SCIENCE CHINA Life Sciences © The Author(s) 2013. This article is published with open access at Springerlink.com life.scichina.com www.springer.com/scp email: hefc@bmi.ac.cn SPECIAL TOPIC: Lifeomics and translational medicine March 2013 Vol.56 No.3: 201–212 • REVIEW • doi: 10.1007/s11427-013-4464-6 Lifeomics leads the age of grand discoveries HE FuChu State Key Laboratory of Proteomics，Beijing Proteome Research Center, National Center for Protein Science (Beijing), Beijing 100850, China Received January 5, 2013; accepted January 10, 2013 When our knowledge of a field accumulates to a certain level, we are bound to see the rise of one or more great scientists. They will make a series of grand discoveries/breakthroughs and push the discipline into an ‘age of grand discoveries’. Mathematics, geography, physics and chemistry have all experienced their ages of grand discoveries; and in life sciences, the age of grand discoveries has ap- peared countless times since the 16th century. Thanks to the ever-changing development of molecular biology over the past 50 years, contemporary life science is once again approaching its breaking point and the trigger for this is most likely to be ‘lifeomics’. At the end of the 20th century, genomics wrote out the ‘script of life’; proteomics decoded the script; and RNAomics, glycomics and metabolomics came into bloom. These ‘omics’, with their unique epistemology and methodology, quickly became the thrust of life sciences, pushing the discipline to new high. Lifeomics, which encompasses all omics, has taken shape and is now signalling the dawn of a new era, the age of grand discoveries. age of grand discoveries, lifeomics, life sciences Citation: He F C. Lifeomics leads the age of grand discovery. Sci China Life Sci, 2013, 56: 201–212, doi: 10.1007/s11427-013-4464-6 Natural science is the “art” of discovery, and discovery is the cornerstone of natural science. Discovery, which ex- plores the known and the unknown, is a mastery that re- quires accumulated knowledge and original innovation. A detailed look at the history of science reveals numerous examples of ‘spurring with long accumulation’: when our understanding of a field accumulates to a certain level, we are bound to see the rise of one or more groundbreaking scientists. These great scientists will trigger a flood of dis- coveries, break the shackles of time and advance our under- standing to new high. The result is an explosive growth in one or more related disciplines, bringing new ideas and fundamental changes and this is when a new era begins, i.e., the age of grand discoveries. Thanks to the rapid develop- ment of molecular biology over the past 50 years, especially in the area of omics over the past 20 years, contemporary life science is once again approaching its breaking point and the trigger for this is most likely to be ‘lifeomics’ (i.e., ge- nomics, RNAomics, proteomics, etc.). 1 The age of grand discoveries in science Our understanding and learning of natural sciences begins with mathematics. Modern science is precisely the pursuit of mathematical laws governing nature. Indeed, many sci- entific breakthroughs were made through the development of mathematics. The Pythagoreans of ancient Greece made remarkable contributions that triggered the first age of grand discoveries in mathematics. They were the earliest people to demonstrate the Pythagorean Theorem and propose the concepts of odd, even, prime, amicable and whole numbers. The Pythagoreans considered arithmetic as an ‘absolute and discrete quantity’, music as a ‘relative and discrete quantity’, geometry as a ‘static and continuous quantity’, and astron- omy as a ‘dynamic and continuous quantity’. They estab- lished the doctrine that ‘mathematics is the basis of every- thing’. Because of this doctrine, the Greek philosopher Plato wrote above his academy entrance, “let no one ignorant of geometry enter here.” He viewed mathematics as an indis- pensable tool for understanding the structure of the universe. 202 He F C. Sci China Life Sci March (2013) Vol.56 No.3 Thereon, the development of mathematics became the cor- nerstone of all disciplines that followed. The age of grand discoveries in geography lasted a mere 40 years, but its impact on the world was felt for hundreds of years. At the turn of the 16th century, the geocentric the- ory and the European compass took us to places and routes unknown to civilization. In 1485, Christopher Columbus discovered North America; in 1497, Vasco da Gama dis- covered the Indian Ocean and India; in 1498, Christopher Columbus discovered South America; in 1519, Ferdinand Magellan sailed to the southern tip of South America and discovered a strait that joins the Atlantic and Pacific Oceans; and in 1521, Magellan crossed the strait and discovered the Pacific Ocean, marking a major turning point in modern Western civilization [1]. These geographical explorations brought forth a spread of revolutionary ideas and commer- cial activities, greatly expanding the universe as conceived by Aristotle and Ptolemy. The change prompted many in- tellectuals in Europe to question the authority of the Church, challenging their age-old beliefs and views about the world. The resulting awakening opened the door to critical thinking and promoted innovation in the revolution of science. Chemistry experienced immense growth during its founding period thanks to the discovery of gases and ele- ments in the 18th century. In 1756, Joseph Black discovered carbon dioxide; in 1760, Daniel Rutherford discovered ni- trogen; in 1766, Henry Cavendish discovered hydrogen; and in 1774, Joseph Priestley discovered oxygen [1]. As a result of these discoveries, in 1789, Antoine-Laurent Lavoisier provided a more scientific explanation for combustion—in terms of oxidation—to challenge the then prevailing phlo- giston theory. After extensive research, Lavoisier wrote the book Traité Élémentaire de Chimie (Elementary Treatise on Chemistry) and presented his definition of an element. Be- cause of his work, more than half of all elements that exist in our universe for billions of years were found in the dec- ades that followed (Table 1). It was nothing more than a glory for human beings. In 1869, Dmitri Mendeleev orga- nized the then known 63 elements into groups with similar properties. He recognized that there was a pattern in the way elements behave and created the first periodic table. The examples above illustrate how some of the greatest discoveries in chemistry were gestated through accumula- tion or evolution of knowledge and