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.

RC revisited

Its been awhile, but let's pull out another of our favorite series Ray Comfort is an Idiot (RCIAI) or Fun Plucking the Low Hanging Fruit.

For today's analysis let's take #9 from....

THE ATHEIST STARTER KIT

If you are a beginner atheist, there's a belief system you should embrace and a language you should learn, or you will find yourself in trouble. Here are ten suggestions for the novice:

9. Blame Christianity for the atrocities of the Roman Catholic church--when it tortured Christians through the Spanish Inquisition, imprisoned Galileo for his beliefs, or when it murdered Moslems in the Crusades.

Ok, while Im not a historian, Im not an ahistorian like Bananaman seems to be.  This screed suffers in so many ways, but first let's just establish some timelines.

Martin Luther the primary figure associated with the Protestantism split from Catholicism was born in 1483 and died in 1546. There were already factions within the Catholic church before this time (as there are always variations within groups), however Bananaman is an Evangelical flavor of a Christian which is a branch of Protestantism. The Protestant Reformation is considered to have begun in 1517 although it is really impossible to stick specific dates to philosophical ideas. Regardless, early 1500s is reasonable.

Ok, now we have a conundrum. When did Christianity start? We have to infer that Bananaman asserts that after 1500ish Catholics were/are no longer Christians. What about before that? Who were the Christians in 1323, 1066, 817, 594, 323? Protestants didn't exist in any real form at these times. Catholicism in some form or another (again these institutions and the philosophies of these institutions constantly albeit slowly changes) was the church.

Peter of the apostles started the church that became the Catholic church. Is he a Christian, were any of the apostles? To move forward and make heads-or-tails of Bananaman's position, I think we have to assume that after Peter, the Catholic church embodied Christianity, but over time lost its way, resulting in the Reformation driven by Martin Luther, and then Christianity was embodied by the Protestants, and ultimately just the Evangelicals, which coincidentally happens to be Bananaman's flavor of Christianity.

Ok, Can we blame the Catholic church on the Spanish Inquisition? Yes.
Can we blame the Catholic church on Galileo's imprisonment? Yes.
Can we blame the Catholic church on the crusades? Yes.

But here are some interesting additional dates. Remember the Protestant Reformation is dated at 1517.
The crusades  1095 - 1291
Spanish Inquisition established  1478
Galileo imprisoned  1564

So Bananaman feels Christianity (Protestants) should not be blamed for things the Catholic church did by using 2 examples that occurred before Protestants existed when the Catholic church was Christianity. For this, he can have Galileo being caused by the No True Christians (which is a logical fallacy in and of itself). Regardless, Bananaman's examples are akin to saying you can't blame the United States for slavery in the South because Hawaii and Alaska weren't states then.

And while I am unwilling to paint all Christians with any kind of brush, there are plenty of non-Catholic Christians today and yesterday that have done plenty of horrible things. Suffice it to say some people suck, some people are Christians, and some Christian people suck. (and yes, you can easily swap atheist for Christian in the previous sentence, as well as plumber, democrat, Ohioan, etc.)

Grants and Rants and the Lotto

This is just my opinion but everyone should know that getting funded is a fucking crap shoot. First, the disclaimer I have been funded by the NIH and am looking to continue that relationship. Second, if you write a crap proposal you will not get funded! period (see there it is ---> . ) end of story.

But if you write an amazingly great grant, then its a crap shoot. I recently had two great proposals get triaged. Triaging is a way an NIH study section can handle the workload, currently (if my sources are correct) ~2/3 to 3/4 of all proposals in my study sections are triaged. This could mean your proposal sucks or that it was awesome, but so were a bunch of other proposals. This is why its a crap shoot. If most proposals submitted are good, and you're a fool to think they aren't, then many good proposals will be triaged and of those not triaged, most still won't be funded.

Your proposal is critically reviewed by 2-3 individuals and if 1 is not orgasmic in his/her enthusiasm you're fucked. So, I submitted 2 outstanding proposals. The first was an exploration in virtually unlimited awesomeness. It was a new approach to an important problem that was guaranteed to yield important information. I knew this proposal was going somewhere. The second, was a study in some totes awesomeness of biology. Easy to do and complete, no worries, but I was less impressed with it personally. See, I submitted this second proposal in a different form previously which focused on a gene family. The reviewers of that unfunded proposal wanted me to focus on one or two genes in the family. This was boneheaded, but I decided to try what they asked. I wrote this new proposal one one or two genes and submitted it, even though I knew my previous approach was correct.

