I "Wonder" what is mandibulofacial dystosis???

Many of you have likely seen the trailer for a new movie in theaters called, “Wonder” with Julia Roberts and Owen Wilson as parents to a boy born with Treacher Collins syndrome (TCS). I have not seen it, but it sure looks like an eye opening and heartwarming film.

TCS, or mandibulofacial dystosis, is expressed by malformation of the cheek and jaw bones (potential airway issues), deformed auricles of the ear, lack of an ear canal (deafness), abnormalities of the eyes (potential vision problem), cleft palate, and other facial distortions. Not all pathologies listed are necessarily present in every person, and the severity of the defects vary widely by individual. TCS is a congenital genetic disorder marked by a mutation in POLR1D, POLR1C, or TCOF1 genes. Some cases are a result of inheritance of the mutation from parents in an autosomal dominant manner for POLR1D and TCOF1 genes and in others, in an autosomal recessive mode for POLR1C. However, a majority of the cases, 60% according to one study, of autosomal dominant mutations result from novel mutations not parental inheritance. The TCOF1 gene is the site of the mutation in 80% of those with TCS. Most children have no cognitive delays and no effect on lifespan.

The POLR1D, POLR1C, or TCOF1 genes code for proteins that are involved in rRNA synthesis which in turn code for the molecular machinery that produce proteins in cells, or ribosomes. A decrease in the production of rRNA will yield a decrease in overall protein production which are critical for overall cell maintenance and growth. It is unknown as to why the pathology is limited to the bones and tissues of the face. In addition, current research is being done in a protein called p53 which is found in abundance in TCS patients. The p53 protein is a tumor suppressor and plays an important role in protecting our body from cancer cells with about half of all cancer cases being attributed to mutations in the gene coding for the p53 protein. It acts as a cell cycle regulator and is involved in apoptosis of unwanted cells (especially cancer cells). It is highly active when DNA damage is detected to stop cell division until the DNA damage can be repaired. If the damage is too great, it enacts the process of apoptosis which is awesome for cancer cells and other real cell issues. In fetuses with TCS, the p53 protein is destroying the cells responsible for normal facial growth. Researchers are looking into turning off the function of the p53 protein in fetuses where its levels are elevated allowing for normal growth. There is still much more preliminary research that needs to be done before any potential clinical trials would begin.

With the help of a plastic surgeon, many of these malformations can be altered to leave the child with a more “normal” appearance. It is suggested that those affected join a support group through The National Craniofacial Association (www.faces-cranio.org/Disord/Treacher.htm) to meet others who can understand what they’re going through.


Sources:

https://rarediseases.info.nih.gov/diseases/9124/treacher-collins-syndrome

https://medlineplus.gov/ency/article/001659.htm

Awful skin disease with bright future!

A couple years ago in Germany, there was a 7 year old boy with an often lethal genetic disorder which affected his skin causing it to be extremely sensitive. He would get blisters all over his back as a baby and infections were common because the skin would be covered in open sores. This genetic disorder is called Junctional Epidermolysis Bullosa (JEB) affecting about 500,000 people worldwide. Those that have this disease are at high risk for skin cancer and more than 40% die before their teenage years. There is no cure. Doctors simply seek to provide relief with pain killers, therapeutic approaches, and when infections occur, antibiotics. JEB affects three genes that code a protein (laminin-332) dealing with proper skin cell growth (LAMA3, LAMB3 or LAMC2).

The boy and his parents presented at the burn unit at a University Hospital in Germany in June 2015. After admission to the hospital, he began to go downhill quick with about 60% of his skin being lost which allowed for two bacterial infections to erupt. The therapeutic approaches failed to provide much relief. Ultimately, the doctors and parents got permission to try a new treatment only tried on a couple of other patients on very small wounds. The plan was to take a small biopsy of skin from an area not affected on his body. Next, a retrovirus was used as a vector to insert the deficient genes into the boys own skin cell (keratinocyte) sample. Then, they grew enough grafts in the lab to cover all of the boy’s wounds which now covered about 80% of his body. He received multiple surgeries to implant the lab grown, genetically altered skin grafts. The doctors believe the skin cells were so successful because they are holoclone (stem cell) heavy. Out of about 3.9 × 10^8 skin cells, about 1.6 × 10^7 were holoclones. There was great success as his skin began to heal. A few years later and many follow up visits to check on him, doctors and researchers are very hopeful that this can become a potential standard treatment for patients with JEB. There has yet to be any negative outcomes of the procedure.



