The Principal Investigator

Interview from Nature News with Anders Ekblom, head of science and integration at AstraZeneca.

Interesting story from Nature News on GlaxoSmithKline’s attempts at recreating the nimble, fast-moving culture of a small biotech firm within their R & D department. About three years ago they created 40 Discovery Performance Units (DPUs) that are tasked with researching a single, specific problem. These DPUs are now up for their first review. GSK evaluates the progress of each DPU and decides whether to expand, shrink, or shutdown each of the units based on their progress over the last three years.

This is an intriguing way to combat the bare pipelines that a lot of Big Pharma companies are facing now. It remains to be seen what this type of internal competition and short time frame will mean for progress within the company. The article is also lacking specifics on the rationale underlying the decision making by GSK executives. For example, what type of progress is required for expansion/contraction? How much? Is part of this based on what is promised in the grant applications? Programs like this, which have been launched by other companies as well, will be watched to see if it is a better model than the current funding structure.

A bit late with this post, but wanted to put this out there. President Obama put out his budget proposal for fiscal year 2013. In an age of austerity, biomedical research received a small bump in funding for the year. I am an extremely biased observer and I like  that research was somewhat protected from budget cuts

A recent paper from a consortium including researchers from the National Institute of Mental Health (NIMH), the Lieber Institute on Brain Development, and Johns Hopkins documents the DNA methylation pattern in the human prefrontal cortex across the lifespan. At first glance this article seems exceedingly technical and not of general interest. Now I may be biased because I study a disease (schizophrenia) with significant developmental aspects, but I believe this paper is full of incredible, novel findings on gene expression. The main points of this paper are concepts that we all should be concerned with. It gets to the crux of the age-old nature vs. nurture argument.

The study generally deals with a relatively new field of study known as epigenetics. Epigenetics deals with changes in gene expression, some potentially heritable, that do not include changes to the underlying DNA sequence. This particular article is concerned with DNA methylation. Long story short, DNA methylation leads to the silencing genes and subsequently less mRNA and protein produced by the silenced gene. More genes are silenced as we age. This makes since as development and growth, both physical and mental, should require the products of a greater number of genes. Interestingly, genes that become silenced as we age consist of many many integral players in what we consider “aging.” These include tumor suppressors and DNA repair genes.

We know that environmental experience can lead to epigenetic alterations that affect gene expression. For example, we know that maternal attention (licking, grooming, etc.) leads to epigenetic changes that facilitate anxiolytic responses in the offspring. This finding gets me to the title of this post: How much of what we now call environmental factors actually exert their effect through changes in gene expression. Potentially long-lasting changes in gene expression. I wonder how many experiences that we think are in our past, both positive and negative, that are still with us epigenetically?

A researcher at a talk I attended made the statement that hypothesis-driven research is the only valid type of research. His point was that taking the time to form a hypothesis served to focus the researcher on the key parts of experimental design.

Generally, I do not agree with absolutes (see what I did there), and this one is no exception. I think valuable research-that is discovery of something new- can be accomplished without a clear hypothesis at the outset. It is difficult, and regularly operating without a hypothesis can lead to ambiguous results, but I think real hypothesis-lacking research is possible.

A recent paper published in Nature proposes a critical role for autophagy in the beneficial effects of exercise. The article shows that exercise (treadmill running) in mice stimulates the process of autophagy. Interestingly, the induction of autophagy is required for some of the positive metabolic effects of exercise (increased sensitivity to insulin, etc.).  Mice with mutations in the autophagy pathway show impaired exercise endurance and do not receive any of the metabolic benefits of exercise.

Autophagy is a critical function for cells. Not only is it an efficient mechanism for clearing debris, but it also facilitates the dynamic regulation of cellular activity. Cells use autophagy to allocate resources toward critical activities at times when these resources are scarce. Additionally, autophagy, through mechanisms that are not entirely clear, is thought to be involved in the pathology of many diseases from cancer to neurodegeneration.

This paper gives us some insight into why exercise is appears to help prevent many seemingly disparate diseases.

On the same day President Barack Obama called upon Americans to “out-innovate, out-educate, and out-build the rest of the world” during his second State of the Union address, the results of a nationwide survey probing what America’s kids understand of science were released – and the findings weren’t pretty.

The science tests, known as the National Assessment of Educational Progress (NAEP), in 2009 assessed close to 308,000 fourth- and eighth and over 11,000 twelfth graders questions on the physical, life and Earth sciences.

For fourth graders, questions varied in level of difficulty from identifying the benefit of adaptation for an organism to designing an experiment that would allow them to compare types of bird food. Questions geared toward students in grade twelve ranged from being able to compare weather data to tell which city has warmer temperatures to whether they could recognize a nuclear fission reaction.

Just thirty-four percent of fourth-graders, 30 percent of eighth-graders, and 21 percent of twelfth-graders reached the “proficient level” in science in 2009, according to the assessment. Twenty-eight percent of fourth-graders, 37 percent of eighth-graders and 47 percent of twelfth-graders failed to meet the basic achievement level for the exam, compared to a mere one to two percent of students at all grade levels demonstrated advanced understanding of science.

My entire research career has been focused on the physiology and treatment of mental illness. Recently, my research has shifted away from depression and anxiety disorders to schizophrenia. These disorders are all considered complex genetic disorders.  This means that variation in many different genes leads to increased “risk” for the development of the disorder. In other words, no single genetic variation or mutation reliably leads to the development of the disorder. This is in contrast to known monogenic diseases like Sickle cell and Huntington’s disease. One difficult aspect of studying complex genetic disorders is the ambiguous etiology of the disorder. Add to that the fact that it is entirely possible, in fact probable, that different individuals with the disorder have different etiologies. Long story short, the genetic causes of schizophrenia and other similar polygenic disorders are complicated and remain to be elucidated.

As genetic and computational technology has advanced, genome-wide association studies (GWAS) have become popular tools of investigation into the potential genetic underpinnings of schizophrenia (and other disorders). GWAS look for genetic variations associated with a particular trait. GWAS, unlike most scientific investigation, is hypothesis-neutral. This is seen as an advantage for the technique because it does not incorporate investigator biases toward pet pathways and takes an objective view of potential causes of disease.

Two recent papers (Bergen and Petryshen, 2012; Collins et al., 2012) got me thinking about the role of GWAS in schizophrenia research. Both of these articles contrast the  strengths of GWAS with the limitations of candidate gene studies. That is a debate for another time. I want to focus this post on the cost-benefit of GWAS as it relates to alleviation of disease burden in schizophrenia.  Are larger, and more expensive-GWAS are very expensive, GWAS the best use of research dollars? I think identification of the genetic risk factors for schizophrenia is a worthwhile scientific goal, but I am not convinced that it is the best pathway to more effective treatments.

Will a therapeutic agent be able to undo the effects of the identified genetic variation? Maybe. As the field pushes full-bore toward the GWAS strategy, we may lose some valuable leads based on the reverse-engineering strategy of investigating and therapeutically targeting endophenotypes present in patients with schizophrenia.