Field of Science

Adrian Smith and Eric Cantor don't understand science, but know it ain't good

Here is a House Committee on Science and Technology member who along with Eric Cantor are enlisting your help (well, not you because you're reading a blog post at Field of Science not Answers in Genesis) to legislatively cut NSF funded grants.

This is being done in order to trim wasteful spending by those socialist bastards in Washington. For the record:

NSFs 2010 budget was                            6.9 billion
2010 costs for the war in Afghanistan      105 billion
DARPA budget was                                3.4 billion
Dept. Homeland Security 2011 budget    43.6 billion
     TNA TSA 2011 budget (see above)   8.2 billion

Interestingly, the DHS was founded in 2003; the NSF was founded in 1950. So, the NSF with its modest budget that has ever so slowly increased is probably wasting your money, unlike the DHS which had money thrown at it left and right and is certainly spending it wisely.

However, recently NSF has funded some grants Smith isn't happy with (unlike every other year when some halfwit legislator tries culling specific grants usually on evolution or birth control not to mention the dreaded stem cell). Thankfully, Smith tells us which ones are problematic by vaguely telling us what the grants are about. Of course, I expect he is misinforming us and he is not clear on the grants in question since he doesn't tell us a grant number, specific title, or PI name. You can find proposals that might be the ones Smith is worried about, but if you read the abstracts they don't say what he says they say.

Since the average family spends $10,000 in federal taxes (note he didn't say income tax, does the 10k  include FICA, I bet it does....douche), "should 75 families work all year to support soccer research?" Notice how he changes the focus? First the research was on computer models to understand the contributions of soccer players, not soccer research. I am not familiar with this work, but can see the implications, for example this may aid in the development of computer models to determine appropriate tactics in police or military teams going into a building, you know without the loss of life, or even to understand hunting behavior in animals (this is the basic research douchebag previously thought was good). I wonder if all the high school graduates in his district had any of those thoughts. Also, if we break it down the numbers, there are ~ 100 million families (I used # households from here) so multiply that by $10,000 and we get $1,000,000,000,000 ($1 trillion). This # is slightly less than the income tax revenue from 2010, so I expect my # of families is reasonable. Of that $1,000,000,000,000, $750,000 is going to fund soccer research says Smith. Except that isn't true (big fucking surprise). The $750,000 is the total for the grant, which is likely funded for 3 years, which is $250,000 of $1,000,000,000,000 or 0.0000025% of the federal income tax money. If we defund NSF entirely it will save 0.69% of the entire budget.

Way to go Adrian, you helped a lot a whole 1/100th of 1/100th of 25/1000ths of 1%!!!

Now the non-sequitur, before it was "what do you think" about some grants Im not really going to tell you about. Now its, go ahead and find grants you don't think support the hard sciences (who thinks Smith knows what the fuck that even means?) or you don't think are a good use of tax payer dollars. There! With that last clause Smith has told every Tom Dick and Harriet that all grants are fair game to be culled. This is despite the fact that most grants are not funded because the applicants couldn't convince experts (ie university academics) this was the best research to be done. I mean its all well and good if scientists that have trained in these areas for decades (you know those Noble Prize winners Smith seemed to think highly of) think this is a good use of tax payer money. What we really need to know is what the cashier at Target thinks about this research. I expect Smith will very soon be recruiting important constituent feedback for the DOD DOE FDA and TSA among others.

To guide his flock constituents, Smith provides some search terms to identify those grants you may not like. Evil words like "museum" and "success." It's almost as if Smith has identified grants he doesn't like and is helping to guide you to find them on your own and then tell him you don't like them. I suggest some different terms to identify grants, how about "Nebraska" or "North Platte" I saw one grant that wanted to renovate the toilets at a University recreational facility (using Smith's framing). I expect Smith will want to move quickly on all the wasteful tax payer money NSF is spending in his district. Other important search terms include "Virginia" and "Richmond" and you may find some grants funding Pakistan, which is where Bin Laden is hiding (again using the framing of Smith and cronies).

Just say it Smith, you don't like those smart fucking kids who got good grades in school and made you feel insecure. It does suck that these 'university academics' are trying to learn something about the universe we live in, which may actually amount to some important new breakthroughs or insights (but may not as well). I wish you had the balls to say you don't like the NSF or at least research that 1. you don't understand; 2. doesn't benefit the industries that fund your elections; 3. you still don't understand. Nope, instead like the coward you seem to be, you try to mobilize the masses to do the dirty work for you, then you can do what you wanted to do and plead that you are just following orders.

Sports and stats and why it doesn't matter

The big news last week in Minnesota is that Brad Childress the head coach of the Minnesota Vikings was fired after leading the Vikings to a 3-7 start this season. Admittedly the Vikings had self-destructed and a large part of that can be laid at the coach's doorstep. So the coach has to go right? Well, I think a few questions need to be addressed first. For example, why did the team self-destruct? and is this season a good example of a bad coach or an aberration?

Is Childress any good as a coach? Current conventional wisdom says the answer is a definitive "NO!" However, conventional wisdom in sports is as good as thinking with your gut when making foreign policy decisions. Let's look at some numbers to maybe get a sense of things. Childress took over in 2006 and the Vikings record each year was:

2006     6-10
2007     8-8
2008     10-6 playoffs
2009     12-4 playoffs/NFC championship game
2010     3-7*

So in Childress' first 4 years the Vikings continually won 2 more games than the previous year and got within a field goal of the superbowl last year. A consistent winner.

For comparison, prior to Childress, we had Mike Tice

2002     6-10
2003     9-7
2004     8-8 playoffs
2005     9-7

So Tice hovered around 50% the entire time he coached. Childress showed consistent improvement until the trainwreck of this year. So either the team got consistently better from 2006-2009 in spite of Childress or maybe Childress had something to do with it. Since the head coach is the head coach, Ill go with the latter hypothesis as most likely.

So why the trainwreck this year? I don't know, but I have a few thoughts. First, it seems likely that there was at least one poisoned apple in the locker room (Im looking at you Favre). One personality can be enough to ruin the good work of the rest of the group. Advice I got when I started my lab and have given others is that it is more important to get good people in your research group than simply warm bodies. These people have to work together and have to have the same basic goals. If one person comes in and makes for an unpleasant work environment or is constantly undercutting the lab head or other important person in the lab, bad things happen. When Brett Favre, almost certainly a hall of fame quarter back, comes in and disparages the leadership of coach Childress, bad things happen. Maybe you're not working as hard as you should and don't know the play book as well. Favre gives you an emotional crutch to not think about your personal failings or mistakes. See its the coach's fault, his play book is stupid, ask Favre, so why should I learn it?

Before Favre joined the team, 2009, the Vikings hadn't made it to the NFC championship game since 2000. So Favre must have made a difference. No question about from me, but the team was already much improved since Childress took over. With the drafting of Adrian Peterson in Childress' second year, the only position of dire need was quarterback. That position has been filled by journeymen since Duante Culpepper was traded after 2005. In fact, Favre was/is a stop-gap measure. So 2009 was phenomenal until the end (interception thrown by Childress Favre). However, there were already Favre-Childress problems, but I think winning kept those problems from flaming. After the loss, Favre retired and the Vikings needed to do something for quarterback....

