Archive for: February, 2013

Condemned to a Skeletal Prison

Feb 28 2013 Published by under Science

*Re-blogged from Amasian Science for Rare Disease Day.


ResearchBlogging.org

Imagine going to sleep and waking up the next morning not able to bend your elbow or knee. Or imagine having difficulty drawing breath because your rib cage is starting to fuse. Imagine being unable to enjoy your favorite cut of steak because your jaw has locked into place. Even worse, imagine having a limb amputated because you've been misdiagnosed with cancer. This is the harsh reality facing patients with fibrodysplasia ossificans progressiva (FOP), a rare, genetic disease affecting 1 in 2 million people (700 known cases worldwide, 185 in the US), where soft tissues--like muscle and connective tissue--are progressively replaced by bone. Often beginning in the neck, ribbons of bone spread through the shoulders, along the back, trunk, and limbs of the body eventually freezing patients in a skeletal cage.

Curiously, FOP patients are born by and large symptom free, the only consistent tell-tale sign being malformed great toes:

Extraskeletal bone formation occurs sometime in the first two decades of life, usually during childhood. Bone formation is preceded by a painful, inflammatory flareup, the cause of which is unknown. A particularly insidious feature of the disease is that trauma or injury can induce these flareups, meaning that undergoing surgery to remove the extra bone only exacerbates the problem. Bumps and bruises we typically overlook cause alarm for FOP patients. Even injections, such as vaccinations, are a source of concern. Currently, while there is no cure, treatment revolves around reducing inflammation and controlling pain using corticosteriods, NSAIDS, or COX-2 inhibitors such as Vioxx (before it was pulled from the market).

A mystery unraveled

While the earliest description of FOP dates back to the late 17th century, the cause of the disease remained an enigma for centuries until 2006, when researchers at the University of Pennsylvania linked the disease to a mutation found in FOP patients (1). The mutation affects one copy of the ACVR1(ALK2) gene, which encodes a protein important in relaying communication between cells. In the body, cells can send signals to instruct other cells to start forming bone via Bone Morphogenetic Proteins (BMP)--thus named for their ability to induce bone growth. ACVR1 is a type I receptor for BMPs and, with the help of the BMP type II receptor, acts like an antenna that receives these signals and transmits the encoded instructions to the cell.

Cellular messaging. Cells communicate with each other by sending proteins "messages" that are received by receptors on the cell surface. BMPs are just one of many types of different protein messages. These messages can instruct other cells to grow, divide, transform into other types of cells, or even self-destruct. This is analogous to people communicating by text message. BMPs and the ACVR1 receptor can be thought of as the text message and the cell phone receiving the text message, respectively.* 

Studies in zebrafish, fruit flies and mammalian cell culture all indicate that the mutant ACVR1 receptor linked to FOP has gone rogue, capable of transmitting the instructions without having to receive the initial BMP signal (2-4). The mutant receptor acts as though its power switch has been permanently flipped to the "on" position. More recently, scientists have provided even more direct evidence that the mutant form of ACVR1 is responsible for FOP. Through a trick of genetic engineering known as "gene knock-in", the researchers at UPenn were able to replace one copy of the normal ACVR1 gene in mice with the mutant form associated with FOP. The resulting mutant mice displayed many of the hallmarks of FOP: "malformed first digits in the hind limbs and post-natal extra-skeletal bone formation" that occurs both spontaneously and as a result of injury (5).

Adapted from Figure 2 (5). (A) Characteristic great toe malformation in FOP patient. (B) FOP mutant mice (right panels) displayed malformation of the first digits of the hind-limbs (circled) at birth. (C) Skeleton of FOP mouse with arrows to indicate extra-skeletal bone formation. Fusion of cervical vertebrae (C3-C5) (D), fusion of costovertebral malformations and fusion of vertebrae (asterisks) (E), and abnormal bone growth (arrows) (F) are observed in the mouse and FOP patients.

One of the limitations of their knock-in technique, however, was that the replacement of the normal ACVR1 gene with the mutant version was incomplete--it occured in most, but not all, of the cells in the mice. This produced chimeric mice, which were mosaics of cells that had one copy of the mutated ACVR1 gene ("FOP" cells) and cells that had two normal copies of the ACVR1 gene. Exploiting this mixed nature of the mice, the researchers were able to study how "FOP" cells interacted with normal cells. Surprisingly, they found that in the presence of "FOP" cells even normal cells were turning into bone. This suggests that cells that have the faulty ACVR1 receptor can also instruct normal cells to turn into bone through an unidentified mechanism.

