Tuesday, October 10, 2006

10 Questions for Bruce Lahn   posted by JP @ 10/10/2006 04:50:00 PM

Bruce Lahn is a Professor of Human Genetics at the University of Chicago as well an Investigator at the Howard Hughes Medical Institute. In 2004, he was on the "Top 40 Under 40" list by Crain's Chicago Business. Specifics of his research can be found on his faculty page. Our 10 questions are in bold below the fold.

1. One of the major trends in hominid evolution has been increasing brain size, with the somewhat confusing caveat that modern humans break that trend, with smaller brains than both Neanderthals and some earlier hominids. Many hypotheses have been proposed to explain this, from sexual selection for intelligence to selection pressures from culture. Do you have a favorite hypothesis? What evidence do you think could settle this issue?

Brain size is just a proxy for cognitive abilities. This proxy is very robust over long evolutionary periods (millions of years). But on a short time scale, fluctuation in brain size may not correlate well with cognitive abilities. Within humans, for example, brain size is only weakly correlated with cognitive test scores such as IQ (only about 15% of the variation in IQ can be explained by difference in brain size). Given this, perhaps we should not make too much out of the cognitive significance of brain size changes on a short time scale.

2. Your work on genes involved in human brain evolution (i.e. ASPM and microcephalin) has focused on amino acid changes. It has been hypothesized that most of the differences between humans and chimps are due to regulatory changes. Do you feel this is still a viable hypothesis? Do you consider your work a challenge to this hypothesis?

The hypothesis that most human-chimp differences are due to regulatory changes is proposed in the absence of any data. So, I don't place too much weight on this hypothesis to begin with. Nevertheless, I acknowledge that this hypothesis has influenced the thinking of many people. Our work showed that coding region evolution is likely to be important for human brain evolution. In this regard, it can be considered to be a challenge to the hypothesis. However, our work by no means argues that regulatory changes are necessarily less important than coding changes. So, the jury is still out.

3. The aforementioned work on microcephalin and ASPM touched some nerves, due mostly to two issues: the difference in frequency of the derived haplotype in different populations, and co-incidence of major moments in human cultural evolution with the appearance of these derived haplotypes. Do you regret anything you wrote in either of those papers?

On the one hand, I don't regret the things we wrote in the papers because they were scientifically justified and the speculative nature of some of our statements was clearly indicated as such. On the other hand, I can appreciate why some people might be concerned over the possibility that our results could be over-interpreted or even mis-interpreted to advance certain ideas about race and ethnicity, especially by people with certain political agenda. Our society, given its sordid history on race-related issues, is very confused about how to deal with racially and ethnically sensitive topics. As a result, science and politics get mixed up when they relate to these topics. I personally feel, like many other scientists, that science should be separate from politics. In particular, science should meet the same burden of proof regardless of what political implications it might have. But this may be too idealistic if not naive. I feel I am still learning how to handle such issues in a way that is honest to the science while at the same time sensitive and respectful to political and cultural needs.

4. You've speculated that humans will, at some time in the future, speciate. The evidence for clinal speciation in other taxa certainly supports this possibility. One possible counterargument is that germ-line genetic engineering or even pre-implantation genetic screening could lead to the human population becoming more homogenized, preventing the evolution of barriers to gene flow. What role do you see for technology in the future of human evolution?

I think we as a species now stand at a watershed moment in the history of life. For billions of years, evolution of life forms has been governed by the Darwinian process of random mutations followed by selection. Now, we are about to revise that principle dramatically by genetic engineering. Instead of starting with random mutations, of which only very few are advantageous, we can now prospectively change our genome (and the genomes of other species) in ways we intend. In a sense, genetic engineering will make Lamarckian evolution a reality. Given the revolutionary nature of this new technology, it is impossible to predict where the technology will take us into the future. But suffice it to say that genetic engineering, coupled with other technologies such as pre-implantation genetic screening, would likely speed up evolution enormously, and create life forms, including those derived from our own species, in ways that the Darwinian process can never hope to accomplish.

5. You've published a paper noting a correlation between mutation rate and the ratio of nonsynonymous to synonymous mutations in a gene. This ratio forms the basis for many tests for selection. What's the best way to interpret such a test? You do much molecular work-- how can one decide, using both statistical and molecular evidence, that the story for selection on a locus has been decided one way or another?

It is still debated among experts as to how to interpret the ratio of nonsynonymous to synonymous substitutions. The major difficult arises from the fact that both positive selection and relaxed constraint produce a high ratio. When a gene has a low ratio, one can argue that it has evolved predominantly under purifying selection. But when a gene has a high ratio, it is not clear whether it is due to strong positive selection, or relaxed constraint, or a bit of both. So, unless the ratio is very much greater than 1, it is not possible to conclude what a high ratio means. This is where other statistical and molecular evidence is needed. There are no clear-cut rules on what evidence can be considered "enough" for establishing (or refuting) positive selection. But the best cases usually involve multiple lines of evidence coming from several independent perspectives that are consistent with each other.

6. A lot of researchers studying human population genetics and evolution are strictly data miners (i.e., they generate/publish no original data). There are limitations to such an approach, as it depends on the available data and prevents certain analyses from being performed. Do you expect to see more research groups turning into pure data mining labs in the future? Or will there still be a place for independent labs generating their own data (for example, resequencing a gene in multiple individuals to study the polymorphism)?

Given the explosion of genomic data in the last decade or so, which shows no sign of slowing down any time soon, there is likely to be a proliferation of pure data miners just because there is a niche for them. But I suspect that many interesting findings will still require the combination of data mining and wet experiments to provide key pieces of data not already available in public databases. In this regard, labs that can do both data mining and wet experiments can have an advantage over labs that can only do data mining.

7. The politics behind the funding of stem-cell research in the US have sometimes obscures the actual science. As someone who works in the field, where is it headed? What is truly feasible in terms of medical progress using an approach based in stem cell research?

I personally feel that the promises of stem cells as a direct reagent in the treatment of disease are grossly exaggerated. I think it will be a very long time before Parkinson's disease or Alzheimer's disease could be treated by introducing stem cells (or their derivative cells) into a patient. However, stem cells offer a model for studying developmental processes. As such, stem cell biology will ultimately make valuable contributions to our ability to better understand disease and develop treatments. So, I believe that the future of stem cell research lies in its potential as a research tool, and to a lesser extent, its ability to provide direct cure for disease.

8. Much of your work on stem cells is done in collaboration with a center in China. What is the attitude towards such research there, and how does it compare with the attitude here in the US?

The attitude is much more progressive relative to the US. Religion is not a dominant force in molding Chinese cultural traditions, and people are generally not married to a particular doctrine. This attitude provides greater flexibility for stem cell research.

9. Ian Buruma has noted that many Chinese dissidents have converted to Christianity, while David Aikman, in "Jesus in Beijing", argues that the Christianization of much of China will alter geopolitics. How accurate do you think is the perception by many Westerners that Christianity is filling the ideological void left by the fall of Marxism-Leninism?

I tend to agree that Christianity is filling an ideological void left by the dying out of the old communist ideology. But whether China will be Christianized is a separate matter. There is plenty of Chinese who are strongly opposed to the idea of allowing religion to play a major role in the culture. I suspect it will be a major uphill battle for one religion, be it Christianity or otherwise, to spread beyond a few limited sectors of society. But this is just my guess.

10. Looking back, would you make any changes in your educational path? If so, what?

Looking back, I might have chosen economics instead of biology, as it might have allowed my work to have a broader impact. But it's a tossup, and my feeling may well have stemmed from my constant impatience with lack of progress in my own work and therefore the perception that grass is greener on the other guy's pasture