We look back on some of the key insights into biomedicine published this year.
Development: Sticking to thalidomide
The sedative and morning-sickness drug thalidomide was withdrawn in 1961 after physicians observed that it caused multiple birth defects, including limb, ear, heart and gut malformations. In recent years, the drug has been reintroduced under strict control for different indications, such as cancer. Yet despite nearly half a century of research, many of the molecular targets underlying the developmental defects caused by thalidomide remain unclear.
This March, Japanese scientists identified a protein called cereblon to which thalidomide binds. In zebrafish and chicken embryos, the researchers showed that thalidomide inhibits the ubiquitin ligase activity of a cereblon-containing complex, stunting limb and fin growth (Science 327, 1345–1350, 2010).
Today, thalidomide is used clinically to treat individuals with multiple myeloma and leprosy, so understanding the molecular targets of thalidomide and their roles in limb formation may help produce safer derivatives of this drug. —AF
Immunology: Injury prone
For years, doctors have puzzled over the molecular similarities between how the body’s immune system reacts to both internal tissue trauma and external microbial infections. Now, scientists have chalked up the common inflammatory response to the shared evolutionary origin of mitochondria and bacteria.
Researchers from the Beth Israel Deaconess Medical Center in Boston tested the blood plasma of 15 trauma patients and found circulating components of mitochondrial DNA and proteins known as formyl peptides. Further dissecting the immune response, the researchers showed these components bind to formyl peptide receptor-1 and Toll-like receptor 9 on the surface of immune cells known as neutrophils, promoting their activation and attracting them to the site of injury (Nature 464, 104–108, 2010).
Notably, these same receptors and signaling pathways are also triggered by invading bacteria, leading to a robust inflammatory response resembling sepsis. —KDS
Metabolism: PPARadigm shift
Earlier this year, after drug regulators severely restricted people’s access to the antidiabetic drug rosiglitazone (Avandia), many experts advised against pursuing similar compounds that activate the nuclear receptor peroxisome proliferator and activator of transcription-γ (PPAR-γ) (Nat. Med. 16, 614, 2010). But a new mechanistic link between obesity and diabetes could reignite the research community to develop the next generation of PPAR-γ–targeting drugs. (Click here to continue reading)
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