finally born from their revolution. So far, we have only mentioned disciplines whose ages of grand discoveries took place at the early stage of devel- opment. People might ask, “can a mature discipline enter the age of grand discoveries once again?” The answer is yes, and astronomy and physics are two great examples. Astronomy and mathematics are the oldest of the natural sciences. These disciplines spearheaded the development of science during the Age of Enlightenment. The emergence of heliocentric theory and telescope technologies at the turn of the 17th century triggered the first age of grand discoveries in astronomy. In 1572, Tycho Brahe detected a stellar ex- plosion in the constellation Cassiopeia. He made detailed observations and records for 16 months before reporting the discovery of a supernova. In 1577, Tycho studied a bright comet for 74 days and, based on his observations, deduced that our planet was orbiting the Sun and that comets were not atmospheric phenomena [1]. In 1576, Tycho received the financial support from Frederick II, the then King of Denmark, to build an observatory on the island of Hven. Since then, Tycho had been studying the movement of stars, planets, the Sun and the Moon, day after day, year after year, for 21 years. He collected a huge amount of observational data before publishing his first comprehensive star cata- logue, which detailed the position of more than 1000 stars. Known as the ‘king among astronomers’, Tycho pushed observational astronomy to new high using naked eyes only. His celestial positions were amazingly accurate, supersed- ing those of any predecessor. In 1600, Tycho offered the talented Johannes Kepler unrestricted access to his wealth of observational data. Based on Tycho’s precise data, Kep- ler worked out the orbits of the planets and developed his three laws of planetary motion. He showed that all planets move in ellipses with the Sun at one focus, proving that the Copernicus’ heliocentric model was indeed correct. Because the planets of our solar system move through space accord- ing to Kepler’s laws, many people called Kepler the ‘legis- lator of the heavens’. Even Kepler’s tomb carries an epitaph he wrote himself, “I measured the skies, now the shadows I measure. Skybound was the mind, earthbound the body rests”. Some say it was only because of Tycho’s precise observations that Kepler worked out the laws of planetary motion. Therefore, for a mature discipline such as astrono- my to enter the age of grand discoveries again, it must first accept a revolutionary hypothesis. Subsequently, discover- ies made in the new age can be used to support the hypothe- sis. The early 17th century saw the birth of another physicist whose achievements equalled those of Kepler—Galileo Galilei. He is considered by many to be the ‘father of sci- ence’, as well as the creator of modern experimental science. In 1604, Galileo derived the first (uniform velocity) and second laws of motion (uniform acceleration); in 1609, he discovered uneven terrains on the moon and created a topo- logical map of the lunar surface using a telescope he made for observing celestial bodies [1]; Galileo discovered Jupi- ter’s four satellites, providing supportive evidence for Co- pernicus’ theory; two years later, Galileo discovered sun- spots, solar rotation and the planetary phases of Venus and Mercury. The chain of discoveries initiated a new age of grand discovery for astronomy. Galileo established a re- search approach that integrates experimental measurements with the- oretical analyses through observations. His famous quote, “measure what can be measured, and make measura- He F C. Sci China Life Sci March (2013) Vol.56 No.3 203 Table 1 Chemical elements that were discovered in the 19th century (52 different elements) Z Year Chemical element Country Discovered by 1 1868 He (Helium) France Pierre Janssen UK Named by Lockyer S. N. 2 1817 Li (Lithium) Sweden Arfwedson J. A. 3 1808 B (Boron) UK Davy H. 4 1898 Ne (Neon) Germany Koch Robert 5 1807 Na (Sodium) Germany Davy H. 6 1808 Mg (Magnesium) France Davy H. 7 1825 Al (Aluminium) Denmarl Oeisted H. C. 8 1823 Si (Silicon) Sweden Bertholius J. J. 9 1810 Cl (Chlorine) Sweden Scheele C. W. UK Named by Davy H. 10 1894 Ar (Argon) UK Rayleigh J. W. & Ramsay W. 11 1807 K (Potassium) UK Davy H. 12 1808 Ca (Calcium) UK Davy H. 13 1879 Sc (Scandium) Sweden Nilson L. F. 14 1831 V (Vanadium) Sweden Sefstrom N. G. 15 1875 Ga (Gallium) France De Boisbaudran L. 16 1885 Ge (Germanium) Germany Winkler C. A. 17 1817 Se (Selenium) Sweden Berzelius J. J. 18 1824 Br (Bromine) France Balard A. J. 19 1898 Kr (Krypton) UK Ramsay W. UK Named by Travers M. W. 20 1860 Rb (Rubidium) France by Bunsen R. Named by Kirchhoff G. R. 21 1808 Sr (Strontium) UK Davy H. 22 1801 Nb (Niobium) UK Hatchett C. 23 1827 Ru (Ruthenium) Russia Klaus K. K. 24 1803 Rh (Rhodium) UK Wollaston W. H. 25 1803 Pd (Palladium) UK Wollaston W. H. 26 1817 Cd (Cadmium) Germany Stromeyer F. 27 1863 In (Indium) Germany Richter H. T. & Reich F. 28 1814 I (Iodine) France Courtois B. 29 1898 Xe (Xenon) UK Ramsay W. Named by Travers M. W. 30 1860 Cs (Caesium) Germany Bunsen R. & Kirchhoff G. R. 31 1808 Ba (Barium) UK Davy H. 32 1839 La (Lanthanum) Sweden Mosander C. G. 33 1803 Ce (Cerium) Sweden Berzelius J. J. Germany Klaproth M. H. Sweden Hisinger W. 34 1885 Pr (Praseodymium) Austria Auer von Welsbach C. 35 1885 Nd (Neodymium) Austria Auer von Welsbach C. 36 1879 Sm (Samarium) France De Boisbaudran H. L. 37 1896 Eu (Europium) France Demarcay E. 38 1880 Gd (Gadolinium) Sweden De Marignac J. G. France First isolated by de Boisbaudran H. L. 39 1843 Tb (Terbium) Sweden Mosander C. G. 40 1886 Dy (Dysprosium) France De Boisbaudran H. L. 41 1879 Ho (Holmium) Sweden Cleve P. T. 42 1843 Er (Erbium) Sweden Mosander C. G. 43 1879 Tm (Thulium) Sweden Cleve P. T. 44 1878 Yb (Ytterbium) Switzerland Marignac J. G. 45 1802 Ta (Tantalum) Sweden Ekaberg A. G. 46 1803 Os (Osmium) UK Tennant S. et al. 47 1803 Ir (Iridium) UK Tennant S. et al. 48 1861 Tl (Thallium) UK Crookes W. 49 1898 Po (Polonium) France Curie P. & Curie M. S. 50 1898 Ra (Radium) France Curie P. & Curie M. S. 51 1899 Ac (Actinium) France Debierne A. L. 52 1828 Th (Thorium) Sweden Berzelius J. J. 204 He F C. Sci China Life Sci March (2013) Vol.56 No.3 ble what cannot be measured”, has inspired many experi- mentalists for dozens of generations. Galileo established a new direction for theoretical physics on the basis of exper- imental science. Because of him, we have boundless free- dom to explore the physical world. Discoveries