...and looked no further than Tavaris Jackson before plan Favre II was quickly worked out. At the last possible second, so he wouldn't have to practice and Childress was desperate to the point of losing his hair. What? He was already bald? OK, and Childress was desperate to the point of sending 3 players to Mississippi on the down-low to get Favre back. So, virtually no practice with his receivers (of course it wouldn't have been helpful throwing to the back up for a few weeks before the primary receivers went down), still recovering from surgery, oh and a grandpa, Favre returns...and lays an egg. Now there are many problems this year and it is BS to lay the 3-7 record at Favre's feet, but Favre, I believe, fanned the fires of discontent for the coach with many others on the team. Favre became a poisoned apple.

Childress had a history fielding a playoff caliber team; Favre had a history of retiring. So now the coach is gone, the season is kaput (barring a non-sectarian miracle), and the quarterback that made the coach expendable is gone this year. Its like Favre left the gas on in the stove right after he moved out of his apartment. Now the Vikings might be fine next year, they need a quarterback and a coach. What I find amusing is that Wilf, the owner, had a coach that took a repeatedly mediocre team without a quarterback and made them winners. Wilf had a coach that added a (formerly) great quarterback and fielded a championship team. So Wilf fires one and will lose the other thereby returning to 2006.

But of course, the team is 3-7 now. Who the hell needs to look at last year, that was last year. I mean we make our own reality right?

On applying to graduate school

This was supposed to be a response to my collective blog partner Psi Wavefunction (who has one of the coolest first name pseudonyms).

Another blog partner Gw/W submitted a post on graduate school applications, to which Psi in part responded:
"I find it quite easy to get in contact with potential supervisors, but that's probably because I usually know about their work first, and then find out where they are and whether they take students, etc. I find meeting them in person at meetings and department seminars helps things a lot. Actually, come to think of it, I haven't contacted anyone I didn't at least have some connection with already, at least through someone else who knows them personally. Then again, I've specialised pretty hardcore already, and in a small field like ours, everyone knows everyone... 
My trouble is with the application process itself, as my grades and GRE scores are...well, shitty. So I have to tailor my application to sneaking past the admissions people rather than appealing to a supervisor. Kind of the opposite problem to what more typical applicants have, it seems. 
I can freely chat with faculty about everything from research ideas to my transcript issues, but blank out completely when faced with personal statements and other formal application stuff. Where do I even begin? That was semi-rhetorical, but some advice would be very helpful! =D"
I posted an, as usual, overlong response, which blogger told me was too long. Since I am not willing to cull my infinite wisdom, I will add even more and make this an entire independent posting (take that blogger!).

Psi my experience comes from personally applying to (as a graduate student) basic biology programs and reading applications to (as a faculty member) a biomedical graduate program. My responses here represent my assumption that you are applying to a PhD program in the biological sciences.

1. In my experience direct appeals to specific PIs do not amount to much. Any decent direct applications I get I forward to our program secretary to be dealt with the official way (most go right in the trash because the student is spamming for a position). However, if you are keenly interested in biofilms and the Univ. of East Bumfuck only has one biologist working on biofilms, it may be worthwhile to see if they are planning on retiring in the next two years. Of course I would point out that it is insane or at least asinine to go to a program for one lab. What if they find someone they want more after you enroll?

2. You mention specialization. Do NOT get yourself stuck in a specific field. You are young (Im assuming), why limit yourself? As an undergraduate I did plant molecular biology research, that was the best shit ever! I applied to molecular biology programs with great plant labs. I rotated in a Saccharomyces lab, that was the best shit ever!! So I got my PhD in molecular genetics in yeast, and then found a post-doc working on a pathogenic fungus with non-existent genetics, and you know what? It was the best shit ever!!!! My point is keep a broad outlook, I still learn so many interesting things in biology. You need to be conversant with Drosophila geneticists, T-cell cell biologists, bacterial structural biologists, etc. at least if you want to be more than a glorified technician. (BTW I am not suggesting changing your field, just not be immune to other fields.)

3. Applications to my program are scored based on GREs, GPA, letters of recommendation, and personal statement. Kind of in that order, although there is much room for variation. We have looked over the last 5-10 years of our program and found that GRE score is the only indicator associated with grad school success (although lack of real bench work is associated with a lack of success, probably because students don't realize what it is they will be doing).

4. So GPAs, they are what they are, but are they? Poor GPAs are problematic, but not all problems are the same. Was your GPA shit early on and get better? That's a good thing. Were your GPAs awesome then get shitty? That's a bad bad thing. Did you do well in your science classes, at least those related to the program you are applying to? If yes, good. In no, reconsider you program. If your GPA was due to a bad year hopefully (as bad as this sounds) there were some obvious extenuating circumstances, such as a death in your immediate family. The committees that look at these things really look at them, so if you suck at art histroy but for some godforsaken reason minored in it, the reviewing committee will know that your sucky GPA is do to the fact you are not a cultural maven (a plus actually to be a scientist). From personal experience, I stunk up the joint my first year of undergraduate (1.8 GPA my first semester). That was basically impossible to recover from, but I was 4.0 my senior year. Overall GPA was garbage, but a more careful analysis showed I was a great student who was too not ready for college from the outset. I survived. Regardless, you need to deal with your GPA in your personal statement.

5. GREs are important, particularly the math component. If you do well there and speak fluent English, verbal is given a pass and the essay is BS to begin with. Write as much as possible in the time allotted to increase your score (word count matters, but shouldn't). The math component is considered strongly, hopefully you did well there. If not you need to deal with it in your personal statement.

6. Letters of recommendation. These are your get out of jail free card. If your GPA and GRE suck, this can easily salvage you. You should have strong relationships with your letter writers. I wasn't planning this ahead of time, but played poker with one of my professors every couple of weeks. Despite taking his money often, I gained a great personal relationship with him as well as several other faculty members. This is important, neigh essential. Be someone, not just a grade. If you have research experience great (although this is almost a requirement). If you have a publication, you are fucking set! Even if its a fourth authorship. The publication shows that you are able to work on a piece of research that is publishable and published, that is currency you should use to its fullest, which takes us to....

7. Personal statement. The personal statement is important, but difficult to write. You need to do several things.
A. Tell the committee why you are interested in their program (each letter to a program should be different at some level to hit this point).
B. Share your passion for science! But do NOT NOT NOT NOT NOT tell us you need to cure cancer because your dear grandma who helped you through the difficult time of middle school bullying died from cancer. Every statement like that makes me feel for the candidate while I put the application in the discard pile. All you convey is that you are only interested and focused on one specific thing. You will not cure cancer during graduate school or learn how do to it while in graduate school, so all you are telling the committee is you are naive and scientifically immature. (If you having an outstanding blog, this may be the place to note it. It demonstrates your writing skills, passion, and intelligence. Although I would not overplay this, because many people (old white guys) still view blogs with some distaste.)
C. Talk about your research experience, what you did, why it was important, what it meant to you. If you have awards flaunt them in you personal statement, don't leave them hidden just in your CV.
D. Finally, and most importantly, while you will obviously highlight your achievements you must address your weaknesses. When you write a scientific paper, you deal with the weaknesses up front, you don't hide them and hope for the best. If you deal with them, your reviewers understand that you are critical and thorough, thus they do not have to be (at least not as much).

