ReExamining Lab Rotations - What should this graduate training experience be about?

One of the first steps in graduate school is to figure out what you want to study and in which lab you want to do your research.  Lab rotations typically involve working in ~3 different labs for 1-2 months each.  The experience provides students an opportunity to shop around a little and the PIs get some insight into which students might fit best in with their group.  Fundamentally, this is a reasonable idea.  In practice however, it is a bit of muddled scramble.  In my time as a postdoc at Harvard, I saw lots and lots of rotation students come through.  The time they spend in the lab is short and they are not yet trained, so their projects are simple and they really cannot see anything through to completion.  The simple projects they tend to get are sometimes tedious and repetitive.  While this is the nature of experimentation, as a first experience, it fails to engage the imagination.  What can be done to improve the rotation experience?

One perspective is to accept that short rotations generally fail to generate useful data and let go of the idea of trying to get a big result or start a thesis project.  Instead, the PI might select a few specific observational experiments that have no point other than to engage the imagination and generate questions and ideas.  

In the Gregg Lab, for example, a rotation experience would ideally expose an individual to major questions and ideas related to: (1) gene expression and bioinformatics, (2) feeding circuits, (3) early life programming, and, (4) feeding and foraging behaviors.    For a four week rotation, each week would be committed to one of these four topics.  A student would carry out an experiment that is short term and very likely to work, and most importantly, leads to lots of opportunity for observation and thought.  To guide the thinking and discovery process, I have taken some ideas from Tim Hurson's useful book, 'Think Better', and generated a simple outline that provides rotation students with a framework to conceptually explore the potential of their data (see Project Planner).  The key is to push yourself to think deeply about what you are observing.  The first round of ideas that come to you will likely be ones that others have considered, but by the time you push yourself to a third round of ideas you may be starting to come up with original material.  

Consider that a simple immunohistochemical stain of neural circuitry in the brain can illuminate a million questions and ideas.  A simple study of animal behavior can force one to reflect on all of the problems the brain must solve to carry out a task and wonder what behaviors the animal is capable of.  A brief bioinformatic study of gene interactions and expression patterns raises numerous questions about how everything works.  The point of the rotation experience is to engage your mind and find a topic that is exciting and important to you and demonstrate to the PI that you are an independent thinker!

Information for Moms

Stephanie Watson at WebMD has written a nice article for a general audience that addresses some of the basic issues related to maternal health and the long-term health of children - "Blame Your Health on Mom?  Not so fast".  In short, an individual's risk for disease can be programmed very early in life.  This is currently some of the most important work in medical research.  We need to greatly improve our understanding of which aspects health and disease risk are programmed early on and how.  Importantly, we also need to find ways to apply what we are learning about early life programming.

Career Resource - PhD to Management

As much as I can, I will post helpful links for career planning for trainees.  While there is a lot of vague crap written about transitioning into industry from academic science, there are a few gems.  The future of PhD education is clearly to train people as innovators who can compete in a wide variety of potential fields.  For several years this has been clear to those of us coming through the current PhD and postdoc system, however the academic community in general is trying to catch up (see the April 21st issue of Nature).  My own view is that this is a fantastic opportunity to reinvent PhD training and that it will start at the grassroots.  A modern PhD should encompass: (1) A major scientific contribution that establishes the creditability of the candidate at an international level; (2)  Successful development and management of a highly innovative project; (3) Development of outstanding communication skills; (4) Development of exceptional data analysis skills; and (5) Development of collaboration and team work skills.  This combination could prepare talented individuals for leadership roles in a wide variety of fields.

A new program at the Keck Institute looks like a good bet for PhDs trained in the sciences who want to use their graduate training to make a major move into management.  Here are some resources to help one start to learn about this avenue:

Science Careers Article

Keck Institute

Keck Institute Postdoctoral Professional Masters

Conceptual Innovators - Good Reading!

When breaking into neuroscience and genomics, it is the concepts that are so important to get hold of.  Conceptual innovation is a primary goal of basic biology.  Technical innovation is often just a necessary step on the road to uncovering important new concepts.  So which labs are the most conceptually innovative, with particular regard to thinking about gene-behavior problems?  

