Friday, February 27, 2009

Why are scientists so cautious?

An article from the New York Times writer Gina Kolata from June 27th, is getting a fair bit of buzz, both around the blogosphere and among my friends on facebook (many of whom are scientists as well).

The gist of it is as follows. The current trend among large scientific research grant agencies is to fund projects that "play it safe". That is, they will not be risky projects, with respect to having significant "productive" output in terms of research articles out the other side (i.e. funds = research articles). Those proposals that may be the most ground breaking (both in terms of basic research, as well as any potential for significant clinical advances) are also often the most risky. This article does a good job getting at the heart of both the political and cultural components of this issue.

However it got me thinking about the culture of science in general, and our mentorship process. In particular about how a major part of the training of scientists with respect to critical reasoning, also leads perhaps to excessive skepticism. Is this possible? Now, I tend to be an overly skeptical person, and like most scientists, and I often look for the flaws in all of the experiments I perform. However, is it possible that we take it to far as a scientific community?

From my own training experience, I know that some of the most valuable time spent was in "Journal club", where a group of students, post-docs and faculty would get together each week over coffee, and argue about a couple of recent papers. However, in most situations, this would turn in to a session to find every possible flaw in the study. While there is certainly value in this (knowing a good experiment from a bad one for instance), I am know wondering if this does not lead to a culture of scientists who are unable to take risks, or appreciate proposals for "risky" science?

This is something I will have to mull over.....

Friday, February 13, 2009

Three cheers for the little guy....

Now, I have something to admit. Some of you may be shocked and dismayed, and perhaps even amazed by my admonition. I work with fruit-flies, and it makes me very happy.... More than that I have to say I even love these little critters.

There, I said it.... I have come clean.

Of course when I say I work with fruit flies, what I mean to say is I work with that particular little guy which is sometimes called the vinegar fly, pomace fly, or with its scientific name, Drosophila melanogaster which loosely translates to "black bellied dew lover". Yes, I mean that dreaded fly who you had to work with in high school biology, and may still haunt you when you fail to rinse out old wine or beer bottles. That little fly.

Why on earth would I say I love these little guys? Am I just one more really strange scientist? Well, I like to think that while I may be a bit quirky, I am not quite that much of an oddball. The truth is, that the love I feel for these little fruit flies is not that of a spouse, or parent or child, but the love of something whose very nature can transform the way that we think of the world.

Oh, so very hokey, I know. However, over the past decade or so that I have worked with Drosophila, I have been truly amazed by the insights we can gain from little more than a small microscope, some mushy bananas and a paint brush. Now this may surprise some people, but I consider myself a little bit of a Luddite. Clearly I can use a computer, well enough, and I even know how to set my DVR (but apparently so does my 3 and half year old...), but when it comes to the rapid changes that are happening in methodologies and technologies in the biological sciences, I have to admit I am a bit of a slowpoke.

Yet, many of the most amazing discoveries made using fruit-flies have been done using basically the same technology as was used in the early 20th century when these first became a "model" for studies in genetics. Basically we play match maker for the fruitflies, and then wait to see what happens. Are their offspring normal, do they have wacky abnormalities? We then go about figuring out what these wacky abnormalities do, and how they are caused.

Ok, so I am oversimplifying. There is a lot more than that. However, what is true is that it is people doing the work (us mad scientists to the rest of y'all) that spend lots of time thinking about how best to do the match-making (what we call genetic crosses). Indeed over a decade ago the Nobel prize was won by three fly geneticists who thought carefully about how to study early development of an organism, how best to set up these crosses and look for abnormalities. The work that they did with not much more than the flies, and some microscopes laid the foundation for almost everything we know about the genetic basis of early development, including in humans.

So as long as you are observant and reasonably patient, you too can be a fruit-fly geneticist!!!

These approaches were then fine tuned to discover literally thousands of other genes, and in particular the use of what are called sensitization screens have found many genes that we now know can contribute to various aspects of human cancers. Pretty impressive work for a little fruit-fly.

Now with the amazing technological and methodological breakthroughs some scientists suggest we are entering the "post-genomic era". What this means is that as it has become much less expensive to find out all letters and words (the genes) of DNA in an organism. These fragments of DNA that are sequenced (our words) can be fed into super-computers (using some very cool computer programs) to reconstruct these words into the sentences, paragraphs, chapters and ultimately the book that is the "genome" of any animal, plant or microbe we want.

Given these breakthroughs, there have been some suggestions that the original model organisms (like the fruit-fly) will become less useful, despite all of the tools and data that has been gathered. That is we will be find out many of the same things in other species, that are perhaps nearer and dearer to our hearts, or at least are nicer to look at. Yet, I do not think the time of the fly has passed. I suspect that Drosophila will continue to claim the hearts of a new generation of scientists, and I imagine that it still has a trick or two to teach us all!

Monday, February 9, 2009

Am I that predictable? Genetic variation and Jewish ancestry

Now I am not one to obsess about genealogy, at least not for my families. That is not to say that I am not interested in my family history, it is just that beyond a few generations (maybe 4-5 on one side), we can not go back very far, alas there is no paper trail.

This is not uncommon for people of Eastern European (Ashkenazi) Jewish heritage, like myself. Indeed, it is not uncommon for a lot of people from many different ethnic groups. Thus, not surprisingly, there are many people who wish they could know something about "where they came from", in a genealogical sense.

So where does the genetics come in ( this is a blog about genes)? Over the past 15 years there has been an explosion of studies that have used genetic variants in humans to help to try and identify the small proportion of the genome that differs between individuals, and use these variants to infer something about the ancestry of different people, and their ethnicity. This has been a fusion of questions from population genetics and anthropology.