Finally, don't take it rejections personally, a good lesson to learn early in science.

Best of luck Psi and other potential graduate students.

Nocturnal visitor redux

So we have been discovered by a "family" of flying squirrels, although I prefer the name Night Gliders.There have been up to three flying squirrels visiting the crook of the aforementioned silver maple. One of the coolest thing is to see one come gliding in from a nearby tree.  I've caught them gliding in twice and both times they appeared  upright (like a standing up person) not flat like a hang glider. Of course it may be useful, at least structurally, to be upright just before you smash into a tree (see figure 1) although its also possible I saw them just before landing.
Figure 1. How not to bonk your head as a flying squirrel.

Figure 2. Nightcrawler and flying squirrel
from here and here respectively.
Another thing I learned is that flying squirrels, at least Northern American flying squirrels, can teleport (Figure 2). It's possible, but unlikely, that they are simply small and fast and its dark out, but I think they can probably teleport up and down and all around the tree. Regardless, these rodents are about the cutest damned furry mammals I've seen in a while. For comparison sake, I have vast experience with your common gray squirrel, which frequents our yard daily for peanuts, seeds, and other sundries. The red squirrel, which is much more shy in the twin cities suburbs, but much less so in the Itasca woods (where gray squirrels are essentially non-existent). We also have several white and black (gray variants) squirrel visitors (named whitey and blackey respectively). Its a great backyard experiment in evolution. The white squirrels are true albinoes, having pink eyes to go with their white fur. The expectation is that the white squirrels survive predation better in the Minnesota winter than either gray or black squirrel. If true, then there should be more white squirrels, as well as some selective pressure for albinoism in gray squirrel populations that live environments with extensive annual snowfall. In other words, there should be fewer white squirrels in Mississippi.

Figure 3. Nom nom nom squirrel.
Cool gray squirrel factoid, when they eat peanuts, they hold the nut in their paws like you might expect (Figure 3). They then rip a few pieces of the peanut shell off, pull out a peanut with their teeth, wedge it between their thumbs, and leisurely eat the nut. Bust off some more shell and repeat for the next nut. The gray squirrels (and variants) are getting to the point of semi-domestication (as are the blue jays that come when you call). The reds not so much. However, the flying squirrels while shy, appear to be getting used to me. I can go outside and provide more sunflower seeds without them bolting to Wisconsin. In fact, they seem to use the 'freeze' defense mechanisms, which makes sense if you are using darkness as a way to avoid predators.

Anyway, the other night I provided some feed for some flying squirrels, which they enjoyed immensely.

However I believe I may have used some genetically modified sunflower seeds,  because when I looked back about 45 minutes later my flying squirrel looked like this:

It was much slower and seemed to have lost its apparation ability. In fact when I went outside to provide some more seeds, it looked at me....

Clearly this is a mutant flying squirrel. It was in the same place only a little bit later the same evening. It was eating the same food, but it lost many flying squirrel properties. Besides its basic lethargy, it also did not bolt when I went outside. As I approached the tree with a fresh supply of seeds and peanuts, it slowly turned, opened its maw revealing a row of dagger-like death and made some demonic hissing noise. Obviously, the rapid growth undergone by the flying squirrel affected its vocalization ability. It also appears to have changed its ability to sexually reproduce with a placenta and immediately evolved a pouch-like sac for fetal development.

Name this nocturnal visitor

Although the title may having you thinking about the caption Brett Favre attaches to pics sent via cell phone, Im interested in the following animal. This little creature has become a nightly visitor to our house in the St. Paul area of Minnesota (actually have seen up to three of them at once). Any guesses based on this lousy digital photograph?

For the record Im focused on the animal not the Maple tree it is attached to.

Why batshit crazy politicians may want to favor science over belief

In 79AD near on the coast of Western Italy near the city of Naples, the Roman diplomat Shimkusius was walking with his friend Pliny (the Elder), a philosopher. They were discussing the recent increase in smoke emanating from Mt. Vesuvius.

"We should consider closing the port and moving the people further from the mountain" stated Pliny.
"Ha! That's absurd my good friend, why should we take such action? If we close the port, ships will simply go to Salernum or Misenum. Senator Gaius would love to get the trade and may entice the traders to continue using their ports. We cannot risk the loss in economic development." responded Shimkusius.
"But, my lord, what if the mountain bursts forth with noxious gases and molten earth? The risk to the people and city is too great!" Implored Pliny.
"You spend too much time with your epistles and lectures Pliny. The people of the town need to see strength of conviction. Have you seen the worried looks on the farmers and farriers? The people want to see from their leaders that there is nothing to fear from a little smoke." Explained Shimkusius.
"Besides my friend, have we not sacrificed our requisite virgins to Vulcan, god of the mountain? And you know we have already found a lovely virgin for the sacrifice in three days. We have been dutiful with rituals, Vulcan is pleased."
Pliny looked Shimkusius in the eye. "You are quick to look to old rituals and trivial gods to ignore real problems. You are supposed to be a leader, lead for once!"
Shimkusius placed an arm around his friend shoulder "Pliny you are a delight. You need to get down on the ground with real people. If the docks are not being used, people won't have jobs loading and unloading them. The merchants, many of whom pay you to tutor their children, will not be making the money necessary to keep the town growing. The people of Pompeii, the real people, believe Vulcan is happy. Why is that so difficult for you to accept? It is rather off-putting for you to discount their ancient beliefs."
"Sigh, I think you're making a mistake Shimkusius, but maybe you're right and as you say another sacrifice is coming up."
Pliny and Shimkusius stroll off to Shimkusius' home and split a jug of wine....

Several days later, Shimkusius and Pliny are on the docks. Shimkusius is beseeching his friend to get on a boat. "Damnit man, we must flee!" roared Shimkusius.
"My wife and sister are back in town, I must try and save them!" screamed Pliny. "Why didn't you listen to me you arrogant bastard." Pliny was livid with anger. "You said the sacrifice would keep Vulcan happy, admit it you were wrong and now the city is destroyed!"
Shimkusius shook his head in self-righteous pity. "Pliny my friend, you must realize, the girl was clearly not a virgin. The whore doomed us, all of us. Well, not us, but the others in the city. Vulcan obviously is full of wrath because of our tainted sacrifice."
Pliny stared at his friend a moment and pulled away running back towards town never to be seen again.
Shimkusius boarded the ship as it cast off and headed towards his winter home in Syracuse thinking all the while that the citizens of Pompeii, like Pliny, must have lacked the faith in the gods to protect them. It must have been their own undoing, because Vulcan would not destroy a city because a senator simply entertained a young woman prior to the celebration.

Of course, its totally different when its global warming and ignoring it because of an extremely suspect interpretation (justification) of a couple of lines from the Bible.

Of course when everything goes to shit, billions are starving, fresh water is virtually non-existant, and war suffering and disease are the norm, this jackass can righteously conclude that indeed the world wasn't destroyed. You know because it still exists.

In which I disagree with a Nobel Prize winner...

This last week my MRU had the privilege in hearing a talk by Dr. J. Michael Bishop entitled "The Cancer Genome of Therapeutics." It was an interesting talk and Dr. Bishop told several good stories, which isn't that surprising since I expect you don't get a Nobel if you can't give a good talk. However, just because you give an interesting, engaging, and thought provoking talk, doesn't mean I have to agree with you.

