Paul Bloom and Tamar Gendler Discuss Alief

My former philosophy thesis advisor from Yale is on Bloggingheads.tv! She is interested on the interaction between the imagination and normal cognition, and she begins by describing her newly coined concept of “Alief” (Pron: uh-LEAF). Basically, an alief describes something that is similar to a belief insofar as it guides our behavior, but different from belief insofar as we know that it is really a product of our imagination.

For instance, we might refuse to eat a piece of fudge shaped like feces even though we know that it tastes like any other piece of chocolate. Here, we allow something that we don’t honestly believe (namely, that the brown object is disgusting) to guide our behavior. Aliefs are interesting to cognitive scientists because they have important implications for how we act in the world. Bloom and Gendler discuss these implications in the context of evolutionary psychology, racial prejudice, video games, etc.

bloom_gendler

Nobel Laureates Endorse Obama

Prof. Martin Chalfie recently won  the Nobel Prize in chemistry along with Profs. Osamu Shimomura and Roger Tsien for their work on fluorescent proteins. Only a few days later, Chalfie posted this video on Youtube:

Chalfie, Shimomura and Tsien join 63 other American Nobel Laureate scientists in an open letter that expresses their support for an Obama presidency. From the letter:

We have watched Senator Obama’s approach to these issues with admiration. We especially applaud his emphasis during the campaign on the power of science and technology to enhance our nation’s competitiveness. In particular, we support the measures he plans to take – through new initiatives in education and training, expanded research funding, an unbiased process for obtaining scientific advice, and an appropriate balance of basic and applied research – to meet the nation’s and the world’s most urgent needs.

For more information about the cadidates’ specific positions, check out ScienceDebate2008.

Human Genomes, For Cheap

Wired Science has a good post about Complete Genomics, a new company that promises to sequence an entire human genome for a mere $5000. This is approximately 5% of the current price tag.

You may have heard of companies, such as 23andMe, offering genomic sequencing for only a few hundred dollars. But these companies focus on specific single nucleotide polymorphisms, or SNPs, that represent a small fraction of the human genome.  They will sequence about half a milion base pairs, but Complete Genomics is hoping to sequence all 3 billion.

Wired explains how these developments could revolutionize biomedical genetics research:

And even at $5,000, the consequences would be enormous: Human genetic research, which is now focused on just a few genomic regions, and ignores types of variation that can’t easily be measured, would finally be able to assume its full form…

The cost and difficulty of sequencing genomes has forced medical geneticists to take a painstaking and limited approach to their work, necessarily looking only at a few genes or mutations. Even whole genome association studies — the gold standard of modern genetics — are misleadingly named: Geneticists search for similarities and differences between people at a handful of genomic locations that are most likely to vary between people, but still ignore most of the genome. Truly-named whole genome associations don’t yet exist.

If non-SNP variations can be correlated with human diseases, then inexepensive whole-genome sequencing could finally help realize the dream of personalized medicine. For now, Complete Genomics hopes to attract business from biomedical researchers. But eventually, the same technology might help ordinary consumers download their entire genome onto their personal computer. In case you’re wondering, you’ll only need about 750 megabytes of disk space.

Elyn Saks: Patient cum Professor

I just finished reading The Center Cannot Hold, a new memior by Professor Elyn Saks of USC. Saks begins her first-person account of schizophrenia by chronicling her life as an undergraduate philosophy major, her time at Oxford as a Marshall Scholar, and her subsequent hospitalization at a British mental institution. Eventually Saks returned to the Unites States and began law school at Yale. There she had a second psychotic break that led to another hospitalization. Saks draws a stark contrast between the British hands-off approach to mental illness and the American system of restraints and punishment. This contrast inspired much of her scholarly work, which has focused on the legality of coercion in psychiatric treatment.

Saks’ success is remarkable in light of the fact that only about 10% of schizophrenic individuals have steady jobs. Saks has not only remained employed, but she has also become a leader in her field and a role model to many who suffer from mental illness. In fact, she credits her career as an enormous source of strength during the most turbulent periods of her life. Saks goes into more detail, and reads several excerpts from her book, in this video:

A New Toy for the Optical Crowd

Increasingly, neuroscientists are using optical techniques to study neurons in the laboratory. The latest installment in their love affair with light is the discovery of light-sensitive ion channels called channelrhodopsins. Scientists have genetically altered neurons to express a channelrhodopsin called ChR2, which was originally isolated from algae. Shining light on these neurons causes positive ions to enter the cell, which depolarizes the neurons and triggers action potentials. Targeting ChR2 to specific types of neurons has allowed researchers to control the behavior of animals with fiber-optics. The New York Times picked up on these developments and recently published a nice review of the field.

