CELL BIOLOGY

Editor(s): Nick Bisceglia |

The starting point for this discipline might be considered the 1830s. Though scientists had been using microscopes for centuries, they were
not always sure what they were looking at. Robert Hooke's initial observation in 1665 of plant-cell walls in slices of cork was followed shortly
by Antonie van Leeuwenhoek's first descriptions of live cells with visibly moving parts. In the 1830s two scientists who were colleagues —
Schleiden, looking at plant cells, and Schwann, looking first at animal cells — provided the first clearly stated definition of the cell. Their
definition stated that that all living creatures, both simple and complex, are made out of one or more cells, and the cell is the structural and
functional unit of life — a concept that became known as cell theory.

As microscopes and staining techniques improved over the nineteenth and twentieth centuries, scientists were able to see more and more
internal detail within cells. The microscopes used by van Leeuwenhoek probably magnified specimens a few hundredfold. Today high-
powered electron microscopes can magnify specimens more than a million times and can reveal the shapes of organelles at the scale of a
micrometer and below. With confocal microscopy a series of images can be combined, allowing researchers to generate detailed three-
dimensional representations of cells. These improved imaging techniques have helped us better understand the wonderful complexity of
cells and the structures they form.

There are several main subfields within cell biology. One is the study of cell energy and the biochemical mechanisms that support cell
metabolism. As cells are machines unto themselves, the focus on cell energy overlaps with the pursuit of questions of how energy first
arose in original primordial cells, billions of years ago. Another subfield of cell biology concerns the genetics of the cell and its tight
interconnection with the proteins controlling the release of genetic information from the nucleus to the cell cytoplasm. Yet another subfield
focuses on the structure of cell components, known as subcellular compartments. Cutting across many biological disciplines is the
additional subfield of cell biology, concerned with cell communication and signaling, concentrating on the messages that cells give to and
receive from other cells and themselves. And finally, there is the subfield primarily concerned with the cell cycle, the rotation of phases
beginning and ending with cell division and focused on different periods of growth and DNA replication. Many cell biologists dwell at the
intersection of two or more of these subfields as our ability to analyze cells in more complex ways expands.

In line with continually increasing interdisciplinary study, the recent emergence of systems biology has affected many biological disciplines;
it is a methodology that encourages the analysis of living systems within the context of other systems. In the field of cell biology, systems
biology has enabled the asking and answering of more complex questions, such as the interrelationships of gene regulatory networks,
evolutionary relationships between genomes, and the interactions between intracellular signaling networks. Ultimately, the broader a lens
we take on our discoveries in cell biology, the more likely we can decipher the complexities of all living systems, large and small.
Image courtesy of Aurora M. Nedelcu.
Through a cell biology lens, the study of gene expression is tightly linked to our understanding of proteins. Since the early work
of Christian Anfinsen in the 1950s, we know that the sequence of amino acids in a protein determines its final three-dimensional
structure. Following from that, scientists have repeatedly observed that protein structure dictates where it will act and what it will do.
Nowhere has this been more obvious than with the function of enzymes. The shape and structure of proteins is a crucial aspect of gene
expression biology and links our understanding of gene expression to the biology of the cell. While primarily concerned with protein
molecules that act on DNA and RNA sequences, such as transcription factors and histones, the study of gene expression also focuses
on where in the cell expression is modulated. In fact, the modulation of gene expression can occur in the nucleus, the cytoplasm, or even
at the cell membrane due to the impact of proteins on RNA in those cellular subregions.

How do scientists study protein shape and function? A technique called mass spectrometry permits scientists to sequence the amino
acids in a protein. After a sequence is known, comparing its amino acid sequence with databases allows scientists to discover if there
are related proteins whose function is already known. Often similar amino acid sequences will have similar functions within a cell. The
amino acid sequence also allows scientists to predict the charge of the molecule, its size, and its probable three-dimensional structure.
The charge and size can later be confirmed experimentally (via SDS-PAGE and double-dimension gels). To deduce the intricacies of
three-dimensional structure, scientists will try to crystallize the protein to confirm its molecular structure through X-ray crystallography
and/or nuclear magnetic resonance spectroscopy (pNMR).

How do scientists study the impact of proteins on genes or other proteins? A good way to study the function of the protein is to see what
happens in the cell when the protein is not present. For this scientists use model systems, such as cell culture or whole organisms,
wherein they can test the function of specific proteins or genes by modifying or mutating them. The expression level of a gene can be
calculated by measuring the transcribed mRNA (northern blot), the expressed protein (Western Blot), or by directly staining the protein or
mRNA when it is still in the cell. New techniques have changed the way we study gene expression — DNA microarrays, serial analysis of
gene expression (SAGE), and high-throughput sequencing allow larger screens of multiple molecules simultaneously and have opened
up the possibility of new and broader kinds of questions. To analyze large datasets and see how networks of molecules interact, a new
discipline called systems biology provides the framework for these larger and more integrated understandings of regulatory networks.

Interestingly, proteins are not the only gene regulators. Regulatory molecules come in the form of RNA and act on other nucleic acids by
changing or disrupting them. One example is the family of riboswitches, ribonucleic acid molecules that form three-dimensional
structures that halt or interfere with transcription, given the proper external signal. Another example of RNA acting on other RNA is the
mechanism of RNA interference (RNAi), whereby double-stranded RNA molecules degrade mRNA before translation, thus effectively
interfering with protein expression. The dissection of this mechanism and its subsequent experimental imitation has been a boon to those
interested in manipulating gene function.

Ultimately, results from these kinds of studies have fundamental relevance, from the basic understanding of normal cell function, such as
cell differentiation, growth, and division, to informing radically new approaches for treating disease. In fact, some human diseases can
arise simply from a defect in a protein's three-dimensional structure. Through the study of gene expression and proteins, it is easy to see
how minute changes at the molecular level have a reverberating impact.
Image: Biochemical Algorithms Library.

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