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The cellular origins of disease – from bench to bedside
Kathleen J. Green

This issue of Journal of Cell Science launches a new Article Series, highlighting how cell science sheds light on mechanisms that drive disease pathogenesis and opens up new avenues for treatment of human disease. This is a propitious time for such a series. A confluence of technical advances in biochemistry, engineering, genetics and optical imaging (see Article Series on Imaging) provide unprecedented opportunities for defining how chemical signaling pathways couple with structural elements in the cell to control cell behavior.

The beautiful cytoskeletal fibers that captured the imagination and curiosity of cell biologists during the heyday of Keith Porter and, later, their associated molecular motors, junctional tethers and linking proteins, are now recognized as substrates for diseases of skeletal muscle, heart, internal organs, nervous system and skin. The elegant work performed by early cell biologists to identify elements of the exo- and endocytic trafficking pathways set the stage for our understanding of lyosomal storage diseases such as Niemann-Pick disease. In addition, germline or spontaneous mutations in membrane signaling receptors and associated signaling circuitry lead to human cancers and other disorders.

It is appropriate that one of the inaugural articles in this series, ‘Keratins and disease at a glance’ by Rececca Haines and Birgitte Lane (J. Cell Sci. 125, 3923–3928), focuses on the keratins, members of a family of cytoskeletal proteins – intermediate filaments – that are responsible for over 80 human diseases. Mutations in the genes that encode IF proteins result in a variety of disorders, including diseases associated with blistering and scaling skin, dilated cardiomyopathy and laminopathies, including progeria. Our appreciation of the role of intermediate filaments in disease began in the 1990s when analysis of transgenic mice that carry mutations of keratin 14, and of human patients with devastating epidermal blistering, led to the realization that mutations in basal epidermal keratin genes cause epidermolysis bullosa simplex. In their Cell Science at a Glance article, Haines and Lane detail key cell biological and biochemical observations that provided a foundation for understanding how these mutations cause disease. This has led to the development of therapeutic strategies to treat keratinopathies. For example, small interfering RNAs that abrogate the expression of mutant keratin 6a, thus ameliorating its dominant-negative interference with IF assembly, have been successfully used in a clinical trial in patients suffering from pachyonychia congenita.

Cell biologists have also established parallels between signaling pathways that usually drive tissue remodeling and those that re-emerge in dysregulated fashion during cancer progression, angiogenesis and development of fibrosis. These concepts are underscored in another contribution in this issue by Maria Antsiferova and Sabine Werner (J. Cell Sci. 125, 3929–3937), who discuss the importance of the TGFβ family member activin in normal processes such as wound repair, but show also that its overexpression might be associated with skin and other cancers. Soluble forms of human activin receptors are being developed to treat cancer patients, as these receptors have been shown to stimulate bone formation and interfere with the development of osteolytic lesions in animal models of myeloma and breast cancer.

As in the cases described above, knowledge about normal cell structures and signaling pathways has provided an entrée to creating novel therapeutic approaches for inherited and acquired disease. Cell biologists of today are working at the forefront of translational science. Both mechanistic and preclinical studies have been facilitated by the availability of new animal models and advancements in imaging technology. Intravital imaging techniques afford cell biologists with the tools to observe cell behavior in vivo, for instance migration of tumor cells or cells of the immune system in response to alterations in the microenvironment. Beyond preclinical studies, cell biologists are now working with patients and clinicians to carry out drug trials in which aberrant cell mechanisms are targeted, with the ultimate goal of providing therapies to a greater number of patients.

New genetic tools, including small interfering RNA and DNA antisense oligonucleotides, have advanced to clinical trials in cases to treat, for example, pachyonychia congenital (see above), Duchenne muscular dystrophy and others. Advances in stem cell biology (see Article Series on Stem Cells) hold much promise for patients with spinal cord injuries, amyotrophic lateral sclerosis, Parkinson, macular degeneration and many other diseases. The early discovery of cytoskeletal poisons that interfere with cell-cycle progression (some of which are still commonly used clinically) has evolved into more sophisticated drug screening and design approaches. Small molecular inhibitors of receptor- and non-receptor-tyrosine kinases and their downstream signaling effectors are widely used for treatment of hematologic and solid tumors.

Indeed, the understanding of the underlying mechanism of action of these signaling effectors has allowed physicians to comprehend the molecular basis of how resistance to these drugs is acquired (e.g. acquisition of second-site mutations in tyrosine kinases), facilitating the next round of therapeutic development. It is noteworthy that drugs that pass clinical trials are those where we have a deep understanding of their cell biological targets and mechanism of action. Thus, cell biologists are essential team players in the war on disease – generating the crucial knowledge about how cells function and, partnering with clinical researchers and physicians, converting these findings into treatments.