Stimulating a specific class of neurons with channelrhodopsins can reveal the role of those neurons in neural circuits. But what if researchers want to test how different types of neurons interact? This would require different types of channelrhodopsins that are sensitive to different wavelengths of light. A new finding from the laboratory of Dr. Karl Deisseroth suggests that researchers may eventually have a whole color palate of channelrhodopsins at their disposal.

The paper, published in the latest issue of Nature Neuroscience, reports the discovery of a novel channelrhodopsin (VChR1) that responds to longer wavelengths of light than ChR2. The researchers scanned a genomic database to find microbial genes that resembled those coding for known channelrhodopsins. They tested the channel’s properties in Xenopus oocytes and HEK293 cells and confirmed that it was indeed a light-gated ion channel with an excitation spectrum distinct from ChR2. Then, by driving the gene with a CAMKII promoter, the researchers were able to express the protein in neurons and show that they could trigger action potentials with light.

As I mentioned, the real goal here is to use two wavelengths of light to selectively excite two types of neurons in the same preparation. Unfortunately, there is enough overlap in the excitation spectrums of ChR2 and VChR1 to make selective stimulation difficult. However, molecular refinement may eventually yield versions of these proteins with sufficiently distinct excitation profiles. Furthermore, the paper serves as a proof-of-concept for using bioinformatic tools to discover new channelrhodopsins.

Make Love, Not War

You’d think that a country renown for its Islamic zeal would have fairly conservative policies toward sex and reproduction. Not so with Iran. Even though Ahmadinejad denies the holocaust, he can’t deny the excessive population growth and burgeoning AIDS epidemic that currently confront his country. That’s one of the reasons why Iran is installing vending machines that dispense condoms and syringes.

Iranian scientists are hopping aboard the love train as well. Apparently some non-zero fraction of said scientists devote their time to sexual enhancement therapies instead of developing nuclear technology. A new paper in Neuropsychopharmacology tests the safety and efficacy of dapoxetine for treatment of premature ejaculation.  Dapoxetine is a selective serotonin reuptake inhibitor (SSRI) that I have written about previously.

While Iran’s nuclear ambitions often take center stage in the media, the country is home to a rapidly growing and diverse community of scientists. The government has relatively liberal stem cell laws, and hopes to use such cutting edge research to enhance its international profile. Eventually, progress in the academic sphere may help temper the fundamentalist elements in Iranian politics.

Rehearsing Abstinence

First there was methadone. Then came bupropion, naltrexone, acamprosate, varenicline and a host of other promising drugs. But the latest anti-addiction medication doesn’t come in a pill; it runs on your PC. ScienceDaily reports on two interesting studies that attempt to help addicts using computer software. Both rely on cognitive behavior therapy, the psychological technique that involves identifying and modifying dysfunctional thought processes that lead to unwanted behaviors.

In the first study, researchers created a virtual reality environment in which alcoholic patients could be exposed to the same cues and stimuli that normally elicit cravings.

[The] VR environments, developed with a company called Virtually Better, feature different scenarios that an addict may find challenging: a bar with imbibing patrons, a house party with guests drinking and smoking, a convenient store with cigarettes and alcoholic beverages within reach, a designated smoking section outside of a building or a room with an arguing couple. The environments use actors in each scene as opposed to computer-generated characters. In addition, the study added another layer of realism. A device sprayed the air with scents the participant may encounter in the various scenarios–cigarette smoke, alcoholic beverages, pizza or aromas associated with the outdoors.

In the second study, researchers developed a computer program that places patients in hypothetical situations and coaches them on how to avoid relapse.

Those assigned to computer-assisted training were exposed to six lessons, or modules, that they accessed from a computer located at the treatment program. Each module included a brief movie that presented a particular challenge to the subjects’ ability to resist substance use — such as the offer of drugs from a dealer. The narrator of the module then presented different skills and strategies to avoid drug use and also show videotapes of individuals employing those strategies.

Unlike the first study, the second scored participants for successful abstinence. Researchers found that subjects who received computer training had fewer positive drug tests compared to traditional counseling alone.

One problem with pharmaceutical interventions like varenicline or naltrexone is the way in which they shift responsibility away from the patient (It’s not me, it’s my brain!). By conceptualizing addiction as purely biological, patients may lose faith in their own willpower. Emerging computer-based interventions are promising because they encourage addicts to take control of their own cravings. Some combination of these approaches may prove most useful in the long run.

