My Dream of a Fantastic Voyage to See the Inner Workings of a Cell

Abstract

What would I give to be allowed to embark on a Fantastic Voyage at the nanometer scale inside the cell! In the 1960's film, humans were shrunk down to merely micrometer scale, but we now know that “nano” is the ticket. Imagine being able to observe cellular structural biology in real time and to see proteins and nucleic acids in action, in the concentrated environment of the nucleus, let alone in the cytosol. I imagine a complex molecular ballroom full of many intricately choreographed dancers, changing partners, switching locations, dying and being born again. Imagine the purpose and chaos governing the survival of the cellular microcosm, there for me (for you) to see and ultimately understand. Eva Nogales. Photo by Paul Fetters for HHMI. As a structural biologist, initially trained as a physicist, cells often seem too complex and far afield from my own research. My scientific presentations typically borrow images from cell biologists' websites, and I warn my audience after the first introductory slides that no more cells will be seen for the rest of the talk. However, as a molecular electron microscopist working on the cytoskeleton and large macromolecular complexes, I boast in front of crystallographers and nuclear magnetic resonance experts that we study fully functional complexes, in as close to physiological conditions as one can possibly expect outside of a cell. However, this is obviously not as physiological as if we were visualizing the native complexes in their cellular context! With fully annotated genomes providing nearly complete cellular parts lists, and with ever more powerful light microscopy, among other 21st century techniques, we have come a long way toward understanding the inner workings of the cell. Still, the dream of visualizing the intact cell's anatomy with molecular resolution seems like science fiction. Is there any hope for visualizing these molecular machines where they function and when it matters, even if it is not through our atomically shrunk, craving eyes? I really want to think so. It may not come from a single instrument, like the Star Trek scope where magnification can be cranked until the bar code on individual atoms becomes clear. However, combining currently available methodologies and then taking them to the next level may, step by step, get us there. The first combined electron and light microscopes are already producing data wherein the fluorescent colors of choice are superimposed on the gray levels of individual molecular density. Spectroscopy readings, with nanometer cube mapping capability, are being carved out of cellular slices in futuristic attempts at spatial metabolomics. Three-dimensional maps of hydrated cells will soon become routine, and as the resolution moves from 100 to 10 Å in my life time (if I take good care of myself), we will be able to identify macromolecules by shapes, in snapshots of cellular life. We will be able to follow the paths of single proteins as they meander their way along the chaotic cellular freeways of the cytoskeleton, or fluidly traffic between cellular compartments. We are almost there. My own personal dream of “visualizing” the complete kinetochore protein network, carrying out the dynamic engagement of chromosomes to the mitotic spindle and thus revealing the force coupling mechanism, may be just around the corner. It is not that images are worth a thousand gels, or movies a million pulldowns (although perhaps they are), it's just my own preferred means of getting to know and understand nature. My wish for the future of cell biology: I want to “see” the cell (I leave smelling it and listening to it to biochemists and theoretical physicists, respectively).