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!

Number One on F1000!

The faculty of 1000 (F1000) is a post-publication peer review process performed by leading scientists that ranks publications in a variety of scientific fields. Our paper has the number one spot in Neuroscience! Fantastic.

See the reviews here: http://www.the-scientist.com/news/display/57742/

Are The Effects of Stress and Anxiety Communicated Through the Germline to Offspring? -- Inconceivable!

Life is full of stress. Jobs are lost, divorces ensue, accidents happen…even wars and terrorism are a part of life for some. There is no doubt that these things impact tremendously on children, but could chronic stress in one generation really influence future descendants for generations to come? It seems daunting to imagine that life works that way or that natural selection gave rise to mechanisms that communicate stressful experiences to future generations. Nonetheless, the evidence is building and I highlight some surprises here.

There has been a major interest in the effects of stress on the development and behavior of offspring for a long time. The work of Michael Meaney and colleagues revealed that patterns of maternal behavior can influence the development of stress responses in rats. This effect establishes a transgenerational form of behavioral inheritance from mother to offspring (Francis et al. 1999). Further work by the Meaney and Szyf groups went on to establish evidence that the transgenerational effects of maternal behavior are correlated with changes in the expression of the glucocorticoid receptor (GCR) in the hippocampus of rats, such that rats exhibiting robust maternal behavior characterized by high licking and grooming of the pups, exhibited elevated GCR expression leading to a feedback effect that dampens the HPA axis response to stress. The increase in GCR expression is proposed to be downstream of increased serotonin signaling and is stabilized in offspring through an epigenetic program in which the methylation status of an alternative promoter for the GCR gene is reduced (Weaver 2004). The loss of this methyl mark is proposed to allow for a stable increase in GCR expression and dampened stress response in the offspring (Weaver 2004). In short, good mothers that groom and care for their pups will trigger an epigenetic program in the offspring that results in those offspring ultimately becoming good mothers themselves and having reduced stress and anxiety-like behaviors. Bad mothers that offer less care to the pups instill a different pattern of epigenetic marks on the DNA of their offspring, such that their pups grow up to be poor mothers and exhibit greater stress responses. Cross fostering of the pups breaks the cycle, revealing that it truly is the early life exposure to maternal behavior that instills this cycle of anxiety and poor mothering.

This work is a striking example of epigenetic inheritance, but has been met with skepticism (see Miller, Science 2010 and Buchen, Nature 2010). A recent study by these groups correlates such processes with early life stress in humans by examining GCR methylation in the brains of 12 suicide victims that were abused as children (McGowan 2009). This is a tough sell for this reader, given that methylation is highly variable in humans and genome wide association studies need thousands of people to detect anything meaningful in a study of this sort. In general, it is likely that the epigenetic story of this one gene is a small piece of a much larger biological picture that involves an epigenetic program that encompasses many genes and other adaptations involving synaptic plasticity, altered cell death, etc. Indeed, new studies are emerging that suggest this is the case. However, the Meaney studies are foundational in that they appear to bring together two disparate fields, namely molecular neuroscience and behavioral neuroscience.

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Recently, the evidence for transgenerational effects of stress have become even more astounding. Two papers have suggest evidence for germline transmission of stress effects to offspring. Over the years our awareness of the transgenerational effects of stress has been growing (Matthews and Phillips, Endocrinology 2010). Children born from survivors of the Dutch famine during WWII exhibit elevated stress responses. Children born from mothers at the World Trade Center attacks have depressed cortisol responses, as do those born from Jewish Holocaust survivors. Most believe that these effects are the result of exposure to a "stressful" environment in the womb, and no doubt that many effects are the result of changes to the uterine environment. However, two independent studies in mice have recently suggested that anxiety-like behaviors can be transmitted through the paternal germline, which may indicate that a stress-related epigenetic signature is carried on the DNA packaged in sperm. These studies appear to be remarkable examples of epigenetic transgenerational inheritance.

The first study is from Rene Hen's group at Columbia (Alter et al. Biol Psychiatry 2009) and is entitled: "Paternal Transmission of Complex Phenotypes in Inbred Mice"

This study used genetically identical BALB/cJ mice and found that males could be separated into those with high anxiety-like (HA) behaviors in an open field test and with low anxiety-like (LA) behaviors. These males were then mated to genetically identical BALB/cJ female mice. Remarkably, correlation matrices and multiple regression models accounting for a variety of variables revealed that the anxiety-like behaviors of fathers were significantly associated with anxiety-like behaviors and hippocampal size of daughters, but with body weight in sons. The authors propose that these surprising and complex associations are suggestive of a nongenetic mode of inheritance through the male germline. The results are very striking. However, from my own experience with mouse genomics, these "genetically identical" inbred mouse strains still have many polymorphic sites drifting through the population. Imposing the behavioral categorization of HA vs LA, may select for subsets of BALB/cJ male mice with sets of polymorphisms that influence anxiety-related behaviors and these polymorphic sites may also influence phenotypes in offspring in a complex and sex specific manner. In this case, the transmission would be genetic. So far the underlying cause(s) of these bizarre effects are not yet clear. It would be nice to know what would happen if the same experiment were performed for mothers.

The second study is from Isabelle Mansuy's lab (Franklin et al. Biol Psychiatry 2010) and is entitled: "Epigenetic Transmission of the Impact of Early Stress Across Generations"

In this study the authors expose pups to chronic and unpredictable maternal separation, which is extremely stressful to the pups. Not surprisingly, these offspring exhibit depression-like behaviors as adults, but the depression/stress related phenotype was restricted to male mice (F1s). This sex bias effect of maternal separation in rodents was observed previously by others. Remarkably however, the offspring of these depressed males also exhibited depressed behavior, but this time the males were normal and the females were significantly affected (F2s). Finally, the normal behaving F2 males were mated to normal females, and despite the fact that the F2 males seemed normal, their offspring still exhibited altered depression-like phenotypes (F3s). However!!….this time it was only the male F3s that exhibited the phenotype, not the female F3s. Thus, a complex transgenerational epigenetic effect is proposed that is transmitted through the paternal germline and interacts with sex effects in offspring to produce stress-related behavioral phenotypes. Finally, the authors note some modest changes to the expression and/or methylation status of a few genes in F1 sperm and F2 brain. However, it seems unlikely that these small effects play a major role in the observed phenotype, thus the underlying mechanisms remain largely unknown. In summary, the study proposes that exposure to chronic stress during early postnatal development leaves an epigenetic signature that can be propagated through the germline to future offspring for at least 3 generations.

The results are hard to reconcile with our current mechanistic understanding of epigenetic programming in the genome. However, several studies that have found evidence for transgenerational epigenetic inheritance report that complex sex effects are associated with the observed phenotype. These complex effects seem to appear in studies of both humans and mice.

These findings are preliminary and require further investigation by others.  However, if this is found to be true, then there is new and fundamental biology to be uncovered.