Sources:

https://www.nature.com/articles/nature24487.epdf?referrer_access_token=s-E8ajCTx238WDjKOmN6v9RgN0jAjWel9jnR3ZoTv0OSWviL8WF5ZttJjAsMRX_zHxS-eQNjkE7AlrtNr3d7gmVvwHkkmE7vOhMpYV1Ib4A-DecWIGUE9ChD7xe0BNdiJzlprMJhBw2PcIVvVSPCbkzP4ncc9xRoZUW990dnSZsI3S7a4xhFuoEbzKfyUgZd06zDDGuRmvusD6jupbVx9nHyGBXwpaKCpyrW5_8TvDM%3D&tracking_referrer=www.nature.com

Belly Bacteria and Colon Cancer Screening!

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and accounts for the second most cancer deaths, in the United States. This is a common disease worldwide, not just in the United States, and it is creating a huge economic burden globally. For the best possible outcome (and most economical), it is critical for early detection of this cancer and treatment. The standard screening is still to have a regular (at least every ten years after age 50) colonoscopy performed to look for polyps or abnormalities in the large intestine down to the anus. As I mentioned in an earlier post, there is currently a huge amount of research being done on the human gut microbiome. Specifically, researchers are trying to better understand how the microbes in our GI tract interplay with the rest of our body (especially the brain and GI tract itself). There are a plethora of papers in the literature from the last few years discussing the potential for using an individual’s gut microbiome data to diagnose things like colon cancer. I have never personally had a colonoscopy performed, yet I can imagine it is not the most pleasant experience even if you are somewhat sedated. Giving a fecal sample and sending it in to have my microbiome analyzed to screen for colon cancer sounds like a much better alternative in my book. There is an FDA approved screening kit created under the name, Cologuard, for those 50 and older at normal risk for colon cancer. Those at higher risk would likely need the traditional colonoscopy, and it would need to be done more often (every few years). With Cologuard, they send you the kit, you provide a fecal sample according the instructions provided, and you send it back in their provided packaging. It will be analyzed in a lab, and according to their website, they can identify 92% of colon cancers and 69% of pre-cancers. Fusobacterium nucleatum a bacteria found in the human gut, and researchers have found that too much of this bacteria is very often correlated with colorectal cancer. There are quite a few other correlations researchers have found between different gut bacteria and CRC. It is truly amazing the breakthroughs that are being uncovered every day that are creating a positive impact now and into the future. I am especially intrigued at the complex role that our gut microbiome play in our overall health and functioning even at a molecular level.

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589167/

https://www.cologuardtest.com/landing?gclid=EAIaIQobChMIm7SQs9Gi1wIVCgtpCh0Q2AOrEAAYASAAEgKMs_D_BwE

Duffy the...malaria slayer???

Malaria is a horrible disease caused by Plasmodium spp. and transmitted to humans by female Anopholes mosquitos. Once infected, a person’s red blood cells are the ultimate site of establishment where they divide and grow until rupturing the red blood cell. Each new parasite goes on to infect a single red blood cell where it will continue the process of division until rupture. This mass rupture of blood cells causes a huge immune response causing inflammation, high fever, headaches, and anemia. In the United States, we no longer worry about malaria as well as in many other developed parts of the world. However, there are still many countries where the threat is real. Now days there are many drugs that are used that exploit the physiology of the parasite to kill it. Most of these are quinine derivatives including Chloroquine, Mefloquine, and Primaquine. Depending on the species of the Plasmodium parasite, a certain medication is most effective. Plasmodium falciparum, the species causing the worst pathologies and associated symptoms, has developed resistance to many of the quinine derivative drugs, so a new drug has been found to be very effective: Artemisinin (comes from Chinese plant).

