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Advances in Understanding Itch

Everyone experiences itching. The sensation of Itching can result from something as innocuous as an insect bite to a more serious chronic debilitating form that can be difficult to treat.

Recent advances in understanding the itching process may help in developing more effective treatments to control itch. It has been known for some time that an irritation to the skin caused by a mosquito bite or poison ivy, for example, results in an immune response by the body releasing histamine. Histamine binds to and activates the TRPV1 receptor found on the endings of sensory nerves in the skin, resulting in the transmission of a nerve signal to the brain and the sensation of itch. This understanding is the basis for the use of antihistamines for treating itch. Realizing that not all itch conditions are helped by histamines, researchers set out to learn more about the causes of itch.

A few years ago, another itch receptor (TRPA1) was discovered that is activated by substances other than histamine. Is there a link between itch and pain?   The findings indicate that neurons containing only the TRPV1 receptor process pain sensation. On the other hand, neurons containing either the TRPV1 receptor or the TRPA1 receptor can transmit itch signals. The results also suggest that pain circuits can inhibit itch circuits, so only one signal is sent at a time—explaining why pain and itch rarely happen simultaneously.

Should you scratch your itch? Apparently scratching an itch has an evolutionary basis–to remove threatening bugs and plants. Scratching stimulates nerve endings in the spinal cord to release natural painkilling molecules. Scratching may bring temporary relief, but continued scratching may injure the skin leading  to a greater sensation of itching.

References

1. National Institute of Arthritis and Musculoskeletal and Skin Diseases. “Investigating the Causes of Chronic Itch: New Advances Could Bring Relief.” Spotlight on Research 2014.

http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2014/chronic_itch.asp

2. Piergrossi, Joseph. “Untangling the Source of Ouch and Itch.” National Institutes of Health, June 12, 2013. NIH article on Itch

https://publications.nigms.nih.gov/insidelifescience/untangling-ouch-itch.html

3.Sutherland, Stephani. The Maddening Sensation of Itch. Scientific American, May 2016, p. 39-43.

A New Direction-  This posting concludes my blog on “keeping abreast on developments in medical research” in order to devote more time to writing a new book on asthma. The blog page on my website will be replaced by a Resources page providing brief discussions of research sources I use as background information in preparing writing assignments. These resources could be valuable to you as well in researching medical topics!

pmi logo

How revolutionary is personalized medicine?

The federal Precision Medicine Initiative announced on January 2015 has enjoyed broad support, but there are detractors. Soon after the announcement,  Dr. Michael Joyner wrote an op-ed in the New York Times with the view that the Initiative will not deliver as promised. his opinion prompted a large number of replies both pro and con. In July 2015, Dr. Timothy Caulfield wrote in a British Medical Journal blog downplaying the notion that personalized medicine should be considered a “revolution” and would likely follow the same path as other so-called genetic revolutions. In May 2015, Larry Husten, a medical journalist writing in Forbes,  takes issue with the rosy predictions of Victor Dzau, president of the institute of Medicine on the future of personalized medicine.

What are we to make of these opinions? In essence, do not look to personalized medicine as a panacea for human illnesses. The initial focus of the Initiative will be on cancer, an area in which personalized treatments are already well underway. Additionally, personalized medicine is showing promise in treating minor diseases  affecting  a small number of people when the disease is due to a single genetic mutation. The personalized medicine approach may not work as well in treating major diseases such as diabetes or heart disease. These diseases are more likely to be manifested due to environmental or lifestyle factors rather than defective genes,

Reservations aside, the Precision Medicine Initiative is a very welcome development. It will identify and test new targets for diagnosis and treatment of diseases, and will advance medical research.  The funds made available for the Initiative represents a small fraction of the National Institutes of Health budget, so will not handicap other vital projects of the NIH.

References

  1. Caulfield, Timothy. “Genetics and Personalized Medicine: Where’s the Revolution?” BMJ Blogs, July 23, 2015. Caulfield-BMJ Blogs
  2. Husten, Larry. “Precision Medicine Approaches Peak Hype.” Forbes, May 6, 2015. Forbes
  3. Joyner, Michael. “Moonshot Medicine Will Let Us Down.” New York Times, Jan. 29, 2015. Joyner-NY Times

PMI Image. Credit: The White House

Personalized Medicine patient

Precision Medicine Initiative

Recognizing the growing importance and promise of personalized medicine, the federal government launched the Precision Medicine Initiative with President Obama’s State of the Union Address in 2015.

