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Mapping of human genome raises serious issues for individual vs. corporate rights.
Unrestricted corporate control of genetic technologies opens a pandora's box for the balance of power between individuals and corporations. This column provides an overview of the issues raised by commercialization of the human genome from a citizen advocate's perspective.
Genomic capital: public cultures and market logics of corporate biotechnology.
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ACAPELLA-1K, a capillary-based submicroliter automated fluid handling system for genome analysis.
The Genomation Laboratory in the Electrical Engineering Department at the University of Washington has been developing an automated, high-throughput, submicroliter-scale fluid-handling system for use in molecular biology, especially as part of the Human Genome Project and other high-throughput DNA sequencing endeavors. Small glass capillaries enable the preparation, handling, and monitoring of 1-microliter reaction volumes. The Genomation Laboratory, with corporate partners Orca Photonic Systems, Inc. and Engineering Arts, has developed modules for aspiration, dispensing, mixing, transport, and rapid thermal processing of biological samples contained in glass capillaries. The ACAPELLA-1K is the first integration of these modules, designed to process 1000 samples in an eight-hour day. It has served as a test bed for the technologies as well as for performing biological experiments in conjunction with the University of Washington Genome Center. This system and related results are presented in this paper. A video of the system in operation is provided at. The Genomation Laboratory is presently developing the next-stage ACAPELLA-5K system based on the results of the ACAPELLA-1K system.
Rapid and accurate pyrosequencing of angiosperm plastid genomes.
BACKGROUND: Plastid genome sequence information is vital to several disciplines in plant biology, including phylogenetics and molecular biology. The past five years have witnessed a dramatic increase in the number of completely sequenced plastid genomes, fuelled largely by advances in conventional Sanger sequencing technology. Here we report a further significant reduction in time and cost for plastid genome sequencing through the successful use of a newly available pyrosequencing platform, the Genome Sequencer 20 (GS 20) System (454 Life Sciences Corporation), to rapidly and accurately sequence the whole plastid genomes of the basal eudicot angiosperms Nandina domestica (Berberidaceae) and Platanus occidentalis (Platanaceae). RESULTS: More than 99.75% of each plastid genome was simultaneously obtained during two GS 20 sequence runs, to an average depth of coverage of 24.6x in Nandina and 17.3x in Platanus. The Nandina and Platanus plastid genomes shared essentially identical gene complements and possessed the typical angiosperm plastid structure and gene arrangement. To assess the accuracy of the GS 20 sequence, over 45 kilobases of sequence were generated for each genome using conventional sequencing. Overall error rates of 0.043% and 0.031% were observed in GS 20 sequence for Nandina and Platanus, respectively. More than 97% of all observed errors were associated with homopolymer runs, with approximately 60% of all errors associated with homopolymer runs of 5 or more nucleotides and approximately 50% of all errors associated with regions of extensive homopolymer runs. No substitution errors were present in either genome. Error rates were generally higher in the single-copy and noncoding regions of both plastid genomes relative to the inverted repeat and coding regions. CONCLUSION: Highly accurate and essentially complete sequence information was obtained for the Nandina and Platanus plastid genomes using the GS 20 System. More importantly, the high accuracy observed in the GS 20 plastid genome sequence was generated for a significant reduction in time and cost over traditional shotgun-based genome sequencing techniques, although with approximately half the coverage of previously reported GS 20 de novo genome sequence. The GS 20 should be broadly applicable to angiosperm plastid genome sequencing, and therefore promises to expand the scale of plant genetic and phylogenetic research dramatically.
The Human Genome Project and the clinician.
The Florida Supreme Court's decision in Pate v Threlkel is an early warning sing of the massive impact human genome research will have on medical practice. Genetic screening is a scientific tool whose widespread use in clinical medicine will expand due to the combined influences of the federally funded Human Genome Project, biotechnology market forces, and corporate and societal pressures to both use and further develop the technique. Once testing becomes cost-effective, clinicians, by virtue of their position as "knowledgeable professionals" and as the primary source of health information for patients with genetic disorders, will be required to act as gatekeepers to the genetic heritage of their patients. This will seriously impact the legal definitions of reasonable care, a physician's duty to warn, the concept of informed consent, and the confidentiality of medical records.