Aside from medication, many of you likely know that in populations where infection with this parasite is still common, the people have gained resistance to infection as evolution has selected for heterozygotes for a blood disorder called sickle cell anemia. As heterozygotes, these people have some RBC in the form of diseased sickle cells while some RBC are completely normal. Homozygotes usually die at an early age because they have only sickle cells which have a crescent moon shape and clog capillary beds leading to eventual organ failure. Heterozygotes have enough normal blood that they avoid these clots in capillary beds, yet enough sickle cells to avoid a heavy infection by parasite causing malaria because the parasite cannot invade the diseased RBC.

Another genetic factor providing resistance specifically against P. vivax is the lack of Duffy blood group antigens on the surface of RBC. This is the glycoprotein receptor where P. vivax attaches chemically to gain entrance into the cell. Without this receptor, the parasite cannot enter. Once again, evolution has selected for this beneficial form of the Duffy blood group in populations where this parasite is still a prevalent threat.

It is amazing the development of the human body as it “feels” the pressures of the physical environment in which it lives to make necessary adjustments in its physiology. Of course evolutionary changes often take generations to really manifest on a grand scale, however, the idea that we are ever evolving to meet the demands of the world we live on is amazing.

Sources:

https://www.ncbi.nlm.nih.gov/books/NBK2271/

Gulf War Veterans...home from war but still suffering

Before I dive into my thoughts on recent research regarding Gulf War Illness (GWI), I want to say thank you to all the men and women who have served or are currently serving in the military, and also, I would like to thank their families for sharing their loved one for the protection of our freedoms and land.

Gulf War Illness (GWI) refers to a clinically undiagnosable disease which has many symptoms associated with it such as fatigue, cognitive issues, and widespread pain. This illness seems to affect multiple body systems and has been thought to be related to mitochondrial issues. Recent research published September 14, 2017 is only the third published research paper that looked into the potential for mitochondrial dysfunction as a cause for the symptoms of GWI. The authors argue that it is a plausible explanation since the worst tissue pathology in patients are in tissues requiring a high amount of energy production such as skeletal muscle and organs. In the paper, 21 patients with GWI participated with 7 healthy patients (control). They obtained blood samples and purified the DNA. Using a special type of PCR assay, they were able to quantify how much mitochondrial DNA backbone damage a patient had based on fluctuations in the amount of DNA polymerized during the PCR. This exploits the fact that a break in the DNA backbone will halt the polymerase action. It was found that the 21 GWI patients had greater average mitochondrial dysfunction (breaks in mDNA backbone) than the 7 healthy patients. They found a correlation between GWI patients and mitochondrial lesions. There of course needs to be much more research done to account for potential confounding variables. Also, the sample size is fairly small. It would be ideal if this test could be performed again on a much larger sample size which could help with accounting for the confounding variables. They could get a group of a few hundred patients with GWI and split them into groups based on age or smoker vs. non-smoker among a host of options. This would help to begin determining if there is only a correlation between GWI and mitochondrial dysfunction, or perhaps, there is a causal relationship.

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599026/pdf/pone.0184832.pdf

Polymer Carriers for Medicine in the Body

Given that I will be a physician one day, I was thinking about how different medicines act in the body at a molecular level to produce the desired beneficial relief to a problem. The study of drug delivery systems is a huge point of research and has been for years. It has researchers in the private sector as well as the academic/public sector staying plenty busy and with substantial funding. There is always a need for new drugs to relieve ailments or yield better outcomes than our current options for treatment. Sometimes, better delivery methods are needed to supply "sustained release" or "quick acting" molecular action in the body to achieve better outcomes for the patient. One of the areas of interest within this broad pharmaceutical research spectrum is affinity based drug delivery. They have gained recent traction in research and use ideas similar to affinity chromatography with protein purification. These systems exploit the interactions between the medicine’s molecular form and the molecular vehicle (delivery system) to control how they attach the medicinal molecule in the lab and release it in the body to perform its proper function. The delivery systems used are polymers designed and produced by chemical engineers and biochemists. In affinity based drug delivery, they design these molecular vehicles to interact with the medicinal molecule in a way favorable to their desired attachment in the lab and release in the body. Many factors must be taken into account when designing a drug delivery system given the complex nature of the human physiology and molecular sensitivities to pH, temperature, and other environmental factors. The benefit of affinity based drug delivery systems is that they are more efficient and more easily controlled than other methods. This is because both the molecular vehicle (delivery system) and the medicinal molecule can be manipulated to produce a controlled molecular unit with affinity interactions that will yield desired release in the body.

