Ratnesh Lal

The Lal lab’s research centers around atomic force microscopy (AFM), including technology development and application to the study of ion channel function and protein folding. In AFM, the surface of a specimen is scanned using a nanoscale probe, allowing imaging, force measurement, and manipulation of matter. Given AFM’s diverse uses, the Lal group aims to make the method more easily and widely used across biology.

AFM analysis of cell uptake of liposome
AFM allows analysis of cellular internalization of drug delivery vehicles. Tapping mode AFM (c–f) images of cells after incubating with liposomes. Height mode images (c, e) and error mode images (d, f) of the same cells. Red arrows, large liposomes; black arrows, internalized liposomes. From Ramachandran et al., Langmuir 2006.

Much of the basic science investigations in the Lal lab, in collaboration with Ruth Nussinov’s group at the National Cancer Institute and Tel Aviv University, have examined the contribution of β-amyloid channels to Alzheimer’s and other neurological diseases. These investigations build on their discovery (using AFM) that non-plaque-forming amyloid peptides form channels, leading to the hypothesis that neurodegeneration may result from excess calcium uptake through these channels. Current work examines their structure and mechanism of membrane insertion. The Lal group has also employed AFM to study a neurodegeneration-associated variant of superoxide dismutase 1 (SOD1), and connexin40, a channel that composes gap junctions between cells in the heart, among other proteins and cellular processes.

A recent key advance in the Lal group’s work towards making AFM more widely useful is their introduction of a system for total internal reflection fluorescence (TIRF) microscopy that could be combined with AFM. As AFM detects shapes and forces, it does not allow straightforward identification of specific proteins; combination with TIRF would overcome this limitation. The Lal lab’s system is unique in its lack of requirement for special objectives or prisms, making it easy to combine with other imaging modalities. Previous innovations include the application of AFM to study regulation of cell volume, combined AFM and ionic conductance measurement, and an integrated multiple patch-clamp array chip for high-throughput analysis of ion channel activity.

Affiliations

Key publications

Meckes B, Arce FT, Connelly LS, Lal R. Insulated cantilevered nanotips and two-chamber recording system for high resolution ion sensing AFM. Sci Rep 2014;4:4454.

Ramachandran S, Cohen DA, Quist, AP, Lal R. High performance, LED powered, waveguide based total internal reflection microscopy. Sci Rep 2013;

Jang H, Arce FT, Ramachandran S, Capone R, Azimova R, Kagan BL, Nussinov R, Lal R. Truncated β-amyloid
peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome. Proc Natl Acad Sci USA 2010; 107(14): 6538–43.