Marching toward a cure

With these findings scientists are beginning to devise strategies and design drugs that can either specifically turn off the expression of the mutant ACVR1 gene or turn off the aberrant activity of the mutant, providing hope that a cure or, at very least, an effective treatment is on the horizon. While some of these avenues are promising, a viable treatment is far from reaching the market. To find a cure will require more research, which in turn requires money. Because FOP is such a rare disease it often flies under the radar when it comes to research funding. Currently, an estimated $1.5 million a year is spent on FOP research, 25% of which is funded by institutions like the NIH and the Orthopaedic Research and Education Foundation. Incredibly, the remaining 75% is generated through donations and FOP family fundraising. If you would like to help or find out more about FOP, please visit the International FOP Association website.

Featured Image: Harry Eastlack, a man who lived with FOP, donated his skeleton to science. His skeleton is on display at the Mütter Museum.

1. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May;38(5):525-7

2. Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest. 2009 Nov;119(11):3462-72. doi: 10.1172/JCI37412

3. Le VQ, Wharton KA. Hyperactive BMP signaling induced by ALK2(R206H) requirestype II receptor function in a Drosophila model for classic fibrodysplasiaossificans progressiva. Dev Dyn. 2012 Jan;241(1):200-14. doi: 10.1002/dvdy.22779

4. van Dinther M, Visser N, de Gorter DJ, Doorn J, Goumans MJ, de Boer J, ten Dijke P. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res. 2010 Jun;25(6):1208-15

5. Chakkalakal, S., Zhang, D., Culbert, A., Convente, M., Caron, R., Wright, A., Maidment, A., Kaplan, F., & Shore, E. (2012). An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva Journal of Bone and Mineral Research DOI: 10.1002/jbmr.1637

*7.10.12 - Updated figure. See this post.

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Vetting My Outsider Reader Candidates

Feb 22 2013 Published by under Late-stage PhD student

I recently went through the process of choosing an outside reader for my PhD thesis. An outside reader is generally faculty from another institution (or sometimes another department) that is brought in “to keep the "inside" people honest, and make sure wacky things aren't going on.” Keep the funny business to a minimum.

Anyway, this was something I took fairly seriously. Influenced, perhaps, by my recent obsession with The West Wing, I came up with a shortlist of candidates and put them through vetting that would make the selection process of some vice presidential nominees look like child’s play (looking at you, McCain ‘08).
I applied multiple litmus tests to the candidates, such as how hir area of expertise would complement the expertise already present on my thesis advisory committee, hir working relationship with my PI, hir proximity to my institution, and of course, hir h-index (kidding). The process, in fact, wasn’t so dissimilar to picking faculty for my thesis advisory committee.

If you went through this as well, I’d like to hear how you chose your outside reader? What were some of your considerations? Or was it just another box to check off?

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#Altcareer in Mixology

Feb 21 2013 Published by under Late-stage PhD student

For all of you PhD's-to-be,

Here are 7 charts depicting the state of the job market for young scientists...just to bum you out a little. Fun stuff.

On a brighter note, if this whole "biology-PhD-career" thing doesn't pan out I think I might have a promising future in mixology.

Behold my latest creation: The Pink Martinez.

pink-martinez-gin-martini-recipe-on-man-fuel

 

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An Eco-Friendly Valentine's Dinner?

Feb 13 2013 Published by under Potpourri

For Valentine's dinner, my girlfriend would like to cook Red Snapper en Papillote. It's basically a fish cooked in a paper bag:

red snapper en papillote

We're trying to do the eco-friendly thing on this one since red snapper is apparently overfished. The Monterey Bay Aquarium Seafood Watch suggests alternatives, but I'm looking for something with a high probability of being found at the local supermarket. Consulting Google I found that cod, snapper, sole, trout, orange roughy, sea bass, grouper, redfish, pompano, rockfish, even tilapia or catfish can all be used.

Sooooo...basically any fish will do? Really?

Help me out folks.

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Chúc Mừng Năm Mới...why I'm bummed out about Vietnamese New Year

Feb 10 2013 Published by under Asian Americanism

It means Happy New Year.

Today is Tết, the Vietnamese Lunar New Year and we're ringing in the Year of the Snake. And while it should be a day to celebrate, I'm bummed out for a couple of reasons--one of which is here at home and the other is all the way out in sunny California.