made by Kepler and Galileo ushered in a new era—the Newtonian era. Issac Newton invented the binomial theorem and differential calculus in mathematics, established the law of universal gravitation in astronomy, laid down the three laws of motion in physics, and discov- ered the visible spectrum and reflecting telescope in optics. Having made these great achievements, Newton in 1686 published Philosophiae Naturalis Principia Mathematica (Mathematical Principles of Natural Philosophy) [1], a masterpiece that epitomizes his work on mechanics and gravitation. Lord Newton once said, “if I have seen further it is by standing on the shoulders of giants”. Many people take these as Newton’s humble words, but if we review them carefully, we realise the true meaning of his words. It was through Tycho’s precise data that Kepler derived the laws of planetary motion; it was through large amounts of experimental work that Galileo derived the first and second laws of motion; and it was through the integration of related laws in physics and astronomy that we arrived at the epito- me of Newtonian mechanics. In other words, Newton un- derstood that it was only through standing on the shoulders of giants like Tycho, Kepler and Galileo that he achieved so much in his lifetime. In the same sense, it was through large amounts of observation, accumulation of experimental data, and grand discoveries of laws that we produced these giants. In the late 19th century, the theoretic building of Newton epitomized the studies of acoustics, optics, electromag- netism and thermodynamics. His ‘universal’ laws worked on all matter, from the smallest of microscopic particles to the largest of heavenly bodies. People felt there were little room for expansion in the development of science. However, there were two ‘dark clouds’ hanging over classical physics: the Michelson-Morley experiment and blackbody radiation. Thanks to these two phenomena, relativity and quantum theory were developed to replace Newtonian mechanics as the more generalized theories of the physical world. In ad- dition, a new ‘hypothesis-driven’ research approach, as op- posed to the conventional “discovery-driven” research ap- proach, emerged. Therefore, can we derive all theories from hypotheses? The answer is not always, even for highly the- oretical disciplines like astronomy and physics where theo- ries are typically derived from observations. Some of these observations rely on hypotheses, while others have com- pletely no theoretical bases. For example, discoveries de- rived from aforementioned geocentric and heliocentric the- ories were driven by and proven from hypotheses. However, the discovery of Kepler’s three laws and Galileo’s two laws did not rely on any hypothesis. They were purely based on scientific observations and vast amounts of scientific data. Even in the case of relativity, which involves a lot of thought experiments, the main assumptions were based on results from the Michelson-Morley experiment. In reality, the hypothesis-driven approach is just as important as the discovery-driven approach when it comes to developing science and technology. Like what the pioneer Galileo once said, to “measure what can be measured, and make meas- urable what cannot be measured.” This should be the basic principle of modern science, especially experimental sci- ence. In light of these examples, we see that only through ac- cumulation of knowledge can we get results. Discovery is a process led by theory and driven by technology. Without discovery, there will be no scientific revolution. 2 The age of grand discoveries in life sciences Life science is an ancient but exciting discipline where new discoveries are being made everyday. Its golden era, as a whole, spans from 500 years ago to the present. Modern life science was triggered by great discoveries in biology during the 16th and 17th centuries. In 1543, the Flemish anatomist Andreas Vesalius gained a thorough un- derstanding of the human anatomy through dissecting ani- mals and human cadavers. His book De Humani Corporis Fabrica (On the Human Body Structure) gave detailed de- scriptions of the human body, including its skeletal system, muscular system, vascular system, nervous system, diges- tive organs, internal organs and sensory organs. The dis- covery was a major triumph over ignorance and Christian supremacy. The book De Humani Corporis Fabrica not only opened a new chapter in the study of life sciences, but also laid the cornerstone of modern medicine. In 1616, Wil- liam Harvey described the structure of the human heart and established the theory of blood circulation. In the 1660s, Marcello Malpighi discovered that the respiratory system of small animals has a higher surface-to-volume ratio than that of higher animals. In 1665, Robert Hooke published Mi- crographia and coined the term ‘cell’ to describe the basic unit of life. In 1683, Antonie van Leeuwenhoek discovered bacteria. In 1688, he gave detailed description of red blood cells. In light of these examples, we can see that discoveries in biology have improved our understanding of the micro- scopic world. The 17th century was an age of grand discoveries for the study of biological species. In 335 BC, Aristotle conducted research and provided detailed description for over 500 animal species. He coined the term “animal” and wrote the first book on zoology, which dictated the academic field for over a millennium. In the 1600s, the number of plant spe- cies known to science was approximately 6000. Then in the 17th century, scientists discovered 12000 new plant species [1], twice the total number found over the last 2000 years. They also found quite a number of new animal species, so evidently the period was an age of grand discoveries for the He F C. Sci China Life Sci March (2013) Vol.56 No.3 205 study of biological species. Owing to the large number of new species being found, there was a growing need of a self-consistent and rational classification system. In 1735, Carl Linnaeus published Systema Naturae (Natural System) and proposed a new sys- tem for classifying plants according to their reproductive organs. Although subconsciously Linnaeus appeared to go against evolutionary views, his classification system ended up pushing new ideas forward. From 1749 to 1788, Georges-Louis Leclerc de Buffon published the mul- ti-volume Histoire Naturelle (Natural History) and pro- posed the radical view that similar organisms may have a common ancestor. He was the first scholar to treat the origin-of-species problem in a