The thrust of the talk was based on the idea that by comparing cancer cells with "normal" cells, we can identify things that are different. Once differences are identified, these are now targets for therapeutic interventions. Now I want to be clear for those not knee-deep into the biological sciences, when I say "targets for therapeutic development," I am not suggesting that therapies exist. This is the 4000 lb. gorilla in the room no one likes to talk about in many scientific areas. Just because you identify a target, does not mean you have any way of hitting it. Two thousand years ago if a hungry hunter saw a fat elk on the other side of a 500 foot gorge (the target to solve the problem of hunger), there was nothing the hunter could do about it. Even if said hunter had a bow and arrow or more likely an atlatl, the elk is still a useless target, since the dead elk would be eaten by wolves, lions, and other animals long before the hunter could climb down the gorge and back up the other side. So having a target does not necessarily mean much.

One way in which these target identification approaches is done is to identify genes that are expressed in one cell type but not another, such as expressed in cancer cells but not in normal cells. This is usually the direction these approaches work too, we look for things that are expressed in the undesired cell, not things that are absent. (Its easier, but not impossible, to target something that's there not something that's missing.) Also, we generally go for genes and not proteins because it is currently much easier to determine what genes are or are not expressed over essentially the entire genome than it is to determine all the proteins expressed in a given cell population. This means our measure for expressed targets is somewhat indirect.

So lets say we find 12 genes are expressed in a specific kind of cancer cell, like breast cancer cells, but no in normal breast tissue. (The reality is many more than 12, but let's keep the numbers small.) Do these 12 genes specify 12 new targets? Well, the short answer is no. See these 12 genes are found in the genome because human beings probably need this gene for something other than causing uncontrolled cell growth in the breast. This is a huge limitation to this kind of approach. Just because you identify an expressed gene specific in a cancer compared to the otherwise normal tissue, does not mean and almost certainly doesn't mean the gene is not normally expressed somewhere. So your newly discovered cancer target may also be a pancreas development target or bacterial combating lymphocyte target too.

This is where I was left wanting. The nobel winning scientist begins their talk by establishing the overarching theme: by comparing cancer and normal cells/tissues, we will identify new targets based on these differences, and begin curing cancers at a previously unknown rate. Sadly, the first thing that came to my mind was all those microbes that have been killing us for generations and are still pretty damn good at it. Bacteria are about as different from us as you can get and you know what, we really have no new ways of combatting them. They kill more of us than cancer, but pharmaceutical companies have been shutting down their anti-microbial divisions to the point few actually exist anymore. (Don't blame the pharmaceutical companies, which can make a ton more money making guys hard, women skinny, and kids easier to oversee in factories schools.) Bacteria, fungi, protozoan parasites. All are extremely different from us at least when compared to cancer cells which are essentially clones of all your other cells.

So I am skeptical that knowing all the differences in expression between cancer cells and normal cells will pay dividends in any rapid way at least not as sold. However, I am not against this approach scientifically (I am against how it is sold to the public though). This will definitely tell us much about cancer biology, it will reveal commonalities and distinctions between different cancers, it may reveal genetic risk factors in patient populations that could impact screening and lifestyle choices (think about the current mammogram controversy), it may also lead to new treatments just not in the one gene = one target paradigm.

There are two ways I can envision genomics leading to targets that are susceptible to therapeutic intervention.

1. Often cancer progression is associated with chromosomal rearrangements. One chromosome recombines with another making a fusion chromosome not found in normal cells. A recombinant chromosome is not necessarily a bad thing and normal cells frequently contain them. However, the recombination can lead to the generation a protein that would never normally be generated. If the recombination occurs in the middle of two distinct genes a fusion gene can be created. One famous case of this is Bcr-Abl, which is associated with certain leukemias. Abl and Bcr are both kinases, although the specific function of Bcr is still not clear. The Bcr-Abl fusion removes an inhibitory domain of Abl, which leads to hyperactive Abl and that is oncogenic (cancer promoting). These types of rearrangements can be detected using new deep sequencing genomic approaches. 

2. Cancer is complicated and not due to a single cellular defect. Cancer requires numerous genetic changes. What we often see is that for a given type of cancer a similar set of cellular pathways act differently, although in the same way in the cancer. Much like specific targets, like a protein, a pathway can be the target for a therapeutic intervention. Actually, pathways are much larger targets since a pathway can be targeted by disrupting any of the proteins that make up the pathway. As before these pathways exist in normal cells as well. However, we could target two or three different pathways that are hyperactive in cancer cells with different therapeutics, which could kill the cancer cells. A normal cell may require one or two of these pathways, but not all three and thus would be 'immune' to the treatment. Admittedly there are a lot of ifs associated with this approach, but it is a viable approach. In fact, this is the approach that has made HAART so successful in treating many HIV infections.

I don't mean to be all gloom and doom, but the scientific community has gotten a fair bit of well-deserved blow back from overstating the impact of our studies to the lay public. Also, the fact that a given approach may not lead to a life-altering new product does not mean it is not worthwhile. If we look back through the history of science, many of the biggest advances were not front page news at the time. One ready example is the initial identification of penicillin by Fleming occurred in 1928 (earlier reports existed but this was the one that stuck), however it took 11 years and another group (Chain and Florey) to purify it for use as an antibiotic. This is a rapid turn around time and probably a poor example, because penicillin changed our lives. None of us were alive when death from bacterial infection was common and normal. People did not generally die of cancer or heart disease. The splinter in your finger you got chopping wood, that could kill you, if you got the wrong bacterium in the wound. Of the ~350,000 Union soldiers that died in the US Civil War, ~220,000 died of disease. Or pre-penicillin, in WWI 16.5/1000 soldiers died of disease/year whereas post-penicillin, in WWII 0.6/1000 soldiers died of disease/year1. The take away point is that new treatments take time and are not often clear from the initial findings. The second point is that we'll probably never see another medical intervention that has the same societal effects as the antibiotic generation.

Vote for reason, that's your reason to vote

November 2nd tomorrow, Election Day. What are you doing? Are you blowing it off because the choices come down Republicans...ah, the golden days of 2008 when republicans were lying their way through 2 wars, the economy was crashing, the ultra-rich were gathering up a greater and greater % of all the wealth...and Democrats, the party of push-overs and dare I say accommodationists that don't want to turn away voters who wouldn't vote for them anyway.

I admit it seems a crapshoot. Not happy with Dems, so vote in Reps? The problem is that the Reps. bring primarily fear, hatred, and blind worship of ignorance. So, Im voting for Dems, but if the Reps actually presented a package that wasnt bat-shit crazy, I would give them the nod. But the Reps. don't appear to think that intelligence and thought are worthwhile activities. Reps. have a 15th century understanding of the world they live in and they like it, worse they call others elitist for actually knowing something more recent than Newton. Yep, that's the mentality I want in office. I'ld rather have the milquetoast party.

If we keep swapping crap for crap (albeit some crap stinks worse than other crap), it will never improve. So let's give a party a reason to stop giving us crap as a choice. If your Ford sucks, you may buy a Toyota, which also sucks but gets better gas mileage, you don't then buy another crappy Ford. Make Ford improve by buying another Toyota, at least you get the gas mileage. When Ford improves its product, Toyota better follow suit or its screwed.

