens of thousands of new long non-coding RNAs.
But what about books? Perhaps we personally observe the degeneration of the teaching methods necessary for successful work in an actively growing field. Almost no one is able to read and comprehend even 10% of articles on any global biological topic, be it apoptosis, diabetes, or the metabolism of amino acids. However, an equally serious problem is the development of new interdisciplinary methods in practice - it is just as difficult for a biologist to understand the difference betweenWith 80 existing programs to align short reads , how difficult is it for a programmer to sense the difference between a primary cell culture and a cell line .
Workshop on Systems Biology 2015
From our point of view, one of the reasonable alternatives is short, intensive schools, combining both theoretical lessons and examples of their practical application. Last year, we tried to conduct such a school with ITMO and the Institute of Bioinformatics , and were extremely pleased with the results.
This year at the end of May, we again arrange it, although in a slightly different format. This time we will organize a school outside the city, which will allow all participants to devote the maximum amount of time to classes.
The coverage of topics remains roughly the same - we will discuss highly efficient sequencing and its application to the analysis of expression, transcription factors, and epigenetic modifications. The issues of integrating transcriptional profiles with metabolic data, and other integrative approaches to bring numerous genomic experiments to an interpreted biological result will be considered. Finally, we will talk about how sequencing allows us to characterize genetic polymorphism, and to link certain genetic characteristics with the phenotype. Both computer science and biologists can participate, applications are accepted until March 22. If you are interested, ask questions, and welcome!
Alexander Predeus
Washington University in St. Louis, School of Medicine, Department of Pathology and Immunology
We need your knowledge, your interest in systems biology, and your motorcycle.