Post-genome integrative biology: so that's what they call clinical science.
Medical science is increasingly dominated by slogans, a characteristic reflecting its growing bureaucratic and corporate structure. Chief amongst these slogans is the idea that genomics will transform the public health. I believe this view is mistaken. Using studies of the genetics of skin cancer and the genetics of skin pigmentation, I describe how recent discoveries have contributed to our understanding of these topics and of human evolution. I contrast these discoveries with insights gained from other approaches, particularly those based on clinical studies. The 'IKEA model of medical advance'--you just do the basic science in the laboratory and self-assemble in the clinic--is not only damaging to clinical advance, but reflects a widespread ignorance about the nature of disease and how clinical discovery arises. We need to think more about disease and less about genes; more in the clinic and less in the laboratory.
Establishing mathematical laws of genomic variation.
As the biological arm of the Rasch community, genomic measurement is concerned with asserting and testing hypotheses regarding the quantitative status of genomic variables, including alleles, genotypes, gene expression levels, and phenotypes, as well as DNA, RNA, and protein sequence information. The defining goal of this scientific paradigm, in contrast to the sample-dependent model-fitting and deterministic hypothesis testing of classical statistical genetics, is the identification, validation, and maintenance of a common unit of genomic measurement that maintains its magnitude and meaning, within an allowable range of error, regardless of the laboratory technology used to generate outcomes or the particular group of individuals or organisms under investigation. Such an invariant metric, the basis of a standard genometric scale and associated system of genomic metrology, can be identified, validated, and maintained through 1) routine implementation of the Rasch family of measurement models to construct sample- and scale-free measures from different types of genomic data and 2) cross-calibration of genomic measurement instruments between and among researchers, laboratories, universities, corporations, and databases. This manuscript provides an introductory overview of the guiding principles of fundamental measurement theory and the work of Rasch, connects these concepts to well-known tenets of population genetics, and highlights the potential benefits, both theoretical and applied, associated with achieving objectivity in genomic measurement.
An automated comparative analysis of 17 complete microbial genomes.
MOTIVATION: As sequenced genomes become larger and sequencing becomes faster, there is a need to develop accurate automated genome comparison techniques and databases to facilitate derivation of genome functionality; identification of enzymes, putative operons and metabolic pathways; and to derive phylogenetic classification of microbes. RESULTS: This paper extends an automated pair-wise genome comparison technique (Bansal et al., Math. Model. Sci. Comput., 9, 1-23, 1998, Bansal and Bork, in First International Workshop of Declarative Languages, Springer, pp. 275-289, 1999) used to identify orthologs and gene groups to derive orthologous genes in a group of genomes and to identify genes with conserved functionality. Seventeen microbial genomes archived at ftp://ncbi.nlm.nih.gov/genbank/genomes have been compared using the automated technique. Data related to orthologs, gene groups, gene duplication, gene fusion, orthologs with conserved functionality, and genes specifically orthologous to Escherichia coli and pathogens has been presented and analyzed. AVAILABILITY: A prototype database is available at ftp://www.mcs.kent.edu/arvind/intellibio / orthos.html. The software is free for academic research under an academic license. The detailed database for every microbial genome in NCBI is commercially available through intellibio software and consultancy corporation (Web site: http://www.mcs.kent.edu/årvind/intellibio . html). CONTACT: arvind@mcs.kent.edu.
Distinct genomic sequence of the CNR/Pcdhalpha genes in chicken.
