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Tackling the great challenges in biology

2017; Springer Nature; Volume: 18; Issue: 8 Linguagem: Inglês

10.15252/embr.201744718

1469-3178

Philip Hunter,

Photosynthetic Processes and Mechanisms

Science & Society25 July 2017free access Tackling the great challenges in biology Beyond evolution, defining the greatest challenges in biology is a challenge itself Philip Hunter Freelance journalist [email protected] London, UK Search for more papers by this author Philip Hunter Freelance journalist [email protected] London, UK Search for more papers by this author Author Information Philip Hunter1 1London, UK EMBO Rep (2017)18:1290-1293https://doi.org/10.15252/embr.201744718 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info In 2000, the Clay Mathematics Institute defined seven major challenges in mathematics and offered the Millennium Prize in Mathematics of US$1 million for solving each of these. To date, only one Millennium Prize has been awarded: In 2003, the Russian mathematician Gregori Perelman won it for solving the Poincaré conjecture. The Millennium Prize inspired suggestions to create a similar award for the life sciences to encourage scientists to address the great challenges in biology. The major question of how the first primitive cells evolved from complex chemicals […] spawns a range of other, fundamental questions at the molecular level … But this idea has faced several objections, one being that problems and solutions are easier to define in mathematics, while no two biologists are likely to come up with the same list of major challenges for the life sciences. There is though broad consensus over the major areas, with the origin and evolution of life being on just about every list. The major question of how the first primitive cells evolved from complex chemicals—which themselves evolved from more simple organic compounds—spawns a range of other, fundamental questions at the molecular level, such as how the current set of proteins evolved from the vast number of possibilities created by the 20 amino acids. … in light of evolution After the first cells emerged, the stage was set for the evolution of eukaryotic cells and multicellular organisms, which presents another major challenge to understand their development underpinned by cell differentiation. This in turn involved the emergence of more complex and sophisticated networks of genes and proteins where the challenge is now to understand how these generate phenotypes that underpin physiology and behavior. In addition to these fundamental questions, there are the more applied challenges in biomedical research. Cancer remains a huge research area that depends on fundamental work in cellular signaling and replication. Then, there is aging, which relies on understanding selective pressures in evolution and the underlying molecular processes. Finally, there are technological challenges, ranging from live imaging and genomics to methodologies such as systems biology, which divides opinion over whether these are fundamental challenges themselves or just approaches for studying the big questions. Not surprisingly, systems biologists view their field as fundamental to the future of the life sciences, the secrets of which can only be unlocked by mathematical or quantitative approaches. “Systems biology is about changing the way we think, because working out how molecules collectively produce phenotype is a very different problem from finding the molecules in the first place,” commented Jeremy Gunawardena, Associate Professor of Systems Biology at Harvard Medical School. “I think it is the fundamental problem we face in biology and I do not believe we will get traction on other problems like consciousness […] or the origin of life if we do not make progress in understanding how molecules give rise to phenotype”. The origin of life John Sutherland, Group Leader at the MRC Laboratory of Molecular Biology in Cambridge, UK, who studies the origin of life, also argues that it requires a “systems chemistry” approach to unravel the events that gave biology its foundations, including the cellular format or the genetic code. “There is great progress being made in Europe and the US especially since the recognition that systems rather than isolated reactions should be considered”, Sutherland added. “The rate of progress is accelerating and young people are rushing into the field which is now more vibrant than ever before”. Not surprisingly, systems biologists view their field as fundamental to the future of the life sciences… His own team has made some progress, first by showing that two of RNA's four building blocks could be made from acetylene and formaldehyde 1. This was taken as support for the hypothesis that RNA was the pioneer of life, as it can both carry genetic information and act as a catalyst. The main alternative hypothesis has been “Metabolism First”: that simple metal catalysts rather than protein-based enzymes created the stew of organic building blocks needed to create other biomolecules. This still begs the question of where acetylene and formaldehyde came from so Sutherland and his colleagues worked