Some Concerns about Negligible Chances: Bisphenol A

Lately bisphenol A has been causing some fuss. Here it is:
The problem is that it looks a little like estrogen:

(Both pictures from the Wikipedia entries for the respective molecules)

Bisphenol A is used to make plastics, like baby bottles, Nalgene bottles, etc. The two OH groups on the end are useful little groups that can do some reactions and make the plastic work right. And if it's used in a baby bottle, and the baby's estrogen receptors react with the bisphenol A ... then strange, bad things could happen in the body. I know some of that plastic gets into the kids' systems: for my boys, sippy cups might as well be chewable rawhide bones from the way they gnawed on them. All those strings of plastic sure look toxic hanging off the end of the spout. But then again, my kids would (and probably do) chew the lawn when I'm not looking, so I'm not going to worry too much about milligram amounts of anything.

The real question is, does the body get confused? Does bisphenol A look enough like estrogen to cause a problem?

You know, it's not out of the question that it could happen in some cases. There are about 10 papers of studies with mice that suggest something could happen (although different stuff seems to happen in each study). And so, if Nalgene wants to stop using bisphenol A, then fine, and if we want to do more studies, we should. The evidence for a wide-scale out-and-out ban, or what Canada is considering, is simply not there.

I'm echoing the recent judgment of a panel convened to look into this is as follows, for current exposure levels to bisphenol A:

Neurological damage to children or infants --> "some concern"

Bad effects on pregnant women, fetuses or adults --> "negligible chance"

I actually have been most concerned about the pregnant woman thing, but the studies so far don't support that concern. I just don't see how bisphenol A looks enough like estrogen to confuse the body's receptors. Remember that there's tons of hormones, include testosterone, that look even more like estrogen but bind different receptors and act differently. Bisphenol A is very different from any of those hormones.

The evidence is not enough for me to suggest a wide-scale ban. Let the plastic bottle-makers make bottles and label them "NOW with NO BPA!" and let the parents buy those if they're worried. But 10 somewhat touch-and-go studies on mammals isn't enough evidence to overturn an industry. Not to mention my own eyes tell me they're not really all that similar. Now, I could be wrong -- sometimes more dissimilar things do interfere -- but I'm going to demand proof before I go against what I can see with my own two eyes.

Here's a link to the American Chemical Society article on the panel's findings:
http://pubs.acs.org/cen/news/86/i16/8616notw6.html

Onward Atheist Church-Goers

Fascinating article in the New Yorker, titled "If God is Dead, Who Gets the House?":
http://nymag.com/news/features/46214/

Buried near the end is the fact that the "four horsemen" of atheism can't agree on a name for their movement (free advice: don't make your own "bright" name, take the disparaging term others hang on you and wear it with pride. Worked for the Big Bang and Christians both). Buried near the beginning is the fact that one of these societies was started about a hundred years ago and seems, well, about as big now as it was then.

I want the atheists to form churches. Then they'll see the same things they criticize with Christianity happening to them. It's like the difference between criticizing parents before you have kids of your own and actually having to be a parent yourself!

And, if the churches take, and they do some good ... then I'll rejoice with the strange unnamed grace that keeps even them afloat. Seriously, they should go for it.

The other nice surprise from this article was that Richard Dawkins likes to sing Christmas Carols. How this jives with his suggestion to replace Christmas with the celebration of Isaac Newton's birthday I'm not sure, but I am sure there's some bad poetry to be contrived in turning carols into secular celebrations of science (first idea: "Jesus Christ the Apple Tree" because "Issac Newton's Apple Tree" and concerns falling apples and falling moons!).

Experimental Biology 2008, Part 3

• There are three phases of cancer immunity: 1.) Elimination 2.) Equilibrium and 3.) Escape (meaning the tumor escapes from the immune system and grows and is detected). NKG2D and friends are involved with step 1, while adaptive immunity is involved with step 2.

• Another talk I didn’t even have on my docket proved to be the star of the day. MICA is apparently very important to the process of a cell going from just a messed up little cell to a full-blown myeloma. It looks like when the cell figures out how to shed MICA it can progress to that worst stage. In fact, some myeloma drugs work by triggering the double-strand-DNA-break response and causing MICA to be put onto the cells. Anti-MICA monoclonal antibodies can vacuum up the soluble, shed MICA and help keep the myeloma in check.