A key component of the Precision Medicine Initiative (PMI) is the creation of a national research participant group, called a cohort, of 1 million or more Americans to expand our knowledge and practice of precision medicine. What is the cohort program?

Cohorts are used in a type of medical research known as an observational study. A prospective cohort study uses defined groups of people who are followed over time to see who experiences an outcome of interest. Cohort studies are useful when experimental studies are not feasible. Cohort studies are notable in requiring large numbers of people that are studied over long periods of time, particularly for less common diseases. For this reason, the PMI Working Group determined that in order to efficiently carry out the goals of the PMI, a very large cohort will be assembled over a period of 3-4 years. Researchers will be able to identify subsets of the cohort suitable for their specialized studies without having to resort to developing their own cohorts.

The participants will volunteer to provide medical history and biological specimens that will be available to researchers studying a variety of diseases and conditions.  The cohort will represent a broad cross section of the U.S. population from diverse social, racial/ethnic, and ancestral populations living in a variety of geographies, social environments, and economic circumstances, and from all age groups and health statuses.

The information obtained from the cohort will include individual variabilities in genetic, environmental, and lifestyle factors.  This knowledge will be used to develop quantitative estimates of risk for a range of diseases by combining environmental exposures, genetic factors, and gene-environment interactions; identification of causes of individual variation in efficacy and safety of commonly used therapeutics; discovery of biomarkers that identify people with increased or decreased risk of developing common diseases, as well as other medical advances.

References

  1.  The Precision Medicine Initiative Cohort Program

National Institutes of Health

PMI Cohort Program

2. The Precision Medicine Initiative Cohort Program –

Building a Research Foundation for 21st Century Medicine

Precision Medicine Initiative (PMI) Working Group Report to the Advisory Committee to the Director, NIH, September 17, 2015

PMI Working Group Report

Genome research

The Genome and Personalized Medicine

Personalized medicine is “an emerging practice of medicine that uses an individual’s genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease,” according to  the National Human Genome Research Institute.

Determining an individual’s genetic profile is based on analysis of his or her genome. What is the genome?

A genome is a person’s complete set of DNA ( deoxyribonucleic acid), including all of its genes. Each genome contains all of the information needed to build and maintain that person. DNA is present in 23 pairs of chromosomes found in the nucleus of cells. DNA consists of units called nucleotides, with the distinguishing feature being four chemical bases. Genes are small segments of DNA, which act as instructions (codes) to make protein molecules.  A large portion of genomic DNA does not code for protein, but may have functions related to regulating the activities of genes. Excellent discussions on the genome, DNA, and genes are available on the internet.

The Human Genome Project completed in 2003 was a landmark study to determine the sequence of all the DNA subunits of the human genome. The long-term aim of the project was to advance the diagnosis and treatment of diseases. Now, over two decades after the project’s completion these benefits are beginning  to be realized, and serve as the basis of personalized medicine.

Coming up next time– progress on the Precision Medicine Initiative.

Further Reading

  1. A Brief Guide to Genomics. National Human Genome Research Institute.

https://www.genome.gov/18016863

2. Genomics. The Broad Institute.

http://www.broadinstitute.org/education/glossary/genome

3. DNA Genes and Chromosomes. virtual Genetics Education Centre, University of Leicester.

http://www2.le.ac.uk/departments/genetics/vgec/schoolscolleges/topics/dna-genes-chromosomes

4. About the Human Genome Project. Human Genome Project Information Archive 1990-2003.

http://web.ornl.gov/sci/techresources/Human_Genome/project/index.shtml

5. Human Genome Project produces many benefits. National Human Genome Research Institute.

https://www.genome.gov/27549135

 

Introduction to Personalized Medicine

Personalized medicine, also known as precision medicine, is much in the news today. What is it, and why is it becoming increasingly important?

Personalized medicine is a new approach to healthcare. Until recently, patient care has been based on the general population, or a “one drug fits all” approach. Treating for the average person, however, can result in a complete cure or no response at all. Also, side effects to the treatment can vary from nonexistent to very severe.

Personalized medicine is now gaining prominence in healthcare as a result of advances in medical technologies. Leading the field is genome analysis, but also includes computational biology, medical imaging, and regenerative medicine. These technologies identify the unique characteristics of each individual, allowing for a more rational and effective means of diagnosis and treatment. Using the full potential of these technologies leads to a true application of personalized medicine.