backward seeking a route to RNA from even simpler starting materials. They succeeded in creating nucleic acid precursors from just hydrogen cyanide, hydrogen sulfide, and ultraviolet light 2. “The chemistry we are uncovering reveals a natural tendency for hydrogen cyanide to be reduced and homologated to a specific set of products that just happens to correspond to a large number of the building blocks of biology and not much else”, Sutherland explained. “This would seem to suggest that we are roughly recapitulating chemistry that played out nearly four billion years ago, although the exact details remain to be worked out and some will probably never be known”. The next step is to understand how these compounds assembled into higher-order structures, as well as how the whole process was powered at the time. “Ultimately I am convinced that the transition of a system from inanimate to living will be demonstrated experimentally and the living system will have so many resemblances to extant biology that people will readily accept that our life arose in a very similar way”, Sutherland said. “In short, I think we should expect to see something mind-blowing—life arose as no more than a consequence of chemistry and so it should be possible for it to happen again, especially under our guidance”. …life arose as no more than a consequence of chemistry and so it should be possible for it to happen again, especially under our guidance. These questions are related to the field of astrobiology, which has attracted increased attention as it has emerged from the realms of science fiction to be taken more seriously. The obvious overlap between astrobiology and the origins of life on Earth has been recognized by the US National Science Foundation (NSF), which funds various joint programs with NASA. “I'm cautiously optimistic that we will soon get some innovative insights into the origins of life on Planet Earth, but also with implications for astrobiology”, said James Olds, Head of the Directorate for Biological Sciences at the NSF. “If one assumes that the laws of physics and chemistry are constant across the galaxy or universe and if we understand the origins of life from interactions in the lithosphere and energy relaxation pathway, that has implications for how life might originate in other planets”. Metabolism and development Another fundamental question about the origin of life is how cells used critical chemical reactions to build metabolic pathways, many of which have been highly conserved across species. Early evolution gradually optimized these reactions for speed, accuracy, and energy demand. Until recently, it had been assumed that reactions were optimized primarily for accuracy, given that errors are potentially fatal. But this may not be the case, according to Oleg Igoshin from the Department of Bioengineering Center for Theoretical Biophysics at Rice University in the USA. His team studies kinetic proofreading, a mechanism for correcting errors in biochemical reactions by which enzymes discriminate between two alternative reaction pathways, one being an irreversible exit step. This comes at the expense of speed, because the correct path has to be slower than the incorrect one in order to make the process as specific as possible. Igoshin's team thus studied the trade-off between accuracy and speed for two systems 3. “To our surprise we see that both systems are very close to the optimal speed but quite far from the optimal error”, he explained. “So even though the whole kinetic proofreading mechanism undoubtedly evolved to reduce the errors, it was not fully optimized to achieve lowest possible error. Interestingly, we found an example in which change of a certain rate could've resulted in both faster and more accurate enzyme (so no trade-off) but here the argument of cost comes about and cost considerations do not allow the system to go in this direction”. By most reckoning, the next big challenge after origin of life is Developmental Biology and the rise of multicellular life. There has been a lot of progress in understanding the early stages of embryonic development when the single-layered blastula is reorganized into the multilayered gastrula, which coincides with the start of cell differentiation. At this stage, the body's fundamental geometry has been established as the cells align along basic axes, which persist for the rest of the animal's life. This also involves separation into three distinct layers, the endoderm, mesoderm, and ectoderm, that determine tissues or organs. As such, gastrulation establishes the blueprint for life in animals and is widely considered the most important developmental event. … the fundamental question is, now that we know most of the molecular players, how do we reconstruct the organism, its phenotype and its behavior from the molecular parts. One major step forward came in 2014 with the demonstration of an in vitro model system for studying gastrulation using mouse embryonic stem cells 4. A team led by Alfonso Martinez Arias, Group Leader at the Department of Genetics, University of Cambridge, UK, applied the model and found that gastrulation appears to be less determined by the position