Basic Stereology for Biologists and NeuroscientistsHow does one determine the size of an organelle? The length of a mass of capillaries? The number of synapses in the brain?

Stereological techniques can be used to estimate the number, length, surface area, and volume of structures in biological cells and tissues. Measurements are made on two-dimensional images or sections of a structure, and then mathematical rules are applied to generate a meaningful description of its three-dimensional geometry. Our newest book, Basic Stereology for Biologists and Neuroscientists, provides a practical guide to designing and critically evaluating stereological studies of the nervous system and other tissues.

“Over the past two decades, a large number of scientific papers have been published that collectively represent a paradigm shift in thinking about how to derive meaningful quantitative data about structural features in biological tissues,” writes the author, Mark West. “These are the design-based, unbiased stereological methods.”

These new stereological methods, the focus of the book, are introduced in “Introduction to Stereology,” a freely accessible article from Cold Spring Harbor Protocols. The book will be essential reading for neurobiologists and cell biologists interested in generating accurate representations of cell and tissue architecture.  For more information, click here.

A newborn’s blood spotted onto a Guthrie card. Photo: The New York State Department of Health Newborn Screening Program.

Over the last 50 years, the spotting of newborn’s blood onto filter paper for disease screening, called Guthrie cards, has become so routine that since 2000, more than 90% of newborns in the United States have had Guthrie cards created.  In a study published online in Genome Research (, researchers have shown that epigenetic information stored on archived Guthrie cards provides a retrospective view of the epigenome at birth, a powerful new application for the card that could help understand disease and predict future health.

DNA methylation, an epigenetic chemical modification of DNA, is known to affect gene activity and play a role in normal development, aging, and also in diseases such as heart disease, diabetes, and cancer.  “But are these epigenetic marks involved in causing the disease, or a result of the disease itself?” asked Dr. Vardhman Rakyan of Queen Mary, University of London and co-senior author of the study.  Rakyan explained that this is impossible to know when samples are obtained after onset of the disease.  Guthrie cards, commonly used to collect blood spots from the pricked heel of newborns to screen for diseases such as phenylketonuria, cystic fibrosis, and sickle cells disorders, might offer a snapshot of the epigenome before disease develops.  Many Guthrie cards are stored indefinitely by health authorities around the world, posing a potential wealth of information about the epigenome at birth.

Rakyan and an international group of colleagues purified genomic DNA and analyzed DNA methylomes from Guthrie cards and verified that this archived DNA yields high-quality methylation data when compared to fresh samples.  The researchers then compared the DNA methylation profiles of newborns to the same healthy individuals at the age of three, looking for epigenetic variations detected in the Guthrie card sample that are stable into the early years of life.

“We found similar epigenetic differences between different people both at birth and when they were three years old,” said Rakyan, who added that these differences, already present at birth, are unlikely due solely to inherent genetic differences between the individuals, but also due to environment or random events in utero.  Furthermore, Guthrie card samples could be analyzed for both genetic and epigenetic differences together to view a more complete picture of the genome at birth.

Guthrie card methylomics is a potentially powerful new application for archived blood spots, which could provide a wealth of information about epigenetics and disease, and could give clues about health later in life.  Dr. David Leslie, co-senior author of the study, added that because national health authorities routinely make Guthrie cards available, and with the proper consent obtained from parents and children, “we are talking about an invaluable, and non-renewable, resource for millions of individuals.”

“The shaking palsy,” as it was first described by James Parkinson in 1817, is a disabling neurodegenerative disorder common among the elderly. Parkinson’s Disease, a new book edited by Serge Przedborski, provides a current review of the disease, from its neuropathological and clinical bases to diagnostic challenges and therapeutic interventions.

The book is “designed specifically to bridge the clinical and basic science aspects of Parkinson’s disease under one cover,” writes Przedborski. It will be useful for neurobiologists, cell biologists, and pathologists pursuing the biological basis of Parkinson’s disease, as well as scientists and clinicians interested in its diagnosis and treatment.

Contributors discuss the mutations in genes encoding proteins such as α-synuclein, parkin, and LRRK2 that cause Parkinson’s disease; the roles of mitochondria, autophagy, protein quality control, and programmed cell death in disease progression; and the chemistry and anatomy of the basal ganglia that are affected. The use of functional neuroimaging and experimental models to probe the neurobiology of Parkinson’s disease are also described. For more information, click here.

