A Slick Solution to a Sticky Problem.

Samir Gautam,†,‡ Lokesh Sharma,† Charles S. Dela Cruz,† and David Adam Spiegel*,‡ †Internal Medicine, Section of Pulmonary and Critical Care, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, United States ‡Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06520, United States A Viewpoint for Biochemistry on the article in Cell, “Immunomimetic Designer Cells Protect Mice from MRSA Infection” In his 2002 essay entitled “Can a biologist fix a radio?Or, what I learned while studying apoptosis”, Yuri Lazebnik chides the biology community for its over-reliance on reductionistic experimental techniques such as genetic deletion to describe complex systems. He humorously illustrates his argument by describing how a biologist might attempt to fix a radio, including the obligatory annihilation of each electrical component “at close range with metal particles” to determine its function, an approach analogous to the murine knockout experiments upon which biologists so depend. In contrast, he submits that an engineer would solve the problem handily based on a facility with standardized technical language (electrical diagramming) that fully and unambiguously describes the mechanical device. The rub, of course, is that radios are built by engineers in the first place; cells, much less animals, are not. Indeed, a principle advantage engineers hold over biologists in terms of “handiness” derives from a hundred years of research into the fundamental principles of electromagnetism and another hundred in refining the practice of electrical engineering, which allows them to create electrical devices according to a standardized methodology. A similar position of privilege is enjoyed by modern organic chemists, who have likewise spent centuries designing and synthesizing a huge array of small molecules and natural products, including the chemical therapeutics that serve as the backbone of modern medicine, to establish a robust fundamental and technical appreciation for how molecules behave. Accordingly, it might be stated that the true understanding of a system, as achieved in areas of physics and chemistry, is indicated by the ability to construct one. In recent years, biologists have made strides toward this lofty goal as they have endeavored to create cells, either from scratch in the case of synthetic biology or by modifying existing cells for therapeutic ends. A particularly successful example of the latter comes from immuno-oncologists, who have genetically engineered T-cells to express specific sensors for cancer antigens called chimeric antigen receptors (CARs). Ligation of these receptors elicits robust effector responses (cytokine release by CD4+ cells and direct cytotoxicity by CD8+ cells), leading to the elimination of targeted tumor cells (Figure 1). The clinical success of CAR T-cells in the treatment of advanced hematologic malignancies is unprecedented; for instance, anti-CD19 CAR-T therapy induces complete remission in ∼90% of patients with chemo-resistant B cell leukemias, in whom life expectancy would otherwise be months. Now, Liu et al. apply this engineering principle to develop a novel therapeutic for infectious disease. They target methicillin-resistant Staphylococcus aureus (MRSA), a Grampositive bacterium that is responsible for more deaths in the United States than any other bacterial pathogen, and can infect virtually any tissue, including blood, lung, and skin. A particularly feared form of MRSA infection is establishment of biofilms on implanted hardware, such as prosthetic joints or heart valves, which almost invariably necessitates surgical removal of the foreign material due to resistance of the associated biofilms to antibiotics. To tackle this problem, Liu et al. construct an elegant genetic network consisting of three principal components (Figure 1): (i) a sensing mechanism for constituents of the S. aureus cell wall, namely, lipoproteins and wall teichoic acids, which are detected via the cell-surface pathogen recognition receptors TLR1, TLR2, and TLR6, along with the co-receptor CD14; (ii) a highly optimized signal transduction module based on the immune transcription factors NFκB and AP-1 and the promoter for interferon-β; and (iii) a response element leading to expression of proteins that function as either diagnostics (secreted alkaline phosphatase) or therapeutics