CNR/Pcdhalpha family proteins have been first identified as a receptor family that corporate with Fyn, a family of the Src family of tyrosine kinase, and known as synaptic cadherins. Here we report the complete genomic sequence and organization of the chicken (Gallus gallus) CNR/Pcdhalpha The total length of chicken CNR/Pcdhalpha is 177kb. The chicken CNR/Pcdhalpha cluster encodes 12 variable and 3 constant exons. The genomic organizations of the chicken, rat, mouse, and human CNR/Pcdhalpha are basically orthologous. The constant-region exons (CP1, CP2, and CP3) are highly conserved between chicken and mammals, with percent identities of 90.9%, 90.7%, and 91.8% at the amino-acid level for chicken versus rat, mouse, and human, respectively. In contrast, the percent identities of the variable-region exons between chicken and mammals were lower: 51.8%, 51.3%, and 52.7%, on average, for chicken versus rat, mouse, and human, respectively, at the amino-acid level. Moreover, the chicken variable-region exons (from v1 to v12) are highly conserved paralogously (91.4%: nucleic acid, 92.4%: amino acid) in comparison with those of mammals. The CG content of each variable exon in the chicken (v1 to v12) is 74% on average and the CpG dinucleotide frequency in each variable-region exon is twice that of mammals. Due to the high CG content, chicken variable exons (from v1 to v12) encode 3 to 4 frame-shifted open reading frames, which span 1.5-3.0kb, in both the sense and anti-sense orientations.
The high road to success: how investing in ethics enhances corporate objectives.
There is a growing gap between the tidal wave of information emerging from the Human Genome Project and other molecular biology initiatives, and the clinical research needed to transform these discoveries into new diagnostics and therapeutics. While genomics-based technologies are being rapidly integrated into pharmaceutical R&D, many steps in the experimental process are still reliant on traditional surrogate model systems whose predictive power about human disease is incomplete or inaccurate. There is a growing trend underway in the research community to introduce actual human disease understanding as early as possible into discovery, thereby improving accuracy of results throughout the R&D continuum. Such an approach (known as clinical genomics: the large scale study of genes in the context of actual human disease) requires the availability of large quantities of ethically and legally sourced, high-quality human tissues with associated clinical information.Heretofore, no source could meet all of these requirements. Ardais Corporation was the first to address this need by pioneering a systematized, standardized network for the collection, processing, dissemination and research application of human tissue and associated clinical information, all of which rest on the highest ethical standards. Based on a novel model of collaboration between industry and the academic/medical community, Ardais has created procedures, structures, technologies, and information tools that collectively compromise a new paradigm in the application of human disease to biomedical research. Ardais now serves as a clinical genomics resource to dozens of academic researchers and biopharmaceutical companies, providing products and services to accelerate and improve drug discovery and development.
Molecular mechanisms of detrusor and corporal myocyte contraction: identifying targets for pharmacotherapy of bladder and erectile dysfunction.
The Post-Genomic age presents many new challenges and opportunities for the improved understanding, diagnosis and treatment of human disease. The long-term goal is to identify molecular correlates of disease processes, and use this information to develop novel and more effective therapeutics. A major hurdle in this regard is ensuring that the molecular targets of interest are indeed relevant to the physiology and/or pathophysiology of the processes being studied, and, moreover, to determine if they are specific to the tissue/organ being investigated. As a first step in this direction, we have reviewed the literature pertaining to bladder and erectile physiology/pharmacology and dysfunction and attempted to summarize some of the critical molecular mechanisms regulating detrusor and corporal myocyte tone. Because of the vast amount of published data, we have limited the scope of this review to consideration of the calcium-mobilizing and calcium-sensitizing pathways in these cells. Despite obvious differences in phenotypic characteristics of the detrusor and corporal myocyte, there are some common molecular changes that may contribute to, for example, the increased myocyte contractility characteristic of bladder and erectile dysfunction (i.e. increased Rho kinase activity and decreased K(+) channel function). Of course, there are also some important distinctions in the pathways that modulate contractility in these two cell types (i.e. the contribution of ryanodine-sensitive calcium stores and the nitric oxide/cGMP pathways). This report highlights some of these similarities and distinctions in the hope that it will encourage scientific discourse and research activity in this area, eventually leading to an improved quality of life for those millions of individuals that are afflicted with bladder and erectile dysfunction.
Distribution of linear antigenic epitopes on GP120 encoded in sibling clones of novel New York HIV-1 subtype B isolates.