In future postings of this blog, I will discuss various aspects of personalized medicine, starting with the human genome. Other topics will include the federal Precision Medicine Initiative, diseases currently treated by personalized medicine, drugs in the pipeline, and challenges faced in the implementation of personalized medicine.

Genetic engineering-Alexander Raths/Shutterstock.com

GERD: Living With Acid Reflux Disease

Gastroesophageal reflux disease, or GERD, is a more complicated form of heartburn or acid reflux, a very common condition. This book is a comprehensive discussion of GERD for the general reader, and provides updates on many recent developments in the field.

The book is presented in question and answer format, describing the essential features of GERD in an engaging and stimulating manner that facilitates learning and reinforcement. The book is rich in illustrations, tables, charts, and boxes that highlight definitions and facts. Web site links refer the reader for more detailed information and videos.

The book is part of the MyModernHealth series published by Mercury Learning and Information. It is available as an ebook or paperback on Amazon.

Gut Microbiome

Can gut bacteria affect your behavior?

The microbiome consists of bacteria and other microbes that normally inhabit the intestinal tract, airways, and skin of the body. The concept of a healthy microbiome is now gaining credibility; that is, it is important to establish and maintain a certain population of microbial species to maintain good health. It is now well known that intestinal microbes can affect digestion, allergies, and metabolic processes. More recently, discoveries have found that the microbiome can have a profound influence on the brain, affecting a person’s mood, anxiety, and stress level. The role of the microbiome on mental disorders such as autism, visceral pain, and multiple sclerosis is currently under study. The communication system between the microbiome and the brain is known as the gut-brain axis.

How is the microbiome able to exert its effects on brain function? Gut bacteria produce neurotransmitters such as serotonin, dopamine and GABA which have a role in mood. Other organisms affect how people metabolize these compounds. Gut bacteria may generate other neuroactive compounds, such as butyrate, that reduce anxiety and depression. Some microbes can activate the vagus nerve, and can be interconnected to the immune system.

How can a disordered microbiome be improved? Probiotics are living organisms present in fermented foods such as yogurt and kefir that can have a beneficial effect of improving microbial balance. Probiotics have found application in treating intestinal disorders, although much needs to be learned about the most effective ways to use probiotics. Probiotics may exert beneficial effects by suppression of pathogenic bacteria, by enhancement of immunity, and by serving as a protective barrier at the intestinal wall to harmful bacteria. A more radical approach of modifying the microbiome is by introducing fecal samples from healthy persons into the gut.

The microbiome can be altered after antibiotic treatments or as a result of certain disease conditions such as irritable bowel syndrome. Researchers have shown interest in controlling how the microbiome is established in the newborn.

Further Reading

1. Dietert, R. & J. Dietert. The Sum of Our Parts. The Scientist. July 2015, pages 44-49.
http://www.the-scientist.com/?articles.view/articleNo/43379/title/The-Sum-of-Our-Parts/

2. Kohn, D. When Gut Bacteria Changes Brain Function. The Atlantic. June 24, 2015.
http://www.theatlantic.com/health/archive/2015/06/gut-bacteria-on-the-brain/395918/

3. Smith, P. Gut Feelings. The New York Times Magazine. June 28, 2015, pages 44-49, 68

4. Williams, M. et al. Probiotics as Therapy in Gastroenterology. J Clin Gastoenterol 2010 Oct. 44(9): 631-636.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094138/

DNA molecule

Accurate Genome Sequencing

Personalized medicine recognizes that individuals respond differently to medicines and that it can be more effective and safe to tailor the dose or regimen to that individual rather than to a “one dose fits all” approach that has been common medical practice. According to the National Human Genome Research Institute, personalized medicine is “an emerging practice of medicine that uses an individual’s genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease.” Personalized medicine can also encompass the application of medical imaging and regenerative medicine techniques.

The effective application of personalized medicine is based on the assumption that the genome of the individual is accurately known. In a recent posting, Jason Koeber of Motherboard points out that even the best genome sequencing techniques have an error rate of around 1%. (1)

Two years ago, the National Institute of Standards and Technology (NIST) hosted a consortium to develop genomic reference standards that could be used to evaluate the accuracy of genome sequencing processes. (2)This consortium is called Genome in a Bottle. The reference standards are designed to overcome problems of bias and “blind spots” among sequencing technologies that lead to significant differences in results.

The results of a pilot study were reported in a recent Nature Biotechnology paper. (3)The researchers studied 14 genome and 3 exome data set results obtained from five sequencing platforms to find regions of agreement or disagreement. An arbitration method was used to overcome biases. A reference genomic data set was obtained that can be used with high confidence to evaluate new sequencing methods.

