What is clear from this recent paper (Neal et.al. Patterns and rates of exonic de novo mutations in autism spectrum disorders, Nature, advance online publication, http://dx.doi.org/10.1038/nature11011) is that ASD is highly polygenic in origin, i.e. hundreds of genes influence autism risk. Getting to this answer, including two genes in particular that were determined to be very strongly linked with autism (CHD8 and KATNAL2), was a real technical achievement in that in involved analyzing the genomes of 175 trios (mother, father, autistic child). Sequencing 525 human genomes is something that would have been unimaginable just a few years ago. While it is clear that we still have much to understand about this complicated disease, the technological limitations that previously limited progress are beginning to fall away. Hopefully many more important clues are just around the corner.

When we think of a detective the first thing that comes to mind is an investigator, either a member of a police agency or a private entity.  However there are unique detectives within the multifaceted arena of medicine.  All though we might already think of most doctors as detectives there are special doctors, units, working at the National Institute of Health’s (NIH) undiagnosed disease program.  Doctors such as William A. Gahl at the NIH are disease detectives that try to elucidate the causes and genetic basis involved in the hundreds of unsolved and mysterious diseases that arise each year.  Dr. Gahl who was interviewed for an article in scientific American explained that his group has accepted 400 out of 1700 special cases of unsolved disease.  The selection process of these cases is tough, determining which cases are new diseases and if there is a possibility of determining the genetic and biochemical basis of the disease.   As each case is worked mutations are identified that are associated with each disease.  But Dr. Gahl States that this is only the beginning of the puzzle.  The challenge becomes to identify the genetics with the pathology.

Dr. Gahls’ group has been working on a case in which a patient has endured pain for approximately twenty years and muscles of their legs have turned as hard as bricks limiting mobility.  It was determined that the patient had a rare condition in which their blood vessels bore a thick coat of calcium that restricted blood flow.  One of the first steps taken in the study was to examine the parents of the patient.  The parents after examination were healthy, which lead the group to believe that the patients’ disposition might be due to a recessive mutation.  Meaning that each parent had only one copy of a unique mutation but upon having children probability lead to the patient receiving two copies of the mutation.  After an in depth study Dr. Gahls’ group identified the location of the mutation and the error prone gene associated.  The gene that was identified is NT5E.  NT5E is involved in the production of the nucleoside adenosine (which is involved in a number of biochemical processes).  To examine this gene closely doctors cultured the patients skin cells and inserted the normal gene of NT5E and even introduced adenosine alone into the cells and miraculously they observed a reduction in calcification.  Through this analysis a better understanding of adenosine in the regulation of calcium has been brought to light.  However Dr. Gahl explains that there are a number of reasons why patients cannot just receive adenosine, but there is a class of osteoporosis drugs that pose as good candidates for treatment and they are waiting to see how these drugs perform.

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For most of the year, deciduous trees are green because of chlorophyll in the chloroplasts.  This pigment helps harness energy from the sun to fuel photosynthesis, or food production.  In the fall, days become shorter and sunlight more sparse, so plants begin to prepare for the winter – a period during which they rely on stored nutrients.   Nutrients are stored and superfluous leaves are shed , but before that, the chlorophyll begins to disappear, revealing other pigments such as yellow and orange that weren’t visible before.  Sometimes during this process, new pigments (such as reds) are produced as well.

This is controlled by up to 35 genes that can turn on and off in response to the reduction of sunlight hours.  It is a great example of the interaction between an organism’s DNA and its environment, a phenomenon many people are unaware of.  The traits and characteristics of all living things are the result of a combination of its genetic makeup and its physical and chemical surroundings.  To learn more about this type of interaction, go to chapter 35, “DNA responds to signals from outside the cell.”

I happen to work at an institution where evolution is revered as the underlying theme that explains life and all of its processes.  For a biology teacher it’s a comfortable place to be.  I suppose I am spoiled. When I travel to schools, I am on occasion told by teachers how happy they are that I am presenting evolution for them.  It is a required part of the New York State science curriculum, but some of the teachers who are supposed to teach it, don’t want to.   It makes me wonder.  Are they uncomfortable with the science?  Are they afraid of parents or students lashing out at them?  Does the scientific theory of evolution somehow conflict with their religious beliefs?   I don’t know the answer.  I’m sure it’s a combination of several factors. 

My gut feeling is that most teacher reticence is due to lack of understanding.   I would feel very uncomfortable if asked to teach a topic I didn’t fully understand, and unfortunately this is what’s happening.   I think we need better teacher training, especially for elementary teachers who receive very little training in science.  Everyone who receives a degree in general education or in science education should have to complete a course in basic genetics and/or evolution.   This would significantly reduce the negativity associated with teaching evolution, and could help produce much happier teachers!

One example of controlled behaviors has stirred up a variety of questions. A species of fungus, Ophiocordyceps unilateralis, infects a type of carpenter ant. What is unusual about the infection is that the fungus somehow directs the ant to move to a location on the leaves of the trees normally inhabited by the ants. The location is highly specific in regard to temperature, humidity, and sunlight – ideal conditions for the fungus to grow.

Once the ant has been guided to the correct site, it is forced to bite down and lock its mandibles in place like an anchor. The ant quickly dies as the fungus takes over and uses the body to grow and produce spores. Any ants walking below are susceptible to the falling spores once they are released. You can check out the fantastic YouTube clip from FreeScienceLectures by clicking here.

How does the fungus control the ant? The scenario does bring up questions about why organisms have certain behaviors and what controls exist to direct them. What about our own behaviors is it predetermined by our genes?