FWIW. I will not vote for any person that has the idea that intelligent design represents a valid scientific theory. It means two things, 1. the candidate doesn't know jack about science (not a deal breaker for me, since there are many things I don't know); 2. the candidate is being advised by, and put their trust in, a bunch of fucking morons (and that is a deal-breaker).

Fungus vs. Hymenoptera (the honey bee edition)

A honeybee colony. Photograph: Haraz N Ghanbari/AP
from  The Guardian
I have already expounded on the awesome power of fungi against mammals (bats), amphibians (frogs), and nematodes (worm), now it is time for the insects to go down...well, maybe. Over the last five or so years, honeybee colonies have been dying off at a dramatic rate, this is referred to as colony collapse disorder (CCD). Basically the bees in a colony go all Roanoke and it is unclear why.

ResearchBlogging.orgSeveral studies of CCD have reported viruses associated with bees from infected colonies, suggesting that the CCD is an infectious disease problem. However, a recent study by Bromenshenk and colleagues identified potential microbial agents associated with CCD. Of particular interest in the the approach that the authors took to identify microbial associations.  In short, bees suffering from CCD as well as healthy controls, were gathered and the proteins were isolated and digested using degradative enzymes. Peptide fragments were then identified by mass spectroscopy (MS). Once the peptide fragments are identified, the original protein can be inferred as well as the source of the protein by analyzing available protein databases. Now it amazes me that the MS data was able to identify microbial peptides from the massive amount of bee protein that must have been in the samples. There may have been steps taken to enrich for the microbial sequences, but I doubt it since most microbial species identified were viral, which I am assuming came from infected bee cells and not free virions (although I could be wrong about this).

From these analyses, the authors determined that CCD-affected colonies were associated with co-infection with a virus and a fungus. The less interesting virus appears to be an Iridovirus, but the more interesting fungus is a microsporidian.  The microsporidia used to be classified with the protists, but are clearly fungi. The microsporidians identified included Nosema apsis, which is known to be associated with honey bees, Nosema ceranae and several other Nosema spp. What is interesting is that the authors grouped the Nosema spp. into group 1 and group 2, but group 1, which contains N. apis, was correlated with CCD, whereas group 2, which contains N. ceranae, was not (Table 1, 3, and the discussion). Finally, CCD correlated with co-infection of the Iridovirus and group 1 Nosema, suggesting that one "pathogen" is not sufficient for CCD, but both cause collapse.

Now the authors take their studies further by testing whether co-infection with IIV-6 and N. ceranae promotes CCD-like disease. (The authors are clear that the cannot be sure IIV-6 and  N. ceranae are the actual causative agents since these organisms were implicated by peptide sequences which could easily be found in related but distinct spp.) Low-and-behold they find that co-infection with both spp. is more virulent than infection by either spp. alone or controls (Figure 3). However, looking at the 50% mean survival times, the results appear to be 9.5 days for co-infection, 11 days for either single infection, and ~16 days for uninfected bees (I extrapolated based on the data presented).

I want to point out that this latter experiment is important and is often not done in these kind of studies, so kudos to the authors. However, I am not yet an enthusiastic supporter of the Iridovirus + Nosema promotes CCD hypothesis. First, the data presented, up to Figure 2, is strictly correlative. Maybe honey bees suffering from CCD are more susceptible to viral and fungal infections or even overgrowth. Karposi-sarcoma viral infections in young men was not the cause of, but a symptom of AIDS. Fungi are decomposers, so if the bees are going south the fungi may just have a leg up by being already associated with the healthy honey bees. Second, I find it problematic that the authors used N. ceranae for their infection studies, since N. ceranae was a group 2 member, but group 1 Nosema spp. were more tightly coorelated with CCD. Maybe any number of co-infections would have similar effects. Clearly the control bees go south regardless of infection, so maybe any combination of stresses simply compounds mortality loss.

Regardless, an interesting paper working on a difficult research area (no petri dish cultures for easy manipulations).

Bromenshenk, J., Henderson, C., Wick, C., Stanford, M., Zulich, A., Jabbour, R., Deshpande, S., McCubbin, P., Seccomb, R., Welch, P., Williams, T., Firth, D., Skowronski, E., Lehmann, M., Bilimoria, S., Gress, J., Wanner, K., & Cramer, R. (2010). Iridovirus and Microsporidian Linked to Honey Bee Colony Decline PLoS ONE, 5 (10) DOI: 10.1371/journal.pone.0013181

A dearth of frogs and how to catch a mole you'ld rather just kill

I have a fairly generic house from the 1950s. A rambler, like all the other ramblers in the neighborhood. However, over its 60 years of existence previous owners have done some nice renovations, including completing a bedroom in the basement. This included putting in a wall to separate the bedroom from the rest of the finished part of the basement, adding a large cedar lined closet, and most importantly putting in an egress window. Yes, the egress window is the most important part, otherwise the bedroom is not legally a bedroom just a glorified storage room. Because this bedroom is in the basement, it happens to also be below the ground. So the window well outside the egress window is about 4 feet deep (in case of fire, you can open the window, climb into the window well and then hoist yourself out of the window well).

We can skip over the safety of having to climb out of the window well in case of emergency, just know that it is physically possible. The point is that we have a rather large and deep window well. Every year, starting around  mid-summer, moles and frogs decide to make the window well their home (read they fall in). Normally I wouldn't care too much, but there are always a few dry leaves in the window well and the moles really love to run over and through these dry leaves starting at about 2AM. Again, I wouldn't normally care, except said window well is directly below the bedroom window right next to my side of the bed. You might be surprised how much freaking noise a 20 gram mole can make using just a few dry leaves in the middle of the night. (Just for the record, frogs are good neighbors and either sleep normal hours or are scared of dry leaves.) So on a fair number of nights every summer, Ill be outside in my slippers and sweatpants (you hope) with a flashlight, a large box, and a small garden rake. One can easily jump into the well, place the box on its side along the wall of the window well (the important thing is to make sure the flaps are open and not bent backwards), then using the rake and flashlight scare the mole around the edge of the wall and into the box. Once in simultaneously close the flaps and tip the box upright (This is actually your second attempt, because the first time the mole went into the box, it escaped while you were dicking around with the flaps, which you left folded backwards). Ensure the mole is in the box by give it a gentle shake (gentleness is inversely correlated to the number of hours I had already been asleep). Of course, it will take several attempts to actually get the damn mole into the box because the flap won't be tight against the wall and the mole will go behind the box, or there will be a small gap between the flap or box and the gravel at the bottom of the window well and the mole will go under it (The number of failed attempts at catching said mole also affects the degree of box shaking gentleness).

Evil mole of satan
Once caught, lift the box up onto the lawn along with the flashlight and hoist you cranky and tired ass up out of the window well. You can then pick your favorite curse to mutter as you realize you left the rake at the bottom of the window well. Back in, and back out with the rake. Vigorously check to make sure the mole didn't go anywhere. Take said box to the woods up the street and dump said mole, feel free to explain to said mole that the Mrs. is the only reason said mole is actually still viable. Back to the house to put away mole catching equipment and drag your sorry ass back to bed.

