Jibril Hirbo hails from a tiny mountaintop town called Marsabit, in northern Kenya. Now, as a population geneticist, Hirbo has completed perhaps the largest-ever genetic study of people from Kenya and other East African nations.
Posted on behalf of Chris Gunter
Believe it or not, some people are complaining that now the ASHG meeting has too much genomics. This comes after years of dire warnings that the society was ignoring genomics at its own peril. Friday morning featured yet another all-genomics platform session, with multiple talks on sequencing whole human genomes.
Matthew Bainbridge of Baylor made crowd laugh by saying all we need is an assay with 100% sensitivity and 100% specificity. In the meantime, he’s using a method of sequencing a genome on two different platforms and comparing the results. He and others at the Baylor College of Medicine extended their work on personal genomes by sequencing in a family with a form of ataxia not due to a triplet repeat mutation, as many ataxias are. As in several talks at the meeting, Bainbridge and colleagues captured the sequence of the exome (or entire set of expressed genes) from key members of a pedigree, and by comparison of genetic variants were able to pinpoint the one gene they think carries the responsible mutation.
Posted on behalf of Chris Gunter
In 2006 I blogged from ASHG’s career development session and hate to say that not much has changed.
Back then I said “The session was kicked off by Bill Lindstaedt, Director of the UCSF Office of Career and Professional Development. He delivered the depressing news first: the median age of first tenure-track positions is 38; the median age of receiving a first NIH research grant R01 is 42; and only 4% of such grants go to first-time investigators.”
Everyone wants to find the genes that “make us human.” The problem is, when we find them, how will we know?
One of the major themes of this meeting is personalized medicine – the promise that some day, doctors will be able to tailor treatments for all of us based on our genetic makeup. Scientists and researchers are excited about the future prospects of personalized medicine, but there are also huge questions about how useful it will really be. Social scientists are wondering: can patients can handle genetic information? Will they overreact upon learning they have some small increase in risk for a disease? Or will the information wash over them like the myriad public service announcements exhorting us to eat right and get more exercise – messages that, apparently, most of us have learned to ignore?
Nature reporter Erika Check Hayden (twittername patsycat21</a>) will be covering this year's <a href="https://www.ashg.org/2009meeting/">American Society of Human Genetics meeting</a> in Honolulu, Hawaii, from 20-24 October. Check back here for her coverage, as well as guest posts from <a href="https://www.hudsonalpha.org/chris-gunter-phd">Chris Gunter</a> (<a href="https://twitter.com/girlscientist">girlscientist), director of research affairs at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, and former Nature editor extraordinaire.
Albert LaSpada of the University of Washington in Seattle was able to reverse Huntington symptoms in a mouse model of the disease using a transgene expressing PGC1alpha. He presented details of his study on Wednesday, but gave a little additional background at a press conference this afternoon. It’s one of those lovely genetics discovery stories that not only offers promise for a devastating disease, but comes together so neatly when looked at in hindsight, I just had to relate it.
LaSpada was a grad student with Kenneth Fischbeck at the University of Pennsylvania in the late 1980s and early 1990s. Together, in 1991, they discovered the genetic underpinnings of X-linked spinal and bulbar muscular atrophy. It was caused by a gene with an abberant trinucleotide repeat. Two years later it was found that Huntington’s disease (HD) worked in much the same way, with an repeated CAG sequence in the huntingtin protein creating a long string of the amino acid glutamine. These repeats prevent huntingtin from folding properly and make it clump up in the brain — a hallmark of many neurological diseases. The relatively high profile of HD made for a lot of excitement LaSpada says, and now there are at least nine of these so-called polyglutamine diseases known.
After he became a PI himslef, LaSpada had a trainee looking to treat HD who was going to test a cannabinoid drug in a mouse model for the disease. LaSpada predicted that the drug might interfere with temperature regulation, so he suggested that they observe temperature closely. They found surprisingly that untreated mice had very low body temperatures, leading them to speculate about the metabolic pathways that might have been contributing to this. In HD there’s the hallmark unfolded proteins, but there’s also dysregulation of transcription and mitochondrial dysfunction. But nothing linked the pathways together. Using the mouse model they were able to show how huntingtin aggregates interfered with the activity of PGC1alpha, a transcriptional co-activator involved in mitochondrial function in the brown fat by which mice maintain their body temperature. They engineered an HD model mouse to overexpress PGC1alpha and it both improved neurological function and cleared the huntingtin clumps. Screening for proteins that PGC1alpha interacts with reveals that it modulates the activity of PPARdelta. Another recent study LaSpada says, further shows that PPARdelta is involved in the response to retinoic acid, thus revealing two potential targets for drugs: ATRA, a chemotherapeutic that works like retinoic acid is already in use for promyelocytic leukemia, and GW 501516, a PPARdelta agonist has been used in clinical trials to modulate cholesterol and go after fat.
