Epigenetics, as it’s name implies is a collection of genome wide alterations that would change the information that is coming out of the genome, without changing the sequence. These changes are heritable from cell division to cell division, and in some cases from parent to offspring. This idea sounds a bit odd the first time around. We get used to thinking about mutation as one of the few ways that gene information can be changed in a heritable way, but it turns out there are more. Biology is smart, or at least it has had allot of time to figure out how to get things done.
As a field toxicology is concerned with the way that the environment effects living organisims and one area of interest has always been genotoxic compounds. Epigenetics adds a new dimension to this as epigenetic changes cause alter gene expression and if you look for examples there are plenty of mechanical changes in the genome of cancer cells that part of the epigenetic machinery. Toxicologist are very interested in what xenobiotics would be involved in altering epigenetic patterns.
Finally there is one more twist that is worth mentioning. I like all biologist of my time grew up thinking of the world using Darwin‘s evolutionary paradigm. There was another contemporary of Darwin that many of us have heard about that is often used as a counterpoint to stress how other scientists of the time thought of change that occurred across species. The cartoon that I can still remember to this day is Jean-Baptiste Lamarck‘s giraffe stretching to eat the leaves higher and higher in the tree. Ridiculous! But wait, epigentics proposes a model by which the environment might actually be able to influence the genome of an organism and produce heritable changes in gene expression. This may not be what Lamarck was thinking of, but it does sound eerily similar.
The toxicology paper is a good review of epigenetic mechanisms and it has a few “gee-wiz” biology examples.. There are however many practical examples of how epigenetics works, and diseases that may have an epigenetic component. I have asked the Tox 1401 students to head on over to OMIM and search using the term “epigenetic”, to find some examples. Look through the comments to see what they have come up with.
Radiation therapy is becoming more and more common and as with many things that we have discussed here, the person to person variation in response to radiation exposure can be large. So what drives this difference in response to radiation dose. An answer is emerging from a series of studies that were undertaken using cells from xeroderma pigmentosum patients. You can read more about xeroderma pigmentosum here, but briefly these patients suffer from a dysfunction in the molecular system that repairs DNA double strand breaks.
In a 2010 Journal of Medical Genetics paper by Abbaszadeh et al. The authors piece together the role that a specific protein, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays double strand break repair induced by ionizing radiation. Ultimately specific alleles of the DNA-PK protein are identified that predispose these individuals to an extreme radiation sensitivity.
The authors leave us with an interesting statement:
“Finally, these data show how seemingly ‘mild’ or undiagnosed defects in DNA repair factors, while consistent with viability, can have catastrophic consequences should such an individual require cytotoxic anticancer RT. Simple pretreatment screening protocols such as measuring the induction of repair of nuclear gamma-H2AX foci in patient cells, to identify individuals at risk, would increase the safety of RT for such patients.”
I am asking the Tox1401 students to look into exactly what “pretreatment screening protocols such as measuring the induction of repair of nuclear gamma-H2AX foci in patient cells” is, so if you would like to know more, head on over to the comments section where they will provide a brief description of the procedure.
Charcot-Marie-Tooth (CMT) disease is named after the three physicians who first reported it in 1886. CMT is a group of genetic diseases that causes muscle weakness and wasting, or atrophy, in the feet, legs, hands, and forearms, as well as diminished sensation in the limbs. CMT disease affects the peripheral nerves-the nerves that travel to the muscles of the limbs and is therefore known as a peripheral neuropathy. Estimated to affect one in 2,500 individuals, it is the most common inherited neurological disorder.
The Tox 1401 students recently went through a 2010 paper where a CMT family was screened by sequencing the genome of a proband (an effected founding individual of a group). In this study the sequence from the proband was compared to reference genome sequence. This analysis which initially started with more than 3 million genetic differences between the proband and the reference genome group ultimately narrowed the genetic difference in this CMT family to the SH3TC2 gene.
If you would like to read more, I am asking the Tox 1401 students to head on over to the OMIM site and give us some background on the SH3TC2 gene product and how mutations in this gene might effect neuronal function.
Characterized more than a century ago, Friedriech’s ataxia is a debilitating neurodegenerative disease, effecting gait (ability to walk), arm movement, and progressive muscular weakness. Symptoms usually are present before 25, but rarely begin before the onset of puberty.
The molecular mechanism was uncovered through familial studies in the 80s and a shared molecular event was identified in the 90s. A common mutation was identified, the change involved the expansion of a GAA nucleotide repeat in the first intron of the frataxin gene. Since the mutation is in an intron the individuals with this mutation can make the frataxin protein, but only at very reduced levels.
With lowered frataxin levels come abnormally high iron levels within neuronal mitochondria. These individuals have mitochondria that are drowning in iron while sometimes presenting in the clinic with iron deficiency by blood test.
From a toxicological point of view, a tough diagnosis.