American Toad
Now I have learned to check the window well occasionally during daylight hours and can often avoid the nighttime ritual of rodent hatred. Under these conditions, if a mole is there it is caught more easily. (Being awake almost certainly has nothing to do with that.) Further, any frogs in the well can be saved. We get american toads, wood frogs, and leopard frogs in the window well. The frogs are easy to catch and I know a 7 year old that I can lower into the window well to catch them.

So 2010 has been an interesting year. Weather-wise there has been nothing remarkable and I have had to capture several moles this year. However, there have been virtually no toads/frogs in the window well, in fact I can only recall a single one.

So what gives? Damned if I know, but one thing I thought about was the rampant world-wide decimation of frogs populations particularly in tropical climes. Entire ecosystems are being upended rapidly because once frogs are gone, animals that feed on frogs are not far behind, also animals that frogs feed on flourish (aka insects), which causes additional disruptions.

The question immediately on your mind Im sure is, "why are frogs populations crashing?" Great question, it turns out the culprit is a fungus called Batrachochytrium dendrobatidis. B. dendrobatidis is a member of the chytridiomycota, aka the chytrids. These are extremely cool fungi (apart from the killing all the amphibians part). They are quite distantly related to the fungi we commonly think about which are Ascomycetes (eg Bakers yeast) and Basidiomycetes (eg Shitake mushrooms). Moreover they are motile!! That's right these SoBs will come to you. Actually it is the spores (zoospores) that are motile via a flagella, not the vegetative cells, but still I expect people in general would state that fungi are non-motile (because most are), but biology is ripe with awesomeness because there is always an exception.

Ok, but Minnesota is generally not considered a tropical clime, so what's a single season lack of frogs in my window well got to do with B. dendrobatidis? Probably nothing, but thinking is fun. A quick google search for B. dendrobatidis and Minnesota came up with this paper (Prevalence of the pathogenic chytrid fungus Batrachochytrium dendrobatidis, in an endangered population of northern leopard frogs, Rana pipiens). It turns out B. dendrobatidis is associated with a reasonable number of frogs in Minnesota! Now at this point there is no indication that B. dendrobatidis is negatively affecting frogs here, but this may be something to keep an eye on.

Blogging with substance - the AbC edition

 Lab Rat tagged me with the "blogging with substance" meme, which I think constitutes a tagging FAIL since I would hesitate to use the term substance as a descriptor for many of my posts. Nonetheless, when one of the collective tags you, it is considered poor taste not to play.
So the meme has 2 requirements:

1. Sum up your blogging motivation, philosophy and experience in exactly 10 words.
Sharing opinions, Learning something, Teaching, Sparing my family said opinions.

There. That took care of the motivation aspect. Experience: still gaining it. Philosophy: I think therefore I am.

2. Pass it on to 10 other blogs with substance.
OK, this is the easy one.

A. Dispatches from the Culture Wars Get your law, rational politics, and biology all in one. No Really Get It NOW!!!
B. Evolving Thoughts A great resource for biological philosophy  (and he has the best freaking named blog)
C. The Renaissance Mathematicus History, Biology, Philosophy all in one...not necessarily concomitant
D. Sandwalk Warning: Curmudeoningly Evolutionary Biologist
E. Adventures in Ethics and Science Ethics with a side of biology
F. Why Evolution Is True because selling books isn't enough
G. C6-H12-O6 Ignoring superscripts, a great member of the collective 
H. Epiphenom The science of religion....what's not to like!?!
I. Study Abroad in Venezuela A shout out to a new student blog 
J. Small Things Considered Read this! You will learn something

Bride of the Educating at the High School:College Interface

Having returned from the Great White North (which was beautifully green) and gotten back to my general level of being behind, I thought it was time to fulfill my promise.

First, my goal of discussing the nature of science was an abject failure. Actually it was a failure to launch as opposed to a failure in practice. In large part this is because I didn't have the time to carefully put together this component, since the students are spending ~ 2 hours setting up an experiment and   analyzing the results, I have less than 2 hours to do any additional instruction (factor in the time that I give the students and myself a break about halfway through to enjoy some great snacks put out by the cooks). I also have to make sure I cover the material included on the exam (not that it matters a whole lot in my experience). So there really is limited time to deal with such a broad topic/issue unless its tied well into one of the former aspects of the class. Since I didn't take a great deal of time trying to do this, clearly I was unable to incorporate this discussion.

Second, one thing I did for most of the sessions was write the words "skepticism" and "trust" on the board before the students arrived. Once class began I asked whether each term had positive connotations or negative connotations. In the four or five sessions I did this, only one group thought "skepticism" was a positive term (although my skepticism leads me to consider that they figured out the "right" answer and may have been sucking up). All the others gave me the answer of "skepticism" is a negative thing and "trust" is a positive thing.

Think about that for a couple of minutes....

This actually depresses the shit out of me.

When looking at 60 of the most intelligent and educationally advanced individuals (from their peer group of high school students using some admittedly subjective criteria), almost all of them lack an appreciation for one of the greatest tools in their intellectual toolbox. I have heard many people stress the importance of teaching/training our students to be critical thinkers. If this cohort of students lack an understanding of the importance of skepticism, then what about those students not going on the college?

I see results like this and have a hard time not wallowing in the sense that our society is fucked. Maybe the gloom-and-doom is overstated and things aren't any worse than they were 100 years ago, hell maybe things are much better since we teach much more information in K-12 compared to 100 years ago. But I would argue that the forces arrayed against the individual are much worse now than ever before. Two words: Fox News. Media no longer provides information, media now basically tell us what to think (its the modern version of the church). Media today is like the automobile of the 1950s, it is an integral part of our lives that we have become dependent upon.

How does one survive in the echo-chamber that represents modern media if we are trained to cherish the trusting side of our nature and disparage the skeptical side?

Ultimate Death Match: Fungus vs Worm

As the newest penultimate addition to the FoS collective (should any group of bloggers ever use the term collective?), I thought I should introduce myself to the other bloggers here at FoS.

Hi, I'm Lorax. Nice to meet you.

Clearly, I am joining a great group of scientists and am happy to add my ramblings here. However, I am also a competitive jerk. So when I read this cool post over at Skeptic Wonder, where Psi Wavefunction waxes poetic about Theratromyxa, I felt a rush of testosterone course through my veins. Amoeba, like Theratromyxa, are basically just free living macrophage *yawn*. Theratromyxa crawls to their prey (nematodes, which are microscopic worms), engulfs it, and then proceeds to eat the nematode. On the plus side Theratromyxa has two things going for it: 1. A single celled organism eating a multicellular organism is inherently cool, 2. Theratromyxa belongs to a group called the Vampyrellid, I mean that is awesomely cool.
However, if you want a truly amazing nematode hunter, let me introduce you to Drechslerella (previously called Arthrobotrys), a group of filamentous fungi that do something truly amazing! Drechslerella species grow as hyphae (the long spaghetti looking things) and can make spores (there's a collection of 5 cells that formed spores just North of center in the picture). OK, I'll admit that they are not much to look at. And unlike the amoeba, Drechslerella is non-motile, so it needs its food to come to it. If you are hunting prey that moves, but you do not, then you have a problem. Drechslerella deals with this problem in a way analogous to how we catch mice while we sleep, it traps it.

