The evolving war on cancer

Building on years of basic scientific discovery, recent advances in the fields of cancer genetics and medicinal chemistry are now converging to revolutionize the treatment of cancer. Starting with serendipitous observations in rare subsets of cancer, a paradigm shift in clinical research is poised to ensure that new molecular insights are rapidly applied to shape emerging cancer therapies. Could this mark a turning point in the "War on Cancer"?     

Discovery genetics: serendipity in basic research

The role of serendipity in science has no better example than the discovery of spontaneous mutations that leads to new mouse models for research. The approach of finding phenotypes and then carrying out genetic analysis is called forward genetics. Serendipity is a key component of discovering and developing mice with spontaneous mutations into animal models of human disease. In this article, the role of serendipity in discovering and developing mouse models is described within a program at The Jackson Laboratory that capitalizes on serendipitous discoveries in large breeding colonies. Also described is how any scientists working with mice can take advantage of serendipitous discoveries as a research strategy to develop new models. Spontaneous mutations cannot be planned but happen in all research mouse colonies and are discovered as unexpected phenotypes. The alert scientist or technician can rationally exploit such chance observations to create new research opportunities.     

Serendipity and new drugs for infectious disease

Serendipity, in various shades of semantic legitimacy, is abundantly evident in the history of the chemotherapy of infectious disease. We may be on the threshold of a new era of rational drug design, but most medications for infectious diseases have arisen, and continue to arise, from chance observation, clinical experience, and the empirical search for substances active against pathogens. Chance does not produce drugs; but where chance has played a pivotal role in drug discovery, the event may be considered serendipitous to a greater or lesser degree. In a deliberate search for new drugs, it is often difficult to assess the degree to which any resulting discovery is serendipitous, and the usefulness of the term becomes debatable. Many therapeutic advances emerge from research involving animals, and a triggering "happy accident" may reside in the most basic aspects of animal care or in the most arcane knowledge of animals. The examples discussed in this article deal mostly with parasitic disease and the use of animal models in the discovery of antiparasitic agents. In this area, as in others, chance has laid the groundwork for scientific advancement and practical benefit. Although the applicability of the word serendipity to drug discovery may often be uncertain, the role played by chance should be recognized and welcomed.     

False discoveries and models for gene discovery

In the search for genes underlying complex traits, there is a tendency to impose increasingly stringent criteria to avoid false discoveries. These stringent criteria make it hard to find true effects, and we argue that it might be better to optimize our procedures for eliminating and controlling false discoveries. Focusing on achieving an acceptable ratio of true- and false-positives, we show that false discoveries could be eliminated much more efficiently using a stepwise approach. To avoid a relatively high false discovery rate, corrections for 'multiple testing' might also be needed in candidate gene studies. If the appropriate methods are used, detecting the proportion of true effects appears to be a more important determinant of the genotyping burden than the desired false discovery rate. This raises the question of whether current models for gene discovery are shaped excessively by a fear of false discoveries.     

Serendipitous insights involving nonhuman primates

Serendipity is discussed as a form of controlled chaos, a phenomenon in a class with synchronicity and other actions affecting research in terms of theory versus observation (e.g., "optional stopping"). Serendipity is a fundamental aspect of basic research, a profitable and normal outcome in the context of "informed observation." The serendipitous finding fits into the following pattern: it is unanticipated, anomalous, and strategic. All observations that have meaning must fit into some context in the observer's mind or suggest a revolutionary new context. It is critically important to maintain access to the resources provided by established primate centers and similar laboratories to capitalize in a timely way on serendipitous findings and to benefit from valuable discoveries made in more directly targeted development investments. Examples are given of serendipitous insights gained in experimentation and observation relative to nonhuman primate research, including both broad and narrow topics. Genomics, which uses comparison-based strategies and capitalizes on the DNA sequences of genetic information, presents what might seem the basis for endless serendipity because nonhuman primates are likely to share most genes present in the human genome. Other topics discussed include infant behavior, birth periodicity, leprosy, cystic fibrosis, environmental enrichment, endocrinology, drug development, and the rapidly expanding study of infectious diseases and pathogen-based bioterrorism.     