Here are some of my favorites for reading (in no particular order):

1.  Eve Marder - Eve Marder uses the lobster as a model organism.  Her work takes advantage of the simplicity of this model to understand how underlying molecular programs relate to the physiological properties of neurons and maintain neuronal homeostasis.

2.  Cornelia Bargmann - Dr. Bargmann uses C. Elegans as a model to understand the link between gene expression/evolution, neural circuit function/organization and behavior.  Her work has extracted several general principles that are influential for understanding the genetic pathways that influence behavioral modifications as species diverge.  In particular, she notes that sensory system are the most rapidly evolving systems in the genome to allow species to adapt to new environments and suggests a central role for neuromodulators in the evolution of novel behaviors.

3.  Eric Lander - Eric Lander leads the Broad Institute and his work is uncovering the nature of the genome.  Many groups are doing important work in this area and other suggestions for reading include John Rinn, Joseph F Costello, Brad Cairns, David Bartel...

4.  Edward Callaway - Understanding neuronal circuit organization is fundamental to understanding the brain.  Many groups have tried to develop effective tools for circuit mapping in the brain.  The Callaway lab has developed the best system that is currently available and they are uncovering important general principles of circuit organization using this rabies virus based system.  Other groups to read in this area include Larry Swanson, Clay Reid, Lynn Enquist, Sydney Brenner.

5.  TJ Sejnowski - A fundamental challenge in neurobiology is to understand how the brain computes information.  Theoretical models are often integrated with experimental data in computational neuroscience to gain insights. The Sejnowski lab is a pioneering lab attempting to understand computational problems in the brain at multiple levels (synapse to system).

6.  Tom Jessell - Developmental neurobiology is a fantastic field that works to explain how an incredibly complex and functional nervous system emerges during embryonic development.  The Jessell lab and former postdocs of the Jessell lab have made some the most significant contributions to this problem.  The work indicates the gradients of signaling molecules establish transcription factor codes that govern cell fate decisions and connectivity in the nervous system.  Publications from this lab are also excellent educational examples of how to write a paper and carry out a project.  Related reading includes publications from Marc Tessier-Lavigne, Dennis O'Leary, Gord Fishell, Andrew Lumsden.

7.  Charles Zucker - Sensory systems neuroscience is one of my favorite areas and many great scientists have impacted this area.  However, my favorite is the Zucker lab, which continues to publish fantastic insights that address fundamental concepts associated with sensory processing, particularly related to taste.  Other groups for reading include Richard Axel, David Julius, David Corey.

8.  Conrad Waddington - An evolutionary biologist whom introduced the important and influential concept of canalization.  Of the many great evolutionary theories that have been contributed, canalization seems particularly important when beginning to consider the organization of molecular pathways and epigenetic regulatory processes.

9.  David W. Stephens - Dr. Stephens is a leading thinker in foraging theory and the ecology of foraging behavior.  He has authored two very influential books.  The concepts that emerge from this field are highly influential for thinking about numerous problems in neuroscience, ranging from decision making and social behavior to motivated behavior, innate drive and the maintenance of homeostasis.

10.  Stephen Hyman - if you want to begin to understand neurological and psychiatric diseases, start by reading Stephen Hyman's papers and thoughts.

11.  Leroy Hood - The father of systems biology.  Dr. Hood is leading a revolution that seeks to integrate high throughput technologies with mathematical modeling to gain a systems level understand of cell function, disease biology, and numerous other biological processes. 

12.  Joe Nadeau - Joe Nadeau's work has been challenging our understanding of  disease and trait inheritence in mice and in humans.  His work is revealing startling transgenerational effects and epistatic interactions that influence complex phenotypes in offspring.  He has argued that we should focus on understanding pathways that modify disease rather than simply uncovering disease causing genetic muations.  

13.  David Barker -  The pioneering physician who uncovered the link between early life environmental effects and increased disease risks in later life.  This is one of the most reproducible and important epidemilogical finds of the past several decades.  It has fundamentally changed how we view disease risk - the path to disease begins early in life.

14.  Eric Charnov - One of the most influential minds in evolutionary biology and economic theory.  Dr. Charnov is best known for developing the Marginal Value Theorem of optimal foraging behavior (1976, Theor Popul Biol), but he has made numerous conceptual contributions to evolutionary biology, foraging theory and economics.  His work is a must read for people interested in such things.