And this is where Drechslerella completely outcools Theratromyxa. I'll let the picture speak for me.
N. Allin and G.L. Barron
The above nematode has crawled into the fungal trap at two points. Along the hypha, a ring is formed by 3 cells. When a nematode enters the ring, these cells rapidly expand (~1/10th of a second) trapping the worm (see below, left and right top two pics). This effectively traps/crushes the worm, think about the last time you stuck your arm in a blood pressure sphygmomanometer (yes that's what those things are called). At this point, cells germinate, sending invasive hyphae into the worm which eats the worm from the inside (see below, right bottom two pics)
This leads to some pretty interesting biological questions. For example, fungal cells are surrounded by a cell wall, how does this expansion occur so quickly? How is the worm detected, are there touch sensors (yes) and do they act like touch sensors in our cells? Are these "trap" cell structures made all the time or only when worms are around? With organisms like this, what does it mean to be multicellular? a differentiated tissue? etc.

Now I should point out that many nematodes are detrimental to plants and biocontrols are sometimes used, including the use of Arthrobotrys (commercially still using the old name).

To conclude: Drechslerella >> Theratromyxa >> Nematodes

UPDATE: Checkout the noob, who bumped me for newest addition. You can learn all kinds of cool things about how the environment affects physiology!

Why we pursue the Truth

For several thousand ought years humans have struggled with Truth. For the last 200 years or so, science has emerged as the only dependable mechanism to establishing many truths. Sure, there are those who say science does not tell us why we find a given piece of art beautiful or moving, why we like a certain genera of fiction, why we love this person but not that person. These truth claims are currently beyond the purview of science. (Notice: I said "science does not" not "science can not", because we are always learning more about how we think and make decisions.) Regardless, even if science does not answer these questions, what does? Surely not the bible or koran or other holy book. Are we really comfortable with revelatory truths? If so, I have a way that you too can feel better for only $19.99 a month.

As scientists, we strive to learn truths about the universe. Admittedly, almost all of us are learning small truths about the universe. However, these small truths provide the foundational truths that allow those truly rare individuals to gain fundamental insights into our understanding of the universe. We strive to be skeptical and rational in our lives. But we fail in this endeavor or even ignore it. I do not worry about why I like a certain piece of art, but not another because it does not matter. However, sometimes we fail in ways that do matter. We might decide to become evangelical christians because water freezes in the winter , we might think vitamin C is a magic bullet. At the end of the day scientists are people just like everyone else.

Sometimes though people make mistakes, we screw up. What's worse is that we realize it, either directly because we figure it out or indirectly because someone points it out to us. The question now is what do we do with this information. As a scientist, I have been trained (albeit informally) that if I screw up I need to deal with it. Actually, I learned this as a child but the mechanisms for dealing with it and the reason why it is important to deal with it became clearly apparent during as I trained to be a scientist.

Let's say I publish a paper with solid data, but later on learn that the data was not so solid. In fact, maybe someone else in my lab cannot replicate the data, we bust our humps trying to figure what's wrong, but it turns out the original data set was flawed in some way that was not previously known. Now I write to the journal and retract the manuscript (this is not a case a fraud but a case of things not being perfect and science being self-correcting). Other scientists may simply keep their paper in a high impact journal and send out a letter to the community saying the study was flawed (this is considered the wrong way to do it, but some people pull shit like this).

Or let's say, I may have strong evidence that a student cheated on an examination. I will almost certainly fail the student based on this evidence. I may even make it known to the class that I failed a student for cheating. But what if additional new information came to light absolving the student of cheating, what to do? Probably the best course would be to apologize to the student, correct the grade, and if necessary point out to the class that no misdeeds were done because you made a mistake. I fucked up, it happens. I think that's what I would do, because I care about my reputation and being right when its known you are actually wrong does nothing to help your reputation. Of course it sucks to be wrong as experimenters, teachers, parents, etc. but hopefully we have enough self esteem to deal with it when we are wrong. Regardless, admitting when we are wrong and dealing with it advances our quest for truth and provides evidence to others that we mean it when we say that we strive for truth.

Educating at the High School-College Interface

In ~3 days I'll be off another foray into the great white north (which is actually extremely green ATM) to teach incoming freshman some biology. Its a way to whet their appetite in different aspects of research and study but mostly it helps the students establish some contacts and colleagues before the chaos of college actually starts.

For the past 3 years I've taught a little module on environmental sensing in microbes and the students do a little morphogenetic experiment that works great. The way I set up the lab, they get exposed to a little actual science because we discuss controls in the experiment (which they have to figure out), among other things. However, there is a good deal of down time for the students, where I lecture on something or other. Last year we discussed logic and arguments. This year Im thinking about talking about the nature of science what separates a scientist from an engineer for example.

This thought comes from how I think the general public views science/scientists. If you ask people what is science or what do scientists do, Im willing to bet the answers you get line up better with what is engineering or what do engineers do. Since Im repeating this 8 times this year, I should get a pretty good sample size on this issue (at least from the biologically minded recent high school graduate demographic anyway). Ill let you know how it looks, if Im completely wrong I should know that early on and Ill go back to getting into arguments with students and looking for logical fallacies (I find the who's a better quarterback Peyton Manning or Tom Brady is a great starting point).

BTW its Peyton Manning.

Poop Transplants, Is Your Microbiota an Organ System

This is some research (subscription required) I have been meaning to write about for awhile but have not found the time. Now its basically too late because Carl Zimmer has written about it and it has been picked up elsewhere. However, I did still want to throw in my two cents.

First, you have to realize that there are at least 10 times as many microbial cells living in and on you than there are human cells making up your body. That means you are basically a microbial community with some human contamination.

Second, we have long known that certain microbes cause diseases, like Vibrio cholerae causes cholera and Plasmodium falciparum causes malaria. We also know that many microbes are beneficial. This beneficialness is described as being shield. If the "good" microbes are there, the "bad" microbes cannot colonize us easily. However, these microbes play important roles in providing nutrients we have trouble getting otherwise, like vitamin K. They also help regulate our immune system, which must combat pathogens, but not combat all the "normal" microbial flora. When the immune system goes after norma flora bad things can happen, for example chronic mucataneous candidiasis (pictured to the right, from Doctor Fungus).

What we are now learning is that it appears that the microbiota can have significant impacts on human health beyond these more clear cut examples. The link between certain microbes (and I would be remiss not to include viruses here) and cancer is well established. It is also beginning to look like your gut microbiota can affect your chances on pulmonary infections and may affect allergic diseases.

Your microbiota is so important that the suggestion has been made that your microbiota should be considered an organ system. Now the research focus of this post is colitis, an inflammatory disease of the large intestine caused by Clostridium difficile. C. difficile is easily detected in ~10% of the population, which means low level colonization is probably much higher, but few individuals come down with symptomatic colitis. In patients suffering severe colitis, the gut microbiota is completely abnormal. (To be clear there is not a specific gut microbiota that is considered normal, but a range of specific species and numbers of each organism that we are beginning to assess as normal. Kind of like height, people come in a variety of heights and we have a mean and median, but there is no specific normal height.) So Dr. Khoruts and colleagues took a stool sample from "normal" individuals (family members) and transplanted it into the colitis patient. Of 15 patients treated, 13 were cured almost immediately. Also, when analyzed well afterwards the cured patients had a microbiota back in the normal range!