Frataxin itself is not well understood. The protein is involved in iron storage and transport, but it does not appear to be a transporter. Under normal conditions there is little free iron in the mitochondria, but with reduced frataxin levels, mitochondrial function is severely compromised.
We have talked a bit in class about mutations that do occur within the coding region of genes and I have asked the toxicology students to describe how such a mutation as a repeat nucleotide expansion in an intron could lead to reduced protein levels. I have also asked them to suggest a genetic test for Friedriech’s ataxia, so if you want to know more, read on.
They will be using Schmucker and Puccio’s 2010 Human Molecular Genetics paper, “Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches” to develop their responses.
We again used our toxicogenomics laboratory to reach out to students in the community. You can read about our previous ASL lab activities here and here. This year we invited 8th graders from Immaculate Conception and Holy Family Schools.
In this lab students genotyped themselves, using genomic DNA prepared from their own cheek cells. You can read more about the lab itself here.
I have asked the toxicogenomics students taking part for feedback. You can read their reflections on this activity in the comments section of this post.
I asked the students to consider:
- How does your service learning experience relate to the objectives of the toxicogenomics course?
- What did you observe?
- What did you learn?
- What worked in the lab? What didn’t?
- Is there something more you could do to contribute to the success of the lab?
- What have you learned about yourself?
- What have you learned about teaching?
- What have you contributed to the students?
- What values, opinions, beliefs have changed?
- What was the most important lesson you learned?
- How have you been challenged?
- What impact did you have on the community/students?
In Akhtar and Benter’s 2007 paper there is a sense of an improved therapy, yet today we still are waiting for those new therapeutics. This feeling is summed up in Aldridge’s 2011 article; “RNA interference – still the great white hope?“.
From 2007 we have this enticing table of currently running clinical or preclinical trials:
The question is; what happened to them?
Okay readers, onto the comments for an update from the Toxicogenomics class…
In their 2009 American Journal of Human Genetics paper “Massively Parallel Sequencing: The Next Big Thing in Genetic Medicine” Tucker et all discuss the basic workings of past and present sequencing technologies. As all of the sequence technologies that we have discussed in class and are detailed in this paper become commonplace we as health professionals and as a society will have to address a number of issues. One of the things that I liked about this paper is that the authors step away from a simple review of technologies to the much harder to describe and interpret area of ethical considerations. They break this issue into four subsections consent, interpreting sequence data, the rest of the data, and storing sequence data.
After reading the paper I want you to choose one of these subsections and address questions within that area. Try to answer the question from the perspective of the patient and the clinician. Explain your answers. Then be sure to to comment on someones else’s take.
In their 1953 “Molecular Structure Of Nucleic Acids” Watson and Crick open with the decidedly unscientific “We wish to suggest…” and in only a short page or so, take us through their thoughts on what shape DNA takes in the natural world. With a tone, that is though decidedly academic, conversational in the way it winds from chemistry to other laboratories take on what structure DNA might take.
The paper is notable for what is not present as well. After a careful description or at least inventory of the facts supporting their structure, they proceed to open up a new avenue of discusion; suggesting how the model might relate to the observed biology. In one of the final paragraphs they lead with “It has not escaped our notice…”. They hint that the structure they have described, suggests that there is a very simple solution to another vexing problem remained unsolved in 1953. How does DNA copy itself, and how does it do so quickly?
Here Watson and Crick speculate that they have solved an important piece of this puzzle, and interestingly do so without directly stating what their speculation is! As is to pass off the impoliteness they assure us that these speculations and more data will follow.
They write as if they are dashing out the door, when in fact they seem to have carefully crafted their thoughts so the reader can follow the unfolding story as if discovering the structure themselves.
If you are in Tox 1401, I want you to carefully read the paper and using a tone and style similar to Watson and Crick describe the three dimensional structure of DNA. The exercise here is not only think about science, but to focus on how it is communicated. After your description, add a short speculation on what other structures DNA might take. Your structure can be made up, but I want to to root your structure in some facts, much like Watson and Crick do. You may have to rewrite this piece a few times before committing it to the blog. Take the time to look over what others have written, and comment on well crafted descriptive pieces.
How Not To Write Boring Literature
There are many ways to write science, but for such an exciting subject many see reading science as pure drudgery. In “How to write consistently boring scientific literature” Kaj Sand-Jensen explores ten examples of scientific writing that we could all do without. In class on January 28th you started to buck the the trend by coming up with ideas how you would like to write scientific literature. In your first post I want to to choose one example of boring scientific writing and one example of what you consider good scientific writing. You can use two papers or both examples can be from the same the same paper. Tell me what you like and dislike about your examples and be sure to comment on two other folks posts.
Brian Deer has written an article detailing fraud, intentional fraud, on the part of the primary investigator attempting to make a connection between the MMR vaccine and autism.
Well worth reading:
How the case against the MMR vaccine was fixed — Deer 342 — bmj.com.