Bugs, drugs and chemical genomics

The serendipitous discovery of penicillin inspired intensive research into how small molecules affect basic cellular processes and their potential to treat disease. Biochemical and genetic approaches have been fundamental for clarifying small-molecule modes of action. Genomic technologies have permitted the use of chemical-genetic strategies that comprehensively study compound-target relationships in the context of a living cell, providing a systems biology view of both the cellular targets and the interdependent networks that respond to chemical stress. These studies highlight the fact that in vitro determinations of mechanism rarely translate into a complete understanding of drug behavior in the cell. Here, we review key discoveries that gave rise to the field of chemical genetics, with particular attention to chemical-genetic strategies developed for bakers' yeast, their extension to clinically relevant microbial pathogens, and the potential of these approaches to affect antimicrobial drug discovery.     

Chance favors the prepared mind--from serendipity to rational drug design

Accidental discoveries always played an important role in science, especially in the search for new drugs. Several examples of serendipitous findings, leading to therapeutically useful drugs, are presented and discussed. Captopril, an antihypertensive Angiotensin-converting enzyme inhibitor, was the first drug that could be derived from a structural model of a protein. Dorzolamide, a Carboanhydrase inhibitor for the treatment of glaucoma, and the HIV protease inhibitors Saquinavir, Indinavir, Ritonavir, and Nelfinavir are further examples of therapeutically used drugs from structure-based design. More enzyme inhibitors, e.g. the anti-influenza drugs Zanamivir and GS 4104, are in clinical development. In the absence of a protein 3D structure, the 3D structures of certain ligands may be used for rational design. This approach is exemplified by the design of specifically acting integrin receptor antagonists. In the last years, combinatorial and computational approaches became important methods for rational drug design. SAR by NMR searches for low-affinity ligands that bind to proximal subsites of an enzyme; linkage with an appropriate tether produces nanomolar inhibitors. The de novo design program LUDI and the docking program FlexX are tools for the computer-aided design of protein ligands. Work is in progress to combine such approaches to strategies for combinatorial drug design.     

Self-treatment of wounds by a capuchin monkey (Cebus apella)

A captive adult female capuchin monkey spontaneously manufactured and used tools to groom her vaginal area and four of her own wounds over a six-month period. The wounds apparently occurred during fights with other monkeys living in the same social groups. The monkey often groomed her vaginal area and wounds with tools she had coated with a sugar-based syrup. The monkey did not use tools to groom other body areas, nor did she use tools that were coated with substances other than syrup. This monkey’s unusual habit developed in the context of manufacturing and using tools in a feeding task. These observations demonstrate that the serendipitous performance of particular behaviours in appropriate contexts can lead to the discovery and practice of simple treatment of wounds by a monkey. The independent discovery of simple medicinal procedures in human cultures may have occurred in a similar manner. Such discoveries could have predated the development of sophisticated cultures in which medicinal practices were embedded and eventually recorded.     

Why modules matter

The serendipitous discovery of the SH2 domain unleashed a sea-change in our conceptual molecular understanding of protein function. The reductionist approaches that followed from the recognition of modular protein interaction domains transformed our understanding of cellular signal transduction systems, how they evolve and how they may be manipulated. We now recognize thousands of conserved protein modules - many of which have been described in structure and function, implicated in disease, or underlie targeted therapeutics. The reductionist study of isolated protein modules has enabled the reconstruction of the protein interaction networks that underlie cellular signalling. Protein modules themselves are becoming tools to probe cellular activation states and identify key interactions hubs in both normal and diseased cells and the concept of protein modularity is central to the field of synthetic biology. This brief word of introduction serves to highlight the historical impact of the very powerful idea of protein modules and sets the stage for the exciting on-going discoveries discussed in this issue.     

Commentary: the year in nuclear receptor control of metabolism

This commentary highlights some of the most important discoveries in the field of nuclear receptor control of metabolism that occurred over the past year (2009 to 2010). As might be expected in a field that encompasses several hundred active laboratories, the task of providing a balanced look at these discoveries was daunting. Thus, to help make the selection of these discoveries, a small panel of colleagues was recruited to help. After selecting the top candidate discoveries from a Google search and a PubMed search, the panel was asked to rank them. These final selections were presented at "The Year In Basic Science Session" of the Annual Meeting of the Endocrine Society, ENDO 2010, the highlights of which are reproduced in this article.     

