Cholesterol is a crucial fat-like substance produced by the liver that is required for bodily functions. It is the main sterol synthesized and transported in the blood plasma of all animals. Cholesterol is responsible for a number of functions such as:

1. Building and maintenance of the cell membranes
2. Production of sex hormones (androgens and estrogens)
3. Production of bile
4. Metabolism of fat-soluble vitamins, including vitamins A, D, E, and K
5. Insulation of nerve fibers
6. Conversion of sunshine into vitamin D

Cholesterol being a crucial part of our development can have a dark side. The gene DHCR7 (7-dehydrocholesterol reductase) found on chromosome 11 is responsible for the production of cholesterol and mutations in the gene may lead to a metabolic disorder known as SLOS (Smith-Lemli-Opitz Syndrome). This disorder currently occurs once out of every 20,000 births. Individuals with SLOS are unable to produce enough cholesterol to support normal growth and development. This leads to developmental delays, physical malformations, mental retardation and issues with major organs such as the heart. Currently the only treatment for the disorder is cholesterol supplementation to improve growth and developmental progress.

SLOS is inherited in an autosomal recessive pattern, basically both copies of the gene within a cell are mutated. This identifies that the parents of a person with SLOS each carry a mutated copy of the gene, however they do not have any symptoms or signs of SLOS. It may be that genetic counseling may be one form of a preventative method for the disorder. This brings up a great question, should genetic counseling be mandatory for potential parents to decrease transmission of severe genetic disorders?

Some students I was teaching thought that this might be possible: to engineer the insulin-producing cells with a correctly functioning gene, a type of gene therapy.  While this has been a goal for researchers, and they have successfully made insulin-producing cells in the lab from embryonic stem cells, they are not appropriate for transplant because they do not release the insulin in response to glucose levels.  Plus, the immune system might still recognize these cells as foreign and destroy them.

So a new study is looking at transforming cells of the gut that don’t have a specific job yet.  These cells receive signals throughout the life of an individual to become many different types of cells that are used for normal gut function.  So could they engineer these cells to receive the signals to become insulin-producing cells?  Also, would the cells only release the insulin in response to blood glucose levels?

Two Columbia University researchers have started finding possible answers to these questions.  Once they turned off a gene that normally plays a key role in the fate of a cell, insulin-producing cells were generated.  Having cells in the gut that make insulin can be dangerous if they did not release insulin in response to blood glucose levels, but these “new” gut cells have glucose-sensing receptors to allow them to do just that. Another remarkable feature was that the gene could be turned off either early on in development, or later on in adulthood, so it wouldn’t matter how old the patient was.

The next step is to take the research that has been done on mice so far, and see if they can mimic this in humans with the use of a drug or chemical.  This method will also need to prove to be safe and more effective than current methods of treatment, not just to avoid the burden of daily injections.

While most students don’t fully grasp this idea, there are a few examples we can use that can help to explain this.  I have always used examples of giraffes and the development of long necks, or antibiotic resistance in bacteria, but these seem to be a bit out of the realm of many 5^th grade students.  So what better example than ourselves!

During another lesson, I introduced the development of lactase persistence, or having the ability to drink and eat dairy products past infancy.  Digesting the sugar in milk (lactose) is dependent on whether or not the cells of your small intestine are producing the enzyme lactase.  Lactase is responsible for breaking lactose into smaller components that then get absorbed into the bloodstream.  For mammals that get milk from mother early in life, this enzyme is essential.  Would a mutation in the DNA that would allow a cell to continue to make lactase past infancy be beneficial?  It all depends on which population of humans you ask.

If it is a population of humans that began drinking the milk of other animals after the development of agriculture, like those of Northern European descent, it would be selected for.  These populations now show the highest frequency of lactase persistence among all human populations.  If dairy was not a part of your diet after infancy, this mutation wouldn’t be considered beneficial and would not have been selected for, such as in African, Asian and South American populations.

So, when teaching evolution and the changes that we see in species over time, it is nice to be able to give an example that we can see in humans.  Using an example that is a recent development in humans over the last 10,000 years, may help students to understand this concept better, and apply it across any species.

Well what do I mean by lasting changes? Research has shown that depending on what your mother eats may influence your genes and health in the long run. The gene agouti is found in humans and mice. The agouti/melanocortin system is an important regulator of body weight homeostasis. Mouse studies have shown that when the agouti gene is not methylated the result is obese yellow coated mice which may be at risk for cancer and diabetes. When the gene is methylated mice are brown, of normal weight and size. The only difference between the two types of mice is the methylation control on the agouti gene. In parallel experiments were carried out where yellow female mice were fed a methyl enriched diet; the offspring grew to be normal weight, size and were brown in color and remained so for the rest of their adulthood. This study identified that an individual’s wellbeing is not only determined by what they eat but also what their parents ate.

References
Nutrition and the epigenome. Retrieved February 8, 2012, from http://learn.genetics.utah.edu/content/epigenetics/nutrition/

This may help to answer many questions.  How can we have so many different types of cells and they all carry the same genetic information?  How is it possible for one identical twin to develop cancer while the other does not?  Can we use this control of the gene expression to help cells that may have lost their way?

It is amazing to think that just about all of the cells of the human body has the same DNA.  The full genetic profile with all of the instructions on how to make a human is in almost every cell.  When most students come through the DNA Learning Center, many of them think that there is different DNA inside of these cells.  That red blood cells have different DNA than bone cells and nerve cells.  One way this is done is through the interaction of small methyl groups (-CH₃) that get added to the DNA molecule, which can help to silence a gene that is not needed in some type of cell or at some point of development.  This is a epigenetic “tag” because there is no change to the sequence of DNA, it is just whether or not there is access to the DNA.  The methyl groups that get added make the cell unable to activate that gene.