Sources:

https://s3.amazonaws.com/academia.edu.documents/45673987/mabi.20100020620160516-21987-ow12fq.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1507909163&Signature=%2FwHYnOYgPH9FQKY%2FLyjSQTFgYlg%3D&response-content-disposition=inline%3B%20filename%3DAffinity-Based_Drug_Delivery.pdf 

PROTEIN is awesome! Need I say more...

My best friend since 1st grade and I started working out together in high school, and we used to joke about consuming insane amounts of protein on the daily. It wasn't until I began learning more about proteins in my college courses that I realized how truly awesome protein is. Proteins are amazing macromolecules that fulfill a wide variety of crucial functions in our cells. The building blocks from which proteins are constructed are known as amino acids which link together in differing numbers and arrangements creating many types of proteins, each with a unique function. Their structure is paramount to carrying out their duties in a cell, therefore it is important to understand the levels of protein structure: primary, secondary, tertiary, and quaternary. The primary structure consists simply of the order of the amino acids of a particular protein. The secondary structure takes into account the folds and coils that form largely because of hydrogen bonding between amino acid side chains. Tertiary structure is the space-filling model of all the folds and coils from the alpha helices and beta sheets plus the intermolecular interactions that give a particular shape to a protein unit. Quaternary structure exists when there are multiple protein units that come together to form a protein complex, but not all proteins join with others to form one of these complexes. Some function on their own without the need of assistance from other proteins. There is a plethora of roles that different proteins fill including enzyme activity, structure, transport, storage, reception and transmission of signals,
gene regulation, and many others. A great example of an enzymatic protein is DNA ligase which
functions in the repair of the phosphodiester bond in the sugar phosphate backbone of
Deoxyribonucleic acid, more commonly called DNA. DNA is found in virtually every cell in the human body, and it is extremely important to life as practically every process within our body is based on the information coded within its genes. DNA ligase is a crucial enzyme which connects the ends of the backbone of a strand of DNA and is not coincidentally also found in virtually every cell in the human body. This keeps our body’s instruction manual, our DNA, intact day after day. Scientist Stuart Shuman noted, “Ligases are elegant and versatile enzymes...”. Indeed, DNA ligase is very
versatile as they exist in prokaryotes such as bacteria, eukaryotes, and even in bacteriophages
and viruses. In the nucleus, it does maintenance in a variety of repair pathways. This upkeep is needed because DNA breakage is a regular occurrence in the cell and often done on purpose by the cell during cell division to swap portions of codons between sister chromosomes. In the eukaryotic mitochondria, DNA ligase III makes repairs to accidental breakage which can be much more serious. Perhaps the most important ligase is DNA ligase IV which repairs breaks that occur in both phosphate backbones at once by most often utilizing non-homologous end joining. This breakage is mainly caused by free radicals attacking the DNA sugar phosphate backbone or gamma radiation. It is especially dangerous to have a double strand break because it can cause the codon order to become altered or some pieces of the genome to be lost altogether. The mechanism by which all DNA ligases function is the same. Ultimately, the ligase, with the help of a cofactor providing energy, brings together the 5’ phosphate group of one DNA strand and the 3’ hydroxyl group on another DNA strand and catalyzes the creation of a phosphodiester bond.

Much of the information about DNA ligase and other proteins and their functions that we have today was obtained using molecular techniques. It is amazing to think about how much progress has been made in the era of molecular biology with its tools and techniques.


Sources:

http://pubs.acs.org/doi/abs/10.1021/cr040498d

https://www.ncbi.nlm.nih.gov/pubmed/18518823

http://www.jbc.org/content/284/26/17365.full