Volume 9 Issue 1, January 2003

Thomas E. Starzl performed the first successful liver transplant, in 1967. But things could have been very different if he had pursued his first love, neurophysiology. Or indeed, his second research passion, cardiac physiology; or third, metabolism. He revealed to Nature Medicine that it was an innate desire not to follow the crowd but to create and develop new concepts that drove him away from these fields and led him to pioneer liver transplantation.

A vaccine that is able to work as a treatment for HIV-infected patients has been an elusive goal. Now experiments on macaques suggest that injections of modified dendritic cells might boost immunity to hold back disease progression (pages 27–32).

Addiction research has become increasingly focused on how addictive drugs affect neural signaling within the brain's reward circuitry. New work shows that the frustration of not receiving drugs when they are expected can also affect the inner workings of reward circuits.

Two new studies suggest that tests based on Cyclin E or microarray analysis have the potential to outperform conventional criteria predicting the outcome of breast cancer.

Heart failure and pathological overgrowth of the heart often occur hand in hand. New data on a biomechanical sensor challenge the viewpoint that cardiac hypertrophy causes heart failure (pages 68–75).

Agents that block the action of specific cytokines have changed the lives of many patients with rheumatoid arthritis and other autoimmune disorders. But frequent self-injections or injections by a physician during a clinic visit are required. Now a new class of anti-cytokine that may bypass such problems appears on the horizon (pages 47–52).

Post-menopausal women are treated with estrogen-receptor binding compounds during hormone replacement therapy. But new imaging studies in mice hint that the estrogen receptor may be responding primarily to estrogen-independent stimuli in some tissues (pages 82–86).

A nucleolar protein, nucleostemin, is now implicated in the control of stem and cancer cell proliferation. Nucleostemin may modulate p53 function through shuttling between the nucleolus and the nucleoplasm.

If vaccines could be administered without needles and syringes ('sharps'), immunization practice would become safer, more accepted and more suitable for mass use. The author explores the status of technologies that could achieve this aim and the barriers that must be overcome for their implementation.

In cell encapsulation, transplanted cells are protected from immune rejection by an artificial, semipermeable membrane, potentially allowing transplantation (allo- or xenotransplantation) without the need for immunosuppression. Yet, despite some promising results in animal studies, the field has not lived up to expectations, and clinical products based on encapsulated cell technology continue to elude the scientific community. This commentary discusses the reasons for this, summarizes recent progress in the field and outlines what is needed to bring this technology closer to clinical application.

Over the past 50 years, significant advances have been made in the development of total artificial hearts (TAH). These advances have most recently led to a clinical trial of a unique, transcutaneously powered TAH.

More than 100 functionally distinct populations of lymphocytes can be identified in the peripheral blood of humans; each of these cell types undoubtedly has a unique role in the organization and effectiveness of an immune response. To distinguish specifically among these cells, however, it is necessary to measure simultaneously at least six to eight different T-cell surface antigens; additional functional correlations require even greater detection capability. For this purpose, flow cytometers capable of independently detecting as many as 12 different molecules now exist. Here we review the history and applications of this technology and discuss future directions.

The conceptual and technical approaches that led to the explosive growth of combinatorial chemistry began approximately 20 years ago. In the past decade, combinatorial chemistry has continued to expand with new chemistries, technological improvements and, most importantly, a clear demonstration of its utility in the identification of active compounds for research and drug-discovery programs. This article describes the conceptual and practical breakthroughs that have been critical for the development of synthetic combinatorial methods and includes the most recent developments and applications of mixture-based combinatorial libraries.

Optical sensing of specific molecular targets and pathways deep inside living mice has become possible as a result of a number of advances. These include design of biocompatible near-infrared fluorochromes, development of targeted and activatable 'smart' imaging probes, engineered photoproteins and advances in photon migration theory and reconstruction. Together, these advances will provide new tools making it possible to understand more fully the functioning of protein networks, diagnose disease earlier and speed along drug discovery.

Engineered antibodies now represent over 30% of biopharmaceuticals in clinical trials, as highlighted by recent approvals from the US Food and Drug Administration. Recombinant antibodies have been reduced in size, rebuilt into multivalent molecules and fused with, for example radionuclides, toxins, enzymes, liposomes and viruses. The emergence of recombinant technologies has revolutionized the selection, humanization and production of antibodies, superseding hybridoma technology and allowing the design of antibody-based reagents of any specificity and for very diverse purposes.

Fundamental changes in the understanding of the primary influences that govern specific gene delivery, combined with rational approaches to engineer the gene transfer vectors, are now transforming targeted in vivo gene transfer from concept to reality. Many viral-based vectors have been designed to avoid gene transfer through their native receptors and redirected to a variety of tissue- and tumor-specific receptors. Non-viral vectors have likewise been engineered to avoid nonspecific gene transfer. Future challenges include advancing these vectors into clinical testing, designing improvements to avoid innate and acquired immunity, and elucidating the mechanisms that govern their biodistribution and pharmacokinetics.

Microarrays permit the analysis of gene expression, DNA sequence variation, protein levels, tissues, cells and other biological and chemical molecules in a massively parallel format. Robust microarray manufacture, hybridization, detection and data analysis technologies permit novice users to adapt this exciting technology readily, and more experienced users to push the boundaries of discovery.

Focus on emerging technologies (those undergoing unusually rapid development) and platform technologies (with broad applications).