Saturday, March 03, 2001

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The Scientist Targeting HIV Therapy with Intelligence
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"With an arsenal of 17 approved drugs and intricate rules for deploying each one, a physician's battle to shut down HIV replication is like chess against an opponent too strong to be driven from the board, so keeping the game going is the only alternative to losing. Today's best strategy for suppressing HIV calls for using three or four inhibitors in combination. As with a chessboard siege defense, conserving pieces while sealing off each new attack, doctors try to pick drug combinations that preserve as many options as possible should HIV mutate into drug resistance.

To help doctors find the most promising combinations in any situation, software called the HIV Therapy Edge combines bioinformatics with artificial intelligence, a computer science discipline grown up on chess problems. Developed by Intelligent Thera-peutic Solutions of Durham, N.C., the product is in final testing, scheduled for market release sometime this summer. HIV Therapy Edge, says John Mellors of the University of Pittsburgh, "does in milliseconds what would take me 20 or 30 minutes sitting down in a quiet room, leafing through a patient's charts, checking the past medical history, virus resistance profiles, drug doses and interactions, pulling together all my knowledge.""

redux [07.06.00]
HMS Beagle Latent resistance
[requires 'free' registration]
"New treatments have extended the lives of AIDS patients and offered hope for a cure, but multidrug-resistant strains can still foil therapy. Researchers used analysis and computer simulations to show that resistance-related treatment failure in patients who consistently take their prescribed drugs is likely due to mutant strains present at the beginning of treatment rather than strains developing during the course of treatment as a result of residual viral replication. The finding stresses the importance of combining drugs with different resistance profiles in order to wipe out all existing drug-resistant strains of the virus early in treatment."

Reference: Ribeiro, R.M. and Bonhoeffer, S. 2000. Production of resistant HIV mutants during antiretroviral therapy. Proc. Natl. Acad. Sci. U.S.A. 97(14):7681-7686."

Proceedings of the National Academy of Sciences Production of resistant HIV mutants during antiretroviral therapy
"HIV drug therapy often fails because of the appearance of multidrug-resistant virus. There are two possible scenarios for the outgrowth of multidrug-resistant virus in response to therapy. Resistant virus may preexist at low frequencies in drug-naïve patients and is rapidly selected in the presence of drugs. Alternatively, resistant virus is absent at the start of therapy but is generated by residual viral replication during therapy. Currently available experimental methods are generally too insensitive to distinguish between these two scenarios. Here we use deterministic and stochastic models to investigate the origin of multidrug resistance. We quantify the probabilities that resistant mutants preexist, and that resistant mutants are generated during therapy. The models suggest that under a wide range of conditions, treatment failure is most likely caused by the preexistence of resistant mutants."

redux [04.05.00]
HMS Beagle Are Computers Evolving in Biology?
[requires 'free' registration]
"I suspect that although the new enthusiasm for computers in biology is genuine, it overlooks some basic problems in implementation. The basic difficulty, as I see it, is that although biologists use computers, they do not trust everything that comes out of them. It is one thing to use them to print up nice-looking graphs, but it is an entirely different matter to use them to think better."

"Francis Crick was once quoted as saying that no biologist had ever made a discovery using a mathematical model. I would reply that no biologist has ever made a discovery by running an electrophoretic gel. They make discoveries by using their brains. Computers, like all scientific tools, are only as good as the person who uses them. If biologists don't understand how computer models are constructed, they won't know their strengths and limitations. Without some foundation of trust, biologists will be unlikely to utilize or accept this powerful method of data analysis."

Friday, March 02, 2001

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Fortune Post-Genome, Celera Now Shoots for Profits
"Last year Celera Genomics and its president, J. Craig Venter, shook up the scientific world by successfully sequencing the human genome faster than anyone--even Venter--had predicted. But when the hype faded, investors were left with one big question: How could Celera turn its accomplishment into financial gain?

The answer wasn't immediately clear."

"Now Celera has turned its focus to a logical new business: drug development."

redux [01.11.01]
Fool.Com Do Biotech Data Deals Mean Real Money?
"Biotech deals announced in the last few days highlight the hottest debate in the biotech world: If and how bioinformatics companies -- the likes of Gene Logic (Nasdaq: GLGC), Incyte Genomics (Nasdaq: INCY), and Celera Genomics (NYSE: CRA) -- can sustain long-term business success. Can they sell their information alone, obtain future milestone payments and royalties on drugs or diagnostics produced from their data, or must they become drug development companies themselves?"

Fool.Com: Message Boards Re: Are royalties the key?
"Currently, big pharma subscribers are paying several million dollars per year, for several years, on a non-exclusive basis. Now if we assume you are correct in that unvalidated targets are worth MUCH less than validated targets (and I'm correct in assuming that first generation genomics targets are evn more likely to be "low margin") then, considering the time it will take to bring an unvalidated target to market, Celera is ripping these guys off (well, that's a little extreme). There's absolutely no guarantee any of this data will yield blockbuster drugs and yet they can charge tens of millions of dollars for it on a non-exclusive basis. Why does pharma buy it? Because several million a year is pocket change for a lot of these companies. Why risk missing out? Suckers.;-)

I realize I'm taking an extreme stance, but it's only to make a point: Celera is making a lot of money from their subscribers. The big question is can they continue to sign companies up at a rate sufficient to fund expansion of an internal drug discovery platform. Here we may have a problem. The subscription rate has been, for most of us, disappointing. Either Celera is going to have to start validating targets (or annotating or value-adding) to attract more customers, or they are going to have to enter into significant collaborations. I think they're going to do both."

GenomeWeb Celera Launches into Drug Target Sector
"Celera Genomics on Wednesday announced moves that signal the beginning of the company's foray into the drug target discovery sector.