It seemed such a tidy path of discovery, definitely inspiring. Even the person following LaSpada at the press conference was a bit stunned. Before presenting his own results following humans with Gaucher disease, Hans Andersson at Tulane Univeristy in New Orleans just had to pause to say, “Cool. That’s a cool story!”
I’ve got another fabulous guest post from Chris Gunter
At the Presidential Symposium, speakers pleaded the case for personal genomes and for Philadelphia. First was Philly mayor Michael Nutter, who assured us he knew absolutely nothing about genetics but joked that geneticists must have big expense accounts and the people of Philly would be very grateful if we could leave some of that money here with them.
J. Craig Venter of the self-titled institute gave us a tour of his publication history and then of his own genome. (In an overlap with the carbon conference that Nature is also currently blogging, he announced that his J. Craig Venter Institute was building the first zero-carbon research building, on the UCSD campus.) As for his genes, he’s heterozygous in 44% of them, and he’s anxious to see this information translate into medical practice. “To me it’s not surprising that pharmaceuticals don’t work on everybody” because we are so different. In fact, “it’s amazing that they work on up to 1/3 of the population.” He reiterated his call for predictive power from the genome: “I have been arguing for some time that going to a preventative medicine paradigm is one of the few ways we have to lower health-care costs.”
Richard Gibbs of Baylor College of Medicine, the second speaker, picked up on the theme but stated that “we” –presumably meaning the genomics community – thought that there would be an orderly transition to genomic medicine, one would just walk into the doctor’s office and get genomic information and interpretation quickly. But we did not foresee the widespread distribution of direct-to-consumer tests, and the confusion that has resulted. We are driven by amazing advances in technology and therefore able to get mountains of genomic information, but we don’t really know what to do with it all. His personal experience, of course, is from sequencing Jim Watson’s genome. “We brought Watson to Houston for a genetic counselling session, which was pretty much a complete failure” because there were 320 loci with “suspicious” differences, based on the existing databases, and the counsellors were just overwhelmed.
Talk about overwhelming: In a plenary session on Wednesday David Kaufman of the Genetics & Public Policy Center told us that 60% of survey respondents would participate in genetic testing for a major medical research survey, and more than 90% of these said they would want to see their individual results (more on their survey here). So, it’s obvious the human geneticists have work to do in developing accurate but understandable interpretations of genetic tests. Any scientists out there who are not geneticists – please feel free to join the field, because we need you. All the better if you come with a big expense account.
Posted on behalf of Chris Gunter, HudsonAlpha Institute for Biotechnology
I couldn’t leave this be. I’ll be writing more about it soon, but these numbers are just staggering. David Altshuler gave a status report on the 1000 Genomes project, which aims to plumb the depths of human variation (I’m still waiting for the 1KG handle to take off). As it nears completion of its three pilot phase projects, it’s generated 3.8 trillion bases of genome sequence. Although they haven’t yet sequenced 1,000 genomes, that is technically 1,000 human genomes worth of sequence data. Altshuler said that if you take the amount of data that was in GenBank at the start of the project, they put in roughly that amount more for each week of September and October. And they’re just a tenth of the way there! It’s useful to remember, Altshuler said, that the Large Hadron Collider, which is similarly expected to heave terabytes of data at researchers, had copious amounts of planning going into its data handling and analysis. 1KG will need to catch up quickly, hence two recent requests by the NIH looking for people with a plan and a heck of a lot of computational power. See here and here.
It’s family history month, explained Ed McCabe of UCLA, president elect of the American Society of Human Genetics. This was at a press conference announcing the society’s statement on ancestry testing, but he wasn’t advertising for direct-to-consumer testing companies. Rather he suggested that this Thanksgiving, we should take the time to ask our elders about where we came from. Learning about the cultural richness of family history, he said, is very different from knowing that your genes say your are 40% european, for example.
I think family history month is largely recognized as October, but it’s a nice sentiment, and I for one wish I had more people around to ask.