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In the past two decades, single-molecule experiments have evolved from being state-of-the-art prof-of-principle demonstrations to nearly routine tools of modern biophysics, enabling one, for example, to monitor molecular processes directly as they unfold in the cell. Yet because of the relative sluggishness of the common probes, deciphering single-molecule signals to infer molecular dynamics remains an elusive goal. In this talk I will report on recent joint efforts of my group with experimentalists toward this goal using the example of one of the most fundamental problems in biophysics, protein folding. I will discuss how intrinsic protein motion can be deduced from random photon sequences in single-molecule fluorescence resonance energy transfer experiments or from the movement of micrometer-sized force probes in single-molecule pulling studies. I will further describe some of the new lessons about protein folding and dynamics learned from such studies.

Professor Bradley is internationally recognized as a pioneer in developing the techniques, technology and tools for genetic manipulation in the mouse over more than 3 decades. He served as Director of the Welcome Trust Sanger Institute from 2000 to 2010. He was honored by election to the fellowship of the Royal Society in 2002. Among many projects that Dr. Bradley has established and led, is the international project to systematically knockout all genes in the mouse genome, the most ambitious use of ES-cell technology ever attempted. Over the last 30 years, Dr. Bradley has authored more than 280 publications. In his lecture, Dr. Bradley will be describing the scientific history and the technology behind the creation of the Kymouse strains which are transgenic for the total human immunoglobulin gene diversity. The platform provides a valuable means to isolate therapeutic monoclonal antibodies. Kymab has also developed single B cell-based methods to capture both the heavy and light chains of antibodies at scale. Combined with deep sequencing of millions of B cells we are able to build networks of histories of B cell families which we use to isolate rare antibodies with unique properties. The combined use of Kymouse with B cell network analysis, facilitates vaccine antigen discovery and predictive pre-clinical assessment of candidate vaccine antigens prior to clinical trials in humans.

Interest in RNA dysfunction in ALS recently aroused upon discovering causative mutations in RNA-binding protein genes. Focusing on the causes and consequences of miRNA dysregulation in amyotrophic lateral sclerosis (ALS) we will understand how advances in sequencing and molecular technologies enable deciphering the contribution of noncoding RNAs to Neurodegeneration. In the past, we identified extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrated that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. These works position miRNAs downstream of the initiating mutations that drive ALS and encourage testing what are the specific miRNAs that play roles in motor neurons and whether mutations in miRNA genes will be able to causatively initiate the disease.

We observe spontaneous Hawking radiation, stimulated by quantum vacuum fluctuations, emanating from an analogue black hole in an atomic Bose-Einstein condensate. The Hawking radiation is observed via the correlations between the Hawking radiation exiting the black hole and the partner particles falling into the black hole. The quantum nature of the Hawking radiation is observed through entanglement, by comparing the Fourier transform of the corre-lations to a measurement of the population. This comparison shows that the experiment is well within the quantum regime, since the measured Hawking temperature determined from the population distribution is far below the upper limit for quantum entanglement. A broad energy spectrum of entangled Hawking pairs are observed. Maximal entanglement is ob-served for the high energy part of the Hawking spectrum, while the lowest energies are not entangled. Thermal behavior is seen at very low energies where the finite extent of the corre-lation function implies frequency dependence. Thermal behavior is also seen at high energies through the agreement of the correlation spectrum with the appropriate function of the Planck distribution. Further insight is obtained by a preliminary experiment in which the horizon is caused to oscillate at a fixed frequency, which stimulates waves travelling into and out of the black hole. The rate of particle production by the oscillating horizon is consistent with the measured Hawking temperature. Furthermore, the observed ratio of the phase velocities of the Hawking and partner particles are consistent with this preliminary ex-periment, as is the width of the Hawking/partner correlation feature. Additional confirmation of the results is obtained through a numerical simulation, which demonstrates that the Hawk-ing radiation occurs in an approximately stationary background. It also confirms the width of the Hawking/partner correlation feature. The measurement reported here verifies Hawking’s calculation, which is viewed as a milestone in the quest for quantum gravity. The observation of Hawking radiation and its entanglement verifies important elements in the discussion of information loss in a real black hole.