scientific spirit. In 1785, James Hutton published his theory on sedimentary rocks and biological fossils. Subsequently, the study of fossils became a scientific discipline and an important basis for understanding biological systems, especially prehistoric systems. In 1801, Jean-Baptiste Lamarck published Système des Animaux sans Vertebres (System for Invertebrates) and proposed the first truly cohesive theory of evolution. In 1809, he published Philosophie zoologique (Zoological Philosophy), which outlined his concept of Lamarckism and coined the term ‘biology’ for the first time [1]. In 1831, Charles Darwin began his five-year voyage around the world, investigating geology and making natural history collection. After extensive investigations, he established the concept of biological evolution. In 1859, Darwin published On the Origin of Species [1], grouping various evolutionary ideas together into one ambitious but convincing theory. It can be said that, without the discovery of biological species and Darwin’s expedition around the world, we would not have the theory of evolution as we know it today. The advent of cell theory in the 19th century triggered a new area in modern medicine, known as experimental med- icine. In 1831, the Scottish botanist Robert Brown discov- ered the nucleus. In 1838, Matthias Jakob Schleiden pub- lished a paper titled Beiträge zur Phytogenesis (Contribu- tions to Phytogenesis), where he stated that “all plants, no matter how complex, are composed of cells” [1]. In 1839, Theodor Schwann published a paper titled Microscopic In- vestigations on the Accordance in the Structure and Growth of Plants and Animals, where he concluded that “all living things are composed of cells”. The theory broke the bound- ary between animals and plants. In 1858, Rudolf Virchow published Cellular Pathology, where he pointed out that “all cells come from other cells” and that “all diseases involve changes in normal cells”. In 1875, Eduard Adolf Strasburg- er published Zellbildung und Zelltheilung (Cell Formation and Cell Division), where he pointed out that “all cells come from pre-existing cells” and that “all nuclei come from other nuclei”. From then on, the cell theory was no longer a hypothesis. It was the guiding force of life scienc- es. As microscope technology matured in the second half of the 19th century, life science ushered in the era of microor- ganisms (Table 2). It was a revolutionary period for micro- biology research, one that was comparable to the theory of evolution. In 1856, Louis Pasteur discovered that “fermen- tation is caused by the growth of microorganisms”. In 1859, he disproved the theory of spontaneous generation. From 1860 to 1880, Pasteur made huge contributions to wine pasteurization, silkworm diseases and infectious diseases just by one word “microorganism”. He proposed the mech- anism by which disease was transmitted. From 1870 to 1890, Robert Koch developed new theories and techniques in bacteriology (e.g., preparing pure culture and staining). He proposed and validated the idea that “an organism can be isolated in every case of a disease”. He also formulated Koch’s postulates, which say that, to establish that an or- ganism is the cause of a disease: it must be found in all cas- es of the disease examined; it must be prepared and main- tained in a pure culture; it must be capable of producing the original infection; and it must be retrievable from an inocu- lated animal and cultured again. Up to date, Koch’s postu- lates remain the iron laws and gold standards of pathology. In 1890, Ilya Ilyich Mechnikov discovered phagocytes and phagocytosis, as well as proposed the cellular theory of immunity. In 1890, Emil Adolf von Behring discovered a serum therapy against diphtheria and tetanus, as well as proposed the concept of humoral immunity. These discov- eries led human beings landing the absolutely new invisible world which species number could be comparable with those of the traditional, visible worlds of animals and plants, defended human rationality against ignorance and Christian supremacy, and triggered a revolution in modern medicine, known as the antibiotic revolution. The 20th century has been described as the century of the gene [2]. The development of genetics happened so quickly, like a fairy tale in life sciences. In 1900, Hugo de Vries, Karl Correns and Erich von Tschermak independently re- discovered Mendel’s genetic laws. From 1910 to 1930, Thomas Hunt Morgan discovered the idea of genetic link- age and produced the first linkage map of the fruit fly Dro- sophila. In his books The Physical Basis of Heredity and the Theory of the Gene, he provided the first working theory of heredity. In 1928, Frederick Griffith [1] discovered a trans- forming factor in Streptococcus pneumoniae. In 1944, Os- wald Avery [1] used biochemical methods to confirm that the transforming factor was, in fact, DNA. In 1937, the Eu- ropean pioneer of structural biology William Astbury pro- posed a structural model for DNA. He took X-ray diffrac- tion photographs of DNA, showing that its structure is strong, rigid and fibrous. In 1951, Maurice Wilkins and Rosalind Franklin [1] obtained high-quality X-ray diffrac- tion photographs of DNA, indicating that its structure is most likely to be a right-handed double helix. In 1952, Al- fred Hershey and Martha Chase used isotope labelling method to prove that the genetic material of bacteriophages is DNA, not protein. In the same year, Erwin Chargaff [1] 206 He F C. Sci China Life Sci March (2013) Vol.56 No.3 Table 2 Discovery Timeline of pathogenic microorganisms Year Pathogen Disease caused Origin Discovered by 1877 Bacillus anthracis Anthrax Germany Robert Koch 1878 Staphylococcus Pyogenesis Germany Robert Koch 1879 Mycobacterium leprae Leprosy Sweden Hansen Armaner 1879 Neisseria gonorrhoeae Gonorrhoea Germany Neisser A. L. S. 1880 Staphylococcus aureus Toxic shock syndrome Scotland Alexander Ogston 1880 Salmonella typhi Typhoid Germany Eberth C. J. 1881 Streptococcus Pyogenesis Scotland Ogston A. 1882 Mycobacterium tuberculosis Tuberculosis Germany Robert Koch 1884 Corynebacterium diphtheriae Diphtheria Germany Edwin Klebs & Friedrich Loffler 1884 Vibrio cholerae Cholera Germany Robert Koch 1884 Clostridium tetani Tetanus Germany Nicolaier A. 1885 Escherichia coli Diarrhoea Germany Ehrlich Paul 1886 Streptococcus pneumoniae Pneumonia Germany Fraenkel Karl & Louis Pasteur 1887 Neisseria meningitides Epidemic cerebrospinal meningitis Germany Weickselbaum Antou 1888 Salmonella enteritidis Food poisoning USA