Now normally, I'd be spending the day with my family honoring our ancestors with offerings of food, incense, and all that good stuff. And on Tết, when I was younger, all the older members of my family would give me  lì xì, or "lucky money" in little, red envelopes--one of the benefits of being the youngest in the family. Now, it's my niece who gets all the lucky money.

lì xì envelopes

And of course, we'd eat. My mom generally prepares a delicious feast for Tết, and my favorite of all the dishes is bánh chưng, which is sort of like a square-shaped pork,mung bean, and sticky rice tamale. Nothing beats bánh chưng sliced-up, pan-fried, and served with pickled shallots and daikon. Bánh chưng is one of the  most traditional Tết dishes--the other being bánh dầy. The creation of both dishes is rooted in Vietnamese mythology, when the legendary king, Hùng Vương, held a competition to choose a successor among his sons. The son who created a dish that best honored their ancestors would assume the throne. While most of Hùng Vương's sons scoured the country for rare and exotic foods for their dishes, Lang Liêu, the poorest son, created his dishes with the simplest of ingredients. When asked about his dishes, Lang Liêu explained that the square-shaped bánh chưng represented the Earth (back when my peoples thought the Earth was square), while the circle-shaped bánh dầy represented the Heavens and that his two dishes brought harmony between Heaven and Earth. Impressed by the simplicity and symbolism of the dishes, Hùng Vương picked Lang Liêu as his successor.

Bánh chưng

Unfortunately for my family and me, "Nemo" just dumped about 2 feet of snow on us and many of the roads still haven't been cleard. So instead of celebrating with my family and enjoying bánh chưng, I'll be spending the day shoveling and digging my car out. Sorry ancestors, y'all will just have to hang tight until next weekend for your food and incense.

But really, it's what's going on in California that has me bummed out the most. While I'm stuck here in the snow, one of the largest Vietnamese communities in the US, "Little Saigon" in Westminster & Garden Grove, CA will be celebrating the New Year with a Tết parade.

Except parade organizers are not allowing Vietnamese LGBT groups to officially march in the parade. In past years, when the city of Westminster organized the parade, LGBT groups were welcome to participate officially. This year, however, since the city was financially unable to organize the parade private groups stepped in to fund it. And they are opposed to LGBT groups participating in the event. Their objections?

"We do respect them," said parade organizer Neil Nguyen. "But that type of life is not accepted yet in our culture. Our culture is based on family values, men and women, husband and wife, God and people." (source)

The Tet parade is a celebration “to pay respect to the founding ancestors, paying respect to elders, educate youth about traditions, heritage and ceremonial celebration of the new year,” Rosen wrote.  Organizers believe that LGBT “has a purpose and a theme that strays and varies from the theme of the Tet parade.” (source)

But as Jimmy Nguyen writes, "the Vietnamese community in Little Saigon and anywhere else will lose nothing of their heritage if LGBT people march in their Tet parade."

Since the parade is being privately funded, they argue that they have the right to deny applications submitted by LGBT groups to participate.  In response, rivaling petitions have popped up on the internet (along with some upsetting comments). LGBT groups have sought help from the courts but "Orange County Superior Court Judge Geoffrey T. Glass declined to grant an injunction requested by the Partnership of Viet Lesbian, Gay, Bisexual and Transgender Organizations." After the court decision, one of the lawyers for the parade organizers stated, "We respect everyone's 1st Amendment rights." Yet strangely, the subject of public kissing was on the negotiating table between parade organizers and LGBT groups. Needless to say, I've spent the past few days frustrated by the feeling that part of my community is a step behind the friggin' Boy Scouts (although, there now seems to be some backpedaling on that front).

I should emphasize here that LGBT Viets are not barred from marching in the parade just LGBT groups under an official capacity. So, I hope that my LGBT brothers and sisters are not discouraged from participating today. I hope that LGBT Viets and their allies will march in the parade and be vocal and be visible to the community. I hope that the New Year brings with it more acceptance of LGBTs in the Vietnamese American community.

 

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Landscape-to-portrait switcheroo

Feb 07 2013 Published by under Late-stage PhD student

If you're like me then you probably prefer reading papers in, well...paper form. Even though I fancy myself a pro-digital kind of guy, I don't really enjoy reading pdf's on a monitor. Not being able to see the whole page of a paper onscreen just kills me. Yes, I know I can zoom out, but then the font's all extra tiny and shiz. Also, scrolling up and down is a pain in the ass.

Then, I noticed what a fellow grad student in the lab did, which I hadn't thought of before. He took his monitor and pulled the ol' landscape-to-portrait switcheroo. Boom, problem solved.

Portrait Monitor

Just turn the monitor dawg

*** UPDATE ***

The same graduate student just reminded me that PubReader offers an enjoyable web-based reading experience for papers archived with PMC--independent of monitor orientation.

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