• In other news, sometimes tumors figure out how to retain MICA inside the ER so it can’t get out. This is an old virus trick – so tumors may be able to pick up on the tricks of those nasty little viruses.

• You can make artificial Antigen Presenting Cells (APCs) with just 5-6 MHC-peptide complexes on them, plus some ICAM-1 and B7-1, and they can activate T cells for you. Could this work with MICA? What coreceptors would be needed?

• I finally figured out what kind of therapy our lab’s super-MICA could be good for: DNA vaccination. A poster showed how DNA vaccination with the NKG2D ligands Rae-1 and H60 helped “helpless” T cells remember how to attack antigen (in this case, ovalbumin). This is perfect for our eventual super-duper-MICA, because it’s encoded in DNA and can be delivered through a DNA vaccine.

• And, in the last talk I saw, I found out that a few years ago someone upended one of the points I make in biochemistry class. It turns out that in collagen, hydroxyproline is not really needed to interact with water and make the hydrophobic proline acceptable to water. Nope, it’s important because it’s an electron-withdrawing group that converts the mostly-cis Pro into mostly-trans hydroxyl-Pro: it helps set the right backbone configuration! The key is that F works as well as OH for stabilizing the molecule. So ... I guess I’ll have to change that slide ... can't I just use the same slides from year to year without them changing from underneath me??

Experimental Biology 2008, Part 2

• NKG2D, my favorite immunoreceptor, is implicated in a mouse hepatitis model and liver cancer as well. An NKG2D domain stuck onto a CD3 tail inside the cells makes for T cells that attack and destroy ovarian tumors in mice.

• In the strange connections between projects department: dimethyldisulfide (very close in structure to diallyl disulfide from our garlic project) is associated in mice with particular MHC molecules (very similar to the MICA proteins I study). It’s how mice can “smell” whether a potential mate has a compatible immune system or not. Weird.

• Rats have molecules like MICA too, and after a liver transplant they pop up all over the liver and may play a role in transplant rejection.

• Walter Englander spoke about hydrogen exchange. He doesn’t agree with the “everything at once” school of protein folding but thinks folding happens in discrete steps. This means folding is not so much a smooth funnel as a mountainside with rivulets (and pools) running down it. The steps of folding are foldons, sequentially stabilized units. One basic kind of foldon is probably the N- and C-termini coming together and forming a surface that the rest of the protein builds off of. Ten years from now he predicted that we’ll be sitting at a conference talking about foldons and how they relate to on/off rates, structural changes, equilibria, etc. Well, I’m interested in the idea because right now MICA sure looks like it’s got an incomplete foldon at the binding surface that depends on the presence of NKG2D to complete. Is this why we got our unexpectedly increased on-rates? Hopefully in 10 years I’ll have something to say about it. In the meantime I hope to figure out how to get access to an LC-MS so I can try HX. (Also, this just occurred to me: what’s the relationship between Englander’s foldons and Schreiber’s binding modules? Both are determined by cooperativity, after all.)

• RosettaDesign’s new “backrub” function looks possibly useful for resolving our current problem with the tryptophan mutant. If it doesn’t work, then it means larger-scale motions are responsible for the good binding.

• An ensemble view of proteins was presented that seems a good explanation for how communication through cooperativity happens, and why it’s so hard to nail down a specific pathway sometimes: because cooperativity may often be an attribute of the entire ensemble of states, not just amino acids lined up like dominos. It’s an example of how order can emerge from random mutations.

• Then some single molecule studies were presented for pulling apart proteins with optical tweezers. It’s fun to watch the proteins fold and unfold. Also, note it's how GroEL works, by pulling the protein apart and giving it another chance to refold. GroEL is a merciful protein!