of cells within the embryo and more by underlying genetics. “There are two important points”, said Martinez Arias. “One is the remarkable autonomy of the developmental processes that emerge in these embryonic organoids, that is, how well they copy the embryo in terms of the timing of the unfolding of the developmental processes”. The second point is that this could have implications for stem-cell based therapies, by influencing how tissues develop in the embryo. “For example we can get the trunk without the head and the head without the trunk”, said Martinez Arias. “We see a mouse, a mammal, as a continuum and yet it is not”, Martinez Arias said. “This has important implications for the understanding of body building, evolution and, I suspect, in the long run, regenerative medicine. […] The most surprising observation of our experiments is that if you get the right initial conditions, you are in a good place to get almost any structure you want”. Therapeutic application may be some long way off, but Martinez Arias is optimistic that there is at least now a new framework for analyzing developmental biology on the animal side. “The most important thing is that our system, which we now have under good and reproducible control, is a launching pad to understand human development which cannot be studied otherwise”, he said. From genotype to phenotype Beyond development, the next challenge in biology is to understand how cells and molecules interact in higher forms of life. “In my view, the fundamental question is, now that we know most of the molecular players, how do we reconstruct the organism, its phenotype and its behavior from the molecular parts”, Gunawardena said. “In one way or another, all biologists are going to be dealing with this question for the foreseeable future, even when they do not describe themselves as systems biologists. This kind of change is not like molecular biology, in which a single insight, about the structure of DNA, opened the door to a vast territory”. …new imaging methods will completely change cell biology, together with the ability to look at single cells and their interactions and to grow organoids. Such studies would allow understanding more complex behaviors in humans, as well as language and consciousness. It also requires insights into the evolutionary processes that drive the emergence of complex traits or behaviors. “I would say these challenges mostly relate to origins”, said Nick Lane, a researcher in evolutionary biochemistry at University College, London, UK, and author of various books on these issues. “We are pretty good at steady-state evolution, but it is the abrupt changes, the major transitions, that are most difficult”. While it is relatively easy to understand how evolution proceeds through step changes as Charles Darwin postulated, it is harder to work out how major innovations emerged, which could not have happened through intermediate steps that, on their own, would not have conferred a selective advantage. A classic example is the evolution of the placenta during the early era of mammals, which seems to have been driven by the capture of viral genes encoding the protein syncytin that helps to mediate placental cytotrophoblast fusion. The protein evolved in viruses to help them fuse host cells to accelerate their spread and the theory is that it became incorporated in a common mammalian ancestor as a result of infection 5. Knowledge versus application Such fundamental questions are often distinguished from applied challenges with environmental or medical implications. But there is also a case for taking a more blurred line. As Lane commented, progress on fundamental questions can have an unexpected payoff for biomedical research. He cited gene editing using CRISPR/Cas9, which evolved as an adaptive immune system in bacteria and archaea to confer resistance against plasmids or phages. The same system allows gene editing in eukaryotic genomes, with great promise in medicine and agriculture. “To me an important point is that it all arose in the late 1980s, 30 years ago, from work on bacterial immune systems, which at the time would have been considered curiosity-driven research with no practical application”, Lane said. “This kind of curiosity over those kinds of timelines desperately needs supporting in today's managerial ethos. It could not have been planned, and today could easily not have been supported”. However, some funding bodies reward and encourage such work, one being the ERC (European Research Council), which was set up specifically to promote innovative work without any preconceived priorities. The ERC therefore would never opine over which fundamental questions were more important, according to Janet Thornton from the European Molecular Biology Laboratory at the Wellcome Trust Genome Campus, who is also a Member of the ERC Scientific Council. “The ERC has been so successful in the past because it has been driven from the bottom up, not creating consortia”, she said. In order to address larger challenges, the ERC is introducing a scheme called Synergy Projects in 2018 to support the collaboration required. “What we find all the time now is that projects are relatively