Is there a basis for novel pharmacotherapy of autism?

No medication has yet been shown to consistently alter the symptoms or the course of autism in the majority of patients. The present pharmacotherapy is mainly palliative and sometimes effective in attenuating specific behaviors. The search for better treatment involves examination of the underlying pathophysiology, the genetic or environmental etiology (including possible iatrogenic causes), and assessment of the clinically-generated evidence of efficacy, including serendipitous or unexplained findings. Subtle neuroanatomic and neurochemical changes are being explored and there are anecdotal reports or limited clinical trials that suggest some therapy might be possible. Secretin is a surprising recent addition to the list of candidates. The pharmacologic mechanism by which these agents might provide such effect is not clear, but hypotheses are beginning to emerge. In addition, the prevention of some uncertain number of autism cases is being investigated by examination of certain vaccinations as putative causative or contributory factors. These topics are reviewed in this article, which has the additional purpose of stimulating novel drug discovery efforts for this enigmatic disorder.     

Biological screening of natural products and drug innovation in China

Natural products have been applied to human healthcare for thousands of years. Drug discovery in ancient times was largely by chance and based on clinical practices. As understanding of therapeutic benefits deepens and demands for natural products increase, previously serendipitous discoveries evolve into active searches for new medicines. Many drugs presently prescribed by physicians are either directly isolated from plants or are artificially modified versions of natural products. Scientists are looking for lead compounds with specific structures and pharmacological effects often from natural sources. Experiences and successes of Chinese scientists in this specialized area have resulted in a number of widely used drugs. The tremendous progress made in life sciences has not only revealed many pathological processes of diseases, but also led to the establishment of various molecular and cellular bioassays in conjunction with high-throughput technologies. This is advantageous and permits certain natural compounds that are difficult to isolate and purify, and compounds that are difficult to synthesize, to be assayed. The transition from traditional to empirical and to molecular screening will certainly increase the probability of discovering new leads and drug candidates from natural products.     

FANCP/SLX4: A Swiss army knife of DNA interstrand crosslink repair

Fanconi anemia (FA) is a rare genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility. The FA proteins are known to function in the cellular defense against DNA interstrand crosslinks (ICLs), a process that remains poorly understood. A recent spate of discoveries has led to the identification of one new FA gene, FANCP/SLX4, and two strong candidate FA genes, FAN1 and RAD51C. In this perspective we describe the discovery of FANCP/SLX4 and discuss how these new findings collectively refine our understanding of DNA ICL repair.Key words: Fanconi anemia, DNA repair, ubiquitin, FANCP/SLX4, DNA interstrand crosslink repair     

New principles of cell plasticity

Recent discoveries demonstrating surprising cell plasticity in animals and humans call into question many long held assumptions regarding differentiative potential of adult cells. These assumptions reflect a classical paradigm of cell lineage development projected onto both prenatal development and post-natal maintenance and repair of tissues. The classical paradigm describes unidirectional, hierarchical lineages proceedings step-wise from totipotent or pluripotent stem cells through intermediate, ever more restricted progenitor cells, leading finally to 'terminally differentiated' cells. However, in light of both the recent discoveries and older clinical or experimental findings, we have suggested principles comprising a new paradigm of cell plasticity, summarized here.     

A short history of plant virology. III. The thirties.