Experimental Biology 2008, Part 1

So I returned last Wednesday night from a San Diego convention. It's unusual for me to attend a convention in the middle of the quarter, but the timing worked out and I had an able and eager sub waiting to step in and teach for me ... so I went. Culinary highlights include In-N-Out Burger and the best $3.50 chorizo burrito ever. Academic highlights I'll include as a multipart bulleted list. These are what I found "worth it" from the convention, and I'll try to make it general but this is part diary, part blog post:

• If you get infected with a virus early in life, it may change your cells so that later in life they learn to attack cancer. The reason is that altered-self peptides get put onto your MHC molecules and seen by T cells. Those altered-self peptides happen when great stress happens: viral, bacterial inflection, or cancer-related stress. What I find interesting is that this is an adaptive immunity version of the mechanism I study in innate immunity. Do the two have anything to say to each other?

• Not only do NK cells have about 10 different kinds of receptors that vary from man to man and mouse to mouse, not only do each of these receptors bind a different array of ligands with different affinities, BUT the receptors (one called 2B4 in particular) can switch from activating the immune system to inhibiting the immune system depending on the number of receptors on the cell surface! AND the same receptor can have an inhibitory tail region or an activating tail region depending on the context! To which I say: yipes. One of the reviewers of my recent grant commented that they’d prefer to see me go around and measure affinities of different receptor-ligand combos so we understand how they work. Maybe I should eventually do that, but if the number of receptors on a cell changes whether it turns things on or off, affinities are obviously only part of the figure (and the most important part to that question is what happens on the surface of a real, live cell – I can only do so much with purified protein). So I’m justifying my current direction, and, after all, that reviewer did give me a good enough score that I got my great renewed, so I guess the objection wasn’t that big.

• We can actually watch T cells, B cells, viruses, and macrophages running from room to room within the lymph nodes now. Cool pictures. Link at http://cbr.med.harvard.edu/labs/vonandrian/Pages/nrivideospage.html

• You can measure low-affinity protein-protein interactions using concentrator filters and SDS-PAGE gels. The only problem is the separation the concentrator can do will vary from box to box of concentrators. I still think it’ll make a good undergrad lab.

(TO BE CONTINUED)

The Haul from the Latest Library Book Sale

Because we had tickets to the (excellent) baseball game Friday night we had to skip the member's preview night for the Seattle Library Book Sale out at Sand Point. So instead after church we packed up and headed out there for half-price day. Generally the tables are getting bare and the pickins slim by this point, but this year ... this year I got everything I wanted and then some.

Here's a partial list:
4-box set of Wagner's Ring Cycle on vinyl with libretto, notes, and a three-disc introduction to the various musical motifs. It even looks nice in the family room! Already listed to Das Rheingold last night and it's gooood.
3-LP set of Bach's St. Matthew Passion
3-LP set of Prokofiev piano music including "music for children"
Two guidebooks on London, one with a map.
Lots of Boxcar children paperbacks for Sam.
One Steve Birnbaum 2007 Disneyland guide for Aidan.

The only thing I didn't find was a good book on Perl, and I don't really need that so long as I can borrow Eric's. (Thanks, Eric ...)

Book Review: The Runner: A True Account of the Amazing Lies and Fantastical Adventures of the Ivy League Impostor James Hogue

This one's a fast read (good thing, too, since it's already overdue), and an engaging story about a man who faked his credentials to land a spot at Princeton. Much of the book started life as a magazine article, and it tells its story (mostly) backward. This choice has the nice effect of "peeling back the layers" of the con man at its center as you devolve through his various identities, but it's not always pulled off gracefully or easily. It also has the disadvantage of starting the story with the con man in Telluride, CO rather than at Princeton, where it's just an ordinary story of a man who lies to people and steals stuff, and you don't get to the real questions -- such as, "How did he lie his way into Princeton?" -- until halfway through the book. Also, the question "Who is this guy really?" has to wait till the end, but that's OK with me because of the deliberate structural choice.

Along the way you get analysis of how he did it and puzzlement as to exactly why. This puzzlement leads to a lot of theorizing, some of it valuable and some, well, not. For an example of the latter, see the chapter titled "Christmas is the Biggest Lie of All." Not sure what that has to do with college admissions or stealing bikes. Generally, when this book talks about the Princeton application it's firing on all cylinders. The rest of it is forgettable, but at least quickly read.

Now I'd better turn it back in before I owe another 50 cents!

