At the last evening keynote address for the MOHG, Jeremy Berg, the head of the National Institute of General Medical Sciences presented some early data coming out of the NIH’s new peer review policies instituted last year. As part of the new system, members of the review committees for grants are instructed to rate individual applications on a scale of 1 to 9 for the quality of five different categories: significance, investigator, innovation, approach, and environment (meaning the institutional support available to the investigator). Although these criteria are not calculated into the overall score upon which research decisions are made, Berg says they can serve as a parallel indicator of what the review panels seem to value the most. Based on 360 grants to the NIGMS as of October 2009, the criteria most predictive of getting a high overall score were, approach (.74), significance (.63), innovation (.54), investigator (.49), and environment (.37). Grant administrators, says Berg, use the data to look closer at, for example, why some highly innovative grants aren’t being awarded high overall scores and to make sure that the emphasis on approach doesn’t mean that study sections are favouring projects that look reasonable and therefore possibly ‘safe.’ It provides, Berg says, another way of looking at our portfolio.

For information on other scientific indicators and how they’re being used, check out our metrics special.

At the MOHB today, Alaine Keebaugh of Emory University presented work that helps to explain a 20-year old puzzle in mouse and human genetics. In the late 1980s Mario Cappechi and Oliver Smithies disrupted the first gene in mouse embryonic stem cells, a mouse homologue of the human gene, HPRT1. The gene was a useful target because it was on the X chromosome, meaning that they only had to knock out one copy in a male embryonic cell line to completely abolish production of the protein. And they had a way to test that the protein had been eradicated. The knockout mice that resulted from this work transformed genetics and earned Cappechi and Smithies a Nobel Prize. But surprisingly, aside from the verifiable lack of the protein, the mouse was unremarkable, not very different from wild type.

In humans, on the other hand, disruption of HPRT1 results in a devastating disorder known as Lesch-Nyhan disease which has confers gouty arthritis, atrophy of the testicles, developmental delay – they never learn to walk – and they tend to be somewhat aggressive. But most puzzling is the severe self-injurious behaviours, including biting and chewing off of fingers, lips—pretty much anything they can get their mouths on. They don’t want to hurt themselves and many have to be restrained for much of the time. Some can even warn their caregivers that an uncontrollable urge to harm themselves is coming. If you haven’t read a heart-wrenching story from The New Yorker on the topic, (subscription required) I recommend checking it out.

Keebaugh was looking to develop a better mouse model of the disease, so she searched for other similar genes in vertebrate genomes and came across the similarly tongue twisting PRTFDC1, which appears to be an ancestral duplicate of the gene that is active in humans but appears to have been inactivated in the mouse lineage.

Suspecting that the difference in activation might somehow account for why knockout mice don’t show much of a phenotype, she engineered a transgenic line of mouse to express the human version of PRTFDC1. When she crossed this with HPRT1 knockouts she found that the offspring males, containing both the active PRTFCD1 and the inactive HPRT1 display some behaviours similar to Lesch-Nyham males. They’re more aggressive, and while they don’t have the neuromuscular defects, when given amphetamine (a standard way to study stereotypical behaviour, apparently) she observed them doing something she’d never seen mice do before, standing on their haunches and nibbling away at their fingernails.

At the MOHB this morning, Pamela Sklar of Massachusetts General Hospital presented data from the Psychiatric Genome-wide Association Study Consortium (PGC). One of its projects on bipolar disorder looked at the genomes of more than 7,000 cases of the disorder against 10,000 or so matched controls trying to find differences that correlate with an increased risk for the disease. What they’ve found was not different from what many genome-wide association studies have found. Four strongly associated genetic regions popped up in their study, but the individual amount of risk for the disorder that they contribute is quite low. For this reason and because many of the variants they find associated with bipolar and other psychiatric disorders aren’t necessarily gene mutations (many have been genetic duplications and deletions), says Sklar, it’s been hard to convince biologists with experience in model systems to delve in and look at how the gene variants might be contributing.

Nevertheless, working with a collaborator with expertise in fly genetics, Sklar presented data on the function of three genes that might be linked to bipolar disorder. They manipulated versions of the genes in Drosophila melanogaster and observed the formation of synapses between neuron and muscle. At these synapses the long neuron cells form little bulbous protrusions known as boutons and these form in well documented ways in Drosophila larvae. When the researchers knocked out expression of their suspect genes in the flies, the neurons formed some normal looking boutons but also some “ghost” boutons that appeared to be immature non-functioning synapses. The results will require more follow up, but are interesting. The GWAS and genome sequencing studies that Sklar and others are doing are producing “real risk genes in schizophrenia and bipolar disorder,” she said to an audience filled with researcher who work primarily on model systems. “They need people like you to study them.”

At the MOHB meeting this morning the topic was sex, specifically that topic sure to stir up the hornets, the differences between sexes. Nirao Shah of UCSF and Melissa Hines from the University of Cambridge talked about how hormone levels might be responsible for shaping brain differences. But Eric Vilain, who studies intersex individuals at UCLA offered some surprising takes on the differentiation in the brain as it may be shaped by epigenetics, that is environmentally influenced changes that don’t affect the sequence of the genome but alter its expression. Specifically he was looking at methylation of DNA, which marks active and inactive genes in a few dozen pairs of maternal twins discordant for sexual orientation. Tongue firmly in cheek, he referred to the field of study as “epigayomics” in his slide presentation. But the results were negative, in 34 twin pairs they found very little difference in the way genomes were methylated between gay and straight males. His group’s research confirms that as twins age their epigenetic profiles diverge more and more, but the maximum difference was very low, he said, calling the methylation patterns “exquisitely similar.”

In Boston this weekend, researchers from diverse fields and backgrounds have converged to discuss how traditional model organisms like yeast, flies and the worm C. elegans, promise to contribute to the understanding and hopefully the treatment of human disease. It’s the third biennial meeting called Genetics 2010: Model Organisms to Human Biology (which has the inexplicably pleasing acronym, MOHB). Scott Hawley of the Stowers Institute and current president of the Genetics Society of America, which organized the meeting, is a fly researcher. In his opening remarks yesterday evening, he noted that the divide between biologists studying human biology and those studying model organisms is often too great. “We want to reach out and have more contact with people doing other things,” he said. With a line up of talks on everything from personal genomics to sex determination neurogenetics and infectious disease, it promises to deliver that kind of contact.