Human Genome Project: Big Science PDF

Hood and Rowen Genome Medicine 2013, 5:79 http://genomemedicine.com/content/5/9/79 OPINION The Human Genome Project: big science transforms biology and medicine Leroy Hood* and Lee Rowen* understanding of cancer. In May 19...

Hood and Rowen Genome Medicine 2013, 5:79 http://genomemedicine.com/content/5/9/79 OPINION The Human Genome Project: big science transforms biology and medicine Leroy Hood* and Lee Rowen* understanding of cancer. In May 1985 a meeting fo- Abstract cused entirely on the HGP was held, with Robert The Human Genome Project has transformed biology Sinsheimer, the Chancellor of the University of California, through its integrated big science approach to Santa Cruz (UCSC), assembling 12 experts to debate the deciphering a reference human genome sequence merits of this potential project. The meeting concluded along with the complete sequences of key model that the project was technically possible, although very organisms. The project exemplifies the power, challenging. However, there was controversy as to whether necessity and success of large, integrated, cross- it was a good idea, with six of those assembled declaring disciplinary efforts - so-called ‘big science’ - directed themselves for the project, six against (and those against towards complex major objectives. In this article, we felt very strongly). The naysayers argued that big science discuss the ways in which this ambitious endeavor led is bad science because it diverts resources from the ‘real’ to the development of novel technologies and small science (such as single investigator science); that the analytical tools, and how it brought the expertise of genome is mostly junk that would not be worth sequen- engineers, computer scientists and mathematicians cing; that we were not ready to undertake such a complex together with biologists. It established an open project and should wait until the technology was adequate approach to data sharing and open-source software, for the task; and that mapping and sequencing the thereby making the data resulting from the project genome was a routine and monotonous task that would accessible to all. The genome sequences of microbes, not attract appropriate scientific talent. Throughout the plants and animals have revolutionized many fields of early years of advocacy for the HGP (mid- to late 1980s) science, including microbiology, virology, infectious perhaps 80% of biologists were against it, as was the disease and plant biology. Moreover, deeper National Institutes of Health (NIH). The US Depart- knowledge of human sequence variation has begun ment of Energy (DOE) initially pushed for the HGP, partly to alter the practice of medicine. The Human Genome using the argument that knowing the genome sequence Project has inspired subsequent large-scale data would help us understand the radiation effects on the acquisition initiatives such as the International HapMap human genome resulting from exposure to atom bombs Project, 1000 Genomes, and The Cancer Genome Atlas, and other aspects of energy transmission. This DOE as well as the recently announced Human Brain advocacy was critical to stimulating the debate and ultim- Project and the emerging Human Proteome Project. ately the acceptance of the HGP. Curiously, there was more support from the US Congress than from most biologists. Those in Congress understood the appeal of Origins of the human genome project international competitiveness in biology and medicine, the The Human Genome Project (HGP) has profoundly potential for industrial spin-offs and economic benefits, changed biology and is rapidly catalyzing a transform- and the potential for more effective approaches to dealing ation of medicine [1-3]. The idea of the HGP was first with disease. A National Academy of Science committee publicly advocated by Renato Dulbecco in an article report endorsed the project in 1988 and the tide of published in 1984, in which he argued that knowing opinion turned: in 1990, the program was initiated, with the human genome sequence would facilitate an the finished sequence published in 2004 ahead of schedule and under budget. * Correspondence: [email protected]; Lee.Rowen@ systemsbiology.org Institute for Systems Biology, 401 Terry Ave N., Seattle, WA 98109, USA © 2013 BioMed Central Ltd. Hood and Rowen Genome Medicine 2013, 5:79 Page 2 of 8 http://genomemedicine.com/content/5/9/79 What did the human genome project entail? University in St Louis, the Joint Genome Institute, and the This 3-billion-dollar, 15-year program evolved consider- Whole Genome Laboratory at Baylor College of Medicine) ably as genomics technologies improved. Initially, the emerged from this effort, with these five centers continuing HGP set out to determine a human genetic map, then a to provide genome sequence and technology development. physical map of the human genome , and finally the The HGP also fostered the development of mathematical, sequence map. Throughout, the HGP was instrumental computational and statistical tools for handling all the in pushing the development of high-throughput tech- data it generated. nologies for preparing, mapping and sequencing DNA