Glue Sniffing and Time Stamping with Roger Tsien

Yesterday I went to a UPENN neuroscience retreat at The College of Physicians of Philadelphia, which happens to be the same building that houses the Mütter Museum. The highlight was an introductory lecture by Dr. Roger Tsien, inventor of calcium-sensitive dyes and Nobel favorite.

Recently his lab developed two novel techniques for imaging brain activity. First, Tsien discussed the Glutamate Sensitive Fluorescent Reporter (GluSnFR aka “Glue Sniffer”). The probe works by Fluroresence Resonance Energy Transfer (FRET). This technique involves two fluoresecent proteins that are matched so that the emission wavelength of the first is the excitation wavelength of the second. If the molecules are close together and oriented properly, then exciting the first protein (say, one that normally fluoresces blue) will in turn excite the second protein (say, one that normally fluoresces yellow). When the fluorescent proteins are separated, only blue light is emitted because FRET cannot take place. When they are oriented in the right way, only yellow light is emitted because all the energy is transferred via FRET.

GluSnFR works by linking blue and yellow fluorescent proteins with a third protein that changes conformation when it binds glutamate. Normally the two fluorescent proteins are close enough to engage in FRET, so excitation results in only yellow light. But glutamate released from neurons can bind the linker domain in GluSnFR and disrupt FRET, causing only blue light to be emitted. The ratio of blue to yellow light emission can be measured with high spatial resolution, facilitating time-lapse movies of glutamate spillover from synapses. This is a cool new tool for imaging neuronal activity. The graduate student who performed the work has a better explanation than I can provide. Paper here.

Tsien began the second half of his lecture by discussing competing theories for memory storage in the brain. The dominant theory has been that learning involves modulation of synaptic strength. However, Tsien stressed new evidence showing that learning depends on the formation of new synapses. TimeSTAMP is a new way of monitoring synapse formation.

Tsien’s lab engineered animals to express modified versions of the proteins normally expressed at the synapse, such as PSD-95. This version of the protein is linked to a hemagglutinin (HA) tag via another protein. The linker protein is actually a cis-acting protease, meaning that it spontaneously cleaves itself. Normally, the linker cleaves immediately after PSD-95 is translated, thus separating it from the HA tag. But when a protease inhibitor is added, all the newly translated PSD-95 will have the HA tag. After the experiment is over, the brain can be stained with anti-HA antibodies to see only the synapses that formed after the addition of the protease inhibitor. The ultimate goal is to administer the inhibitor before a learning experience and then observe the when and where of synapse formation compared to an animal that did not have that learning experience.

TimeSTAMP isn’t quite as cool as GluSnFR becasue the results are obtained retroactively with immunohistology instead of real time optical imaging. However, this approach is advantageous because it allows you to view the whole brain instead of just the superficial areas that light can penetrate. Another problem is that there may be high turnover of proteins like PSD-95 even at old synapses. The perfect marker will use a synaptic protein that is only translated during synapse formation, although it is unclear whether such a master molecule exists.

Needless to say, Tsien’s research is pretty awesome.

It’s over.

Is this what postpartum depression feels like? I just took the MCAT on Saturday, and now I don’t know what to do with myself. I thought most of it was manageable, but I definitely made a couple dumb mistakes along the way. My scores on the practice tests rarely correlated with my subjective impression of how I did, so I guess I’ll just have to wait a month in order to find out. Speaking of which, what part of grading a (mostly) multiple choice exam takes 30 days?

To those who plan on taking this test one day, here are my two cents:

  • Start Early. I began studying about 3 months ago, though I only got serious about it 2 months ago. I also took last week off work, which was probably unnecessary. Anyway, the longer you have to study, the more comfortable you will be with the test’s format and timing.
  • Expect the unexpected. While the scope of material on the exam is relatively limited, the questions are always applying these concepts in unfamiliar settings.
  • It’s in the passage, dummy! It’s true that a good chunk of the questions can be answered without reference to the passage. But if you stumble across one that doesn’t make any sense, you probably skimmed over a subtle clue in the text. This is also true for VR, where the correct answers are usually paraphrased literally from the text.
  • Practice, practice, practice. I used a combination of Kaplan Full Lengths and AAMC exams to prepare. The actual test was somewhere in between in terms of difficulty.

Signs of Life

It’s been a long time since my last post, so I figured that my loyal readers (are you out there?) deserve some kind of explanation. As I may have mentioned before, I am about to apply to a bunch of Medical Scientist Training Programs (MSTP) in the hopes of earning both an MD and a PhD in neuroscience. Unfortunately, that means that every moment of free time that used to go here now goes toward the behemoth that is the MCAT.  Now I’m one month away from Test Day, and I look forward to resuming my normal posting schedule after this is all over. In the meantime…

Calvin

…Wish me luck.