The Thirties testified on the outstanding development of plant virology: the new discoveries formalized the concept of virus on a physicochemical background. Plant viruses, which had received their own taxonomical position at the end of the Twenties, were no longer considered as simple "infective pathogens" as their size, shape and chemical nature were determined, particularly for one of them--tobacco mosaic virus (TMV). This paramount contribution was achieved as a consequence of a functional interaction between biology on one side, and chemistry and physics on the other side, from the development of which molecular biology was born. The chemical characterization of TMV developed from the first determination of nitrogen presence in purified virus, performed by Carl Vinson, through the identification of TMV as Wendell Stanley's infective, autoreplicative protein macromolecule, to the final discovery of its nucleoprotein nature by the British group of Frederick Bawden. Thorough analytical techniques--in particular electron microscopy--led to disclose the exact shape and size of TMV particle. These discoveries, that opened a new era of virology, were corroborated by new knowledge that, although less explosive, can be considered of great importance for the development of plant virology. The methodologies to estimate viral activity; the study of the relationships between viruses and insect vectors; the studies on virus spread within plants; the identification of non-sterile type of resistance and of correlation between single plant genes and viral pathogenesis benefited plant virology of a set of knowledge that, together with the discoveries on the physico-chemical properties of TMV, raised plant virology from a secondary branch of plant pathology to a new independent science by itself.     

Chance Favors the Prepared Mind - From Serendipity to Rational Drug Design

Abstract

Accidental discoveries always played an important role in science, especially in the search for new drugs. Several examples of serendipitous findings, leading to therapeutically useful drugs, are presented and discussed. Captopril, an antihypertensive Angiotensin-converting enzyme inhibitor, was the first drug that could be derived from a structural model of a protein. Dorzolamide, a Carboanhydrase inhibitor for the treatment of glaucoma, and the HIV protease inhibitors Saquinavir, Indinavir, Ritonavir, and Nelfinavir are further examples of therapeutically used drugs from structure-based design. More enzyme inhibitors, e.g. the anti-influenza drugs Zanamivir and GS 4104, are in clinical development. In the absence of a protein 3D structure, the 3D structures of certain ligands may be used for rational design. This approach is exemplified by the design of specifically acting integrin receptor antagonists. In the last years, combinatorial and computational approaches became important methods for rational drug design. SAR by NMR searches for low-affinity ligands that bind to proximal subsites of an enzyme; linkage with an appropriate tether produces nanomolar inhibitors. The de novo design program LUDI and the docking program FlexX are tools for the computer-aided design of protein ligands. Work is in progress to combine such approaches to strategies for combinatorial drug design.

Dans les champs de l'obsérvation le hasard ne favorise que les ésprits préparés. Louis Pasteur (1822–1895)     

Biocatalysis for the synthesis of pharmaceuticals and pharmaceutical intermediates

Biocatalysis has been increasingly used for pharmaceutical synthesis in an effort to make manufacturing processes greener and more sustainable. Biocatalysts that possess excellent activity, specificity, thermostability and solvent-tolerance are highly sought after to meet the requirements of practical applications. Generating biocatalysts with these specific properties can be achieved by either discovery of novel biocatalysts or protein engineering. Meanwhile, chemoenzymatic routes have also been designed and developed for pharmaceutical synthesis on an industrial scale. This review discusses the recent discoveries, engineering, and applications of biocatalysts for the synthesis of pharmaceuticals and pharmaceutical intermediates. Key classes of biocatalysts include reductases, oxidases, hydrolases, lyases, isomerases, and transaminases.     

Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity

Background  

Virtual screening methods are now well established as effective to identify hit and lead candidates and are fully integrated in most drug discovery programs. Ligand-based approaches make use of physico-chemical, structural and energetics properties of known active compounds to search large chemical libraries for related and novel chemotypes. While 2D-similarity search tools are known to be fast and efficient, the use of 3D-similarity search methods can be very valuable to many research projects as integration of "3D knowledge" can facilitate the identification of not only related molecules but also of chemicals possessing distant scaffolds as compared to the query and therefore be more inclined to scaffolds hopping. To date, very few methods performing this task are easily available to the scientific community.     

FANCP/SLX4

Fanconi anemia (FA) is a rare genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility. The FA proteins are known to function in the cellular defense against DNA interstrand crosslinks (ICLs), a process that remains poorly understood. A recent spate of discoveries has led to the identification of one new FA gene, FANCP/SLX4, and two strong candidate FA genes, FAN1 and RAD51C. In this perspective we describe the discovery of FANCP/SLX4 and discuss how these new findings collectively refine our understanding of DNA ICL repair.