Well, I get my scores back. Awesome Proposal #1 crappy pathetic scores. Less Awesome Proposal #2 really good scores (not good enough to pass the triage line but pretty fucking close). WTF!!11!

Of course I read the critiques the reviewers wrote for both proposals, but the important thing is the review for proposal #2. Guess what, they thought it was boneheaded to focus one or two genes and not the family. God, Im an idiot sometimes. If you know you're right and you are, stick to your guns.

Confirmation Bias

In order to do good high quality and fun science, we general have a question we want an answer to, which is more often referred to as a hypothesis. (Not all good science is done this way, some is strictly and/or initially observational.) Now when we ask a question, we may very well have a personal stake in the answer.

An example may be warranted. Let’s say it’s 1940 and you’re a scientist interested in the question does smoking cause lung cancer? Your hypothesis is probably along the lines of “I hypothesize that smoking leads to lung cancer.” If your dearest grandmother and father died of lung cancer, you may already think the hypothesis is correct; if you happen to collect a paycheck from Phillip-Morris and smoke yourself, you may think the hypothesis is wrong.

Now having a pre-established bias is not inherently problematic, it’s inherently human. What you do with this bias is the issue. In the above example, it is fairly clear what the biases are and why they exist and these biases are likely to be identified by a scientist who’s worth her salt. One of our jobs as good scientists is to identify sources of bias. In the above example there are strong personal sources of bias, but in the day-to-day workings of a research laboratory there are more subtle biases. The I-think-this-is-a-cool-idea bias (probably the most common), or the this-result-could-result-in-a-glamour-mag-publication bias, or my-competitor-has-another-idea bias., the list goes on. So, it is important to identify your biases. But this begs the question WHY?

One reason I want to address here, because it goes well beyond the laboratory, is the issue of confirmation bias. Confirmation bias is what happens when you conflate positive data (results that affirm your preconceived notions) and/or diminish negative data (results that contradict your preconceived notions). Confirmation bias helps the casinos make several billion dollars in profit every year. Confirmation bias leads to the retraction of some high profile publications every year. Confirmation bias makes pundits and those that parrot them look like idiots.

So, using our smoking/lung cancer hypothesis above scientist #2 might use a few 2 pack/day smokers without cancer as her sample population. Whereas scientist #1 might recruit her study population in the cancer wards. Although my examples are over the top, the choices made by a scientist that are a product of confirmation bias could be much more subtle and not apparent to other scientists who may be reviewing the work for a publication. This is why good scientists are, or at least try to be, vigilant about their biases and take steps to ensure they aren’t screwing up.

Say for instance you think there is a link between Chronic Fatigue Syndrome and XMRV or that there is a link between the MMR vaccine and autism. Do you find the one poorly designed study that supports your position while simultaneously excluding the plethora of other studies that don’t? If so, you may be a confirmationally biased redneck.

This goes well beyond the sciency stuff. Do you go to Vegas and proclaim the $250 jackpot you won, while failing to point out the 32 $20 bets you lost? The casinos aren’t making billions in profits every year on paying out more than they take in.

Do you have a problem with illegal aliens in Arizona as a recent threat to our well being? Maybe you note whenever an illegal is arrested for a crime as proof of a problem while ignoring fact that crime is lower* in Phoenix in 2009** than in 2002**?

Do you think atheists have split into the old pleasant docile type and some New type that is the root cause of most problems in America? Maybe you’ll take the word of a sockpuppet identity thief because they agree with what you already think over many real voices that disagree.

Hot today...global warming is true. Cold tomorrow...global warming is a myth.

*This is a 10 year comparison for Phoenix specifically.

**Compare pages 21 and 14 in the 2009 and 2002 years for a simplified breakdown.

Sometimes things come out right...mostly

Well here they are. Minnesota State Science Standards for k-12 students.

As a member of this committee, we worked quite hard on these standards to try and get them as strong as possible. In the case of high school biology, we were working under the premise that this information was required for every Minnesota student. I gained some interesting insights from serving on this committee, but that is the focus of an upcoming post.