The HGP produced a curated and accurate reference. At the inception of the HGP in the early 1990s, sequence for each human chromosome, with only a small there was optimism that the then-prevailing sequencing number of gaps, and excluding large heterochromatic technology would be replaced. This technology, now regions. In addition to providing a foundation for sub- called ‘first-generation sequencing’, relied on gel electro- sequent studies in human genomic variation, the reference phoresis to create sequencing ladders, and radioactive- sequence has proven essential for the development and or fluorescent-based labeling strategies to perform base subsequent widespread use of second-generation sequen- calling. It was considered to be too cumbersome cing technologies, which began in the mid-2000s. Second- and low throughput for efficient genomic sequencing. generation cyclic array sequencing platforms produce, in a As it turned out, the initial human genome reference single run, up to hundreds of millions of short reads sequence was deciphered using a 96-capillary (highly (originally approximately 30 to 70 bases, now up to several parallelized) version of first-generation technology. Al- hundred bases), which are typically mapped to a reference ternative approaches such as multiplexing and genome at highly redundant coverage. A variety of sequencing by hybridization were attempted but not cyclic array sequencing strategies (such as RNA-Seq, effectively scaled up. Meanwhile, thanks to the efforts of ChIP-Seq, bisulfite sequencing) have significantly ad- biotech companies, successive incremental improve- vanced biological studies of transcription and gene regula- ments in the cost, throughput, speed and accuracy of tion as well as genomics, progress for which the HGP first-generation automated fluorescent-based sequencing paved the way. strategies were made throughout the duration of the HGP. Because biologists were clamoring for sequence Impact of the human genome project on biology data, the goal of obtaining a full-fledged physical map of and technology the human genome was abandoned in the later stages of First, the human genome sequence initiated the compre- the HGP in favor of generating the sequence earlier than hensive discovery and cataloguing of a ‘parts list’ of most originally planned. This push was accelerated by Craig human genes [16,17], and by inference most human Venter’s bold plan to create a company (Celera) for the proteins, along with other important elements such as purpose of using a whole-genome shotgun approach non-coding regulatory RNAs. Understanding a complex to decipher the sequence instead of the piecemeal biological system requires knowing the parts, how they clone-by-clone approach using bacterial artificial chromo- are connected, their dynamics and how all of these relate some (BAC) vectors that was being employed by the to function. The parts list has been essential for the International Consortium. Venter’s initiative prompted emergence of ‘systems biology’, which has transformed government funding agencies to endorse production of a our approaches to biology and medicine [21,22]. clone-based draft sequence for each chromosome, with As an example, the ENCODE (Encyclopedia Of DNA the finishing to come in a subsequent phase. These paral- Elements) Project, launched by the NIH in 2003, aims to lel efforts accelerated the timetable for producing a discover and understand the functional parts of the genome sequence of immense value to biologists [16,17]. genome. Using multiple approaches, many based on As a key component of the HGP, it was wisely decided second-generation sequencing, the ENCODE Project to sequence the smaller genomes of significant experi- Consortium has produced voluminous and valuable data mental model organisms such as yeast, a small flowering related to the regulatory networks that govern the expres- plant (Arabidopsis thaliana), worm and fruit fly before sion of genes. Large datasets such as those produced taking on the far more challenging human genome. The by ENCODE raise challenging questions regarding gen- efforts of multiple centers were integrated to produce ome functionality. How can a true biological signal be dis- these reference genome sequences, fostering a culture of tinguished from the inevitable biological noise produced cooperation. There were originally 20 centers mapping by large datasets [25,26]? To what extent is the functional- and sequencing the human genome as part of an inter- ity of individual genomic elements only observable (used) national consortium ; in the end five large centers in specific contexts (for example, regulatory networks and (the Wellcome Trust Sanger Institute, the Broad Institute mRNAs that are operative only during embryogenesis)? It of MIT and Harvard, The Genome Institute of Washington is clear that much work remains to be done before the Hood and Rowen Genome Medicine 2013, 5:79 Page 3 of 8 http://genomemedicine.com/content/5/9/79 functions of poorly annotated protein-coding genes will fostering a more cross-disciplinary culture [1,21,38]. It is be deciphered, let alone those of the large regions of the important to note that the HGP