metabolic pathway 代謝途徑
biosynthetic pathway 生合成途徑
Going by the book
Jan 10th 2008
From The Economist print edition
A group of Chinese scientists has discovered the main biochemical pathways in drug addiction—and without having to do a single experiment
MODERN biology has a lot of “omes”. The genome—all the genes that go to make up an organism—is a familiar idea. The proteome—all the different proteins—is becoming so. But there are also the transcriptome (RNA), the glycome (sugars), the lipidome (fats) and the metabolome (all the miscellaneous odds and ends not covered by the others). And then there is the bibliome—all the mentions in research papers of known biomolecules. There are now so many of these papers, and the databases linking them are so good, that it is possible to use scientific methods to investigate the bibliome in its own right, just as any of the other, wetter “omes” may be investigated. Which is exactly what a group of researchers from Peking University, led by Wei Liping, have done to get at the biochemical heart of drug addiction.
Dr Wei and her colleagues wanted to answer three questions. First, what are the genes and biochemical pathways in addiction? Second, does addiction to different substances involve the same core biochemical mechanisms? Third, does anything in those mechanisms explain why addiction is so hard to shake off?
Many people, of course, have asked these questions before, and partial answers have emerged. What Dr Wei hoped to do was to take these fragmentary answers and patch them together to make something approaching the whole truth. And, in a paper just published in the Public Library of Science, she seems to have managed just that.
It looks good on paper
Dr Wei's group looked at more than 1,000 studies of the biochemistry and genetics of drug addiction. They were interested in the four sorts of drug reckoned most addictive: alcohol, cocaine, nicotine and opiates (heroin, methadone and so on). About 1,500 genes were implicated by one or more of the studies, but in only 396 cases was that implication backed by at least two independent lines of evidence. It was on these confirmed cases that Dr Wei concentrated her fire.
Biochemistry is about pathways and networks of pathways. A pathway is a series of enzymes (each of which is encoded in a gene) that perform a task in sequence, like workers on an assembly line. Dr Wei therefore ran her 396 genes through a database of all known pathways to see which involved several enzymes encoded by those genes.
She found 18 that were involved in addiction to at least one type of drug. Five, however, were common to all four types, and these five pathways therefore look as though they are at the core of the process of addiction. Three of the five were already under suspicion. Dr Wei's result provided strong statistical evidence to back up what had just been hunches. Two other pathways, however, had not previously been considered as being involved in addiction.
The existence of these five central pathways helps explain a lot about addiction. First, it gives weight to the belief that some people are more susceptible to all sorts of addiction than others are. That contrasts with the thought that addictions are substance-by-substance phenomena, though the two ideas are not mutually exclusive since changes in the 13 substance-specific pathways clearly also result in addiction.
Second, the particular pathways involved help to explain why addiction is so hard to reverse. Several of them take part in strengthening the connections between nerve cells, which is the underlying basis of learning. Unlearning something by breaking these connections is hard.
Third, Dr Wei was able to link the five central pathways together into a network, and show that this network has four positive-feedback loops in it. Work on other species in other contexts suggests that the mixture of loops she found was one that often results in rapid and irreversible biological processes—which is exactly what is seen in addiction.
None of this, of course, directly helps the addict, though it reinforces the message that it is better not to start taking these drugs in the first place. But working out how the addiction machine operates may point those looking for therapies in the right direction. And this study also shows that the old cry “more research is necessary” is not always true. Sometimes all you need to do is look at what you already have in a different way.
Liping Wei, Ph.D.
Center for Bioinformatics, College of Life Sciences