Genetics and Obesity

 Genetics and Obesity

            Obesity, classified as a chronic disease by the World Health Organization (WHO) is regarded as having irregular or excessive fat accumulation. It can be measured and quantified by examining ones body mass index (BMI), where on average, anyone over 30kg/m2 would be classified as obese (WHO 2012). Obesity is followed by a large number of health risks (including diabetes, cardiovascular diseases, cancer and more) and generally decreases life expectancy. What has been discovered recently is that genetics plays a large role in obesity, specifically the role of melanocortin 4 receptors (MC4R) and how dysfunction of the receptors can lead to an onset of obesity (Logan MG et al. 2010).
            Although obesity is commonly known to be caused by the imbalance in calorie consumption and energy output, recent research has illustrated the genetic factor that can be taken into account for certain individuals, therefore making obesity a multi-factorial disease. MC4R has largely been known to maintain energy homeostasis by regulating the body’s food intake. It does so by providing an anorexigenic signal, which is a result of the binding of an agonist (alpha-melanocyte-stimulating hormone) to the receptor, allowing one to have the sensation of being full (Logan MG et al. 2010). Due to the multiple mutations that MC4R is susceptible to some individuals will be more likely to become obese than others with the pathogenic MC4R. MC4R polymorphisms do not actually impair an individual’s rate of energy expenditure, but rather affects their appetite causing a hyperphagic state. Phenotypes that usually follow this kind of mutation include increase in fat or growth, eating disorders (binge-eating) and hyperinsulinaemia (abnormally high levels of insulin circulation). The reason that MC4R polymorphisms result in such phenotypes is largely due to the hindered functionality of the MC4 receptor (Logan MG et al. 2010). Mutated MC4R is observed to have decreased or absent ligand binding, decreased cell surface receptor expression, incorrect protein formation, and reduced signal transduction. Of these defects, those that interfere with intracellular reception (compromises the functionality and activity of the receptors) are linked to more severe forms of obesity. This allows fairly accurate predictions to be made about the onset and severity of obesity in people with pathogenic MC4R mutations. More importantly, carriers of pathogenic MC4R have an 82% chance of passing it onto their offspring, increasing the odds of being obese by almost 5 times (note that ethnicity is also a variable) (Logan MG et al. 2010). Lastly, the polymorphism or mutation that can be identified in the MC4R gene does not imply that either the mutation is involved in the pathogenesis of the disease and that the subject will have the observed phenotypes.
            There are simply too many factors that can come into account when attempting to overcome such an epidemic as obesity; however by understanding how genetics affects obesity treatments can be enhanced and diversified to create more effective treatments for patient. By being able to predict such abnormalities through the mutations of MC4R, obesity can be prevented before onset. Theorized treatments aim to suppress appetite by increasing neural sensitivity to insulin and leptin; however current research has yet to bring forth concrete solutions to this disease (Christian N 2012).

Life Without A Fingerprint : The Immigration delay disease

 Life Without A Fingerprint : The Immigration delay disease
Fingerprints have been known as the universal identification tool in the society. For example, sometimes passport is not enough to get you through the border of  several countries and your fingerprints will be recorded for identification purposes. Fingerprints are also often presented in the court as a valid evidence to identify crime suspects and put them behind bars. But have you ever imagined living without your ‘identity’? In fact, this case does exist. Such condition in the medical term is known as adermatoglyphia, where the epidermal ridges are partially/completely missing and the biometric fingerprint scanner would not be able to recognize the fingerprints (Figure 1) .

Figure 1

Apparently, adermatoglyphia is such a rare disease that only 4 families have been known to be affected by this disease, and apart from its function as an identification tool, there is not much physiological function that fingerprint is known to have. However, Sprecher et al. (2011) mentioned in this paper that the presence of fingerprints may increase the gripping ability by increasing the friction force. Whether this difference is significant or not, there is another common feature that people with adermatoglyphia would usually have. According to Sprecher et al. (2011) and Burger et al. (2009), the histological analysis of the patients he was observing all shows a reduced capacity of hands transpiration (Figure 2). In conclusion, people with adermatoglyphia would usually have lesser number of sweat glands especially around the hand area (Burger et al. 2009) .

