The Principal Investigator

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 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.

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.

Hello all,

Wanted to start things off with a quote from one of my favorite movies, Coming To America, to announce that The Principal Investigator is back in business. Please excuse the extended hiatus. Our fearless leader/editor Jenn has been extremely busy. We should be able to get back to a more regular schedule with the links, some original pieces, and interviews that you may find interesting.

This post is just to let you know why we decided to start this blog and why we feature the content that we do:

In the Fall of 2004, while waiting for a seminar given by a visiting neuroscientist to begin, I overheard a disturbing conversation between two of the more established faculty members in the Department of Neuroscience at UPenn. They were discussing the state of NIH funding for the coming fiscal year and the outlook was not rosy. The full details of the conversation are fuzzy, but one statement has stuck with me over these last three years: “Thank god I’m not a postdoc or a young investigator trying to start a lab right now!” The timing of this comment was significant to me because it was during my first semester as a graduate student and, embarrassingly, I had never thought about what it actually takes to maintain a career in the field that I was entering. That conversation got me thinking about funding from a different angle. I knew that I loved the pursuit of knowledge and I knew that I believed neuroscience research was important. Fortunately, that is not enough to guarantee a well-funded research program. I say fortunately because this requires us to be more than isolated bench scientists. It forces us to convey our findings in terms that allow nonscientists to fully grasp the importance of the work. It’s fascinating that Researcher X was able to knock out gene Y in a mouse, but why is that important to someone who drives a cab or sells insurance? More importantly, why should the taxi driver and insurance salesman pay Researcher X (through their taxes) to carry out his work?

Last Thursday, Barack Obama gave a speech on the state of the economy. The prognosis was dire, but he expressed hope. I am hopeful not only because I believe that President-elect Obama is a competent leader, but also because the focus of his plan is on investment. Scientific research is an investment. It is often a long-term investment that does not produce immediate “value” for society. New discoveries take time to become a useful product/service for the public. During the next few months, Obama will be under great pressure to cut funding for valuable research/projects that John McCain and Sarah Palin called pork-barrel spending during the campaign. Hopefully, he will have the resolve needed to face these challenges.

Those of us engaged in biomedical research at universities and medical schools are dependent on the National Institutes of Health (NIH) for the bulk of our funding. Therefore, we depend on each and every taxpayer for the advancement of our work and by extension the advancement of science. Since no one likes to pay taxes we must constantly justify our existence by illustrating the importance of our work. To this end, the major purpose of this blog is to highlight some of the (in our opinion) best research being done and attempt to explain why it is important to all of us. This daunting task will be carried out by an extremely talented journalist (not me) with some assistance from a neuroscience graduate student (me).

Hopefully, you have found The PI interesting so far. We’ll try to keep things going by highlighting some more cool research.

Karen Heller, a columnist for the Philadelphia Inquirer, wrote an interesting piece on The Franklin (formerly The Franklin Institute). Her thesis was that we are doing society a disservice by going for the lowbrow when it comes to science education. In fact, what passes for “science” is no more than high-priced entertainment

Normally, I’m not a fan of Heller’s work, but I agreed with her points in this column. It is hard for an organization that needs to make money to serve the public good.

This topic deserves a longer post and I am currently working on one about a number of institutions that I think would be better served through government support. I know, I know I’m a socialist and should move to France. However, I like the US of A and I think, with a few changes this could be the greatest country in the world once again.

Sleep must be important. I say this because all organisms that can sleep die if they are deprived. However, despite the obvious importance of sleep, very little is known about why exactly sleep is required. The majority of sleep research has been done on mammals. This was due to the fact that researchers believed that sleep was a behavior unique to “advanced”species like us. Recently, sleep-like states have been identified in invertebrates including Drosophila and c. elegans. These are important findings in light of the inability to crack the sleep nut in mammals. The vast number of genetic tools available in worms and flies will allow for more in depth investigation of the mechanisms that underlie sleep physiology.

Monday, I linked to an article that highlighted a new finding that was made possible by the addition of the Drosophila model to sleep research. Amita Sehgal and colleagues identified a new gene, SLEEPLESS, that is required for normal sleep patterning in Drosophila. Mutants that lacked the gene displayed a marked decrease in total sleep time and an absence of rebound sleep after deprivation. In support of the critical nature of sleep, the mutants also displayed a shortened lifespan.

There is still work to be done to determine exactly how SLEEPLESS modulates sleep homeostasis. The authors preliminary work, presented in this paper, show that the protein is enriched in the brain and modulates potassium currents. This would suggest that the protein modulates sleep by affecting the excitability of sleep controlling neurons.

A major weakness in research that utilizes model animals systems, in terms of translation to human physiology, is the evolutionary distance between the model systems and humans. In this case, genomic screens do not show a SLEEPLESS homolog in humans. The functions of SLEEPLESS may be performed by a structurally distinct protein or this may be a function that is completely unique to Drosophila. As a researcher that uses models systems, I believe that the strengths outweigh the weaknesses. Given the sheer number of mutants that need to be screened in order to generate a measurable phenotype, this type of hypothesis-neutral research would not be possible.

Today is July 1st. If you are reading this post, then this date probably has special meaning for you. This is the first day of fiscal year 2009. I thought this would be the perfect time to touch on an issue that is a constant concern for those of us who work in science research. That is government funding, or the lack thereof. It may seem callous during these difficult economic times to gripe about the level of government support for research when that support registers in the billions of dollars, but these tough economic times, in my opinion are a direct result of our lack of focus on basic research and preparation for the future.

Although the tone of this blog will not be overtly political, we will discuss politics as they pertain to the conduct of scientific research. The graph above represents, in our opinion, a major problem facing the United States and the world.

Oil is at over $140/barrel, gasoline is at $4.15/gallon in our corner of the Keystone State, and all commodities from corn to natural gas are at record prices. The solutions put forth by politicians and pundits are wholly inadequate. “Drill for more oil!” “Let’s have a gas tax holiday!” “Give everyone $600!” The real solution lies in the inversion of the above graph. Research and development needs to be a higher priority than fighting an endless war to secure a worn-out resource.

In the year 2008, the price of oil should be irrelevant. We should have moved away from powering transportation through the combustion of oil derivatives a long time ago. This is where government research comes in. You can’t blame oil companies or other private industry for not providing the innovation. Oil companies were not going to leave money on the table. In essence, “wasting” oil by making the product obsolete before it ran out. Other private investors were not going to fill the void because it would have cost too much money and taken too long for any single company to ever see a profit from their efforts.

We find ourselves in a situation (global warming, overcrowding, etc) of our own making. Luckily for us, we can get out the same way we got in: through basic research and invention.

The graph above shows government-supported research funding levels compared to money spent on the Iraq War. Research funding statistics from www.sciencemag.org and Iraq War numbers are from the Congressional Budget Office.