popularized the idea of non-coding portions of the genome that are transcribed. making data available to the public immediately in user- What is signal and what is noise is a critical question. friendly databases such as GenBank and the UCSC Second, the HGP also led to the emergence of proteo- Genome Browser. Moreover, the HGP also promoted mics, a discipline focused on identifying and quantifying the idea of open-source software, in which the source the proteins present in discrete biological compartments, code of programs is made available to and can be edited such as a cellular organelle, an organ or the blood. Pro- by those interested in extending their reach and improving teins - whether they act as signaling devices, molecular them [41,42]. The open-source operating system of Linux machines or structural components - constitute the cell- and the community it has spawned have shown the power specific functionality of the parts list of an organism’s gen- of this approach. Data accessibility is a critical concept for ome. The HGP has facilitated the use of a key analytical the culture and success of biology in the future because tool, mass spectrometry, by providing the reference the ‘democratization of data’ is critical for attracting avail- sequences and therefore the predicted masses of all the able talent to focus on the challenging problems of bio- tryptic peptides in the human proteome - an essential re- logical systems with their inherent complexity. This quirement for the analysis of mass-spectrometry-based will be even more critical in medicine, as scientists need proteomics. This mass-spectrometry-based accessibil- access to the data cloud available from each individual ity to proteomes has driven striking new applications such human to mine for the predictive medicine of the future - as targeted proteomics. Proteomics requires ex- an effort that could transform the health of our children tremely sophisticated computational techniques, examples and grandchildren. of which are PeptideAtlas and the Trans-Proteomic Fifth, the HGP, as conceived and implemented, was Pipeline. the first example of ‘big science’ in biology, and it clearly Third, our understanding of evolution has been demonstrated both the power and the necessity of this transformed. Since the completion of the HGP, over 4,000 approach for dealing with its integrated biological and finished or quality draft genome sequences have been pro- technological aims. The HGP was characterized by a duced, mostly from bacterial species but including 183 clear set of ambitious goals and plans for achieving eukaryotes. These genomes provide insights into how them; a limited number of funded investigators typically diverse organisms from microbes to human are connected organized around centers or consortia; a commitment to on the genealogical tree of life - clearly demonstrating that public data/resource release; and a need for significant all of the species that exist today descended from a single funding to support project infrastructure and new tech- ancestor. Questions of longstanding interest with nology development. Big science and smaller-scope implications for biology and medicine have become individual-investigator-oriented science are powerfully approachable. Where do new genes come from? What complementary, in that the former generates resources might be the role of stretches of sequence highly con- that are foundational for all researchers while the latter served across all metazoa? How much large-scale gene adds detailed experimental clarification of specific ques- organization is conserved across species and what drives tions, and analytical depth and detail to the data produced local and global genome reorganization? Which regions of by big science. There are many levels of complexity in the genome appear to be resistant (or particularly suscep- biology and medicine; big science projects are essential to tible) to mutation or highly susceptible to recombination? tackle this complexity in a comprehensive and integrative How do regulatory networks evolve and alter patterns of manner. gene expression ? The latter question is of particular The HGP benefited biology and medicine by creating a interest now that the genomes of several primates and sequence of the human genome; sequencing model organ- hominids have been or are being sequenced [34,35] in isms; developing high-throughput sequencing technolo- hopes of shedding light on the evolution of distinctively gies; and examining the ethical and social issues implicit human characteristics. The sequence of the Neanderthal in such technologies. It was able to take advantage of genome has had fascinating implications for human economies of scale and the coordinated effort of an inter- evolution; namely, that a few percent of Neanderthal national consortium with a limited number of players, DNA and hence the encoded genes are intermixed in the which rendered the endeavor vastly more efficient than human genome, suggesting that there was some inter- would have been possible if the genome were sequenced breeding while the two species were diverging [36,37]. on a gene-by-gene basis in small labs. It is also worth