Figure 2 : The hand transpiration test



To examine what might be the cause of this rare condition, Sprecher et al. (2011) extracted the DNA from the person affected and their relatives, also some DNA from a person whose fingerprints are present. Through a series of process of PCR and DNA sequencing, 17 genes are suspected to be the main cause of adermatoglyphia. One of those is called SMARCAD1, and the short isoform of this gene is abundantly found in the skin fibroblasts. Sprecher et al. (2011) examined closely at this particular gene, and found mutation in one of the base that composes SMARCAD1. The DNA sequencing graph showed a clear representation of the transversion, where a guanine base is replaced with an unknown nucleotide compared to the DNA sequencing result of normal person (See Figure 3).

Figure 3. The mutation noted by the red arrow



This sequence change is believed to inactivate the first exon of the gene, hence interrupts the skin formation process. As mentioned before, people with adermatoglyphia would usually be associated with reduced hand transpiration capacity, and therefore Sprecher et al (2011) speculates that this gene might also have something to do with sweat gland development. However, it has not been scientifically proven and their research was more focused on what causes the fingerprint absence in people with adermatoglyphia. Now that we know why, hopefully none of the criminals in the world would get a SMARCAD1 gene mutation – it would be very beneficial for them don’t you think!

Is creativity an illness? But then... what is an illness?

 Is creativity an illness? But then... what is an illness?

Are you creative? Do you ever feel that when your creativity strikes you become absolutely compulsive about your "inspiration," and totally depressed when, for some reason, your inspiration wanes? It always strikes me to read about how some of the most beautiful works of art were created: their creators were obsessed, compulsive, borderline dysfunctional. Gabriel Garcia Marquez sold his car and had his family live on credit for eighteen months so he could write One hundred years of solitude. Brunelleschi's obsession was the dome of Santa Maria del Fiore, Antoni Gaudi's obsession was La Sagrada Familia. It seems to me that obsessions may ruin your life (or most likely the life of your closest ones) when you have them, but they may also lead to the most wonderful things.

So, is creativity a good thing or is it an illness?

My friend and collaborator Tanmoy Bhattacharya brought to my attention an interesting BBC post that discussed the issue. The article came up in a Facebook discussion because it raised the question: "How do you define illness? When, exactly, does a behavior trespass the normality threshold and becomes an illness?" I really liked Tanmoy's take on the issue, and I asked him permission to repost it here on the blog. It's the best thing I could get since he won't do a guest blog for me. :-)

I think he raises excellent points on the complexity of the brain, its stimuli as well as its constraints. I enjoyed reading it, I hope you will too. And if after reading this you have questions for Tanmoy, go ahead and post them in the comments and I will forward them to him.

TB: In a system as complex as the brain, which interacts with such diverse environments, it is difficult to define health and disease. There has been a long standing hypothesis that certain brain functions like deductive logic and creativity are kept in check evolutionarily because the same "structure" that can give rise to very highly creative adaptations in one environment would give rise to maladaptive behavior in a different environment. The interest in the research is, therefore, understanding the architectural limits on the brain, not to stigmatize writers or expect every bipolar to pen out a story about an old man and the sea.

EEG: That's a very interesting theory. All greatest masterpieces required such great energy and dedication from their creators that these individuals had to, at some level, become unsociable, as focused as they were on their creation. I can see how, at a species level, "being socially fit" puts a constraint on the amount of time and "obsession" the brain can dedicate to a certain task.

TB: I do not believe that we yet have a definition of illness which is "biologically" meaningful. Sure, there is a diagnostic manual that tells a doctor today when to diagnose a particular mental illness, but it is more an expression of "social" reality than a "biological" reality. So, for example, the discussion of whether homosexuality is a disease is not argued on any grounds about what it does or does not do to the person, but rather whether the majority of doctors consider it within the "normal" spectrum of behavior. No wonder its classification changed from a disease to a non-disease as the social acceptability of homosexuality grew: not because such acceptance lessened the mental load on the person with the trait (it is now not considered a disease even when the person with the trait lives in a non-accepting community), but because it became "socially" acceptable as a "normal" behavior. Currently, there is a similar debate about whether bereavement distress should be considered normal even when it leads to behavior sufficiently aberrant to otherwise merit a diagnosis of clinical depression. In other words, the question is not whether the person is depressed after a loss: the question is whether it is a disease (possibly temporary like say getting the 'flu is a disease) or whether it is not a disease because it is "normal". The classification is not done based on any kind of biological reality, except whether it is considered normal; which is determined by methods of social science, not biology.