In a bone marrow transplant, a patient’s own marrow is destroyed and replaced with tissue from a donor. The donor marrow contains healthy hematopoietic stem cells (HSCs, adult stem cells in the blood) which repopulate the patient’s body with healthy red and white blood cells for oxygen transport and immune defense. Just as with other varieties of organ donation, tissue-type matches are critical. In the case of the AIDS patient, another screen was also applied: his doctors searched for donors whose cells were also resistant to HIV infection.

In order to infect a white blood cell, HIV must latch onto 2 receptors on the cell’s surface: the cd4 receptor and the CCR5 receptor. Some people have no CCR5 receptors due to mutations in the genes encoding the protein—those people are highly resistant to HIV infection. The AIDS patient received bone marrow from a donor whose HSCs (and subsequent white blood cells) could not produce the CCR5 receptor: his new cells cannot be infected by the HIV that decimated his old cells. The AIDS patient was, rather ironically, cured by receiving “defective” cells. The absence of a CCR5 receptor does not appear to affect normal physiology.

Bone marrow transplants are, unfortunately, not a feasible treatment option for the 33.4 million people infected with HIV worldwide. Patients receiving the transplant are at major risk for infection as they wait for their immune systems to regenerate: between 10 and 30% of patients die from the procedure. In addition, there are very few HIV resistant donors relative to the number of infected individuals. On average, 1 of every 1,000 Europeans carries 2 copies of the defective gene while the mutation (a 32 base pair deletion) is very rare in people of Asian and African descent.

The tidings are not all together grim, however. This case shows that HIV can be treated by inhibiting CCR5 expression. If a patient’s HSC could be removed, rehabilitated via gene therapy, and returned to the patient, future AIDS treatment might not require life-long drug courses or dangerous transplants.

Scientists have used genome-wide studies to define a relationship between body mass index and polymorphisms in the FTO gene (Fat Mass and Obesity Associated Gene). Recently, insights into the function of the gene has revealed some very interesting data that gives rise to optimism. Fischer et al. (2009) have shown that mice who do not have the FTO gene product are capable of decreasing fat tissue. In addition they have shown that down-regulation of the FTO gene seems to provide protection against calorie-induced obesity. These findings verify the importance of the FTO gene for the regulation of body weight. The results of this research will become very important for the development of new ways to treat obesity.

Reference: Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, Ruther U: Inactivation of the Fto gene protects from obesity. Nature 2009, 458(7240):894-898.

In a recent review of autism research, Brent Bill and Daniel Geschwind (Current Opinion in Genetics & Development Volume 19, Issue 3, June 2009, Pages 271-278) survey the latest advances in tackling autism spectrum disorders. As is explained in the review, pinning down traits and genes is extremely difficult for mental illnesses which involve aspects of cognition that are still only just beginning to be understood.

When it comes to eye color, even a 5 year old can tell you that someone has green, blue, or brown eyes. If we wanted to be a bit fancier, we could imagine that with a chart and camera, we could put eye colors into dozens of systematic categories. But measuring and evaluating the cognitive defects that characterize autism (impaired social behavior, language deficits, repetitive behavior, ect.) is far more challenging.

That is not to say that defining where along the autistic spectrum an individual is an impossible task, but that it is as yet still somewhat imprecise. After all, can you imagine characterizing other complex cognitive traits, humor for example? How funny is a particular comedian? Maybe there is funny or unfunny, but what is the difference between Jerry Sienfeld funny and Victor Borge funny?

Difficulty in characterizing the traits of autism also hampers the high throughput techniques that have made finding genes for other simpler illnesses much more effective. As mentioned in the paper, increases in orders of magnitudes of subjects in some studies have not yielded the desired results, and further increases in subjects will be needed. This is not to mention the further confounding fact that traits which appear similar on the surface may have vastly different genetic causes. After all, if you were looking at humor, and only counted something as funny based upon someone laughing, would that really tell you a lot the difference between Three Stooges funny and Woody Allen funny?

Despite these challenges, there has been progress in identifying some areas of the genome that may have a significant role in autism

I currently teach genetics and molecular biology to middle school students, high school students, teachers, and the general public. One of the greatest skills I have learned in my current position is the importance of engaging your audience and making the material you are introducing easy to understand. Instead of trying to impress people with fancy facts and complex ideas, I was taught to present information in a simple matter. In my initial observations of my fellow teachers, I was intimidated and thought that everyone around me had to be more intelligent. I heard one teacher describe the DNA in one cell as a cookbook and the genes as recipes. I was shocked at the simplicity of the analogy and went home to compare it with the complicated writing in my old textbooks. What I found was that the once foreign language of the textbooks was transformed. Not only could I grasp what they were saying with ease, but I was also able to identify the sections that were poorly explained. I felt empowered and began to search for new ways to describe biology in simple terms.

Getting the facts correct when teaching is equally important as enabling an audience to find a bridge between what they already know and what you are introducing them to. I continue to read about genetics from various resources and try to incorporate as much diversity into my lessons as possible. I enjoy using DNA from the Beginning to describe specific concepts and experiments. I recommend reading the descriptions and the checking out the animations for each section. Also, here are some of my favorite sites for introducing genetics and getting excited about DNA:

DNA interactive

The Human Genome Website: Genetics 101

American Museum of Natural History: The Gene Scene

For example, many genes are pleiotropic, meaning they affect more than one phenotype. How about the recent development on red heads and anasthetics? I happen to live with a red head, from a long line of red heads, so in our family this was a topic of discussion for days. The mutation that causes red hair, also induces the production of a hormone that stimulates a brain receptor associated with sensitivity to pain. In short, if you have red hair, you are likely to need more Novacaine at the dentist.

Dentists supposedly have known this for ages. I wonder how many other interesting pleiotropies like this one have been observed, and are touted as old wives-tales (or dentist tales, as it were), but may actually have scientific validity?