From exercise to aging, metabolism plays a central role in normal physiology. Metabolic imbalances contribute to major diseases such as obesity, cancer, and diabetes. Our new volume Metabolism and Disease combines some of the most stimulating work on metabolism and its dysregulation.

The book’s 44 chapters are based on presentations by researchers at last year’s Cold Spring Harbor Symposium on Quantitative Biology. Contributors review the latest advances in our molecular understanding of energy consumption, storage, and homeostasis.  Topics include cell signaling and gene regulation in metabolic control; fat metabolism and its regulation; circadian clocks and aging; apoptosis and autophagy; and cancer.

Articles are also available online at For more information, click here.

Type 1 diabetes affects millions of people worldwide, and has seen a profound increase in the past several decades. Understanding how insulin-producing β cells in the pancreas are destroyed by the body’s immune system is essential for identifying a cure. Our latest book, Type 1 Diabetes, offers a current review of the disease, focusing on key causative and therapeutic areas that drive research in the field.

In 18 chapters, contributors discuss genetic risk factors, environmental triggers, and our current understanding of the autoimmune response underlying the condition.  Treatment strategies, such as immunosuppressive drugs, pancreas and islet transplantation, and the use of stem cells, are described, as are diagnostic markers and tools.

Type 1 Diabetes was edited by Jeffrey Bluestone, Mark Atkinson, and Peter Arvan. “With this effort, we hope to provide a coherent and concise review of the state of the field and, with it, a path forward for researchers,” they write. The book will be useful for immunologists, physiologists, cell and developmental biologists, and geneticists, as well as medical scientists and physicians who are interested in the pathology and treatment of this difficult disease. For more details on the book, click here.

Your genes determine much about you, but environment can have a strong influence on your genes even before birth, with consequences that can last a lifetime.  In a study published online in Genome Research (, researchers have for the first time shown that the environment experienced in the womb defines the newborn epigenetic profile, the chemical modifications to DNA we are born with, that could have implications for disease risk later in life.

Epigenetic tagging of genes by a chemical modification called DNA methylation is known to affect gene activity, playing a role in normal development, aging, and also in diseases such as diabetes, heart disease, and cancer.  Studies conducted in animals have shown that the environment shapes the epigenetic profile across the genome, called the epigenome, particularly in the womb.  An understanding of how the intrauterine environment molds the human epigenome could provide critical information about disease risk to help manage health throughout life.

Twin pairs, both monozygotic (identical) and dizygotic (fraternal), are ideal for epigenetic study because they share the same mother but have their own umbilical cord and amniotic sac, and in the case of identical twins, also share the same genetic make-up.  Previous studies have shown that methylation can vary significantly at a single gene across multiple tissues of identical twins, but it is important to know what the DNA methylation landscape looks like across the genome.

In this report, an international team of researchers has for the first time analyzed genome-scale DNA methylation profiles of umbilical cord tissue, cord blood, and placenta of newborn identical and fraternal twin pairs to estimate how genes, the shared environment that their mother provides and the potentially different intrauterine environments experienced by each twin contribute to the epigenome.  The group found that even in identical twins, there are widespread differences in the epigenetic profile of twins at birth.

“This must be due to events that happened to one twin and not the other,” said Dr. Jeffrey Craig of the Murdoch Childrens Research Institute (MCRI) in Australia and a senior author of the report.  Craig added that although twins share a womb, the influence of specific tissues like the placenta and umbilical cord can be different for each fetus, and likely affects the epigenetic profile.

Interestingly, the team found that methylated genes closely associated with birth weight in their cohort are genes known to play roles in growth, metabolism, and cardiovascular disease, lending further support to a known link between low birth weight and risk for diseases such as diabetes and heart disease.  The authors explained that their findings suggest the unique environmental experiences in the womb may have a more profound effect on epigenetic factors that influence health throughout life than previously thought.

Furthermore, an understanding of the epigenetic profile at birth could be a particularly powerful tool for managing future health.  “This has potential to identify and track disease risk early in life, said Dr. Richard Saffery of the MCRI and a co-senior author of the study, “or even to modify risk through specific environmental or dietary interventions.”

In the mammalian brain, each neuron may receive and extend 10,000 or more synapses, transmitting information that allows an individual to see, move, think, and remember. These structures and how they work are the topic of a new book edited by Morgan Sheng, Bernardo Sabatini, and Thomas Südhof called The Synapse.

“This book tries to capture in a single volume the recent progress and excitement across the breadth of synapse biology,” write the editors. “We have gathered numerous leaders in the study of synapses to write chapters that are both educational and cutting edge.”