not- Fourth, the HGP drove the development of sophisti- ing that one aspect that attracted governmental support to cated computational and mathematical approaches to data the HGP was its potential for economic benefits. The and brought computer scientists, mathematicians, engi- Battelle Institute published a report on the economic neers and theoretical physicists together with biologists, impact of the HGP. For an initial investment of Hood and Rowen Genome Medicine 2013, 5:79 Page 4 of 8 http://genomemedicine.com/content/5/9/79 approximately $3.5 billion, the return, according to the determining whether these hits reflect the mis-functioning report, has been about $800 billion - a staggering return of regulatory elements. The question as to what fraction on investment. of the thousands of GWAS hits are signal and what frac- Even today, as budgets tighten, there is a cry to with- tion are noise is a concern. Pedigree-based whole-genome draw support from big science and focus our resources on sequencing offers a powerful alternative approach to iden- small science. This would be a drastic mistake. In the tifying potential disease-causing variants. wake of the HGP there are further valuable biological Five years ago, a mere handful of personal genomes had resource-generating projects and analyses of biological been fully sequenced (for example, [53,54]). Now there are complexity that require a big science approach, including thousands of exome and whole-genome sequences (soon the HapMap Project to catalogue human genetic variation to be tens of thousands, and eventually millions), which [47,48], the ENCODE project, the Human Proteome have been determined with the aim of identifying disease- Project (described below) and the European Commission’s causing variants and, more broadly, establishing well- Human Brain Project, as well as another brain-mapping founded correlations between sequence variation and project recently announced by President Obama. specific phenotypes. For example, the International Can- Similarly to the HGP, significant returns on investment cer Genome Consortium and The Cancer Genome will be possible for other big science projects that are now Atlas are undertaking large-scale genomic data collec- under consideration if they are done properly. It should be tion and analyses for numerous cancer types (sequencing stressed that discretion must be employed in choosing big both the normal and cancer genome for each individual science projects that are fundamentally important. Clearly patient), with a commitment to making their resources funding agencies should maintain a mixed portfolio of big available to the research community. and small science - and the two are synergistic [1,45]. We predict that individual genome sequences will Last, the HGP ignited the imaginations of unusually tal- soon play a larger role in medical practice. In the ideal ented scientists - Jim Watson, Eric Lander, John Sulston, scenario, patients or consumers will use the information Bob Waterston and Sydney Brenner to mention only a to improve their own healthcare by taking advantage of few. So virtually every argument initially posed by the prevention or therapeutic strategies that are known to opponents of the HGP turned out to be wrong. The HGP be appropriate for real or potential medical conditions is a wonderful example of a fundamental paradigm change suggested by their individual genome sequence. Physi- in biology: initially fiercely resisted, it was ultimately far cians will need to educate themselves on how best to ad- more transformational than expected by even the most vise patients who bring consumer genetic data to their optimistic of its proponents. appointments, which may well be a common occurrence in a few years. Impact of the human genome project on medicine In fact, the application of systems approaches to dis- Since the conclusion of the HGP, several big science pro- ease has already begun to transform our understanding jects specifically geared towards a better understanding of of human disease and the practice of healthcare and human genetic variation and its connection to human push us towards a medicine that is predictive, prevent- health have been initiated. These include the HapMap ive, personalized and participatory: P4 medicine. A key Project aimed at identifying haplotype blocks of common assumption of P4 medicine is that in diseased tissues single nucleotide polymorphisms (SNPs) in different hu- biological networks become perturbed - and change dy- man populations [47,48], and its successor, the 1000 namically with the progression of the disease. Hence, Genomes project, an ongoing endeavor to catalogue com- knowing how the information encoded by disease- mon and rare single nucleotide and structural variation in perturbed networks changes provides insights into dis- multiple populations. Data produced by both projects ease mechanisms, new approaches to diagnosis and new have supported smaller-scale clinical genome-wide associ- strategies for therapeutics [58,59]. ation studies (GWAS), which correlate specific genetic vari- Let us provide some examples. First, pharmacogenom- ants with disease risk of varying