What is population genetics you may ask? As the name implies it is the study of genetic variation within and between populations. It is a framework that we use to study evolutionary changes while considering variation within genes (alleles).

Population of what? Any organisms.. Including, and to most of you I may guess most importantly.. humans...

Now these studies of human population genetics have been given lots of press, and rightfully so. They are both extremely cool, and require all of us to think about what if any implications they may have. Of course the most important results have actually been known for along time. Most of the variation found in humans can be found within a population. That is, you do not need to go to some far flung tribe to find genetic diversity, you can probably go next door to your neighbors.

Now what does any of this have to do with the title of this post ("Am I predictable?"). Well there is a recent study by Anna Need et al. from the lab of David Goldstein entitled
"A genome-wide genetic signature of Jewish ancestry perfectly separates individuals
with and without full Jewish ancestry in a large random sample of European

While the title may be mouth full, in all fairness I have to say my jaw dropped a bit when I read it. Why? Basically, the authors suggest that based on a very large (500 000) number of genetic markers that vary among people (genetic polymorphisms in the lingo), Jews of Eastern European ancestry (Ashkenazi Jews) can be perfectly identified as such, when compared to other people of European descent (we will come back to this last part at the end of the post).

Given that all of my grandparents were of Ashkenazi descent, this means that if they "genotyped" me (that is extracted my DNA and then checked me for all of these markers) they would be able to (almost) unequivically identify me as having Ashkenazi heritage. Of course the formal possibility exists that in fact my ancestors were not all Ashkenazi Jews, in which case, they could identify this as well. Of course, given that my physical appearance has been at one time or another been variously compared to David Schwimmer, Jeff Goldblum, David Krumholtz and Albert Einstein, I think the latter is a remote possibility.

Now, in the past few years there have been a number of studies that have suggested that the genetic ancestry of Jewish people is of Semitic descent. That is to say, Jews who hail from Europe appear to be more closely related to other Jewish people (whether from Europe, North Africa, Iraq or many of the other parts of the world that Jews settled and formed communities), rather than being genetically similar to their host communities. Thus despite a prolonged presence in places like Europe, North Africa and the middle east, Jewish populations have been maintained in large part by endogamy (which means Jews tended to have children with other Jews), and their has been relativey little local conversion to Judaism, providing an infusion of new genetic material.

Perhaps the most famous example of this has been the work on the markers on the Y chromosome. The Y chromosome is passed from father to son, and is remarkable in that bits of it do not undergo genetic recombination. This means, that regions of the Y chromosome do not get shuffled in the same way that other parts of the genome do. For reasons I will not go into right now, this provides an unusually informative set of genetic markers to help infer ancestry.

In a study a while back by Hammer et al., they examined 18 such markers on the Y chromosome for 29 populations including European, Arab, North African and Sub-Saharan African in addition to individuals from Jewish communities from all of these regions. What did they observe? Most of the jewish populations clustered with each other, and with non-Jewish groups of Arab descent (Syrian, Lebanese, Kurdish and Palestinian). Thus this evidence was consistent with Semetic ancestry for Jewish groups.

However, this (and other studies based on markers on the Y chromosome) only represent a small fraction of genetic polymorphisms (despite being quite informative), and more importantly only tell us about ancestry from father to son. We would like to make our conlcusions based on more than that right?

last year, two papers came out in the Journal PLOS Genetics

Where they mined large data sets collected originally for mapping genetic variants that contribute to disease susceptibility to examine the similarities and differences within and between populalations of people of European ancestry. Unlike the previous studies, that were based on a relatively small number of genetic markers, these studies used hundreds of thousands of polymorphic markers, spread throughout the genome.

These two studies found very similar observations with respect to European populations. First you could distinguish ancestry of people of European descent (i.e. people of Irish descent clustered with other people of Irish descent, people of German descent clustered with other people of German descent). However, the more interesting finding in my mind was that Ashkenazi Jews not only clustered together, but were quite distinct from other European groups. Not surprisingly, the European groups that Ashkenazi Jews were most similar to were the Mediterranean populations (Greeks, Italians and Spaniards). Indeed, I interpreted part of these results to suggest that Ashkenazi Jews were slightly more "Mediterranean ", than the other Mediterranean groups. However, given that this comparison was just among European groups, it does not in itself point to broader Semetic ancestry. However in combination with the previous results, the results are looking pretty solid.

So given all of these results, why was I so surprised by the paper by Anna Need and collegues? They suggest that not only do Ashkenazi Jews seperate out from other Europeans, but genetically can be very clearly distinguished, as I mentioned above. This is astonishing given that as a geneticist, I am used to thinking about probabilities. Normally when such genetic studies are performed, and indeed if you yourself get genotyped to find out about your ancestry, at best you will usually get an answer like "you have a 21% chance of being of X ancestry, 17% chance of being of Y ancestry). In other words, you seem to be a perfectly good human being, and anything else would be mostly guess work.

However, this study suggests that at least with respect to comparisons with Europeans, the probability of correctly identifying your ancestry to Ashkenazi Jewish ancestry is much higher. Is it going to really be a 100% accurate? No of course not, and the authors did not suggest this. Indeed they make the very careful point that is only in comparison to European populations. After adding information for Arab populations, it is clear that Ashkenazi Jews resemble some combination of European Mediterranean populations and near Eastern populations, and represent one more set of points along a continium as opposed to some discrete group. It is likely that as more Mediterranean and near eastern populations are examined (say people from Turkish, Armenian and Kurdish descent) there will be more overlap with these groups.

ok... I think I have said enough..

until next time