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Dogma derailer

June 11, 2009


Li-Na Wei.

A dynamo in the field of pharmacology, Li-Na Wei has made profound discoveries about how cells work.

Photo: Patrick O'Leary

Upsetting long-held scientific ideas has made pharmacology professor Li-Na Wei stand out

By Deane Morrison

In the world of science, challenging an idea that has become enshrined as "the rule" is no cake walk. Researchers who discover exceptions, even with solid data on their side, often find it takes moxie to swim against the current.

Meet Li-Na Wei, pharmacology professor and upstream freestyler extraordinaire. Still in mid-career, she has already upset enough established ideas about cells in general and neurons in particular to fill several professional lifetimes.

Recognizing her formidable contributions,  the University's Graduate School recently named Wei one of four new Distinguished McKnight University Professors (see sidebar). In nominating her, Wei's department head, Horace Loh, characterized her impact on science as a "persistent and bold challenge in defying dogmas to reshape the course of studies in her field. ... [M]ost of her findings turn out to be fundamentally and generally significant."

Vital vitamin work

In a major discovery, Wei upset a long-held notion that hormones always act on genes by turning them on—not off.

"The dogma was that hormones always activate the genome," she says. "Of course, I went along with what everybody said. When you get a result that goes along with the  mainstream, you talk about it, but if it's against the mainstream, you hide it."

In good company

Besides Li-Na Wei, these faculty members are new Distinguished McKnight University Professors: Marla Spivak, entomology; Bin He, biomedical engineering; and Joseph Konstan, computer science and engineering.

She worked with retinoic acid, a form of vitamin A that acts as a hormone. In the old view, when a hormone like retinoic acid or estrogen gets into a cell, it flicks a biochemical "on" switch for a gene or genes. The cell then reads and carries out the instructions encoded in the genes.

Retinoic acid was thought always to turn on a certain gene that plays a role in all essential life processes, including embryonic development. In studying a particular line of embryonic cells, Wei found the same thing--until the cells began differentiating into adult cells.

"What people missed was that when [the cell] goes into differentiation, if you treat it with the same compound [retinoic acid] , the [gene] activity can be opposite--that is, it goes down," Wei says. Shutting off gene activity is called repression, and Wei was the first to find that the same hormone could both activate and repress a gene.

This came as a bit of a shock to many researchers. But since Wei's 1998 report, many other hormones have been found to do the same thing. The implications are profound.

"A lot of drugs are developed based on a compound that can alter gene activity," explains Wei. Knowing that a hormone-based drug could sometimes repress a gene is vital for developing an effective drug and treatment regimen.

Factory pharms

In studying neurons that respond to opiate drugs, Wei scored a second major discovery that really ruffled scientific feathers.

Neurons have a spidery appearance, with a roundish cell "body" that contains the nucleus and many long extensions for receiving or passing on information. One such extension is called an axon, and those that run from cell bodies in the spinal cord to the tip of a toe, for example, can easily exceed two feet in length.

"I was called 'provocative' when I first proposed this"--and no one meant in the nice sense.

That makes for a long line of communication from genes in the nucleus to structures on the "front line" in a toe.

Sitting on the outer cell membrane of an axon are proteins that allow it to receive information. Like proteins in general, these "receptors" are made in cellular factories that store the machinery for "reading" messages from genes and translating them into proteins. In most cells, it's a short distance for proteins to travel from these factories to their final destiny.

The old dogma held that in neurons, translation of messages into protein occurs only in their cell bodies, not way out in the boonies at the tips of axons. If that were so, proteins destined to become receptors had to be made in the cell body and then transported down the axon as cargo, a process that could take a day or more.

But what if a neuron has to respond to a sudden flood of opiate drugs or other stimuli? In responding, neurons typically add (or remove) receptors to amplify (or dampen) these signals; this kind of activity plays a key role in neuron activities, including drug addiction and numerous other responses to the environment. Must the highly active but remote parts of axons sit around waiting for the next shipment of receptors?

Wei realized the answer was no. The translation factories that churn out receptors had to be closer to the places where the receptors were used.

"I proposed mobile factories," she explains. "In early 2000, I put forth a theory that you need to have certain messages from genes [about what proteins to make] ready to go to the assembly line [the factory] and produce proteins at a moment's notice. This means a neuron can be flexible in response to anything in the environment, and at any distance [from the cell body].

"I was called 'provocative' when I first proposed this"--and no one meant in the nice sense.

Since then, however, evidence has vindicated Wei: Neurons do run minuscule "railroads" that transport messages from genes to the remote areas of axons. There the messages set up shop, ready to churn out receptors or other proteins on cue.

Also, she says, blockage of such transport can be implicated in several diseases, including Alzheimer's disease. She cautions that this transport system may not operate in all neurons; however, it certainly does in neurons that respond to opiates, and it's important to know in what other neurons it does, too.

 As she continues her quest for knowledge, Wei is driven by insatiable curiosity about how the myriad biochemical processes in cells are regulated.

"That's most of life," she comments. "I want to understand how cells with the same [genetic information] behave so differently." 

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