"We are looking to identify new drug targets," Peter Chambre, Celera?s chief operating officer, said at a company presentation at the JP Morgan H&Q conference."

redux [06.29.00]
Forbes Celera's Worth Still Up In The Air
"Great discoveries do not necessarily make great businesses. Businesses have to sell something. Celera Genomics doesn't sell or make anything tangible. It hawks service and information. It sells access to lists of genes and computers that can sort through those messy lists. Samuel Broder, the company's executive vice president and chief medical officer, makes Celera sound like some kind of consulting company, or perhaps a library."

"In a market filled with companies that acquire knowledge and then use it to produce chemicals and drugs with immediate importance, Celera is charging an arm and a leg for a library with really nifty computers.

But the Human Genome Project, like the public library, is offering similar services for free. Certainly, its computers are less nifty. But it has a relatively good draft of the genome. A lot of companies and universities may pay for Celera's cleaner, clearer books, its faster computers, and its richer catalogs of where the genes are and what they do. But this all seems speculative. It would certainly be nice if they had an exclusive human genome to sell."

"Venter's quest could be a fable, with all sorts of morals about the power of capitalism and the importance of a single, brilliant, willful individual who used the market to shake the ivory towers of science. But those morals only hold if Celera succeeds, if business and science blend to propel the company into the future with breathtaking speed without rocketing it into the realities of the marketplace. Celera could become one of the great business success stories. It could also be a financial train wreck."

Right now, that makes it a very volatile stock."

Thursday, March 01, 2001

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British Medical Journal Safeguards for research using large scale DNA collections
"Declining confidence in the governance of clinical practice has serious implications for medical research. Recent studies looking at public opposition to genetically modified foods and the social psychology of risk have shown that the level of trust in the institutions governing a particular activity is the key factor affecting public perceptions of risk in that area.2 The loss of confidence in the Ministry of Agriculture, Fisheries, and Food and the agencies responsible for food safety following the uproar over bovine spongiform encephalopathy laid the foundation for widespread public scepticism about the safety of genetically modified foods. If there continues to be erosion of trust in the medical profession there is a real danger that controversial areas of research, such as genetics, will provoke increasing levels of public opposition. It is in this context that the proposals for the creation of a very large collection of DNA samples for genetic research should be examined."

British Medical Journal Safeguards for research using large scale DNA collections
"Current and emerging technologies will allow rapid identification of mutations causing well described single gene disorders, single nucleotide polymorphism profiling, and genomic sequencing. These powerful technologies may enable the identification of predispositions to common, multifactorial disorders and predict individuals' responses to conventional therapeutic interventions. On the basis of discussions with general practitioners and practice nurses, and the findings of a recent informal survey among general practitioners in South Wales about attitudes and knowledge of genetics (unpublished data), I think that few professionals in primary care would be confident in explaining the nature of these techniques and the importance and implications of the data that would be generated. This would seriously limit the ability of professionals in primary care to obtain informed consent and answer questions that arise over the years of the study. The long term nature of the proposals reinforces the view that education and training in genetics, and particularly in the basic science that underpins the subject, are a priority for medical, nursing, and associated professions at the basic, specialist, and continuing education stages. The success of the proposed study and future population genetic studies are dependent on this educational need being immediately and effectively addressed."

redux [02.17.01]
The Scientist Gene Pool Expeditions
[requires 'free' registration]
"A good gene pool, like love, is where you find it. Now genomics researchers have two new ones to swoon over: one from Estonia, a crossroads of Scandinavian cultures and the northernmost of the former Soviet Union's Baltic republics; and from Tonga, an island kingdom half a world away where a Polynesian people has lived in near-perfect isolation for close to 3,500 years. Tonga and Estonia laid final plans last November and December, respectively, for national gene pool exploration programs aimed at discovering disease-associated genes and developing therapies based on the discoveries.

They follow the trail blazed by Iceland,1 where for several years the gene pool of 275,000 Icelanders has been the fishing preserve of Reykjavik-based deCODE Genetics which is hunting for gene variants that affect serious, often chronic diseases by finding statistical links between Icelanders' genotypes and their inherited illnesses."

redux [06.15.00]
New England Journal Of Medicine Rules for Research on Human Genetic Variation -- Lessons from Iceland
"DNA molecules are entirely separate from medical records. In the future, however, the DNA molecule and the medical record are likely to merge into one when it becomes possible to sequence a person's entire genome and put that information on a computer chip or disk. This is not deCODE's current project, but we should not wait until this step is taken to explore its implications. The most important questions would then be who has the authority to make such a disk in the first place; who owns the disk; who controls the use of the disk; and whether the disk containing the genome should be treated as specially protected medical information, as is the case for psychiatric and drug-dependency records? In clinical settings, it seems reasonable to treat such a disk as containing particularly private and sensitive medical information. It also seems reasonable to permit patients to agree to have their entire genome scanned without detailing the tens of thousands of tests that would be run. This is akin to consent to a battery of tests during an annual physical examination.

On the other hand, in a research setting, or when a specific genetic disorder is suspected, the creation and use of an individual patient's genome disk should be subject to the informed consent of the patient. And since they can be both separated from the medical record and readily recreated, research subjects should retain the right to have the files containing their genetic information destroyed at any time.

Iceland's experience with deCODE provides a useful catalyst for formulating fair and ethical rules for research on genetic variation. The Icelandic experience demonstrates that people are concerned about how genetic research is done, that medical-records research and DNA-based research are not the same, that community consultation is necessary but not sufficient to justify DNA-based research ethically, that the probable benefits of such research should be spelled out as clearly as possible, and that international standards for consent to and withdrawal from research should apply directly to research on human genetic variation. Rules for such research will retain their relevance even after it becomes possible to transfer all the genetic-sequence information in a DNA molecule to a computer disk."

redux [02.13.00]
The Daily Davos Beyond the Genome
"By the spring of this year, the first draft of the human genome -- the sequence of all the genetic instructions needed to make up a human being -- will be published on the Web. But that is only the end of the beginning. Scientists still have very little idea of what most of the 100,000 or so human genes actually do, and finding out will take them into a very different area of research.