We have initiated studies to characterize the predominant subtypes of HIV-1 which account for infections in a defined cohort of intravenous (IV) drug addicts. A region of ENV encoding the C2 to the V5 regions was amplified from the leukocytes of two subjects currently enrolled in a methadone maintenance program at the Addiction Research and Treatment Corporation (ARTC), in Brooklyn, New York. This region of the viral genome encodes the principal neutralizing determinant (PND) located in the V3 loop, the immunogenic CD4-binding site, and six other linear antigenic epitopes in the envelope glycoprotein, gp120. Phylogenetic tree analysis of the nucleotide sequences showed that the sibling clones RT1.4, RT1.15, RT1.17, RT1.21 and RT3.6, RT3.10, RT3.11, RT3.12 and RT3.15 derived from the isolates, RT1 and RT3, respectively, cluster with "group B" viruses at 99% confidence level. Marked intra-patient and inter-patient sequence variation was apparent in the V3 loop. The divergence included the presence of a previously unreported hexapeptide GPWGTF at the cap of the loop in the clones from RT1. The North American consensus hexapeptide, GPGRAF, was identified in the cap of the loop from the clones of RT3. Four of the five sibling clones from RT3 were closely related whereas the other clone, RT3.15, displayed five amino acid mutations downstream of the V3 cap. To assess the effect of sequence variation on the distribution of linear antigenic epitopes, complementary computer software programs, were used to analyze the gp120 residues. Eight analogous antigenic epitopes were identified in the clones from both isolates despite the marked divergence in the primary sequences.(ABSTRACT TRUNCATED AT 250 WORDS)
The case for caution--being protective of human dignity in the face of corporate forces taking title to our DNA.
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A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities.
High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.
Obtaining the sequence of the rice genome and lessons learned along the way.
Rice holds the record for the largest number of separate genome projects and for having the genome of two subspecies sequenced. This might be a short-lived record in the genomics era, but it highlights the significance of rice as a food staple and as a model plant for cereal species. Clearly, obtaining the genome sequence four times seems redundant, yet the rationale and motivation for each of these projects is valid; whether it is serving corporate shareholders or the general scientific community. Although the multiple projects resulted in some duplicated efforts, the value of data sharing was obvious and the winner in the end will be the global public.
Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals.
BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste d'accueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).
The effects of business practices, licensing, and intellectual property on development and dissemination of the polymerase chain reaction: case study.
INTRODUCTION: Polymerase chain reaction (PCR) was a seminal genomic technology discovered, developed, and patented in an industry setting. Since the first of its core patents expired in March, 2005, we are in a position to view the entire lifespan of the patent, examining how the intellectual property rights have impacted its use in the biomedical community. Given its essential role in the world of molecular biology and its commercial success, the technology can serve as a case study for evaluating the effects of patenting biological research tools on biomedical research. CASE DESCRIPTION: Following its discovery, the technique was subjected to two years of in-house development, during which issues of inventorship and publishing/patenting strategies caused friction between members of the development team. Some have feared that this delay impeded subsequent research and may have been due to trade secrecy or the desire for obtaining lucrative intellectual property rights. However, our analysis of the history indicates that the main reasons for the delay were benign and were primarily due to difficulties in perfecting the PCR technique. Following this initial development period, the technology was made widely available, but was subject to strict licensing terms and patent protection, leading to an extensive litigation history. DISCUSSION AND EVALUATION: PCR has earned approximately $2 billion in royalties for the various rights-holders while also becoming an essential research tool. However, using citation trend analysis, we are able to see that PCR's patented status did not preclude it from being adopted in a similar manner as other non-patented genomic research tools (specifically, pBR322 cloning vector and Maxam-Gilbert sequencing). CONCLUSION: Despite the heavy patent protection and rigid licensing schemes, PCR seems to have disseminated so widely because of the practices of the corporate entities which have controlled these patents, namely through the use of business partnerships and broad corporate licensing, adaptive licensing strategies, and a "rational forbearance" from suing researchers for patent infringement. While far from definitive, our analysis seems to suggest that, at least in the case of PCR, patenting of genomic research tools need not impede their dissemination, if the technology is made available through appropriate business practices.