2018 Everhart Lecture Series
"Engineering Ultrasound Sensors with Lego-Like Proteins"
Fundamental biological events inside living organisms occur in deep tissues, the visualization of which is crucial to our understanding of the processes underlying health and disease. Today's most advanced tools for observing cellular and molecular processes are based on optical imaging. However, light has limited reach into deep tissues and larger animals due to absorption and photon scattering. On the other hand, clinical modalities for non-invasive imaging of internal tissues and organs, such as ultrasound, have limited capacity for real-time monitoring of molecular and cellular processes due to the lack of appropriate imaging agents. This problem could be solved by developing ultrasound sensors - molecules that 'light up' in ultrasound imaging in response to specific cellular activity. In this talk, I will discuss how we have engineered proteins called 'Gas Vesicles' or 'GVs' to accomplish this task.
Gas Vesicles ― hollow protein-shelled nanostructures produced by buoyant microbes, have emerged as a new class of imaging agents for ultrasound. GVs scatter acoustic waves to produce robust ultrasound contrast. GVs are naturally occurring proteins that can be encoded within an organism's DNA, providing a unique genetic engineering platform for tuning their mechanical, acoustic and surface properties. We have harnessed this potential to create a versatile molecular engineering toolkit for ultrasound imaging, by treating the two main constituent proteins of GVs as 'molecular Legos'. This molecular Lego platform contains an inner structural protein that forms the backbone of the GV shell and a modifiable outer protein that is attached on the surface of the GV backbone. The outer Lego piece can be removed and modified without compromising the structural integrity of the inner backbone, and these modifications can be used to give GVs new functionalities for diagnostic or therapeutic applications.
The molecular Lego platform enables us to produce GVs that give enhanced signals for non-invasive imaging deep inside live organisms, target specific cell types such as cancer and immune cells, as well as create multi-color ultrasound images. We have extended this platform to engineer GV-based ultrasound sensors, whose acoustic signals change dynamically in response to the activity of specific molecules in their environment. In addition, we have recently succeeded in transferring the genetic code of gas vesicles from their species of origin into a variety of other microbes that do not naturally produce these agents, moving closer towards unlocking their full potential as ultrasound sensors. These molecular sensors present the next generation of acoustic imaging agents that show promise for improving and extending the capabilities of biomedical ultrasound, paving the way for improved diagnosis, monitoring and treatment of diseases.