Gaertner A. A. H. 1892 Clostridium perfringens Gas gangrene USA Welch W. H. 1892 Haemophilus influenzae Meningitis and pneumonia Germany Pfeffer Wilhelm 1894 Yersinia pestis Plague Germany Independently discovered by Kita- sato S. & Yersin A. J. E. 1896 Clostridium botulinum Botulism Belgium van Ermengem E. M. P. 1896 Salmonella paratyphi Paratyphoid France Achard Charles 1898 Shigella dysenteriae Dysentery Japan Shiga K. 1911 Treponema pallidum Syphilis Japan Hideyo Noguchi 1906 Bordetella pertussis Pertussis France Bordet J. & Gengou O. 1909 Bartonella bacilliformis Bartonella disease South America Albert Barton 1973 Rotavirus Infant diarrhoea Australia Bishop R. F. 1975 Hepatitis A virus Hepatitis A Germany Stephen M. Feinstone 1976 Ebola virus Ebola hemorrhagic fever Africa Bowone & Pattyn 1977 Hantaan virus Hemorrhagic fever with renal syndrome Korea Lee Ho-wang 1977 Legionella Legionnaires’ disease USA & Philippines McDade 1978 Hepatitis D virus (HDV) Hepatitis D Italy Mario Rizzetto 1981 Human T-lymphotropic virus 1 (HTLV-1) T- cell lymphoma, leukaemia USA Bernard Poiesz & Francis Ruscetti 1982 E. coli. O157, H7 Hemorrhagic colitis USA Riley 1982 Human T-lymphotropic virus 2 (HTLV-2) Hairy cell leukaemia Japan Kalyanaraman V. S. 1982 Borrelia burgdorferi Lyme disease USA Burdorfer 1982 Enrterocytozoon bieneusi Intractable diarrhoea USA Gourley 1983 Human immunodificiency virus (HIV) AIDS USA & France Robert Gallo & Luc Montagnier 1983 Helicobacter pylori Chronic gastritis, peptic ulcer Australia Barry J. Marshall & Warren J. Robin 1986 Human herpesvirus 6 (HHV-6) Early childhood roseola USA Robert C. Gallo 1983 Hepatitis E virus (HEV) Hepatitis E Russia Balayan 1989 Hepatitis C virus (HCV) Hepatitis C USA Michael Houghton 1989 Ehrlichia chafeensis Human ehrlichiosis USA Burt E. Anderson 1990 Human herpesvirus 7 (HHV-7) Heat rash, CNS infection USA Niza Frekel 1991 Gunarito virus Venezuelan hemorrhagic fever Venezuela Salas R. 1991 Encephalitozoon hellem Meningitis, diffuse lung diseases USA Didier E. S. 1991 A new species of Babesia Atypical babesiosis USA Quick R. E. 1992 Vibrio cholerae Cholera Asia Filippo Pacini 1993 Sin Nombre virus Adult respiratory distress syndrome USA Terry Yates 1994 Sibia virus Brazilian hemorrhagic fever Brazil Barry M. 1995 Human herpevirus 8 (HHV-8) AIDS-related Kaposi’s sarcoma USA Enrique A. Mesri 1995 Hepatitis G virus (HGV) Hepatitis D USA Simons J. N. 1996 Prion New Creutzfeldt–Jakob disease USA Stanley B. P. Prusiner 1997 Transfusion Transmitted virus (TTV) Post-transfusion hepatitis Japan Nishizawa T. 1997 Avian influenza virus (H5N1) Influenza Hong Kong de Jong 1998 West Nile virus Nile fever Uganda Smithburn K. C. 1999 Nipah virus Encephalitis Malaysia Chua K. B. 2003 SARS-CoV Sever acute respiratory syndrome China 2003 H9N2 Influenza China 2005 Human bocavirus Pneumonia Sweden Allander 2010 Severe fever with thrombocytopenia syn- drome bunyavirus Fever with thrombocytopenia syndrome China Xuejie Yu He F C. Sci China Life Sci March (2013) Vol.56 No.3 207 showed that DNA has percentage base pair equality (%A=%T and %G=%C). Based on the finding, James Wat- son and Francis Crick [3] discovered the DNA double helix in 1953. They suggested that the specific pairing of bases may be the replicate mechanism for genetic materials, and that the linear sequence of bases may be the code for carry- ing genetic information. These revolutionary conjectures represent the essence of the DNA double helix. They have made a huge splash in life sciences and took the study of molecular biology to new high. In addition, they have un- covered secrets of the biological world and made genetic engineering one of the most successful scientific disciplines. The 20th century was, without a doubt, the golden era of life sciences, especially the age of grand discoveries. In 1955, Severo Ochoa demonstrated the first synthesis of RNA. In 1957 Arthur Kornberg isolated the first DNA polymerase and synthesized the first artificial DNA. The finding played a key supportive role in the explanation of the genetic code (Nobelprize.org). In 1955, Frederick Sang- er [4] determined the amino acid sequence of bovine insulin. In 1958, John Kendrew and co-workers [5] determined the three-dimensional structure of myoglobin; and Francis Crick [6] published the groundbreaking paper On Protein Synthesis where he proposed his ‘sequence hypothesis’, discussing the relation between the sequence of bases in DNA and the sequence of amino acids in proteins, as well as the ‘central dogma’ (from DNA to RNA to protein). In 1960, François Jacob and co-workers [7] put forward the concepts of mRNA and ‘operon’, detailing the regulatory mechanisms that underlie genetic information transfer and protein synthesis. In 1961, Marshall Nirenberg and Heinrich Matthaei [8] cracked the first codon of the genetic code. In 1970, David Baltimore [9], Howard Temin and Satoshi Mi- zutani [10] discovered the reverse transcriptase and ex- panded the ‘central dogma’, with molecular biology being well-established. Molecular biology was largely inspired by the reduction- ist approach of the 1970s, which proved to be extremely successful and helped to unravel many of the basic molecu- lar and cellular processes. Two groups, one led by Stuart Linn and Werner Arber [11] and the other led by Hamilton Smith and Kent Wilcox [12], independently discovered two useful ‘tools’ for cutting and ligating DNA: the restriction enzyme and the modification enzyme. In 1970, Daniel Na- thans used these enzymes to demonstrate the cleavage of DNA in vitro. In 1971, Paul Berg used these enzymes to create the first recombinant DNA. In 1976, Yuet Wai Kan reported the first case of DNA diagnosis in monogenic dis- eases. In 1977, John Michael Bishop [13] discovered the oncogene src. In 1975, Frederick Sanger and co-workers [14] discovered a DNA sequencing method and used it to decode the whole genome of bacteriophage φX174 two years later. In 1978 and 1981, Sidney Altman and Thomas Cech independently discovered the catalytic abilities of RNA. In 1979, David Goeddel successfully used genetic engineering to coax bacteria into mass-producing insulin. In 1982, Richard Palmiter and Ralph Brinster produced trans- genic mice, supermice (that express a growth hormone). In 1985, Kary Mullis and her team [15] developed PCR tech- nology for amplifying DNA in vitro. The genetic techniques have now become a series of indispensable magic tools in gene sequencing, genetic recombination, DNA diagnosis, genetic engineering, gene transfer and gene amplification. Evidently, there had been many continuous and overlap- ping periods of profound discoveries in the history of con- temporary life sciences. At every stage of the game, there would be one or more leading scientists showing great fore- sights, turning things around and opening up new avenues of research. These great scientists could pierce through the dark sky and guide the discipline forward into a new age of grand discoveries. 