The Histone Code

Lately there’s been a lot of buzz within the scientific community about a “Histone Code”. What is it and why is it important? To understand the importance of this code, we need to set our focus at the origin of this topic. The story starts off with DNA.

The genome, comprised of DNA, is arguably the most important molecule in a cell. Encoded within a DNA molecule are the endless permutations of a repeating code comprised of only four repeating elements, the genome contains the all information needed for that organism to thrive and function; it represents the instruction manual encoding all the instructions on how to build the all the necessary machinery that will be required throughout the organism’s lifetime. The magnitude of this is simply astounding. The situation with DNA is analogous to having every instruction booklet required to build an airplane on one piece of paper, but the paper’s dimensions is that of an extremely long fortune cookie fortune; simply put DNA is a long molecule. Too long, in fact, for a cell to keep it laid straight and still keep it inside the cell. So the cell does the same thing that we do when we have a long piece of rope or unruly string of Christmas lights; the DNA is kept rolled up until it is needed. To accomplish this the cell utilizes a set of proteins, called histones, to start this process of condensing the DNA. In fact the cell uses to so many histones to do this, that it is one of the most prevalent type of proteins in a cell.

Proteins, like DNA, can be thought of as strings (albeit much much smaller) of repeating sequences of different amino acids. These strings of amino acids are almost always folded into different structures. Sometimes proteins are “woven” into sheets, other times into these globular structures as if the string had been tied into a large knot. Interestingly enough, it is that the order of the amino acids themselves that is the main determinant for what kind of shape the protein will form into; this is the case for histones. The sequence of amino acids for a histone causes it to fold into a predictable shape. There are a few different kinds of histones in cells, each with a unique sequence of amino acids and therefore a unique shape. From a cell’s histone arsenal, it utilizes a few different histones to create a multi-protein structure that resembles a neat barrel-like structure that DNA can wrap around; this is referred to as a nucleosome.

Once the DNA is rolled onto these histones, the cell still needs an easy method to lock the DNA away (so it cannot be unrolled) and to release it (so it can read the encoded blueprints); this process is accomplished by histone modification. These modifications are relatively small compared to the overall size of the histone, but they have profound effects.

A cell might modify a histone by adding an acetyl group, a small functional group, to it. In some instances, this modification causes the histone to loosen its grip on the DNA; sometimes it causes a different histone to tighten that grip. Now it might seem a little weird that the same modification causes opposite results. But returning to this “proteins are like strings” analogy, imagine what happens if you take the two ends of a knotted string and pull. What happens? Sometimes the knot gets tighter, other times the knot unravels; the outcome depends on what kind of know it is. A similar situation is occurring with these histones, the result of the modification depends on the structure of the histone.

This is what is the term “histone code” refers to, the attempt to decipher how modifications result in changes in DNA accessibility. Studying the outcome of histone modifications and how they effect the interaction between DNA and histones is currently a hot area of research. The implications of this effect are significant, if a segment of DNA cannot be removed from a histone, the blueprints encoded on the sequence of DNA cannot be read and the cell will miss out crucial pieces of instructions (imagine a plane without a left wing). On the other hand, if a histone cannot hold onto a DNA segment, that segment will be read inappropriately causing to the cell follow the instructions (imagine a plane with extra wings sticking out at odd angles of its body). This is why the histone code is so important; it acts a set of mechanisms that allow the cell the to control when the message from a DNA segment is enacted upon. Histone modifications don’t change the information in a piece of DNA, they just regulate if the message can be read or not.

The NK Linked Lecture Series: The Uniqueness of the Human Brain

An outstanding presentation given by Dr. V.S. Ramachandran. This presentation focuses on neuronal cross-wiring resulting in phenomena such as phantom limbs and synesthesia. This presentation is part of a lecture series by IBM.

A Protein's Manifest Destiny

Do human beings have free will? Or are we subject to some form of manifest destiny, that our calling is pre-ordained? Many people have invested much thought and effort to questions relating to these themes. Due to the nature of such questions and the way that our society works, perhaps there will never be a unified consensual agreement to the answer of these questions.

If we look, an analogous situation is presented in cells. Proteins are subject to diffusion and brownian motion, the molecular equivalent of free will albeit mindless free will. They diffuse haphazardly, randomly; such could be said for an individual's life. A protein could interact with other proteins, aggregating for a while, moving on down a chemical or electrical gradient. But they are not completely free to wander around the cell aimlessly. Within the protein itself exists a manifest destiny, it's signal sequence. Many secretory proteins have an initial sequence that will ultimately be cleaved by a peptidase, but nonetheless this sequence acts as a address on an envelope, labeling the protein. This label determines where it ends up, free floating in the cytosol, packaged into a secretory vesicle, or firmly planted into a membrane.

Maybe the determinants among us can take this as an argument that bolsters their theory but it necessarily isn't. There are exceptions to this rule, many proteins are not labeled with a signal sequence. Once translated they are free to wander about as they please, until they find a suitable partner to interact with or until they age, becoming less functional and eventually inactive.

Free will or determinism. Even a molecular level, we cannot say which is the case.