interdisciplinary and need different expertise to come together”, Thornton explained. Thornton cited aging and its medical implications as one big challenge her own group is working on. “Ageing frankly is not that well understood”, she said. “We know things that happen as we age and there are several theories around that seek to explain ageing, which is common across all life. Understanding the causes of ageing is a huge challenge”. Thornton is generally optimistic though that progress will be made on aging and other big questions, partly through real-time imaging at the molecular level, such as X-ray crystallography, which enable the observations of molecules in vivo. “It's quite amazing how much we've learnt from crystallography, despite the fact that it is static, because the structure is critical for understanding how molecules behave in solution. If you don't know a three-dimensional structure to begin with, knowing how they wobble around doesn't help very much”, Thornton commented. She added that “new imaging methods will completely change cell biology, together with the ability to look at single cells and their interactions and to grow organoids”. Making sense of data Such methods increasingly yield insights not through direct observation but via data analysis, which has created another challenge in its own right, according to Robert Weinberg, Director of the MIT (Massachusetts Institute of Technology) Ludwig Center for Molecular Oncology. “The greatest overarching challenge for all the life sciences is how to take complex datasets and extract some meaningful conceptual conclusions from them”, he said. “This applies to all of the life sciences, in which vast improvements in data acquisition has led to an enormous flood of data. The flood has been created by enormous improvements in analytical procedures, such as DNA sequencing and RNA expression analyses, without comparable increases in analytical methods that would allow us to interpret the full meaning of these data”. The greatest overarching challenge for all the life sciences is how to take complex datasets and extract some meaningful conceptual conclusions from them. This was holding back progress in several fields, Weinberg argues, including the analysis of what he calls biological integrated circuits: the interactions between signal-processing proteins within cells. These, as he pointed out, are the complex circuitries that determine cell behavior, and understanding how they operate is a fundamental challenge. “A prerequisite to such improved understanding would be detailed biochemical analyses that describe the signal-processing parameters that the individual protein components of these circuits exhibit, an area in which minimal progress has been made”, Weinberg explained. “Independent of this, there is little progress in trying to understand the behavior of the circuits as a whole, an analytical problem of great complexity that continues to resist attack. Progress in this area will ultimately shed light on a variety of pathological states but may require another decade or two to be realized”. Given the long list of fundamental, applied and technological challenges in the life sciences—which can include many more items—an equivalent of the Millennium Prize might help to inspire scientists to tackle these problems. However, not all biologists think so and reckon that the life sciences are already well rewarded. “Biology already gets to ’double-dip’ by having 1.5 Nobels, all of physiology and medicine and typically half of chemistry prizes”, said structural biologist Venkatraman Ramakrishnan, President of the Royal Society in the UK who won the Nobel prize for Chemistry in 2009. “Hard core chemists already complain about biologists invading ’their’ prize”. This view is more or less shared by Weinberg. “I do not think that a new prize for biology would serve any useful purpose, given the existing Nobel and Breakthrough prizes”, he said. Prizes or not, biology offers enough puzzles for scientists intrigued by intellectual challenges. References 1. 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Mi S, Lee X, Li X-P, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang X-Y, Edouard P, Howes S et al (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403: 785–789CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 18,Issue 8,August 2017Cover: Twin baby sisters are playing rope skipping to depict the coupling model of sister chromatid cohesion establishment and chromatin replication through Rtt101‐Mms1 E3s. Twin baby sisters represent two newly replicated sister chromatids, while the rope stand for the moving replication fork. Rtt101‐Mms1 E3s and nucleosomes with histone H3K56ac/K121K122ubi markers are depicted by the sachet and chignons, respectively. The Chinese character on the sachet means “together with, harmonious”. From Jingjing Zhang, Di Shi, Xiaoli Li, Huiqiang Lou and colleagues: Rtt101‐Mms1‐Mms22 coordinates replication‐coupled sister chromatid cohesion and nucleosome assembly. For detail, see Article on page 1294. Cover illustration by Yuyao Du and Yifan Lei. Volume 18Issue 81 August 2017In this issue ReferencesRelatedDetailsLoading ...