The raw material of the genome program has been anonymous samples of DNA, manipulated by complex laboratory machines that turn out information like a production line turns out widgets. But the new era of post-genome research involves analysing real people and their confidential medical records. The records are needed to match the genes that people carry with the diseases they may develop. Only then will gigabytes of genetic data into new treatments for cancer or heart disease. And that is why socialised healthcare is a vital part of post-genome research.

Countries such as the U.S., which provide healthcare through private enterprise, are useless for this sort of genetic inquiry. Only those countries which have organized the delivery of healthcare to their population in a way that is independent of the marketplace have built up the universal medical records necessary to make sense of the patterns of disease."

Wednesday, February 28, 2001

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PENN Database Research Group K2/Kleisli and GUS: Experiments in integrated access to genomic data sources
"The integration of heterogeneous data sources and software systems is a major issue in the biomedical community and several approaches have been explored: linking databases, ``on-the-fly'' integration through views, and integration through warehousing. In this paper we report on our experiences with two systems that were developed at the University of Pennsylvania: an integration system called K2, which has primarily been used to provide views over multiple external data sources and software systems; and a data warehouse called GUS which downloads, cleans, integrates and annotates data from multiple external data sources. Although the view and warehouse approaches each have their advantages, there is no clear ``winner''. Therefore, users must consider how the data is to be used, what the performance guarantees must be, and how much programmer time and expertise is available to choose the best strategy for a particular application. Our experiences also point to some practical tips on how updates should be published by the community, and how XML can be used to facilitate the processing of updates in a warehousing environment."

redux [01.17.01]
The Collection of Computer Science Bibliographies Bibliography on Mediation, Database Integration, Database Interoperability and related topics
"personal bibliography on query mediation, database integration, database interoperability and related topics, concentrating on projects in genomic research. "

Tuesday, February 27, 2001

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The Financial Times Opinion: No price should be placed on the book of life
"Let me be frank here: my view is, and always has been, that the information in the genome is our genetic heritage and should not be profited from directly. It is not for sale. This is a pro partnership, not an anti-business, stance. We want to ensure that the entire world has equal access to the data, so that the potential health benefits are reaped by the many, rather than the few.

As Prime Minister Blair said: "The knowledge contained in the map of the human genome has the power to touch the lives of everyone on the planet." It is for precisely this reason that our commitment should be for the entire world to use this data so the benefits can be realised by all, and major killers such as malaria, tuberculosis, river blindness and leprosy will not be neglected."

The Economist Science and profit
"ONCE upon a time, pure and applied science were the same. Sir Humphry Davy discovered seven chemical elements, and invented the miner’s safety lamp. Louis Pasteur investigated the properties of molecules, and worked out how to stop milk spoiling. Everybody thought that was admirable. Somehow, things have changed. Today the feeling is widespread that science and commerce should not—must not—mix. There is a queasy suspicion that the process of discovery is in some way corrupted if it is driven by profit."

"Far from compromising science, profit in both these cases—the development of new medicines and the elucidation of the genome—has animated it, and directed it towards meeting pressing human needs. It is a happy marriage. Davy and Pasteur would surely have approved."

Saturday, February 24, 2001

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Stanford Medical Informatics Preprint Archive One Size Does Fit All: Acquiring Semantic Web Contents with Protege-2000
"One of the most recent trends in the evolution of the World Wide Web is the growing awareness of the need for a Semantic Web, a Web of information that machines can understand and process. The requirement to encode machine-interpretable information on the Web led to the development of a number of languages for representing this information. These languages are coming from different communities that have different sets of requirements and goals in mind. The languages that are emerging have many similar features, but each of them is different from the others. Currently, there is no consensus on which language or set of languages should become the standard and researchers and developers continue to experiment with the existing languages and to develop new ones. Protege-2000 is an ontology-development and knowledge-acquisition environment developed in our laboratory. It has a graphical user interface which enables ontology developers to concentrate on conceptual modeling without knowing or thinking about syntax of an output language. Protege-2000 has a flexible knowledge model and an extensible plugin architecture. These two features allow developers to adapt Protege-2000 quickly and easily to work as an ontology-editing environment for new Semantic Web languages; there is no need to create new tools for these languages from scratch. As a result, developers obtain a graphical and easy-to-use editor for conceptual models in the new language. They can experiment with the features of the language, decide if the language itself is sufficiently expressive, or sufficiently flexible to meet their requirements. In this paper, we describe how Protege-2000 can be adapted for editing models in different Semantic Web languages. We describe as examples Protege-based editors for RDFS and OIL."

redux [05.10.00]
The XML Cover Pages XML and Semantic Transparency
"We may rehearse this fundamental axiom of descriptive markup in terms of a classical SGML polemic: the doubly-delimited information objects in an SGML/XML document are described by markup in a meaningful, self-documenting way through the use of names which are carefully selected by domain experts for element type names, attribute names, and attribute values. This is true of XML in 1998, was true of SGML in 1986, and was true of Brian Reid's Scribe system in 1976. However, of itself, descriptive markup proves to be of limited relevance as a mechanism to enable information interchange at the level of the machine.

As enchanting as it is to contemplate the apparent 'semantic' clarity, flexibility, and extensibility of XML vis-à-vis HTML (e.g., how wonderfully perspicuous XML <bookTitle> seems when compared to HTML <i>), we must reckon with the cold fact that XML does not of itself enable blind interchange or information reuse. XML may help humans predict what information might lie "between the tags" in the case of <trunk> </trunk>, but XML can only help. For an XML processor, <trunk> and <i> and <booktitle> are all equally (and totally) meaningless. Yes, meaningless.

