Nanodomains and Super‑Resolution Microscopy in Heart Disease

Our bodies are composed of approximately 30 trillion cells, each working in harmony to perform essential functions for survival. This intricate cellular communication is crucial for everything from muscle contraction to thought processes. Dr. Izzy Jinger, Head of the Department of Molecular Medicine at UNSW, discusses her research into cell signaling in heart disease and the technological advancements that allow scientists to study these processes at a microscopic level.

The Importance of Cell Signaling and Calcium Ions

Cell signaling is fundamental to life, enabling cells to communicate within themselves and with each other. This communication dictates the identity and function of different cells, organs, and tissues. While some communication, like electrical pulses between cells, is rapid, intracellular communication is more subtle and targeted.

Calcium ions (Ca²⁺) are vital messengers in this intracellular signaling. Due to their compact, atomic size, calcium ions can move rapidly, facilitating quick responses such as heartbeat and muscle contraction.

Nanodomains: Cellular Communication Hubs

Dr. Jinger's research focuses on "nanodomains," which are specialized regions on the cell membrane where proteins involved in cell signaling congregate. These nanodomains act as communication hubs, aggregating proteins that interact to pass, block, or amplify signals. They are named for their small size, typically hundreds of nanometers, and their clearly defined nature as areas dominated by signaling and modulatory proteins.

Nanodomains are present in most cells that utilize calcium signaling, particularly in muscle cells (cardiac and skeletal) and neuronal cells, where they are densely packed. A single heart cell, for instance, can contain between 30,000 and 100,000 nanodomains.

Nanodomains in Heart Disease

The role of nanodomains in heart function has been recognized since the 1950s, though visualization was challenging until recently. Around the turn of the millennium, nanodomains became a focus in heart disease research due to observed structural changes. A key question arose: are these changes a cause or a consequence of the disease? While the exact relationship is still being investigated, it's clear that structural alterations in nanodomains negatively impact cell function. Therefore, reversing or recovering these changes is a significant area of interest.

Targeting individual proteins in chronic diseases like heart failure is complex and often insufficient for a cure. However, understanding the mechanisms driving nanodomain changes can improve disease management and quality of life. While drugs targeting these mechanisms exist, their clinical application is still under development.

Super-Resolution Microscopy and Expansion Microscopy

Dr. Jinger specializes in super-resolution microscopy, a technology that has revolutionized the study of cellular processes. Unlike traditional microscopes, super-resolution microscopes are not defined by a specific shape but by the concept of achieving higher resolution. This technology allows scientists to visualize individual proteins and biomolecules in their native cellular environment, observing their placement and interactions with neighbors—a level of detail previously unattainable even with electron microscopy.

The images produced by super-resolution microscopy are not just pictures; they are digital maps encoding information about protein function. This allows for quantitative analysis, such as counting proteins, comparing their locations, and observing their behavior, which serves as a benchmark for drug testing and monitoring disease progression.

Another innovative technique used in Dr. Jinger's lab is expansion microscopy. This method addresses the limitation of visualizing structures too small for even super-resolution microscopes by physically enlarging the sample. It involves creating a 3D imprint of the cellular structure onto a water-absorbing gel, which then expands, making the nanodomains visible. This technique, developed about eight years ago, has advanced significantly, allowing samples to inflate thousands of times, effectively overcoming the limitations of optical microscopy by relying on chemical processes.

These methods are broadly applicable, extending beyond cardiac health to plant cells, human tissues, whole organisms (like worms and flies), and even individual proteins. The challenge now is to disseminate these techniques throughout the scientific community, encouraging adoption despite traditional practices.

Science in Extreme Conditions and Advocacy for Diversity

Dr. Jinger's research also has implications for sports science, particularly in understanding how the heart and muscles function under extreme conditions, such as those experienced by athletes in high heat. This research provides a backdrop for understanding human physiology in various states, from disease to normal performance and even enhanced performance through pharmacological means.

Beyond her research, Dr. Jinger is a strong advocate for equality in STEM, particularly for the LGBTQ+ community. Her motivation stems from two core beliefs: 1. Duty of Care: STEM workplaces, like any other, have a responsibility to care for all colleagues, regardless of background. Research indicates that LGBTQ+ individuals often face disproportionate negative experiences in these environments. 2. Scientific Advancement: Science benefits society, including the LGBTQ+ community. Ensuring representation within the scientific community is crucial, as diverse perspectives and life experiences foster creativity and progress in research.

Dr. Jinger highlights that a diverse workplace leads to better progress, especially in academic scientific research, which is a creative process. Protecting this diversity is essential.

Resources for LGBTQ+ in STEM

For those interested in supporting or engaging with LGBTQ+ inclusion in STEM, Dr. Jinger recommends several resources:

• Organizational Networks: Most large organizations have LGBTQ+ networks that provide safe spaces and representation.
• UK-based Societies:
  • Pride in STEM
  • LGBTQ+ STEM
  • oSTEM (a global network)
• Events: The LGBTQ+ STEMinar is an annual conference for LGBTQ+ scientists, technologists, and engineers to present their work in a supportive environment.
• Ally Resources: The Royal Society of Chemistry has developed a toolkit on creating inclusive workspaces for LGBTQ+ individuals.

"Invisible Rainbows" and Pride in STEM

Dr. Alfredo Carpini, an astrophysicist, science journalist, and social activist, discusses his new book, "Invisible Rainbows," which explores the relationship between astronomy and human perception, focusing on light beyond our visible spectrum. The book delves into how technologies allow us to "see" the universe through infrared, radio waves, and other wavelengths, revealing phenomena like the methane rivers on Saturn's moon Titan and the mysterious radio emissions from pulsars.

Carpini is also the founder of Pride in STEM, a UK-based charity celebrating its 10th anniversary. Pride in STEM began as an informal group for LGBTQ+ scientists to connect and march in Pride events. It quickly became clear that there was a significant need for a formal organization to provide resources, advice, and a network for queer individuals in STEM. The charity has contributed to parliamentary guidance on improving STEM retention and was pivotal in establishing the International Day of LGBTQI+ People in STEM (November 18th). Pride in STEM continues to host events and conferences, showcasing the contributions of LGBTQ+ scientists and fostering a supportive community.