Book Review: The Brief Wondrous Life of Oscar Wao

Ordinarily this book would look too much like typical fiction for me to read it, because it's the story of a family from the Dominican Republic suffering under the Trujillo dictatorship of the mid-20th century. Well, not only is it supposed to be a particularly well-written example of the genre, but the title character, Oscar Wao, is actually a Dominican fantasy nerd who reads Tolkien and Asimov and everything inbetween. So, being a fantasy nerd myself, I wanted to see how the author did in writing a character like that realistically.

The answer is that Diaz nailed it. His portrait of Oscar Wao is so precise that even though a Dominican fantary nerd may never have existed on the earth, he gets the kind of details that are so accurate that they hurt. Reminds me of parts of high school that have been long since forgotten. Now, Oscar is more of a fantasy nerd than anybody else I know, taken to extreme in his focus, and that exclusion of other aspects to his life is about the only part of his characterization I can find fault with. What music does he listen to? What god does he believe in? You find out some of that through his actions, but I would have liked to know more.

This is a very well-written book, and it's only partially about Oscar. His mom and sister and sister's boyfriend get equal billing and narrative viewpoint passages. The book jumps back and forth in time and employs the Lost storytelling technique of starting in one time and then jumping back and forth to show us why that person is such a jerk, or ran away from home, or whatever. Actually, Lost stole that technique from comic books, so it's particularly appropriate for this kind of book.

The unmitigated Sauron-like evil of the Trujillo regime becomes slowly apparent as the book progresses. After reading about what it was like to live under that dictator, I was reminded of Jared Diamond's book Collapse, where he argues that for all its faults, the Trujillo regime was actually pretty good on environmental protection. For instance, you can see the Haiti-Dominican border from the air, because on the Haiti side the forests have been cut down straight to the border, while on the Dominican side they are untouched. Diamond recognizes that lauding Trujillo in any way is problematic, but I don't think he knows just how problematic it is. I think he should read this book -- I'd like to know if it would change anything for him.

This is indeed a bloody book, as its cover indicates. It captures the Caribbean character better than any other book I've read, but it certainly takes a bit out of you to read it and live in that world. Be warned.

How to Bridge the Worlds

On the mp3 player during the commute this morning was a talk by Darrel Falk, professor at Point Loma (I think), a Christian and biologist who writes about evolution. He first talked about the obstacles he faced publishing his book, and especially getting a prominent evangelical to write the forward to it. It seems there was a prominent leader who privately agreed with his book but wouldn't write a forward to it, even though they were good friends, because of the politics of the situation among evangelicals. Then a prominent ID proponent agreed to write a forward, was gracious in person, but ended up writing a forward saying that science and Christianity must "get a divorce," much the opposite of the book's own conclusion. So that wouldn't do either. Finally Francis Collins came along and wrote the forward.

After a story like that of frustration and private/public splits, I was expected a talk about the book itself. But that's not what Falk did. Instead he launched into a detailed, nuanced and sympathic discussion of why there is this split at all, with a focus on what kind of "loose ends" are so troubling in accepting science's view of the world. His tone and demeanor were the most Christian response I can think of (and, to my shame, they were not my automatic response when I heard his story!). He ended his talk with a discussion of how to bridge the worlds, that Christians with different views of the origins questions should deliberately get together and make videos or statements about what they believe and what they agree on. Now that would be right in line with what Jesus said about how the world will know us.

And then I realized another category of unity, perhaps the most essential one to the whole enterprise: if we are going the bridge the philosophical gaps between these two camps of Christians, the thing we need more than anything else is to worship together. All the manifestos and TV programs and everything would follow from that. If we spend thirty minutes, side by side, singing, reading, praying, then I think we'll find that the gap is not as wide as it looked before those thirty minutes. In fact, if we don't do that, I don't think we'll be able to bridge the gap at all.

This is what worship does, it brings us together. And that's why I think the worship part of the service is more crucial than the sermon, no matter how insightful or interesting the preaching. Worship is what we're about, and if it forms the foundation then we can do things where it looks like there's no hope, most important because we won't be doing it.

And while we're at it, bridging the worlds, let's pattern our worship off Revelation, to deal with the gaps in understanding that book too.