Just like its parent metalanguage (SGML), XML has no formal mechanism to support the declaration of semantic integrity constraints, and XML processors have no means of validating object semantics even if these are declared informally in an XML DTD. XML processors will have no inherent understanding of document object semantics because XML (meta-)markup languages have no predefined application-level processing semantics. XML thus formally governs syntax only - not semantics."

redux [10.13.00]
Scientific American Hooking up Biologists: Consortia are forming to sort out a common cyberlanguage for life science
"Imagine that your co-worker in the next cubicle has some information you need for a report that's due soon. She e-mails it to you, but the data are from a spreadsheet program, and all you have is a word processor, so there's no possibility of your cutting and pasting it into your document. Instead you have to print it out and type it in all over again. That's roughly the situation facing biologists these days. Although databases of biological information abound--especially in this post-genome-sequencing era--many researchers are like sailors thirsting to death surrounded by an ocean: what they need is all around them, but it's not in a form they can readily use.

To solve the problem, various groups made up of academic scientists and researchers from biotechnology and pharmaceutical companies are coming together to try to devise computer standards for bioinformatics so that biologists can more easily share data and make the most of the glut of information resulting from the Human Genome Project. Their goal is to enable an investigator not only to float seamlessly between the enormous databases of DNA sequences and those of the three-dimensional protein structures encoded by that DNA. They also want a scientist to be able to search the databases more efficiently so that, to use an automobile metaphor, if someone typed in "Camaro," the results would include other cars as well because the system would be smart enough to know that a Camaro is another kind of car."

"Eric Neumann, a member of both the Bio-Ontologies and BioPathways consortia, is a neuroscientist who is now vice president for life science informatics at the consulting firm 3rd Millennium in Cambridge, Mass. (no relation to Millennium Pharmaceuticals). He says Extensible Markup Language (XML) is shaping up to be the standard computer language for bioinformatics."

redux [09.15.00]
The Rand Corporation : Scaffolding the New Web: Standards and Standards Policy for the Digital Economy The Emerging Challenge of Common Semantics
"With XML has come a proliferation of consortia from every industry imagineable to populate structured material with standard terms (see Appendix B). By one estimate, a new industry consortium is founded every week, perhaps one in four of which can collect serious membership dues. Rising in concert are intermediary groups to provide a consistent dictionary in cyberspace, in which each consortium's words are registered and catalogued.

Having come so far with a syntactic standard, XML, will E-commerce and knowledge organization stall out in semantic confusion?"

"How are semantic standards to come about?"

SemanticWeb.Org Tutorial on Knowledge Markup Techniques
"There is an increasing demand for formalized knowledge on the Web. Several communities (e.g. in bioinformatics and educational media) are getting ready to offer semiformal or formal Web content. XML-based markup languages provide a 'universal' storage and interchange format for such Web-distributed knowledge representation. This tutorial introduces techniques for knowledge markup: we show how to map AI representations (e.g., logics and frames) to XML (incl. RDF and RDF Schema), discuss how to specify XML DTDs and RDF (Schema) descriptions for various representations, survey existing XML extensions for knowledge bases/ontologies, deal with the acquisition and processing of such representations, and detail selected applications. After the tutorial, participants will have absorbed the theoretical foundation and practical use of knowledge markup and will be able to assess XML applications and extensions for AI. Besides bringing to bear existing AI techniques for a Web-based knowledge markup scenario, the tutorial will identify new AI research directions for further developing this scenario."

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BioMedNet The cost/benefit analysis that defeated Darwin
[requires 'free' registration]
"Darwin's struggle to explain the dung beetle's diversity of horns in terms of the benefits such variety bestowed is shelved by research published tomorrow. An American ecologist shows that it is not the benefits so much as the physiological costs of a horn's position on other traits that cause the adaptive range."

""The reproductive benefits of horn production may explain why horns are large, but they cannot explain why beetle horns occur in so many different forms and in so many varied locations," he writes. His latest findings show that horn location influences the production of other traits."

redux [04.25.00]
UniSci Selfish Gene Theory Of Evolution Called Fatally Flawed
"In the current issue of Advances in Complex Systems (February-April), Dr. Yaneer Bar-Yam, president of the New England Complex Systems Institute and an expert on the application of mathematical analysis to complex systems, contends that the selfish-gene theory of evolution is fatally flawed.

If his mathematical proof gains general acceptance, it will shut the door on controversial "gene-centered" views of evolution.

Bar-Yam, in the upcoming article, proves that the "selfish gene" approach is not valid in the general case. He demonstrates that the gene-centered view, expressed in mathematical form, is only an approximation of the dynamics actually at work."

"The key to Bar-Yam's analysis lies in recognizing three levels of structure in nature: the gene, the organism and the group (or network) of organisms."

Thursday, February 22, 2001

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The New England Journal of Medicine Genome-Wide Views of Cancer
"Nearly coincident with the publication of the article by Hedenfalk et al. (1) in this issue of the Journal are reports of the complete DNA sequence of the human genome. (2,3) This remarkable point in biomedical history marks the beginning of an era in which we expect to learn the molecular basis of all human diseases. How long this will take is uncertain, but the boundaries of the problem are now clear. The increasing understanding of molecular medicine will shift clinical practice from empirical treatment to therapy based on a molecular taxonomy of disease."

"The study by Hedenfalk et al. illustrates the potential of genome-wide views to influence the diagnosis of cancer. Complex patterns of gene expression can serve as proxies for abnormalities in entire molecular pathways, without the need to identify the particular gene that causes the disturbance. It is likely that in the future, the integrity of functionally important pathways in tumors will be evaluated by transcriptional profiling rather than by the sequencing of individual genes within the pathway, most of which are still unknown. The study by Hedenfalk et al. also illustrates the way in which the difficulty of sequencing large genes like BRCA1 can be partially overcome through the use of transcriptional profiling based on DNA microarrays."

redux [11.20.00]
GeneLetter Genome project leader says clinicians are unprepared for gene-based medicine
"A decade from now, predictive genetic tests will be available for some 10 to 12 conditions, and interventions will be available for several of these, yet the medical profession is far from ready to practice this kind of medicine, Dr. Francis S. Collins, director of the National Human Genome Research Institute, told healthcare leaders at a conference this morning."