statistical significance ics has identified more than 70 genes for which specific based on case–control comparisons. Since 2005, over 1,350 variants cause humans to metabolize drugs ineffectively GWAS have been published. Although GWAS ana- (too fast or too slow). Second, there are hundreds of ‘ac- lyses give hints as to where in the genome to look for tionable gene variants’ - variants that cause disease but disease-causing variants, the results can be difficult to inter- whose consequences can be avoided by available medical pret because the actual disease-causing variant might be strategies with knowledge of their presence. Third, rare, the sample size of the study might be too small, or the in some cases, cancer-driving mutations in tumors, once disease phenotype might not be well stratified. Moreover, identified, can be counteracted by treatments with cur- most of the GWAS hits are outside of coding regions - rently available drugs. And last, a systems approach and we do not have effective methods for easily to blood protein diagnostics has generated powerful new Hood and Rowen Genome Medicine 2013, 5:79 Page 5 of 8 http://genomemedicine.com/content/5/9/79 diagnostic panels for human diseases such as hepatitis information relates to functionally and evolutionarily will and lung cancer. be important. Developing the ability to rapidly analyze These latter examples portend a revolution in blood complete human genomes with regard to actionable gene diagnostics that will lead to early detection of disease, variants is essential. It is also essential to develop software the ability to follow disease progression and responses to that can accurately fold genome-predicted proteins into treatment, and the ability to stratify a disease type (for three dimensions, so that their functions can be predicted instance, breast cancer) into its different subtypes for from structural homologies. Likewise, it will be fascinating proper impedance match against effective drugs. to determine whether we can make predictions about the We envision a time in the future when all patients will structures of biological networks directly from the infor- be surrounded by a virtual cloud of billions of data mation of their cognate genomes. Indeed, the idea that we points, and when we will have the analytical tools to can decipher the ‘logic of life’ of an organism solely from reduce this enormous data dimensionality to simple hy- its genome sequence is intriguing. While we have become potheses to optimize wellness and minimize disease for relatively proficient at determining static and stable gen- each individual. ome sequences, we are still learning how to measure and interpret the dynamic effects of the genome: gene expres- Impact of the human genome project on society sion and regulation, as well as the dynamics and function- The HGP challenged biologists to consider the social im- ing of non-coding RNAs, metabolites, proteins and other plications of their research. Indeed, it devoted 5% of its products of genetically encoded information. budget to considering the social, ethical and legal as- The HGP, with its focus on developing the technology pects of acquiring and understanding the human gen- to enumerate a parts list, was critical for launching sys- ome sequence. That process continues as different tems biology, with its concomitant focus on high- societal issues arise, such as genetic privacy, potential throughput ‘omics’ data generation and the idea of ‘big discrimination, justice in apportioning the benefits from data’ in biology [21,38]. The practice of systems biology genomic sequencing, human subject protections, genetic begins with a complete parts list of the information ele- determinism (or not), identity politics, and the philo- ments of living organisms (for example, genes, RNAs, sophical concept of what it means to be human beings proteins and metabolites). The goals of systems biology who are intrinsically connected to the natural world. are comprehensive yet open ended because, as seen with Strikingly, we have learned from the HGP that there the HGP, the field is experiencing an infusion of talented are no race-specific genes in humans [65-68]. Rather, an scientists applying multidisciplinary approaches to a var- individual’s genome reveals his or her ancestral lineage, iety of problems. A core feature of systems biology, as which is a function of the migrations and interbreeding we see it, is to integrate many different types of bio- among population groups. We are one race and we logical information to create the ‘network of networks’ - honor our species’ heritage when we treat each other ac- recognizing that networks operate at the genomic, the cordingly, and address issues of concern to us all, such molecular, the cellular, the organ, and the social network as human rights, education, job opportunities, climate levels, and that these are integrated in the individual change and global health. organism in a seamless manner. Integrating these data allows the creation of models that are predictive What is to come? and actionable for particular types of organisms and in- There remain fundamental challenges for fully under- dividual