The Genome's Dark Matter

Here is a link to an entertaining and thought provoking article about transgenerational effects published by MIT tech review:

The article does a nice job of describing some of the troubles with modern genetics and potential alternative explanations:

The Genome's Dark Matter

Thanks for the Histones, Mom!

Several papers have emerged over the last year or so indicating transgenerational effects that influence the behavior and/or physiology of offspring. For example, a recent study in Nature from Margaret Morris's group at the University of New South Wales proposes that obese father's transmit an epigenetic signature through the germ line to female offspring, resulting in impaired beta cell function, impaired insulin secretion and glucose intolerance (Ng et al. Nature 2010). Other recent studies have found similar evidence for paternal inheritance of non-genetic information (for example, see Pentinat et al. Endocrinology 2010; Nelson et al. Epigenomics 2010). However, an outstanding issue relates to the identity of the underlying molecular mechanisms that are involved in these effects. In this blog entry, I highlight some emerging pathways that might potentially contribute to epigenetic inheritance through the germ line.

Two major studies have characterized modified histones in human and mouse sperm (Hammoud et al. Nature 2009; Brykczynska et al. Nat Struc Mol Biol 2010). Previously, it was thought that modified histones were unlikely to be a major component of the highly compact chromatin contained in sperm. However, these two studies indicate that approximately 30% of human promoters contain modified histones. Further, many of these epigenetic signatures are conserved between humans and mice. It has been postulated that these histone signatures are retained in the zygote and play an important role at early stages of development in offspring. However, direct evidence for this model is not yet strong. Interestingly, two noteworthy studies in C. elegans suggest that modified histones established in the parental germ cells transmit essential information to offspring through the germ line (Furuhashi et al. Epigenetics 2010; Rechtsteiner et al. PLoS Genetics 2010).

Both of these studies pickup on an older study by Susan Strome's group, in which she found 6 loci, including the H3K36 methyltransferase MES–4 [an NSD homolog], that are required for normal germ cell development in offspring (Capowski et al. Genetics 1991). Null MES-4 mutant offspring undergo normal germ cell development when MES–4 is expressed by the mother, but not if the mother is homozygous. Thus, a transgenerational maternal effect occurs. In the two most recent studies, it was found that MES–4 establishes H3K36 trimethylated histone marks independent of transcription, and this maternally established epigenetic signature is required for normal germ cell development in offspring. The authors propose that MES–4 transmits a memory of gene expression in the parental germline to offspring.

Taken together, these early observations suggest that epigenetic signatures in the form of modified histones in eggs and/or sperm might impact upon gene expression and the development and physiology of offspring.

Eppendorf & Science Prize for Neurobiology

Thank you to everyone sending congratulatory messages regarding the Eppendorf & Science Prize.  A link to my essay is provided here:

Parental Control Over the Brain

This work is the result a major collaborative effort.  Jiangwen Zhang at Harvard FAS Computing played a central role in the development of the informatics pipeline.  While next generation sequencing data analysis is becoming more mainstream, there was absolutely nothing to help in early 2007 (beyond Eland and a few other aligners) when we started and Jiangwen's work was essential to getting it up and running.  David Haig at Harvard played a vital role in the development of the statistical analysis and data interpretation.  Gary Schroth and Shujun Luo at Illumina kindly collaborated by sharing their early versions of an RNA-Seq protocol and by carrying out some pilot sequencing studies for us to determine if the approach would succeed (yes, the initiation of the study predated publication of RNA-Seq).  Jim Butler worked on the qPCR analysis of Il18 heterozygous mice.  The entire study was carried out under the guidance and mentorship of Catherine Dulac in her lab in the Molecular and Cellular Biology Department at Harvard.

Also, thank you to the Jaenisch lab for sharing mice and the outstanding members of the Dulac lab for discussions and ideas.

The work was funded by the Klarman Family Foundation for Eating Disorders, the Howard Hughes Medical Institute, and an award from Merck.  I was funded by the Human Frontiers Science Program and the Alberta Heritage Foundation for Medical Research.

Thank you to the Canadian Press for highlighting the prize at home!