Science and Engineering Indicators 2006

Find yourself wondering about the state of the science enterprises in the US or abroad? Well, allow your pondering to be inundated with data from the, Science and Engineering Indicators 2006. This report was prepared by the NSF and contains a ridiculous amount of facts, figures and survey results about K-12 science education, labor forces, industry and academic R&D, public attitudes and world-wide S&E economic trends.

A sample of entertaining, interesting and/or depressing data:

"According to one report, "TV weathercasters are often the most visible representatives of science in U.S. households" (NIST 2002)." 1

According to a survey 1/4 of the US population in 2004 did not know that the earth revolved around the sun. 2

"...doctors and scientists received the highest prestige rankings out of 22 occupations. In fact, these were the only occupations seen by more than half of adults (52%) as having very great prestige." 3

The NK Linked Lecture Series: Nobel Laureate Richard Roberts

Nobel laureate Richard Roberts begins the lecture by advocating open-source publishing, where the content of a journal is made freely available on the internet by a website such as PubMed Central. He then goes to speak about restriction enzymes.

Enjoy.

Prions

Zombies at the Molecular Level

We've seen the cheesy zombie films. Mindless living dead creatures with the only goal to harass the living, often with the intent to dine on their brains. Where the newly and unfortunately lobotomized victims soon after also become zombies with the same insatiable platelet. Soon after everyone in town is transformed.

As incredulous as this sounds, a story along these lines is a plausible threat and a cause for much concern. Although the gravity of the situation is great, the scale at which these mutants operate is minuscule. I refer to the "mutated" proteins known to as prions.

Prions arise from endogenous proteins (referred to as PrPc) found in brain tissue, its native function has not been fully elucidated. The functional PrPc can undergo a conformational change (the exact mechanism is also not fully elcudiated) altering it to the infectious prion state (dubbed PrPSc). The conformational change is initiated by contact of PrPSc with PrPc. The basic reaction scheme is listed below.

PrPc + PrPSc → 2PrPSc

Just one inital infectious protein, PrPSc, could be enough to transform all native PrPc. While the main transformation method requires PrPSc, it is not fully understood how the first PrPSc is formed; the twist on the chicken or egg conundrum. Although there is evidence showing that cows that have ingested the brain matter of diseased cattle will also contract the disease, the question on how the formation of the inital PrPSc occurred is still unanswered.

If the conformation into the PrPSc form resulted in a minimal behavioral difference from PrPc, there probably would be little cause for concern. Unfortunately, this conformational change coincides with drastic functional changes, reinforcing a main staple of biochemistry that "form equals function".

Once formed, PrPSc begins to congregate extracellularly, forming amyloid plaques that will ultimately disrupt the normal function of the tissue. Amyloid plaque formulation results in transmissilbe spongiform encephalopathies (TSE), a lethal condition. The most notable disease caused by prions is "mad cow disease" due to past media attention. In humans, prions have been associated with Creutzfeldt-Jakob disease, Gerstmann-Straussler-Schninker syndrome, Fatal familial insomnia, sporadic fatal insomnia, Alpers syndrome and Kuru.

The NK Linked Lecture: DNA and the Brain

A lecture given by Dr. James Watson that was made possible by Authors@Google series. Dr. Watson comments on his role in the discovery of the DNA double helix and reports on some of the research being conducted at Cold Springs Harbor, of which he is The Chancellor (I assume this position is equivalent to the director).

Most notable quote of the lecture: " This century will see the coming together of psychology and biology in the way that the last century was the coming together of chemistry and biology."

Dr. Watson's lecture focuses on the genetic roots of autism. Autism being a neurological disorder, which the disease manifests via spectrum as opposed to "present/not present". Looking for phenotypic patterns present in the progenitors of autistic children, Dr. Watson comments on research where subjective mental state assessments have been gathered for autistic progenitors and then compared to the prevalence of autistic child births between these individuals. An example being that the average IQ for autistic progenitors is 112, when the over-all average is 100.

Here's where it gets tricky though. Another researcher, Simon Baron-Cohen, came up with the categories of the female mind and male mind (Which in my opinion is a very poor choice of names for these categories). Where the male mind is defined as a systemizer, an individual that is mathematics based, logical and the female mind is defined as an empathizer, an individual that is good at connecting with other individuals. I believe that the terms male and female mind need to go; just use empathizer and systemizer instead. This choice of nomenclature will just inhibit these findings by miring them in unnecessary politically correct battles. Aside from the poor nomenclature, Dr. Watson states, that two individuals who are assessed as systemizers (male-mind oriented) are more likely to have an autistic child.

This appears to make sense, that individuals with a phenotype to systemize as opposed to empathizing will produce offspring more prone to systemizing, assuming that empathizer-systemizer spectrum holds true. But what genetic or neurological reasons are there for these parameters to be mutually exclusive? I believe that I have encountered many people who I would categorize as both strong systemizers and empathizers. Furthermore, according to this theory, that autism can be described as an individual at the extreme systemizer end of the empathizer-systemizer spectrum,then there should also be examples of neurological disorders on the opposite end of this spectrum.

Although I found this lecture engaging, I believe that I need to read more of Baron-Cohen's research to fully understand his position.

Well, enjoy the presentation.