"By 2010, many physicians will find themselves practicing genetic medicine, yet such individualized gene-based treatment is now a foreign concept in the examining room. "I think that most physicians are not really ready for this phase, through no fault of their own," he said.

redux [06.08.00]
GeneLetter Managed care needs to prepare for biotech revolution
"Unless they begin preparing now, health plan executives and medical directors could be blindsided by the revolution in medicine that will come with the mapping of the human genome, members of a managed care conference keynote panel warned on Monday."

"You think the genetic revolution is still 3-to-5 years off for your health plans," said Dr. Billings, who also serves as deputy director and chief medical officer of the Heart of Texas Veterans Health Care System. "I have to tell you, you better wake up. The tsunami is on the horizon," he warned.

For example, Schering-Plough's Dr. Haverty predicted that gene-based information could lead to the identification of many different types of asthma. As a result, health plans will need to develop many new codes and to upgrade their information systems, he said."

redux [03.30.00]
JAMIA Integration and Beyond: Panel Discussion
"I think one of the toughest things we all have to deal with is updating our dictionaries. In the simplest cases, the name of an organism is changed and we just have to do the maintenance. It is tougher, when, as with Citrobacter, they do genetic studies and say, "Oh, it's really six different organisms, not one." We have the human genome project coming very quickly. Even that is just the tip of the iceberg. We're not only going to see all the genes; we're then going to see clinical tests based on gene expression. Essentially, you'll be able to look at something on the order of 180,000 gene products and whether they're up or down regulated. How are we going to integrate such an incredible amount of data at a time when we're going to also be changing how we think about these processes? Classification and simple mapping are not going to work, because the lumpers and splitters are going to be arguing furiously on a daily basis."

redux [04.19.00]
Wired News Biotech Can Be Fun
"Scientists should quit fretting about how to classify organisms and start figuring out how to make biology a unifying influence for researchers, doctors and their patients, biology pioneer Dr. Leroy Hood said Tuesday."

""I think we can revolutionize and transform the teaching of biology if we look at it as an informational science," said Hood, who began his career at Caltech, where he developed some of the first DNA sequencing machines."

"He said the most important place for that shift to take place is in medical schools."

Wednesday, February 21, 2001

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GenomeWeb Sun Forms Industry-Wide Collaboration to Develop Open Platform for Life Sciences
"Sun Microsystems said Wednesday it would partner with the Biotechnology Industry Organization, the National Cancer Institute, and several commercial bioinformatics vendors to support a collaborative effort to develop an open platform for the life sciences based on Java and XML.

The proposed initiative, temporarily referred to as Life Force or LI4 (Lifescience Informatics Interoperability Infrastructure Initiative) aims to develop an open platform to support data integration and interoperability and to focus the growing number of standards efforts"

"Sun intends to contribute the underlying infrastructure for the open platform, which the company hopes will form the eventual hub for a broad variety of life science computing needs, including bioinformatics, cheminformatics, genomics, proteomics, pharmacogenomics, metabolomics, and clinical informatics."

redux [01.17.01]
Bioresearch Online Bioinformatics market to double by 2004, to $110 million
"According to new findings by Silico Research (London), the market for bioinformatic platform software and services is currently worth $52 million a year and is growing by 17%. Data volumes, increased confidence in the technology, and the evolution of bioinformatic tools combine to drive market growth. The market is expected to reach $110 million by 2004.

The new research was issued as part of Silico’s e-R&D Insights Program. Companies competing in the bioinformatic platform sector include: Applied Biosciences, Compugen, Genomica, Genome Informatics, IBM, Informax, LION Bioscience, and NetGenics."

The Collection of Computer Science Bibliographies Bibliography on Mediation, Database Integration, Database Interoperability and related topics
"personal bibliography on query mediation, database integration, database interoperability and related topics, concentrating on projects in genomic research. "

Tuesday, February 20, 2001

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The New York Times Humbled by the Genome's Mysteries
[requires 'free' registration]
"Human complexity cannot be generated by 30,000 genes under the old view of life embodied in what geneticists literally called (admittedly with a sense of whimsy) their "central dogma": DNA makes RNA makes protein — in other words, one direction of causal flow from code to message to assembly of substance, with one item of code (a gene) ultimately making one item of substance (a protein), and the congeries of proteins making a body. Those 142,000 messages no doubt exist, as they must to build our bodies' complexity, with our previous error now exposed as the assumption that each message came from a distinct gene."

"The collapse of the doctrine of one gene for one protein, and one direction of causal flow from basic codes to elaborate totality, marks the failure of reductionism for the complex system that we call biology..."

1999 Pacific Symposium on Biocomputing Gene Expression and Genetic Networks
"Biology is currently undergoing a shift from a mostly qualitative to an information rich, quantitative science. Using large-scale biological technologies, we are gaining global views of structural and dynamic information in the form of whole genome sequences and the corresponding gene activity patterns at the RNA and protein level. These data reflect the molecular workings of a complex information processing system. In many ways these systems can be effectively viewed from the perspective of genetic feedback networks, given that the fundamental step of biological information flow resides in gene activation and its control through the activity of regulatory genes."

"The following sets of nine papers deals with the modeling of molecular networks, inference of functional relationships from gene activity profiles, and networks approach to structural evolution. We begin with a review by Szallasi in which he explains shy integrative approaches have been ignored in the traditional search for "dominant" molecular genetic mechanisms, and why this is no longer tenable in light of the evidence for combinatorial molecular causes for e.g. complex human diseases."