3 The age of ‘omics’ Life forms are the most complex physical systems known thus far. Take the human body as an example. From a re- ductionist point of view, as we move from organs to tissues and from cells to molecules, our research subject gets di- vided into tens or millions individual pieces. Moreover, the number of interactions among these individual pieces grows exponentially. From a systems theory point of view, we need to study not only the multi-level dynamical changes of the human biology, but also the complex physical and chemical factors of the human environment, the numerous symbiotic microbes of the human ecology, and the various psychosocial factors of the human society. Our awareness of life is like Zeno’s circle: when our circle of knowledge becomes greater, our contact with the unknown world also becomes greater. Life may look like a magnificent and po- etic painting in the eyes of ordinary people. Under the mi- croscope, however, this painting is nothing but pixels, lines and blocks of various shades and colours. In this new age of life sciences, scientists are puzzling over how to connect dots, lines, planes and solids to make something artistic, something that is neither The Blind Men and the Elephant nor Giuseppe Arcimboldo’s Vertumnus (Figure 1). Lifeom- ics is like a Russian doll. Just when you think you under- stand the situation, another mystery of life emerges. The reductionist approach seeks to understand living systems through the study of their constituent parts—from total syntheses to regulatory mechanisms of various biomacro- molecules. By taking the reductionist approach to the ex- treme, we can get to the bottom of the problem, turn it into a theory and make the most of our time. The holistic approach seeks to integrate all constituents into one single system, which could turn something simple into something extraor- dinary. Only a ‘grand master’ who understands the magic of this approach can push the discipline to new high. The re- ductionist approach begins with ‘ome’ and ends with 208 He F C. Sci China Life Sci March (2013) Vol.56 No.3 Figure 1 Giuseppe Arcimboldo’s Vertumnus. ‘o,m,e’ (‘O’, ‘m’ and ‘e’ are respectively to ‘ome’ what ‘subset’ is to ‘set’ in mathematics.), whereas the holistic approach begins with ‘o,m,e’ and ends with ‘ome’. Ge- nomics, RNAomics, proteomics and metabolomics are ex- amples of the latter. This is why lifeomics, which uses unique epistemology and methodology, quickly became the thrust of life sciences. The development of omics has led to many great discov- eries in life sciences since the late 20th century. In 1953, Watson and Crick proposed the double helix structure of DNA and said, “the precise sequence of the bases is the code which carries genetic information”. In 1958, Sanger from the same laboratory established the method for deter- mining amino acid sequences of protein (http://www.no- belprize.org/nobel_prizes/chemistry/laureates/1958/sanger.h tml). In the 1970’s, he established the method for analysing DNA sequences [16]. Because of these two achievements, Sanger won the Nobel Prize in Chemistry twice. As the king of DNA sequencing, Sanger turned our dreams of reading and writing genetic information into a reality. He made DNA sequencing a part of life. Through DNA sequencing, scientists could integrate biotechnology with information technology. In 1986, the first generation of fluores- cence-based DNA sequencers with automated analysis was born. Since then, our DNA sequencing capacity has been growing exponentially. Our current daily data output is in the Gb range [17], a rate that could rival Moore's Law. Pro- tein sequencing technologies based on mass spectrometry represent another force to be reckoned with. Biological mass spectrometry, for example, was awarded the Nobel Prize in Chemistry in 2002. At that time, scientists could only identify several hundreds of proteins in a given sample. Today, biological mass spectrometry could identify several thousands of proteins in a single sample, which is about the size of a transcriptome. These high-throughput sequencing technologies are set to open up new avenues of research and trigger an age of grand discoveries in lifeomics. The US government launched an international scientific research project, dubbed the Human Genome Project (HGP), four years after the birth of the first DNA sequencer [18]. Since then, countries like Germany, Japan, UK, France and China have joined the project. When the project first began, there were only 100000 bases pairs in all of the human genes known. Ten years later, scientists have not only se- quenced the 3 billion base pairs that make up the human genome, but also the genomes of Saccharomyces (budding yeast), Escherichia coli, Mycobacterium tuberculosis, Treponema pallidum, Nematoda (nematode), Drosophila (fruit fly), Arabidopsis thaliana (mustard plant), Oryza sa- tiva (rice), Mus musculus (mouse), Plasmodium, Anopheles (mosquito), as well as several other important pathogens and model organisms. The project has triggered a great number of follow-up projects, for example, the International HapMap Project in 2002, the 1000 Genome Project in 2008, the 10000 Microbial Genomes Project in 2009, as well as the 1000 Plants and Animals project and the Genome 10K project in 2010. A decade has passed since the publication of the first human genome (October 2011), but we have already resolved the genomes of over 1200 biological spe- cies. The National Center for Biotechnology Information (NCBI) holds 2.08 Pb (1 Pb=1015 b) of genomic data as of 14 June 2012, 10 billion times the amount when the project first started. Chinese scientists, in particular, have contrib- uted more than 0.64 Pb of data, which accounts for 30% of the total. They made outstanding contributions in three par- ticular areas: genetic information, gene function and medi- cal genetics. In terms of genetic information, although we can only interpret some and not all of the information, the genome sequencing has enabled us to read into the evolu- tionary process that lasted for hundreds of millions of years. Having the genetic