How to find your way in E. coli without stopping for directions

One of the keys to success in life is to regulate your genes properly. Genes are regulated by transcription factor proteins, which have to navigate their way around the genome and bind particular DNA targets. The problem is that there are only a few correct targets and the genome is large. So an obvious question is, why don’t transcription factors get lost? Do they stop and ask for directions? Where is the information for genome navigation coming from?

The answer to this question is still being worked out for eukaryotes, but it has been solved for E. coli. Peter von Hippel and Otto Berg largely figured out the answer in their classic 1986 paper “On the specificity of DNA protein interactions.” E. coli’s solution for making gene regulation manageable is simple and elegant, because this bacterium has the virtue of possessing a small genome. Let’s take a look at how genome navigation works in a bacterium: Continue reading “How to find your way in E. coli without stopping for directions”

I don’t understand my CD player or my genome

There is something dissatisfying about our current explanations of how the genome exerts its effects on the cell. This is particularly true of the non-protein-coding regulatory regions of the genome, which, as we all know, make up a substantially larger fraction of the genome than those DNA sequences that encode proteins.

So what is that we don’t understand? Rather than give a wordy and abstract explanation, let’s go with an analogy: our poor understanding of how the genome operates is like my poor understanding of how a CD player works.

Let’s start with what I do know about CD players (with a little help from Wikipedia, which I hate but still refer to dozens of times per day.) The data in a CD is encoded as little pits in a polycarbonate surface. Behind the polycarbonate surface is the shiny layer of the CD, and so the pattern of pits can be scanned by using a photodiode to detect laser light that is reflected off the CD. The pits change how the light is reflected, which changes the electrical signal that is emitted by the photodiode. Those output electrical signals are amplified, passed to a loudspeaker and finally to my ears and slightly buzzed brain. (Obviously I’m talking about listening to music after work.) Continue reading “I don’t understand my CD player or my genome”

Personalized medicine versus human nature

Is genomics a medical game changer?

A brief review in the NY Times of recent books on ‘omics medicine:

In “Am I My Genes?,” the psychiatrist and ethicist Dr. Robert L. Klitzman plunges readers into the world of genomic medicine as it exists today: a barely mapped terrain of immense overlapping uncertainties. Many thousands of patients are bravely stumbling along in there: The book is based on interviews with 64 whose family history suggested a risk for the mutations associated with breast and ovarian cancers, the neurological killer Huntington’s disease or the destructive lung condition alpha-1 antitrypsin deficiency… Dr. Klitzman moves through all the basic landmarks, including the big ones: “Do I want to know?,” “Whom should I tell?” and “Why me?”

But for uninvolved observers, perhaps most striking is the book’s clear demonstration that science of the future notwithstanding, human beings faced with illness or its likelihood tend to react in the same old human ways. They protest, weep, change their diet, blame stress, consult a psychic, consult another psychic, accept the inevitable and generally muddle through valiantly.

In other words, the genomic revolution may not wind up changing the landscape of illness quite as much as its proponents may envision: patterns of thought and reaction run deep. As one of Dr. Klitzman’s patients remarks calmly, “It might run in families, but I don’t think it’s genetic.” She may have the family cancer, but “now, everyone is showing up with cancer.”

Well, when personalized, ‘omic medicine does more than just predict disease outcomes, when it actually and reliably leads to cures, remissions, etc., then people will have to accept the inevitable less often. I don’t imagine that this will put psychics out of business, but it will relieve a lot of suffering.

Genomycism: “Deflating the Genomic Bubble”

Genomycism – the unsubstantiated belief that the cataloging of the genomic sequence of an individual conveys useful understanding about their ancestry, current characteristics, and disease risk with high degrees of accuracy and predictive power.

An important policy forum article has appeared in the most recent issue of Science discussing the expectations for the benefits of genomics, the issues created when those expectations are unrealistic, overinflated, and over-hyped[1]. Continue reading “Genomycism: “Deflating the Genomic Bubble””

Trends in Genetics

Although it may not be obvious here, I also occasionally write formal scientific stuff, like a review article for Trends in Genetics:

Joshua T. Witten and Jernej Ule, “Understanding splicing regulation through RNA splicing maps,” Trends in Genetics (1, 2011). Continue reading “Trends in Genetics”

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