On Semiotic Modeling Code-Duality and the Semiotics of Nature
"Through centuries biological theories have been molded to conform to the view of nature established in classical physics. An apparently infinite succession of deep-rooted controversies bear witness to the fact, that this was not at all an easy fit. Vitalism, teleology or finalism have perpetually been called upon to account for living systems. But the authority of physics was such, that in the end those deviations from the ideal was always defeated - to reappear, nevertheless, in new disguise in the next generation.

With the birth of molecular biology and especially molecular genetics in the fifties and sixties a strange thing happened. Suddenly a new and very foreign vocabulary was introduced into biology, that of cybernetics or information theory. Terms like 'program', 'genetic code', 'information', 'messenger-RNA', 'feedback' and the like became respectable or even indispensable notions. Such terms, however, clearly played no role in the world view of classical physics.

This contradiction disappears when it is recognized that these new terms did not mean the same thing in biology as they did in general language. Facilitated by a widespread indifference to epistemological problems among biologists the concept of genetic information became for all practical purposes identified as the sum of the genes which carried it."

"We highly suspect the fruitfulness of this paradigm."

redux [07.11.00]
Biospace.Com Big Picture Biology
"For most of us, formal biology education begins with complex systems--the traditional dissection of a frog in high school biology class is virtually a rite of passage in the U.S.

But the way many people learn about and invest in biotechnology is at the smallest end of the spectrum--the genome, now often described as the "periodic table" of biology. Genomics and all its related buzzwords have been responsible for much of the media attention, government grants, and investment capital heaped on the biotech industry over the past decade.

But just as there is a whole lot of chemistry that happens in between the periodic table and a birthday cake, there is a lot of biology in between the genome and a living organism. With the completion of biology's periodic table within sight, academics and industry players alike are pondering the best way to apply our hard won knowledge.

The only problem is, the path from genome to system seems to get harder the more we learn."

Sunday, February 18, 2001

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Wired News Genome Effort Hits Home
"A new distributed computing project is comparing gene data with protein structures to determine their genome sequences.

"Genome@home is the second project from Stanford University's chemistry department, which also runs the Folding@Home project.

"Whereas Folding@Home is designed to learn how genomes fold into proteins, Genome@Home was launched this week to try and reverse engineer known proteins by guessing the genome sequence of their structures."

redux [02.02.01]
The Standard Juno Online Launches Into Outerspace
"Facing shrinking ad revenues, ISP Juno Online is jumping into a new field that to date has enjoyed its greatest fame from the search for extraterrestrial life.

The New York-based company announced Thursday the creation of Juno Virtual Supercomputer Project, a distributed computing effort that would tap the computing power of Juno's 4 million subscribers. Juno hopes to sell that vast power to large-scale research projects, initially focusing on bioinformatics and pharmaceutical work, said Juno President and CEO Charles E. Ardai."

redux [10.09.00]
ACM CrossRoads The SETI@Home Problem
"The SETI@Home problem can be thought of as a special case of the distributed computation verification problem: "given a large amount of computation divided among many computers, how can malicious participating computers be prevented from doing damage?" This is not a new problem. Distributed computation is a venerable research topic, and the idea of "selling spare CPU cycles" has been a science fiction fixture for years.

In real life, distributed computation has been used since at least the late 1980's to create "farms" of machines for rendering 3-D images. Farms allow graphic artists to create large images without needing to buy a supercomputer. More recently, the needs of scientific computation have led to the creation of frameworks such as Parallel Virtual Machine (PVM) and Beowulf, which make it easier to distribute computations across many machines. The machines involved are usually owned by the same entity and a machine is either "good" or "bad" if it is operating or malfunctioning. There are no blatantly malicious machines.

The Internet makes it possible for computation to be distributed to many more machines. However, distributing computing around the internet requires developers to consider the possibility of malicious clients."

"The general study of secure multiparty computation has produced much interesting work over the last two decades. Less well studied, unfortunately, are the tools and techniques required to move the theoretical results to the real world. The old dream of massively distributed computations is finally coming true, and yet our tools for building and analysing real systems still seem primitive. The challenge of the next few years will be to bridge this gap."

redux [08.09.00]
BBC Screensavers could save lives
"Your computer could be helping to save lives when you are not using it to play games or surf the internet.

Instead of it sitting idle, it could be taking part in scientific experiments being distributed across thousands of computers on the internet.

Drugs to beat cancer and flu are starting to be tested in simulations split up and run on personal computers that would otherwise be doing nothing useful." [via slashdot.org]

PC Magazine New Apps Exploit Connectivity
"A natural complement to distributed file-sharing capabilities is distributed computation. The idea behind distributed computation is that a really big problem gets split into discrete, independent chunks, which are then parceled out to individual computers whose owners have volunteered their idle processor time to the cause. In aggregate, the users' computers form a sort of distributed supercomputer. The concept was first popularized by U.C. Berkeley's SETI@Home project, a 1999 PC Magazine Technical Excellence finalist that's now been downloaded by more than 2 million users. Though SETI@Home is a single-purpose tool designed solely to scour radio-telescope signals for signs of extraterrestrial transmissions, you can expect to see general-purpose mechanisms for distributing all kinds of massive computations. United Devices, for example, is a company that will use distributed computing for projects in areas such as bioinformatics research, drug design, and climate studies."

redux [07.22.00]
The Standard Distributed Computing Goes Commercial
"The distributed-computing model could be one of those rare cases where capitalism and pure scientific research mesh. Not every lab can afford to pay $200,000 for an eight-processor Origin 2000 SGI supercomputer, much less $1 million for a 40-processor machine, says David Fenstermacher, director of scientific computing for the medical school at the University of North Carolina at Chapel Hill. (Fenstermacher is also acting director of the campus' Center for Bioinformatics and a United Devices adviser.) And even the most powerful supercomputers need time to process data.