information (the blueprint of life) of thousands of species represents a huge advantage, but this is only the tip of the iceberg. We expect to see more discover- ies not only in the number of species, but also in the realisa- tion of richer genomes through whole or single-cell genome and transcriptome sequencing. These breakthroughs will give us the ability to synthesize and create life. In terms of gene function, HGP has already identified more than 20000 protein-coding genes, when scientists only knew a fraction of these genes just a century ago. The findings will help unveil the mysteries behind the human genome, transcrip- tome and proteome, as well as make a splash in comparative genomics and animal genomics. Studies have shown that He F C. Sci China Life Sci March (2013) Vol.56 No.3 209 less than 3% of the human genome is protein-coding genes. Therefore, following the surprising discovery of dark matter and dark energy in physics, we might find astonishing ‘dark information’ in life sciences. DNA sequencing technology is now within reach of ordinary people thanks the rapid rise in capacity and the sharp decline in price over the past 20 year. It has become a common tool in biological research and clinical diagnosis. In the area of medical genetics, for an example, we could take genome-wide association study (GWAS). GWAS has existed only for less than ten years, and during this period of time we have studied more than 700 diseases and discovered more than 5000 dis- ease-causing genes and susceptibility loci, ten times the number found 100 years ago. Although China was a late starter in genomics research, the country’s achievements in the field are still remarkable (Table 3). This is in line with what Watson said ten years ago, “all biology in the future will start with the knowledge of genomes and proceed hopefully”. Genome sequencing is like the winds of a rising storm. To better understand the human genome, we must part the clouds and swirl things around. In the month that the draft of the human genome was published, the launch of the Hu- man Proteome Organization (HUPO) was announced. In the following year, the Human Proteome Project (HPP) was initiated. Given the variety of proteins (at least 100 times the number of genes), the huge dynamic range of protein abundance, the diversity of post-translational modifications, the complex issue of space-time specificity and the great number of interactions between the proteins, HPP launched a series of pilot projects during its initial phase. In 2002, HPP launched the Human Liver Proteome Project (HLPP) and the Human Plasma Proteome Project (HPPP). After this, HPP launched the Human Brain Proteome Project (HBPP), Human Kidney and Urine Proteome Project (HKUPP) and Human Cardiovascular Initiate (HCVI). It has also launched Proteomics Standards Initiative (PSI), Human Antibody Initiative (HAI) and Disease Biomarkers Initiative (Table 4). In 2005, HPPP generated a core dataset of 3020 proteins, the first human body fluid proteome of its kind. In 2010, HLPP released a core dataset of 6788 proteins, the first hu- man organ proteome of its kind [51]. Over half of these proteins were identified in the human liver for the first time. Moreover, about a quarter of them were newly discovered at the protein level. In 2009, Chinese scientists discovered over 1000 acetylated proteins by using high-throughput protein analysis and studying metabolic enzymes across different species [52]. In addition, they identified the role of acetylation in the regulation of metabolic enzymes. In 2012, Chinese scientists used bacteria, yeast, nematode, fruit fly, mouse and human as research subjects and, through large-scale quantitative proteomic data analyses, found three universal patterns in the overall distribution of protein abundance [53]: protein abundance is positively correlated with the protein’s origination time or sequence conservation during evolution; protein abundance is negatively correlated with the protein’s domain number and positively correlated with domain coverage in protein structure; and proteins that act on material conversion and transportation are more abundant than those that act on information modulation. The findings demonstrated that the large-scale dataset of omics could be the resource for the discovery of the laws of life. Other organ/tissue proteome projects have also gener- ated 1000–3000 proteins. With increasing technological capabilities in recent years, biological mass spectrometry can now identify 7000–9000 proteins in a cell line sample, with gene expression coverage reaching 60%–90%. Re- search on protein interaction networks has also made amaz- ing progress. In 2005, two research groups in Germany and USA independently established human protein interaction networks featuring 3169 pairs and 2,754 pairs of proteins [54]; in 2011, China scientists established a human liver protein interaction network that encompasses 3484 interac- tions among 2582 proteins [55]. In the three studies we just mentioned, there had only been 54 cases of overlapping protein interactions. The number suggests that more than 90% of protein interaction network is still unknown and waiting to be discovered. In 2011, research on human en- dogenous protein complexes has identified more than 11000 products of gene expression, which accounts for about 50% of the total. In addition, HAI released the 7th version of its database, which covers 10118 products of coding genes. In 2009, OVA1, the first proteomics-discovered cancer bi- omarker discovered by Daniel Chan and his team received approval from the USA Food and Drug Administration (FDA) for detecting ovarian cancer (http://www.fda.gov/ NewsEvents/Newsroom/Press-An-nouncements/ucm182057 .htm). The event signals the advent of more great discover- ies and clinical applications in proteomics. Genomics and proteomics are the two most active areas within the field of lifeomics. After the completion of HGP, it was found that protein-coding sequences make up only about 2% of the human genome [56]; among the non-coding DNA and RNA sequences, about 1/4 are tRNA and rRNA, and 3/4 are snRNA, snoRNA, shRNA, microRNA and lncRNAs (long non-coding RNAs), which have important roles in chromatin remodelling, transcriptional regulation and translational regulation [57], affecting biological de- velopment, cell proliferation, cell differentiation, as well as the development of cancer, metabolic diseases and viral diseases. Since the advent of ‘RNAomics’ in 2000, more than 35000 non-coding RNA have already been