DNALC Blogs » Jermel Watkins

Bad Cholesterol

Jermel Watkins — Thu, 12 Apr 2012 15:27:17 +0000

When someone mentions cholesterol many will say, how is your HDL? Cholesterol travels through the blood attached to lipoproteins. From a health prospective we try to maintain the good cholesterol (High density lipoproteins or HDL) and decrease the bad cholesterol (Low density lipoproteins or LDL). The HDL aids the body in removal of bad cholesterol in the blood whereas LDL causes build up of plaque within arteries restricting blood flow and hardening of the arteries that may result in heart disease. Control of cholesterol levels is through a number of ways such as low cholesterol diets, weight loss and drugs.

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?

Controlling gene expression through diet

Jermel Watkins — Thu, 16 Feb 2012 14:30:43 +0000

Epigenetics is the study of chemical reactions that control the on and off switch of genes at specific times and the factors influencing them. Environment is a factor that influences epigenetic change which may encompass behavior, stress or diet. The easiest of the three to make observations from is diet. When we think of food, rarely do we think of chemical modifications to DNA and restriction of gene activity. Commonly we think of foods coming in and being broken down into nutrients to be utilized in metabolic pathways to make components the body can use. Interestingly one of the pathways utilized produces methyl groups, the chemical (epigenetic) tags used to shut off genes. Research has shown that diets rich in methyl donating nutrients in early development and as an infant can cause lasting changes.

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/

Traveling Genomes

Jermel Watkins — Tue, 03 Jan 2012 21:24:46 +0000

Many individuals are concerned with the dietary components of foods they consume. However, scientists from Nanjing University in China have given us a different perspective as to what we eat, they have discovered fragments of genetic material known as microRNAs making their way from vegetables into the human bloodstream.” (Stanley 2011)

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

Trying to unlock a new door…..

Jermel Watkins — Mon, 28 Nov 2011 21:59:10 +0000

How is drug development moving along? Well, this is a very good question for we are still plagued by some elusive diseases, cancer for example. There have been many drugs developed targeting proteins involved in disease states some of which have proven to be quite effective. However today the steam engine for identifying drug targets to proteins involved in disease is becoming ever more difficult.
Apparently over the past decade or so, the number of new drugs targeted toward disease has declined. This is primarily due to the fact that developing new medicine has become more difficult to do. It turns out that this is partly because we have sifted through all the ideal proteins that can be targeted by a drug. The remaining proteins are not ideal for developing a targeted drug. These proteins dawn small cavities or binding pockets and are relatively flat allowing for little to no interaction with a drug target. Its been said that 15% of proteins can be targeted by drugs. The percent of proteins that modify disease is 10 to 15 %. In order to alleviate this problem scientist have acquired the help of computer modeling to more thoroughly identify and test favorable small molecules that can block the activity of these undruggable protein populations related to disease. Dr. Stockwell an Associate professor at Columbia University, has attempted computer modeling and has come across compounds to target a class of E3 ligases, which are characteristically undruggable, and involved in just about every disease. Of these compounds one in particularly was a potent inhibitor. Dr. Stockwell will be publishing his findings in the next few months on the efficacy of the inhibitor. If it proves worthy this new drug will have an impact on cancer and neurodegenerative disease.

The Medical Sleuth

Jermel Watkins — Mon, 31 Oct 2011 12:52:49 +0000

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.

Will insulin come to the rescue of AD patients?

Jermel Watkins — Tue, 27 Sep 2011 13:20:34 +0000

Alzheimer disease (AD) is a neurodegenerative disease of the brain that is divided into early- and late-onset groups. AD is characterized by the build up of amyloid plaques, neurofibrillary tangles and the loss of connections between neurons. It is the most common type of dementia especially in the elderly. The exact causes of AD are elusive at the moment but are most likely the result of genetics and other factors. Scientist have been working hard to identify individual and or groups of genes responsible for the disease. Although the scientific community has identified may genes involved in early and late onset groups, a new discovery has shed some light on the subject. In the intimate interplay of activities within the cells of the brain scientists have identified a key player, insulin. It is thought that dysfunction of insulin plays a crucial part in the exacerbation of symptoms.

The regions of the brain such as the hippocampus and the frontal cortex are densely populated with insulin receptors. As well they are found in synapses in which insulin signaling participates in synaptic remodeling and synaptogenesis (1,2). In parallel insulin regulatesthe utilization of glucose in the hippocampus and other regions of the brain to promote optimal memory in normal metabolism (3). In AD, it has been shown that reduced levels of insulin and insulin activity exist (4,5). Interestingly insulin has a tight relationship to amyloid beta, a toxic peptide responsible for the onset of the disease. Insulin can regulate the levels of amyloid beta to deliver protection from the degenerative nature of the peptide on neurons (6-8).

A pilot clinical trial published in the archives of neurology titled, Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment, has shown insulin’ ability to be a protective new therapy in the fight against AD. The trial hosted 104 participants, of which 30 participated in the use of a placebo, while insulin at 20IU and 40IU were delivered to 36 and 38 participants respectively. The insulin was administered through a nasal drug delivery device for a total of 4 months. Surprisingly the 20IU and 40IU group experienced improved memory recall and preserved general cognition.