Focusing on chemical synapses, the contributors describe the structures of the pre- and post-synaptic regions, trafficking mechanisms that transport vesicles, neurotransmitters and their receptors, and the formation and plasticity of synapses. They also discuss synaptic dysfunction in disorders such as autism and Alzheimer’s disease.

The Synapse will be valuable for neurobiologists, cell and developmental biologists, and anyone wishing to understand how the basic building blocks of the brain are put together and communicate. For more information about the book, click here.

The human gut is home to a teeming ecosystem of microbes that is intimately involved in both human health and disease.  But while the gut microbiota is interacting with our body, they are also under constant attack from viruses.  In a study published online in Genome Research, researchers have analyzed a bacterial immune system, revealing a common set of viruses associated with gut microbiota in global populations.

Viruses that prey on bacteria, called phages, pose a constant threat to the health of bacterial communities.  In many ecological systems, viruses outnumber bacterial cells ten to one.  Given the richness of bacteria in the human gut, it was not surprising that scientists have found that phages are also highly prevalent.  But how can viruses targeting gut microbiota be identified?  How do viral communities differ between people and global populations, and what could this tell us about human health and disease?

In this report, a team of scientists from Israel has taken advantage of information coded in a bacterial immune system to shed new light on these questions.  Bacteria can “steal” small pieces of DNA from phages that attack them, and use these stolen pieces to recognize and respond to the attacker, in a manner similar to usage of antibodies by the human immune system. The stolen DNA pieces are stored in specific places in the bacterial genome called CRISPR loci (clustered regularly interspaced short palindromic repeats).

“In our study we searched for such stolen phage DNA pieces carried by bacteria living in the human gut,” said Rotem Sorek of the Weizmann Institute of Science and senior author of the study.  “We then used these pieces to identify DNA of phages that co-exist with the bacteria in the gut.”

Sorek’s team used this strategy to identify and analyze phages present in the gut microbiota of a cohort of European individuals.  They found that nearly 80% of the phages are shared between two or more individuals.  The team compared their data to samples previously derived from American and Japanese individuals, finding phages from their European data set also present in these geographically distant populations, a surprising result given the diversity of phages seen in other ecological niches.

Sorek explained that their findings mean that there are hundreds of types of viruses that repeatedly infect our gut microbiota.  “These viruses can kill some of our gut bacteria,” said Sorek. “It is therefore likely that these viruses can influence human health.”

The authors note that as evidence for the beneficial roles played by bacteria in the healthy human gut continues to mount, it is critical that we understand the pressures placed upon the “good” bacteria that are vital to human health.  “Our discovery of a large set of phages attacking these good bacteria in our gut opens a window for understanding how they affect human health,” Sorek added.  Researchers can now begin to ask how phage dynamics in the gut changes over time, and what it might tell us about diseases, such as inflammatory bowel disease, and how to more effectively treat them.

A method called high-resolution episcopic microscopy (HREM) produces remarkably detailed images of embryos, allowing one to visualize fine structures such as the whisker pores on the snout of a 14.5-day-old mouse embryo. This month’s issue of Cold Spring Harbor Protocols features a protocol describing the first step in the HREM procedure: embedding embryos in preparation for imaging. It is written by Tim Mohun and Wolfgang Weninger, who developed the HREM technique.

In HREM, embryos are embedded in plastic that contains fluorescent dyes. Sequential images of the block face (i.e., “episcopic” images) are captured before sections are removed from the block with a microtome. This eliminates the need to align images from individual sections; furthermore, there are no distortions due to sectioning, section stretching, or section mounting. A typical HREM volume data set consists of about 1000-4000 block-face images. These images are put together using computer software to create a 3D model of the internal and external structures of the embryo. (more…)

“If you are a scientist, chances are that your self-awareness and interpersonal skills are not as well developed as your technical skills,” write Carl Cohen and Suzanne Cohen. “This limitation can impede your work.” They address this issue in a brand new edition of their book Lab Dynamics: Management and Leadership Skills for Scientists.

Cohen and Cohen offer practical advice on communication, self-awareness, relationships, motivation, negotiation, and mood management, and describe effective ways to interact with others. “We provide concepts, concrete tools, and exercises that will help you improve these skills,” they write. “Our approach is designed to aid you in overcoming the barriers to knowing yourself, what to do, and how to do it.”

This new edition of Lab Dynamics has been completely revised and includes new chapters. It will be of interest to all scientists and technical professionals, postdocs, and graduate students seeking career satisfaction and success. For more information on the book, click here.