discovered in mammals. The mutual regulation between DNA, mRNA, protein and non-coding RNA has attracted wide attention from the community. The technology RNAi won the 2006 Nobel Prize in Physiology and Medicine only eight years after it was discovered. Such case is rare in the Nobel Prize history. Coincidentally, systems biologists have taken an interest in ‘glycomics’, which studies the structure and recognition molecules of oligosaccharides, polysaccharides 210 He F C. Sci China Life Sci March (2013) Vol.56 No.3 Table 3 GWAS conducted by Chinese scientists Year of publication Disease studied Research group Reference 2009 Psoriasis Xuejun Zhang et al. [19] 2009 Systemic lupus erythematosus Xuejun Zhang et al. [20] 2009 Leprosy Furen Zhang et al. [21] 2010 Nasopharyngeal cancer Yixin Zeng et al. [22] 2010 Vitiligo Xuejun Zhang et al. [23] 2010 Hepatocellular carcinoma Fuchu He & Gangqiao Zhou et al. [24] 2010 Oesophageal cancer Lidong Wang et al. [25] 2010 Agronomic traits of indica rice Bin Han et al. [26] 2010 Polycystic ovary syndrome Zijiang Chen et al. [27] 2011 Coronary artery disease Qing Wang et al. [28] 2011 Oesophageal cancer Dongxin Lin et al. [29] 2011 Atopic dermatitis Xuejun Zhang et al. [30] 2011 Lung cancer Hongbing Shen et al. [31] 2011 Graves’ disease Huaidong Song et al. [32] 2011 Gastric cancer Hongbing Shen et al. [33] 2011 Schizophrenia Lin He et al. [34] 2011 Schizophrenia Dai Zhang et al. [35] 2011 Leprosy Furen Zhang et al. [36] 2011 Flowering time and grain yield of rice Bing Han et al. [37] 2011 Pancreatic cancer Dongxin Lin et al. [38] 2011 Ankylosing spondylitis Jieruo Gu et al. [39] 2011 IgA nephropathy Xueqing Yu et al. [40] 2011 Non-obstructive azoospermia Jiahao Sha et al. [41] 2012 Kawasaki disease Jer Yuarn Wu et al. [42] 2012 Coronary artery disease Dongfong Gu et al. [43] 2012 Polycystic ovary syndrome Zijiang Chenet al. [44] 2012 Thyrotoxic periodic paralysis Annie Wai Chee Kung et al. [45] 2012 Oesophageal cancer Dongxin Lin et al. [46] 2012 Prostate cancer Yinghao Sun et al. [47] 2012 Hepatocellular carcinoma Long Yu et al. [48] Table 4 Progress of the Human Proteome Project Year of initiation Sub-project Dataset Release year 2002 Human Liver Proteome Project ProteomeView, 6847 proteins (6788 [51]) 2010 2002 Human Plasma Proteome Project Human Plasma PeptideAtlas, 1929 proteins (3020 [49]) 2005 2003 Human Brain Proteome Project 1832 (human)/792 (mouse) proteins 2010 2003 Proteomics Standardization Initiative Protein information, mzML Molecular interaction, PAR/MIAPAR/PSICQUIC Protein separation, MIAPE-GEL/MIAPE-CC/MIAPE-CE 2010 2005 Human Kidney and Urine Proteome Project Human Kidney and Urine Proteome Project, 3679 proteins; the final standards for non-protein urine and urine proteome 2009 2005 Human Antibody Initiative The 10th edition of database encompasses 14079 coding genes 2012 2005 Human Disease Glycomics/Proteome Initiative Comparison of full-spectrum analysis methods for O-glycosylation; full-spectrum analysis of glycoproteins in cancer cells 2010 2005 Mouse Model of Human Disease More than 1400 mouse secreted proteins have been identified 2006 2006 Human Cardiovascular Initiative 1333 proteins with more than 10000 GO annotations; more than half of which are from human data 2009 2007 Proteome Biology of Stem Cell Initiative Stem cell markers, stem cell signalling pathways and stem cells & diseases 2009 2009 Disease Biomarkers Initiative Markers for cancer, cardiovascular disease and pulmonary disease 2010 2010 Model Organism Proteomes Advances in model organisms 2010 2010 Chromosome-based Human Proteome Project J Proteome Res, Publication Date (Web): January 11, 2013 2013 He F C. Sci China Life Sci March (2013) Vol.56 No.3 211 and various sugar chains, as well as ‘metabolomics’, which studies the endogenous metabolites and their responses to external stimuli. Much progress has been made over the past ten years, and these omics are becoming a major force in life sciences. Like the Chinese saying goes, “when spring comes, all flower blossoms”. Different omics have made varying lev- els of contributions to life sciences. In 2005, HPP initiated the Human Disease Glycomics/Proteome Initiative (HGPI), a project that aims to identify useful glycobiomarkers for detecting life-style diseases by integrating proteomics with glycomics. In 2011, HPP formed Chromosome-based Hu- man Proteome Project (Ch-HPP), a joint project that uses proteomics technology to determine the gene product of each chromosome. Ch-HPP brings together the best talents from HPP and HGP. Like the Chinese saying goes, “life does not discriminate for benevolence”. We should treat all ‘omics’ as equally important. And lifeomics, which inte- grates genomics and RNAomics with proteomics, gly- comics and metabolomics, has taken shape and is now ready to take on any challenges. Looking back at the history of natural sciences, especial- ly in life sciences, we can draw an analogy between the age of grand discoveries and nuclear fusion. We understand that only through fusion can we release large amounts of energy. However, to obtain enough energy to trigger the fusion process, we need nuclear fission. Therefore, HGP was not just a beginning. It was the fis- sion point that triggered the development of various omics. Lifeomics, which encompasses all these omics, is set to achieve something big. To our knowledge, projects utilizing a similar research approach have only appeared twice in human history: once in the Manhattan project and once in the Apollo program. In both cases, the scientific discoveries made have had far-reaching impact on our society. With life come organic, as the biological world is the culmination (organization) of, for and over the physical world (from inorganic to organic to biological). With life also come human cognition, and this is the magic that con- nects the biological and the physical world. Because of this, we trust that life science is going to be the epitome and as- semble of all disciplines of natural sciences. Furthermore, lifeomics is the backbone for life science. Thus, it is going to be the rising star of natural sciences in the coming future. I thank the Academic Divisions of the Chinese Academy of Sciences, Sci- ence China Press, Forum on Frontiers of Science and Technology and the standing committee of the Academic Division of Life Sciences and Medi- cine for their support on the 7th forum on frontiers of science and technol- ogy:Lifeomics and Translational Medicine Symposium. 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