A project that would take several months on a supercomputer – creating a 3D model of a protein's linear be accomplished in much less time using thousands of distributed computers"

redux [04.05.00]
egroups : Decentralization Description
"* Is decentralization ever a good idea? If so, when? Is there non-anecdotal evidence on costs and benefits?
* What protocol issues are there? Can we begin assembling a good protocol for decentralized messaging? To what degree do the protocols for Freenet, Gnutella or WorldOS meet the need? Do we need an application protocol or something lower level? Can HTTP do the job? Can we implement peer routing as an add-on to existing protocols? Is there a call to develop an IETF working group?
* Given that authoring and versioning are critical but hard in a decentralized environment, how can we approach the job? Is it possible to integrate WebDAV with peer networking?
* What are the business issues? Who are the players? Who else stands to win or lose, and why?

At present many people and groups are working on the issues in isolation, some for competitive reasons and some for lack of an alternative. My belief is that a communal approach will be more productive."

Saturday, February 17, 2001

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The Scientist Gene Pool Expeditions
[requires 'free' registration]
"A good gene pool, like love, is where you find it. Now genomics researchers have two new ones to swoon over: one from Estonia, a crossroads of Scandinavian cultures and the northernmost of the former Soviet Union's Baltic republics; and from Tonga, an island kingdom half a world away where a Polynesian people has lived in near-perfect isolation for close to 3,500 years. Tonga and Estonia laid final plans last November and December, respectively, for national gene pool exploration programs aimed at discovering disease-associated genes and developing therapies based on the discoveries.

They follow the trail blazed by Iceland,1 where for several years the gene pool of 275,000 Icelanders has been the fishing preserve of Reykjavik-based deCODE Genetics which is hunting for gene variants that affect serious, often chronic diseases by finding statistical links between Icelanders' genotypes and their inherited illnesses."

redux [06.15.00]
New England Journal Of Medicine Rules for Research on Human Genetic Variation -- Lessons from Iceland
"DNA molecules are entirely separate from medical records. In the future, however, the DNA molecule and the medical record are likely to merge into one when it becomes possible to sequence a person's entire genome and put that information on a computer chip or disk. This is not deCODE's current project, but we should not wait until this step is taken to explore its implications. The most important questions would then be who has the authority to make such a disk in the first place; who owns the disk; who controls the use of the disk; and whether the disk containing the genome should be treated as specially protected medical information, as is the case for psychiatric and drug-dependency records? In clinical settings, it seems reasonable to treat such a disk as containing particularly private and sensitive medical information. It also seems reasonable to permit patients to agree to have their entire genome scanned without detailing the tens of thousands of tests that would be run. This is akin to consent to a battery of tests during an annual physical examination.

On the other hand, in a research setting, or when a specific genetic disorder is suspected, the creation and use of an individual patient's genome disk should be subject to the informed consent of the patient. And since they can be both separated from the medical record and readily recreated, research subjects should retain the right to have the files containing their genetic information destroyed at any time.

Iceland's experience with deCODE provides a useful catalyst for formulating fair and ethical rules for research on genetic variation. The Icelandic experience demonstrates that people are concerned about how genetic research is done, that medical-records research and DNA-based research are not the same, that community consultation is necessary but not sufficient to justify DNA-based research ethically, that the probable benefits of such research should be spelled out as clearly as possible, and that international standards for consent to and withdrawal from research should apply directly to research on human genetic variation. Rules for such research will retain their relevance even after it becomes possible to transfer all the genetic-sequence information in a DNA molecule to a computer disk."

redux [02.13.00]
The Daily Davos Beyond the Genome
"By the spring of this year, the first draft of the human genome -- the sequence of all the genetic instructions needed to make up a human being -- will be published on the Web. But that is only the end of the beginning. Scientists still have very little idea of what most of the 100,000 or so human genes actually do, and finding out will take them into a very different area of research.

The raw material of the genome program has been anonymous samples of DNA, manipulated by complex laboratory machines that turn out information like a production line turns out widgets. But the new era of post-genome research involves analysing real people and their confidential medical records. The records are needed to match the genes that people carry with the diseases they may develop. Only then will gigabytes of genetic data into new treatments for cancer or heart disease. And that is why socialised healthcare is a vital part of post-genome research.

Countries such as the U.S., which provide healthcare through private enterprise, are useless for this sort of genetic inquiry. Only those countries which have organized the delivery of healthcare to their population in a way that is independent of the marketplace have built up the universal medical records necessary to make sense of the patterns of disease."

Friday, February 16, 2001

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MIT Technology Review Upstream: Biology in Silico
"Computers capable of mimicking life have long been the stuff of sci-fi nightmares—think The Terminator or 2001's HAL 9000. But for researchers struggling to make sense of vast amounts of new biological data, and for drug companies anxious to cut costs and speed development, having accurate computer simulations of living systems is still a dream. To make that dream come true, they are turning to "in silico biology," building computer models of the intricate processes that take place inside cells, organs, and even people. The ultimate goal: an entire organism modeled in silicon, allowing researchers to test new therapies much as engineers "fly" new airplane designs on supercomputers."

redux [11.27.00]
BusinessWeek A Software Model That Fathoms the Human Heart?
"What do a Boeing 777 and the human body have in common? Both are complex systems, dependent on millions of complex parts, whether they be a jet-propelled engine or a pumping organ such as the heart. The big difference: Engineers can design and build highly accurate computer models of the way a Boeing 777 will behave in flight. The human heart? Its complexity has long stymied efforts by researchers intent on turning drug development into a predictive science, much like building airplanes.

But that's changing. A handful of companies are developing software that can model single cells, whole organs, cellular metabolism and toxicology, diseases throughout a patient's body, and even an entire clinical trial."

redux [02.24.00]
HMS Beagle Virtual Cures
[requires 'free' registration]
"For a brief period, supplying the data was enough. More genes meant more potential drug targets. But now the victims of the data flood are crying for help. Companies like Entelos, Inc. (Menlo Park, California) are coming to the rescue by building models that integrate all those data into a single, homeostatic, interconnected whole. The models allow researchers to run virtual drug trials to determine the best drug targets, treatment regimens, and patient populations."

