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.

http://commons.wikimedia.org/wiki/
File:Arthrobotrys_spores_160X.png

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.