Monday, August 3, 2009

Thoughts from a meeting: Honoring Victor McKusick, and looking to the genomic future

We spent a foggy, drizzly but perfect morning at one of the most beautiful places we know, Pemaquid Point in Maine, a few days ago, a good excuse to post this photo. We're now at the dairy goat farm in Vermont that Anne's sister runs with her husband, being kept very busy milking goats and making cheese, so here is a rambling tour of the Bar Harbor symposium--we don't have time to make it short.

The meeting was interesting. Even without Francis Collins, who couldn’t be there because of his upcoming confirmation hearings to head the National Institutes of Health. The event was in celebration of the Short Course in medical genetics that has been offered by Jackson Labs for 50 years, started by Victor McKusick, one of the first physicians to be interested in human genetics in the modern era, and often called the “Father of Medical Genetics”. He and his wife attended every Short Course for 49 years; he died last year, but not before he helped to organize this commemorative day. (Actually, to be fair without in any way diminishing Dr McKusick’s contribution, the British physician Archibald Garrod is generally said to be the founder of modern biomedical genetics, back at the beginning of the 20th century. He studied recessive metabolic diseases in close relatives, showing that human inherited disorders followed Mendel’s principles.)

Most of the speakers at the Bar Harbor meeting had a personal connection with Dr McKusick, so his presence was strongly felt throughout the day. The talk we thought was most interesting, perhaps because it was about a subject that we know something about, was by Richard Axel, a neuroscientist who won a Nobel Prize in 2004 for his work on smell. He talked about the neuronal connections that stretch from the odor receptors in the olfactory epithelium in the nose to the olfactory bulb in the brain, the only neurons that single-handedly, so to speak, connect the external world to the brain without synapsing with another neuron along the way. But, that’s largely because it’s a short path twixt nose and olfactory bulb.

Axel’s main thrust was that understanding how the brain interprets messages about smell that are delivered to it from the nose is still poorly understood. It’s clear that single odorant receptor genes (ORs) are expressed in each cell in the olfactory epithelium, although we have about 900 genes that code for ORs and each cell picks up a different odor. Most odors trigger a combination of ORs and it’s that combination that has to be interpreted in the brain.

What happens next is called the “binding problem”, a problem not restricted to the sense of smell, but one that applies to all our senses. How does our brain put together the many different pieces of information our eyes absorb (color, angle, form, etc), how we build sound from all the bits of information our ears take in (frequency, loudness, timber, and so on) into a single sound, sight, or odor? Axel demonstrated the binding problem with this picture by Salvador Dali—do you see the head of Voltaire or two nuns? How and why we see one and only one at a time is not at all clear.

Odorant detection reflects an intriguing but unsolved problem that is much more widespread. Of the 900 OR genes (actually 1800 since we have two copies), each cell picks only one of the two copies of only one of the 900 genes to express. These genes are located on almost all human chromosomes, so some form of communication among the chromosomes, and among genes within clusters of them on the given chromosome, must take place to exclude 1799 genes, differently, in each olfactory receptor cell. Many other genes also manifest what is called allelic exclusion, and this appears to be similar to the process that inactivates genes on one of a female’s two X chromosome (a phenomenon that’s long been known but still is only partly understood).

Another talk was about stem cells, and how iPS (induced pluripotent stem cell) technology has rapidly advanced the field, and it’s now possible to envision stem cell therapies using any patient’s cells as progenitors. But, according to this speaker, the understanding of how to direct differentiation of stem cells into any cell we want is in its infancy. And, cloned animals will never be normal, thus he’s not sanguine about human reproduction through cloning. Never is a long time, but at least the point is that the great promise of stem cell research is being worked on but not yet here.

Yet another speaker does research on epistatic processes—changes in DNA that aren’t in the DNA sequence itself, but instead in the chemical properties of DNA. Methylation is the most well-studied of these, and this speaker suggested that aberrant methylation may explain most cancers, and other diseases.

Ken talked about evolution as more of a cooperative process than a competitive one, and suggested, as we have in this blog and in our book, that natural selection is a less powerful force in evolutionary change than most people believe. He talked about the weakness of the link between genotype and phenotype, and the many ways to get to a single phenotype. Some simulation work was presented from Ken’s and Brian Lambert’s ForSim simulation program, that showed why connections between specific genotypes and phenotypes is likely to be weak, with poor predictive power, an important point both in relation to evolution and in the biomedical context of assigning genetic causation (a subject we’ve dealt with many times in this blog, and will again when we have time).

Joe Palca, a science reporter for National Public Radio, moderated panel discussions with the speakers at several points during the day. Ken was asked if he could give 2 examples of traits that have evolved, which was a rather surprising question from an audience of scientists, since the journals are filled with such examples. He was also asked if humans are still evolving. Even Darwin shared the misconception that humans are no longer evolving because, as he said, they have culture, and culture overrides evolution. But, as Ken pointed out, there are always mutations in DNA, the stuff of evolution, and in humans, the fact that we have culture may moderate the effects of change (infertility is treated, or previously fatal diseases treated), but it can’t prevent it. We have evolved, from the beginning, to adapt with and to an environment that includes culture (language, tools, fire, clothing and shelter we make, cooperative hunting and gathering, and so on). It’s not new, and it may not be of exactly the same kind of adaptive evolution found in other species, but it’s evolution in every meaningful sense of the term.

Eric Lander, head of the Broad Institute in Cambridge, MA, summed up the events of the day in an after-dinner talk. He summarized each talk briefly, and then went on to predict where genetics will be in the next 50 years. He had worked closely with McKusick, who was a great believer in catalogues. He initiated the catalogue of human diseases called Mendelian Inheritance in Man, now OMIM (Online MIM). Lander believes that, in the McKusick tradition, all genetic diseases will soon be catalogued and we now need to move on to cataloguing all cell states—“whether 500 or 5000”. He’s more optimistic than we would be, and indeed we think humans cannot eliminate all diseases. If we could eliminate all currently known or named diseases, then whatever was left that we didn’t like would come to be viewed as ‘disease’. Or society would find new ways to identify its fringe states or members.

We think elimination of ‘all’ diseases is unrealistic and probably not a responsible thing to hint at. But that’s not the same as saying, which we don’t, that the assault on major biomedical problems won’t have major, even wonderful positive successes. The amount of effort being made, barring major social catastrophe that pulls the research plug, can safely be predicted to have such successes. The debate is, or should be, about what approaches are best to take to have the most or best success. And there’s plenty of room for that debate.

But now we have to go help milk the goats.

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