It was very important to identify a method of administration of insulin properly and direct to the brain without disrupting blood sugar levels. When taken as a nasal spray it reaches the brain in just a few minutes with no apparent adverse affects on the body. Although a very promising study, it is still a preliminary study, more research will have to be carried out to ensure the safety and effectiveness of insulin as a therapy for longterm use against AD.

Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708-719. PUBMED
Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 2009;1792(5):482-496. PUBMED
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93(4):546-553. PUBMED
Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50(1):164-168. FREE FULL TEXT
Steen E, Terry BM, Rivera EJ; et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. PUBMED
De Felice FG, Vieira MN, Bomfim TR; et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106(6):1971-1976. FREE FULL TEXT
Gasparini L, Gouras GK, Wang R; et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21(8):2561-2570. FREE FULL TEXT
Lee CC, Kuo YM, Huang CC, Hsu KS. Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol Aging. 2009;30(3):377-387. PUBMED

Olive Oil and Nutrigenomics

Jermel Watkins — Tue, 28 Sep 2010 13:11:30 +0000

The effect of foods on gene expression is a fairly new area of science termed nutrigenomics. Many people are highly interested in how they may protect or prevent disease or conditions by applying diets appropriate to ones genetic make-up. Although early in its stages nutrigenomics has identified some very interesting findings. One interesting find was a clinical trial linking olive oils to the anti-inflammatory response

Extra virgin olive oil has been shown to reduce the expression of 98 genes involved in the inflammatory response by researchers from the University of Cordoba (Camargo A et al. 2010). Polyphenols are the primary beneficial compounds, which are found at high levels in extra virgin olive and not virgin olive oil, that deliver an advantageous nutrigenomic effect on many of the genes responsible for inflammation. The study exposed participants to breakfast diets with extra virgin olive oil versus virgin olive oil to determine the health benefits. After careful observation it was shown that participants on the virgin oil had 79 pro-inflammatory genes that were higher in comparison to those on the extra virgin oil. In addition 19 anti-inflammatory genes were higher in those who ate extra-virgin olive oil. Quite impressive that something as simple as olive oil can aid in cardiovascular health.

Could taking a nutritional supplement keep you young?

Jermel Watkins — Wed, 14 Jul 2010 19:14:34 +0000

It might be more real than not. Scientists working at the biotech giant Geron Corporation have isolated a molecule, TA-65, which has the ability to increase telomerase activity (It is important to note that his find has not been evaluated in published peer reviewed studies as of yet). This is an exciting breakthrough for telomerase is an enzyme that adds DNA sequence repeats to the 3′ end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, giving stability to the chromosomes. These telomere DNA sequences shorten with every cell division thereby leading to the eventual aging of cells. Geron Corporation may have found the elixir of life.

Geron licensed the product as a nutritional supplement to bypass FDA approval. In 2007 a number of physicians have sold TA-65 pills and patients have reported enhanced athletic, visual, and cognitive performance. In order to give backing to these claims research showing TA-65 effects on density, immune function, and age-related biomarkers will be submitted for peer-reviewed publication this year. Geron is on the move, not only is the company on the cutting edge sustaining youth, they have another telomere therapy that promises to fight cancer, lets definitely keep an eye out on that one.

HIV halts brain disease

Jermel Watkins — Wed, 17 Mar 2010 15:29:54 +0000

Adrenoleukodystrophy is a rare inherited disorder identified in patients with a defective gene that produces a protein called ALD; which leads to progressive brain damage. ALD is a transporter required for the break down fats. Defects in ALD lead to the build up of fats and the eventual damage of the myelin sheath that protects nerves. For many years the only treatment for this has been bone marrow transplants, which is limited in the availability of donors and let us not forget the number of complications that could arise.

A new treatment has shown itself in the form of gene therapy. Bone marrow cells can be treated with a modified and inactivated HIV virus carrying the correct message for the ALD gene and infused back into patients with adrenoleukodystrophy. The blood cells with the correct message would then be carried to the brain where ALD will be produced and utilized to improve the disease. At present HIV is the only virus that can deliver a therapeutic gene into the nucleus of non-dividing cells. Who would have thought that HIV virus could have a positive side?

Getting an edge on breast cancer

Jermel Watkins — Wed, 03 Feb 2010 12:24:55 +0000

Cancer is a life threatening disease characterized by uncontrolled growth of cells coupled with malignant behavior. The causes leading to cancer are believed to be genetic, environmental, or a combination of the two. Chemotherapy is one of a number of treatments for cancer. It utilizes a regiment of chemicals toimpair cell division and/or induce programmed cell death.

Research carried out by Dr Yang Li and colleagues at Harvard Medical School, the Technical University of Denmark, and the Université Libre de Bruxelles, have highlighted two genes – LAPTM4B and YWHAZ – that may inhibit the response of anthracycline-based adjuvant chemotherapy for breast cancer. The group found that patients who have a high expression of the genes show a reduced sensitivity to anthracycline-based adjuvant chemotherapy (though they remain somewhat susceptible). Conversely, patients with these genes switched off, showed a heightened sensitivity to the chemotherapy.

This breakthrough will allow doctors to take our clinical treatments to next level – personalized medicine. Genetic profiles of patients and of specific cancers will enable doctors to selectively determine chemotherapy regimes with the most potential for preventing relapse. A continued effort will have to be made to decipher how these two genes block the action of anthracycline-based adjuvant chemotherapy.

Reference:
1. http://www.nhs.uk/news/2010/01January/Pages/Genes-affect-cancer-treatment.aspx