Does this concept of normality depend on a biological reality? In other words, is there a way, other than surveying doctors (the social science method), to figure out whether some one is abnormal? Remember that we know pretty much that all of us are different in many ways, if you defined me abnormal simply because I am unique (which I certainly am), then everyone would be abnormal. One could always say that one should not look at the totality (which made everyone unique), but trait by trait, and ask whether I have traits that very few other people have? Defining abnormality this way would, of course, make Picasso abnormal; but during a mass hysteria, it would classify everyone as normal. We again see that this definition fails to capture the abnormality that is relevant to defining disease.

I claim that the only way people have found to capture the relevant abnormality is by taking the design stance: human brains (and bodies) are supposed to be "for" something. When the organ (or the totality) is carrying out this function, it is normal; when it fails to carry out this function, it is abnormal. Note that this does not solve the underlying problem: someone still has to define the function, but that turns out to be an easier problem.

We could define a disease objectively as a malfunction if we could define function objectively. And, here, biology can bring an insight: the function of brains (and bodies) is to survive and use the environment, physical, biological, and social, to further the fundamental goals of long term survival of the traits. This is usually called reproduction, but it is far more subtle: for example, one can help raise grandchildren and contribute to the long term survival; under appropriate conditions, one can help other helpful members of one's community to help survival of the helpfulness trait. The mathematics is not simple, but recent work has made much of this clearer, and it is far more than pure reproduction. The part relevant to this discussion is that for a social animal this survival depends a lot on social calculations as well as other considerations.

So, then, we can define function as being able to properly calculate and take appropriate action; but that depends on the environment one faces. The same trait of fast decisive action to take the life of an unexpected person is wonderful in times of violent combat but completely malfunctional in a peaceful society. Similarly, it is easy to show that a mental make up that helps everyone, whether or not they are helpful to others, is malfunctional in the sense that it does not help its own survival except in societies that pays a high moral premium on that. Now, since most traits will find themselves in various environments, the malfunctional has to be defined as an intermediate: it should not be "fatal" in any of the environments that an individual is likely to face. But, this depends on the environments one is "likely" to face.

Given this situation, therefore, most traits tune themselves to intermediate values, because extreme values are typically extremely ill suited in some environments one is likely to face. And, all this is further constrained by the possible organization of the brain: for example, it is completely possible that the brain is composed of two parts, one that can analyze and model its environment in terms of an "open-loop" system controlled by impersonal physical laws which constrain and guide change, and a social system that can alternately assign agency (or "will") to parts of the environment. If this simple separation of thought patterns is an useful approximation, the division of resources between the two will affect a lot of behavior: a lot of resources devoted to the physical system will make one unable to understand complicated social dynamics; whereas too high a reliance on the social system might make one unable to understand that physical phenomenon often do not have wills and desires. Both of these taken to an extreme are obviously malfunctional, and, therefore, diseased: one can think of autism or schizophrenia as examples illustrating such symptoms. But, where exactly one stops being analytical and starts being high-functional autistic will depend on what environment one is defining with respect to: when the norm is highly complex social environments, one will probably classify some highly analytic people as diseased because they cannot function in society (i.e., the "mad scientist" or "computer geeks" will get classified as "mad" or "autistic"), whereas when complex physical systems but with little social structure are the norm, some people who see willful patterns in the universe will find themselves considered ill (e.g., a "religious fanatic" will be considered "mad").

So, what have we done through all this argument? We started by arguing that DSM (diagnostic manual) definitions depend on a certain standard of normal and are not objective. Through the chain of arguments, I have tried to establish that the former (i.e. dependence on the standard of normal) is inherent part of the problem, and cannot be removed except in the trivial sense that some things have never been normal. I have also argued, however, that this dependence does not need to be subjective: what is important is not what the "doctors" have experienced as normal, but rather the environments that the *person* being diagnosed has experienced and is likely to experience.