Modelers feel that their time has come. "Leaders in the genomics field are all coming to this realization that model building is becoming the rate-limiting step," says Palsson. "There's a major shift taking place in the biological sciences." Math is back, he says, and "biology is going to become quantitative."

Biospace Virtual Drug Development: Start-ups Put Biology in Motion
"One way of animating our growing store of static information is through computer simulation. It is an area that is beginning to emerge slowly in the life sciences, with only a handful of academic and commercial players active in the area. But for a fledging discipline, there is a great variety in the scope of work being undertaken. While academic labs try to create accurate simulations of red blood cells and simple bacteria, the private companies are taking on bolder projects--simulating human organs and even human diseases in their entirety."

redux [09.06.00]
UNISCI Nobelist To Lead Web-Based Project On Cell Signaling
"Nobel laureate Dr. Alfred Gilman, chairman of pharmacology at UT Southwestern Medical Center at Dallas, will lead a $10 million-per-year project allowing researchers around the world to pool their efforts in studying one of the biggest unsolved problems in biomedicine -- how cells interact with, or signal, each other."

"Work of these Alliance for Cellular Signaling (AFCS) researchers in the post-genome era ultimately could lead to the development of a "virtual cell" that could be used to test new drugs.”

"When we have a complete virtual cell, it can be used as a drug discovery engine to test drugs on the computer, rather than on cells or animals. It would be a wonderful way to understand what the optimal point would be to place a drug to achieve a specific goal in a specific patient in a specific kind of disease," Gilman said."

"NIGMS has called the AFCS funding "glue grants -- grants to glue together different sorts of people for a common goal," Gilman said. "We actually are gluing together people's brains and their ideas, but the research is not going to be done in their individual labs."

Instead, the researchers will use the Internet as their joint laboratory."

The Alliance for Cellular Signalling General Goals and Statement of Purpose
"The current and pending availability of complete genomic sequences inspires confidence that complex biological phenomena and systems can be understood completely. These feelings are heightened by rapidly expanding capabilities to manipulate gene content and expression in mammalian cells and organisms, detect protein-protein interactions, and quantify the activities of macromolecules in vivo. Such understanding implies the capacity to predict quantitatively the altered behavior of these systems that results from their genetic or environmental (including pharmacological) perturbation. We can envision, rather than simply imagine, the construction of a virtual cell."

The overall goal of the Alliance for Cellular Signaling is to understand as completely as possible the relationships between sets of inputs and outputs in signaling cells that vary both temporally and spatially. The same goal, stated from a slightly different perspective, is to understand fully how cells interpret signals in a context-dependent manner. This will involve identification of all the proteins that comprise the various signaling systems, the assessment of time-dependent information flow through the systems in both normal and pathological states, and finally the reduction of the mass of detailed data into a set of interacting theoretical models that describe cellular signaling."

redux [08.12.00]
GenomeBiology Whither genomics?
"The flood of data from genome-wide analysis is transforming biology. We need to develop new, interdisciplinary approaches to convert these data into information about the components and structures of individual biological pathways and to use the resulting information to yield knowledge about general principles that explain the functions and evolution of life."

"Genomics increases the chance that biology will experience a split like the one in physics, between those who collect and those who analyze data. This will challenge the majority of biologists who believe that modeling, simulation, and theory have little to contribute to biology. This prejudice rests on insecurity engendered by most biologists' weakness in mathematics (including my own) and previous efforts to model systems using more variables than there were data points. If we keep clinging to this prejudice, we will drown in a sea of data."

redux [07.13.00]
Nature Segmentation in silico
"A new mathematical biology is emerging. Building on experimental data from developing organisms, it uses the power of computational methods to explore the properties of real gene networks."

"Our understanding of gene networks is at an early stage. We perceive their complexity only after it has been filtered by the limitations of the techniques used to study them. Genome databases and DNA-chip technology, which enables huge numbers of genes to be screened for activity, will undoubtedly provide more, and much more complicated, data than anything produced by Drosophila genetics. If a relatively simple gene network such as the segment-polarity system is hard to understand intuitively, we can be certain that modelling will be essential to make sense of the flood of new data.

But this will not be elegant theoretical modelling: rather, it will be rooted in the arbitrary complexity of evolved organisms. The task will require a breed of biologist–mathematician as familiar with handling differential equations as with the limitations of messy experimental data. There will be plenty of vacancies, and, on present showing, not many qualified applicants."

redux [04.05.00]
HMS Beagle Are Computers Evolving in Biology?
[requires 'free' registration]
"I suspect that although the new enthusiasm for computers in biology is genuine, it overlooks some basic problems in implementation. The basic difficulty, as I see it, is that although biologists use computers, they do not trust everything that comes out of them. It is one thing to use them to print up nice-looking graphs, but it is an entirely different matter to use them to think better."

"Francis Crick was once quoted as saying that no biologist had ever made a discovery using a mathematical model. I would reply that no biologist has ever made a discovery by running an electrophoretic gel. They make discoveries by using their brains. Computers, like all scientific tools, are only as good as the person who uses them. If biologists don't understand how computer models are constructed, they won't know their strengths and limitations. Without some foundation of trust, biologists will be unlikely to utilize or accept this powerful method of data analysis."

redux [02.24.00]
Science Revealing Uncertainties in Computer Models
[summary - can be viewed for free once registered]
"Computer simulations give the impression of precision, but they are founded on a raft of assumptions, simplifications, and outright errors. New tools are needed, scientists say, to quantify the uncertainties inherent in calculations and to evaluate the validity of the models. But making uncertainties evident is a tough challenge, as evidenced by several recent workshops.”