Science

Ignoring Proper Channels: The Fun Side of Fluoride

When Professor Chris Miller began his address to the less than capacity crowd in the Caspary Auditorium at Rockefeller University I couldn’t help noticing this felt underwhelming. This same auditorium has seen talks by countless Noble Laureates, at which times the room has suffered from such sever overcrowding that the lectures were halted until people were removed.

Now, an older gentleman looked out on the modest crowd with bright eyes and explained he would be talking about an ion channel (a designated avenue to move a specific element in or out of a cell) that allowed the passage of fluoride (a largely ignored element in biology) in bacteria, plants, protists, and simple invertebrates (all the types of life that have the least in common with human cells). This lecture had all the makings of an arcane and esoteric ramble in an uninteresting and unimportant field of biology.

But Dr. Miller is as much a showman as he is a world-renown scientist, and for the next forty-five minutes he proceeded to engage and enlighten the audience, proving why his lab has a tendency to produce legions of excellent researchers and teachers. Fluoride, Dr. Miller contends, has never gotten it’s time in the sun. Overshadowed by the heavier and more notorious chloride ion, fluoride is present everywhere in amounts as high as 100 micromolar (just under 1 part per million), and it is a known inhibitor of several essential cellular processes, namely metabolism and reproduction; or as Miller said, “it blocks food and sex.”

fluoride

Fluoride

Because of the chemistry of the cell, fluoride can enter a cell by permeating the membrane in the form of hydrogen-fluoride. Once it enters the cell, the hydrogen is stolen away and the potentially toxic fluoride is left to its own devices. Luckily, as Miller discovered, these cells have exhaust valves for fluoride – specific channels made of protein acting like pores to release the fluoride out of the cell. Channels allow passive movement (requiring no energy) where transporters are proteins that actively move ions (requiring energy). Dr. Miller’s channels, named FLUCs, (pronounced “flukes”) regulate the internal fluoride concentrations and effectively save the cells.

This in-and-of itself is a great finding; however Dr. Miller was taken by certain oddities about this channel. For the remainder of the lecture, Miller painted a beautiful picture of how this weird channel defied convention in numerous ways – it was incredibly specific; it works very fast; it has an “antiparallel” architecture, in which the two subunits are identical but the interact with each other when rotated 180 degrees; the ‘channel’ actually has four internal pores! Each of these findings is interesting to a hard-core physiologist or biophysicist. Dr. Miller managed to make each impressive to an even broader audience.

miller

Chris Miller PhD is a professor at Brandeis and has trained a generation of biologists.

In a talk peppered with nerdy jokes (“at least in Massachusetts, we do not violate electronegativity”) acknowledging the at-times cumbersome nomenclature (“it’s not voltage-dependent, not calcium-dependent, not N-A-P-O-D-whatever dependent” – NADPH is an import substrate that stands…for something) and even prone to editorial (“this channel just sits there like a moron with it’s mouth open!”) Miller managed to jam enough fundamental cell biology in to make even the surest biologist confident they were learning something. His delivery mimicked Lewis Black, from his intonation, to his hand waving, to his occasional excoriation of some unseen foe (“‘channel, transporter, same thing’ – NO THEY’RE NOT the same thing!”)

Having studied biophysics, to me Miller did the unthinkable – he made an hour-long lecture about an ion-channel incredibly fun and informative. His approach and mentality are key – I was fortunate to speak with him after the lecture and ask him some questions and he relished in the opportunity to further discuss FLUCs, fluoride, and anything even remotely related to his research. The enthusiasm he has is true and unfettered.

Perhaps most impressive is the fact that he is able to inspire so many graduate students, post-docs, fellows and researchers to continue in this field. Many are drawn to sexier and higher-paying research targeting cancer, or heart disease. As Miller put his work, “it is completely removed from the bothersome problem of human health. That way, I can enjoy the protein for itself!”

FLUC.jpg

The actual FLUC channel as represented with protein structure software (memprotein.org). The white/grey sphere is an oddly placed central sodium ion. Weird!

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