The interesting question is that supposing we take a bunch of brains and tune up their creativity (by changing whatever neurotransmitter chemistry or electrochemical connections that we need to). Now, in some environments and depending on the rest of the circuits in the brain, this will work perfectly fine and be very useful in understanding and modeling otherwise-hard-to-model systems (somewhat similar to a physical effect called "annealing"). If the same tuning is done to a different brain which does not have the same set of controls, this tuning could lead to a bipolar disorder. Basically this hypothesis would say that creativity needs to be balanced by other control systems, so any means of independent inheritance will quite often lead to getting the creativity structures without the control structures, leading to madness. Under this hypothesis, creative people are not insane, but biology would dictate that they are at a higher risk of having insane relatives (children/siblings/etc.) than less creative people.

But, there is a different possibility as well: the "control" unit hypothesized in the previous post may not be inherited much, but developed based on experiences; or its need may be dependent on the environment. In this case, the only difference between creative people and people with some forms of insanity would be the environments they have faced or will face. Creative people can then look at bipolars and paraphrase Bradford "But for the grace of environment, there go I". We do not know if either of these hypotheses are correct, but I hope I have explained why I find it interesting to ask these questions, and why the data presented in the article is consequently interesting.

Why You Should Eat Your Broccoli

 Why You Should Eat Your Broccoli



Many of us hate broccoli along with all vegetables. But, there is something different about this one along with its cruciferous kind, which includes cabbage, bok choy, and brussel sprouts. That is, it has been recently discovered that these vegetables contain a compound, sulforaphane (SFN) that has not one but two mechanisms in preventing cancer.

Historically it was believed that genetic abnormalities and mutations were the primary underlying cause for diseases. Now epigenetics has become a field of study that is recognized as having greater than or equal importance in discovering disease susceptibility. Epigenetics studies how diet, toxins and other forces can change the expression of genes without altering the DNA sequence.

Sulforaphane was found to have the ability to fight cancer despite a person’s DNA sequence. Studies have shown that it involves a mechanism called histone deacetylases or HDAC’s. This is a family of enzymes that interfere with the genes that suppress tumors. There are also HDAC inhibitors, which include the compound SFN, and these can undo this interference by restoring the essential balance in preventing cancer.
                                  

New studies by researchers in Linus Pauling institute at Oregon State University have discovered another epigenetic mechanism, DNA methylation (DNMT), which plays a similar role. These two mechanisms work together in maintaining proper cell function. As they are both influenced by sulforaphane, this compound can help to fix disruptions in these mechanisms. SFN is able to adjust the process of HDAC and DNMT so that they are in balance.

The effect of sulforaphane on DNA methylation was explored in a study published in the journal Clinical Epigenetics. It examined the methylation of the gene, cyclinD2, in prostate cancer cells. The results of the study gave insight into how SFN regulates gene expression. It demonstrated that it is an agent in preventing prostate cancer. The positive effect of SFN is not limited to prostate cancer but researchers say that the mechanisms are relevant in other types of cancers such as colon and breast cancer.

“It’s increasingly clear that sulforaphane is a real multi-tasker”, said Emily Ho, an associate professor at OSU College of Public Health and Human Sciences, “the more we find out about it, the more benefits it appears to have.” She believes that broccoli may be one of the strongest anti-cancer fighters known today.

Another study conducted at John’s Hopkins school of medicine found another health benefit of sulforaphane. It is able to kill helicobacter pylori, a bacterium that causes stomach ulcers and potentially deadly stomach cancers. It was even found to be able to kill types of helicobacter that is resistant to common antibiotics.
                             

It is certainly confirmed that broccoli is a super vegetable in having this cancer-preventing compound!

RNA Virus

RNA Virus

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can have an impact on the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low 1 error in every 10–100 million bases—due to the "proofreading" ability of DNA polymerases.(Without proofreading error rates are a thousand-fold higher; because many viruses rely on DNA and RNA polymerases that lack proofreading ability, they experience higher mutation rates.) Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure.Chemical damage to DNA occurs naturally as well, and cells use DNA repair mechanisms to repair mismatches and breaks in DNA—nevertheless, the repair sometimes fails to return the DNA to its original sequence.

In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations. Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence—duplications, inversions or deletions of entire regions, or the accidental exchanging of whole parts between different chromosomes (called translocation).