This addition of methyl groups, called methylation, also can change throughout the course of our life.  So as we get older the interaction of these groups with our DNA can change.  So even with identical twins, who are born with the same DNA, their epigenetic “tags” can vary and occur independent of one another.  And even more, certain lifestyle choices and experiences throughout the life of a person can change the epigenetic profile of an individual.  And then this gets passed on to our children.  So even what a mother eats while pregnant can affect the tags that get passed to their child.  This ultimately will affect the expression of genes in the child.

And now we are using this information to help treat disease, such as cancer.  So if a gene is turned on that shouldn’t be, could we add methyl groups to that section of the DNA to turn it off?  This has started being used as a new therapy for the treatment for certain cancers.

MicroRNAs are found abundantly in humans and regulate gene activity through repression mechanisms. But to find microRNAs from plants still thriving post digestion was quite surprising. Even more shocking it was identified that fragments of these plant genomes come with consequences. Scientists revealed one such microRNA molecule, called MIR168a—which is abundant in rice and plays a role in plant development. This molecule has the ability to pair up with a piece of human RNA that helps remove “bad” LDL cholesterol from the bloodstream. Studies in human cell cultures confirmed that MIR168a interferes with the production of a cholesterol-clearing protein. Studies carried out in mice found those eating rice had a higher level of LDL cholesterol in the blood than the control mice who had no rice. More studies will have to be performed to identify the overall pros and cons.
Dr. Chen-Yu Zhang of Nanjing University says “many microRNAs, of a non human source, have beneficial effects”. He has identified an herb utilized in traditional Chinese medicine that in preliminary mouse studies has provided evidence of a microRNA that aids in fight against the flu virus.

Reference:
1. Stanley, S. (2011 December 22): Genome of Vegetables Remains Active After You Eat Them Retrieved on January 1, 2012 From Discover Magazine. http://discovermagazine.com/2012/jan-feb/18

This has recently been reported for patients with Hemophilia B.  Hemophilia B, also known as Christmas disease, is due to a deficiency of the clotting factor IX (FIX).  The first reported case of Hemophilia B due to a decrease in FIX was in 1952, and was called “Christmas Disease” after the first patient diagnosed was named Stephen Christmas.  Without this clotting factor, the blood does not form clots and results in severe bleeding episodes, especially in the joints and muscles.

Bettert reatment for this disorder began back in the 1960’s where they would inject FIX concentrates into the blood of patients with hemophilia B.  This increased the average age of death of 24 to a median lifespan of 63 years of age.  So with the success of the protein therapy, why try to fix the genes?  With each treatment costing $150,000 to $300,000, a patient needing clotting factors for hemophilia could incur a lifetime cost of $20 million.

So there needs to be a way that a patient can have a more effective treatment option that will cost less.  This new treatment option offers some hope.  Using a new virus for the administration of the gene, patients have seen an increased production of FIX protein for longer periods of time, and were able to stop or decrease the amount of concentrate injections they would need.  With one injection of the virus only costing about $30,000, dramatic cost savings have already been seen.  While this does offer new hope for the treatment of clotting disorders, follow-up with a larger number of patients and for longer periods of time will be needed to fully weigh the benefits and risks of this technique.  Once this has been done, hopefully we will see gene therapy used more in practice and maybe even for more than just clotting disorders.

Ponder, Katherine P.  Merry Christmas for Patients with Hemophilia B. The New England Journal of Medicine 10.1056; December 10, 2011.  Nathwani A.C., Tuddenham E.G.D., Rangarajan S., et al.

Pharmacogenomics is the ability to study the differences in the DNA of a person to see how they are going to respond to a certain drug.  The DNA contains instructions on how to make proteins.  These proteins then go on to carry out life’s basic functions.  A disorder that may result because of changes in the production of these proteins resulting from mutations in the DNA has been a major area of research for some time.  But now we have to look into how some of these proteins are interacting with the medications that we are taking to treat the disorder.  It is a major shift in the way many people think about DNA and how it affects our health.

Pharmacogenomics is a relatively new area of science that is now looking into these differences in the DNA that cause a person to respond to a drug in a certain way, if at all.  There are a whole group of proteins that are in charge of metabolizing, or breaking down, the medications we take into their active forms.  The instructions in the DNA that make these proteins are different from person to person, so it is these variations that will either make a person make more of the proteins, less, or none at all.  These different levels then cause a person to respond to a drug in a certain way.

For example, if a patient is taking the blood thinner Warfarin to treat blood clots, and they are making too much of the protein that metabolizes this drug, they will break it down too fast and this could possibly thin the blood too much.  If they are a patient that either makes less or none of this protein, the clots will still form, which could still cause serious problems for that patient.  So if we could gather all of the variations in the DNA that lead to certain reactions to drugs, we could use this information to better treat future patients.

A DNA test could be done before the medication is prescribed.  If a patient is showing a similar variation in the DNA to a previous patient that was not able to metabolize a drug, the doctor may want to think twice about prescribing that drug to their patient.  Since we now know that one size does NOT fit all, studying the variations in the DNA to see how their patients will respond to certain drugs will help in prescribing the correct drug and at the right dose.

Featured image from: http://www.genomicslawreport.com/index.php/tag/personalized-medicine/

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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