I cannot overemphasize how incredibly cool all this is. Gross? Yes. Totally awesome? Definitely.

I think these research results lead to some interesting follow up questions. For example, if we consider C. difficile exists in people at a low level normally, what leads to overgrowth and/or colitis? Are there specific competing microbes that keep C. difficile in check? This question is important because it could demonstrate an underlying mechanism of health. If you have organisms X, Y, and Z, then you need to have organisms A, B or C, and D or E to be healthy.

The microbiota and allergies/asthma. Huffnagle GB.PLoS Pathog. 2010 May 27;6(5):e100054

Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. J Clin Gastroenterol. 2010 May-Jun;44(5):354-60.
Conceptualizing human microbiota: from multicelled organ to ecological community. Foxman B, Goldberg D, Murdock C, Xi C, Gilsdorf JR. Interdiscip Perspect Infect Dis. 2008;2008:613979.

HIV: Basic Research IS the Force behind Translational Research

AIDS is a humongous problem. It is a epidemic with ~33 million infections worldwide. To put that in perspective using numbers that make sense to people ~1 in every 200 people in the world are infected. We have individual classes at my university that on average should have 2.5 HIV+ students.

To date, there is no cure, and no vaccine.

If you live in a rich country like the USA, there is a treatment called HAART. If you live in a poor country, well you are pretty much dying of a nasty opportunistic infection. However, even in a rich country ~50% of all patients fail HAART therapy in the first year. This is due to toxicity (the drugs can have real nasty effects) and resistance (HIV doesn't like to be kept in check). So even in the countries with the best health care (not the US) treating HIV is hit or miss, but mostly miss.

This is our problem, we need new therapeutics. Well a vaccine would be better and we are working on it, but until then new therapeutics are desperately needed. This is the translational side of the equation, getting better treatments to the 1.1 million HIV+ patients in the US alone. (BTW ~21% are undiagnosed, hope you didnt have sex with one of those 231,000 people recently.)

Ok, here is where basic science comes in.

First, let's introduce epidemiology:  the study of factors affecting health in a population.

Well, we know a bunch of things about HIV infections (which many characters besides epidemiology generated). For example, HIV binds to a protein receptor on cells called CD4. Not many cells are CD4+ cells, but those that are are infected and killed by HIV. A critical type of T-cell is CD4+, aptly termed the CD4+ T-cell. CD4+ T-cells are the directors in the movie called "The Immune System." So when the CD4+ T-cells are killed by HIV, the movie comes to a screeching halt and then some generally benign microbe comes along and kills you.

Now not only does HIV bind to CD4, it also binds a co-receptor: a protein called CCR5, which is also found on CD4+ T-cells (and a few other cells). What's important, and we can thank epidemiology, is that ~1% of all people carry a mutant form of CCR5 (called CCR5∆32) that is not expressed. People are diploid, they have 2 copies of every gene, so of those 1% many have the mutant copy and the normal, wild-type, copy (the are heterozygotes CCR5∆32/CCR5). However, a small fraction of the population carries both mutant alleles (CCR5∆32/CCR5∆32) and do not express CCR5 on any cell. Based on epidemiological studies CCR5∆32/CCR5∆32 individuals are resistant to HIV and CCR5∆32/CCR5 individuals showed delayed onset of disease.

So what does this information get us? Well maybe a drug could be made that blocks CCR5 from HIV or inhibits CCR5 expression. Enter Maraviroc. Maybe we could help someone using this information. Well in 2006 an HIV+ patient came down with leukemia (like shit isn't bad enough). One treatment for leukemia (at least certain types) is a bone marrow transplant (BMT). Basically you destroy the patients immune system, which is where the leukemic cells come from, with radiation and/or chemicals and then restore the immune system with bone marrow, the source of the cells of the immune system, from a healthy donor. Here the doctors got clever and found a CCR5∆32/CCR5∆32 individual for a donor. 

WHAMOO, the HIV+ patient is currently free of HIV and leukemia. w00t!!11!leventy!!1

However, BMTs suck and most patients would opt for the HAART therapy over a BMT. But the point is that this fucking worked!!! Some basic epidemiology set on top a large set of immunology, cell biology, and virology led to a fucking cure! Not treatment, CURE! Basic research for the translational win.

Now let's be real, this approach is not going to be used to treat the current 33 million, I mean 32,999,999 HIV+ patients. Many if not most patients would refuse this treatment even if cost effective. So what can we do now.

Let's introduce molecular biology, biochemistry and genetics: the study of molecules and inheritance in living cells.

If we can get rid of CCR5 in HIV+ patients, we have a cure. Well, many years basic biochemistry, genetics, and molecular biology have identified proteins that cleave DNA called nucleases. These fields also identified a protein motif called a zinc finger that binds to specific DNA sequences. Finally some nucleases are in fact zinc finger DNA nucleases. Now if we take our knowledge of zinc fingers, we should be able to make a zinc finger nuclease that cuts DNA at a specific DNA sequence. Like a specific DNA sequence in the CCR5 gene. This would allow us to make human cells CCR5∆ in the laboratory.

Let's introduce cell biology, cancer biology, and stem cell biology: the study of the properties of cells in general, in cancer, or pluripotent.

Based on the work in these fields, we know how to get at least certain cells from people grow them in the laboratory and manipulate them. We know how to introduce new bits of DNA, such as DNA that encodes our zinc finger DNA nuclease that targets CCR5. So we can take some cells from an HIV+ patient, make them CCR5∆, put them back in and in principle cure the patient of HIV. This also avoids issues of donor:patient incompatibility since the cells come from you not a donor.

But how can we test this?

Let's introduce zoologists, immunologists, and veterinary scientists: those who studies animals the immune system and diseases of animals, respecitvely.

We know a lot about the mouse, and in many ways the mouse is like a human (although in many ways its not, which may be the focus of a future post). Further, we can destroy the immune system of a mouse, just like we can a human, and do some things to give the mouse a more human immune system. Sounds very Dr. Moreauian doesn't it. I mean, why would we want to make a mouse with a human-like immune system? Well, for one mice don't get HIV. They can't catch it, don't transmit it, and basically suck as a model to study. If we have mice running around with human CD4+ T-cells, instead of mouse CD4+ T-cells, well they can be infected with HIV and come down with AIDS. So we can use a humanized-mouse to actually see if this CCR5∆ stem cell, made using a zinc finger nuclease, treatment is a viable approach. This is translational research at its best.

and you know what? A study by Holt et al (see below) suggests this approach fucking works!!! 

Translational research is da bomb!! But only if we forget that all of this research is the culmination of years of research by diverse labs using diverse organisms learning basic biology. Basic research is da fucking bomb!!!

 Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, Crooks GM, Kohn DB, Gregory PD, Holmes MC, Cannon PM. Nat Biotechnol. 2010 Jul 2. [Epub ahead of print].

Can the new humanized mouse model give HIV research a boost. Shacklett BL. PLoS Med. 2008 Jan 15;5(1):e13

This post was inspired by a seminar given by Dr. Cannon the senior author of the Holt study given months before it was pubished.