patients. These goals require developing new standing the human genome. For example, as yet at least types of high-throughput omic technologies and ever in- 5% of the human genome has not been successfully creasingly powerful analytical tools. sequenced or assembled for technical reasons that relate The HGP infused a technological capacity into biology to eukaryotic islands being embedded in heterochromatic that has resulted in enormous increases in the range of repeats, copy number variations, and unusually high or research, for both big and small science. Experiments low GC content. The question of what information that were inconceivable 20 years ago are now routine, these regions contain is a fascinating one. In addition, thanks to the proliferation of academic and commercial there are highly conserved regions of the human genome wet lab and bioinformatics resources geared towards whose functions have not yet been identified; presumably facilitating research. In particular, rapid increases in they are regulatory, but why they should be strongly throughput and accuracy of the massively parallel conserved over a half a billion years of evolution remains second-generation sequencing platforms with their cor- a mystery. related decreases in cost of sequencing have resulted in There will continue to be advances in genome analysis. a great wealth of accessible genomic and transcriptional Developing improved analytical techniques to identify bio- sequence data for myriad microbial, plant and animal logical information in genomes and decipher what this genomes. These data in turn have enabled large- and Hood and Rowen Genome Medicine 2013, 5:79 Page 6 of 8 http://genomemedicine.com/content/5/9/79 small-scale functional studies that catalyze and enhance transcript, and different start and termination sites. Last, further research when the results are provided in pub- it is exciting to contemplate that the ability to parallelize licly accessible databases. this process (for example, by generating millions of One descendant of the HGP is the Human Proteome nanopores that can be used simultaneously) could enable Project, which is beginning to gather momentum, al- the sequencing of a human genome in 15 minutes or less though it is still poorly funded. This exciting endeavor has. The high-throughput nature of this sequencing may the potential to be enormously beneficial to biology eventually lead to human genome costs of $100 or under. [71-73]. The Human Proteome Project aims to create The interesting question is how long it will take to make assays for all human and model organism proteins, includ- third-generation sequencing a mature technology. ing the myriad protein isoforms produced from the RNA The HGP has thus opened many avenues in biology, splicing and editing of protein-coding genes, chemical medicine, technology and computation that we are just modifications of mature proteins, and protein processing. beginning to explore. The project also aims to pioneer technologies that will achieve several goals: enable single-cell proteomics; create Abbreviations BAC: Bacterial artificial chromosome; DOE: Department of Energy; microfluidic platforms for thousands of protein enzyme- ELISA: Enzyme-linked immunosorbent assay; GWAS: Genome-wide linked immunosorbent assays (ELISAs) for rapid and association studies; HGP: Human Genome Project; NIH: National Institutes of quantitative analyses of, for example, a fraction of a drop- Health; SNP: Single nucleotide polymorphism; UCSC: University of California, Santa Cruz. let of blood; develop protein-capture agents that are small, stable, easy to produce and can be targeted to specific pro- Competing interests tein epitopes and hence avoid extensive cross-reactivity; The authors declare that they have no competing interests. and develop the software that will enable the ordinary biologist to analyze the massive amounts of proteomics Acknowledgements data that are beginning to emerge from human and other The authors gratefully acknowledge support from the Luxembourg Centre for Systems Biomedicine and the University of Luxembourg; from the NIH, organisms. through award 2P50GM076547-06A; and the US Department of Defense Newer generations of DNA sequencing platforms will (DOD), through award W911SR-09-C-0062. LH receives support from NIH P01 be introduced that will transform how we gather genome NS041997; 1U54CA151819-01; and DOD awards W911NF-10-2-0111 and W81XWH-09-1-0107. information. Third-generation sequencing will em- ploy nanopores or nanochannels, utilize electronic signals, and sequence single DNA molecules for read lengths of Published: 13 September 2013 10,000 to 100,000 bases. Third-generation sequencing will solve many current problems with human genome References 1. Hood L: Acceptance remarks for Fritz J. and Delores H. Russ Prize. The sequences. First, contemporary short-read sequencing ap- Bridge 2011, 41:46–49. proaches make it impossible to assemble human genome 2. Collins FS, McKusick VA: Implications of the Human Genome Project for sequences de novo; hence, they are usually compared medical science. JAMA 2001, 285:540–544. 3. 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