The FDA recently granted marketing approval for the first next-generation genomic synthesizer, Illumina’s MiSeqDx. (4) They have been working with the NIST to develop genomic reference standards.

References
1. Koeber,Jason “If We Can’t Get Genome Accuracy Right, Personalized Medicine Is a Pipe Dream” March 1, 2014

http://motherboard.vice.com/read/if-we-cant-get-genome-accuracy-right-personalized-medicine-is-a-pipe-dream

2. How Well Did You Sequence that Genome?’ NIST, Consortium Partners Have Answer

http://www.nist.gov/mml/bbd/dna-022514.cfm

3. Zook, Justin, et al. “Integrating human sequence data sets provides a resource of benchmark SNP and indel genotype calls.” 32, 246-251 (2014) doi: 10.1038/nbt.2835

http://www.nature.com/nbt/journal/v32/n3/full/nbt.2835.html

4. Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development. October 2013.

http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/UCM372421.pdf

Selecting Studies for Meta-Analysis: Publication Bias

Meta-analysis is a statistical method of combining the results of individual studies. Meta-analysis may allow a more precise estimate of treatment effects, and may explain differences between the results of individual studies. Although meta-analysis can be a powerful and useful technique, they must be designed carefully to ensure that the results are not misleading.
The identification and selection of individual studies used in a meta-analysis is critical. Publication bias has a direct impact on this selection.
Publication bias refers to the greater likelihood of papers showing positive results to be published than negative results. If the sample of studies selected for meta-analysis is biased, the conclusions drawn from the analysis may be invalid. Turner(2) analyzed the publication status of antidepressant drugs. He found that 97% of the positive studies were published versus only 12% of negative studies. The inclusion of negative studies in the analysis reduced the positive effects of the drugs.
Statistical tests have been developed to identify and assess the impact of publication bias in meta-analysis.
Attempting to locate unpublished studies is time consuming, difficult, and can use methodology hard to assess.(1)
In evaluating the results of meta-analyses (as well as for individual studies) it is important to be aware of who is sponsoring the studies and whether the authors have any vested interests.
Is it possible to overcome the problem of publication bias? The National Institutes of Health keeps a registry of all studies it supports, and the FDA keeps a registry and database in which drug companies must resister all trials they intend to use in applying for marketing approval or for changes in labeling.
Prospective meta-analysis looks forward to meta-analysis in the planning stage of individual trials. Researchers of these trials agree, prior to knowing the results of their studies, to combine their findings when the trials are complete.(3) The researchers agree on trial design as well as outcome measures which facilitates the analysis of results.

References
1. Rothstein, Hannah, Alexander Sutton & Michael Borenstein, eds. Publication Bias in Meta-Analysis: Prevention, Assessment and Adjustments. 2005. John Wiley & Sons

http://www.wiley.com/WileyCDA/WileyTitle/productCd-0470870141.html
2. Turner, Erick, et al. Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy. N Engl J Med. 2008; 358: 252-60. Trials (BioMed Central) 2011;12:104

http://www.nejm.org/doi/full/10.1056/NEJMsa065779
3. Turok, David et al. The methodology for developing a prospective meta-analysis in the family planning community.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103448/
4. Walker, Esteban, et al. Meta-analysis: Its strengths and limitations. Clev Clin J Med. June 2008; 75(6): 431-439.

http://www.ccjm.org/index.php?id=107937&tx_ttnews[tt_news]=360745&cHash=c4f41096946e87f82f539928262b817f

DNA molecule

Big Data Advances Personalized Medicine

Personalized medicine is much in the news today. What is it and why is it important?

Until recently, patient treatment has been characterized by a one size fits all approach. Patients with a given condition are given a set medication; many respond as expected, while others either do not respond or react unfavorably.

An important factor in variability in response to treatment is the underlying genetic makeup of individuals. Drug response is affected by the extent (variability) of drug delivery to the sites of drug action as well as by the effectiveness with which the drug interacts with specialized receptors or enzymes. The activity of these processes are influenced by genetics.

Roden, Dan & Alfred George. The Genetic Basis of Variability in Drug Responses. Nature Reviews Drug Discovery, Vol. 1, Jan. 2002, pp. 37-44.

http://www.nature.com/nrd/journal/v1/n1/full/nrd705.html

Dramatic reductions in costs of genomic analyses have resulted in real advances in personalized medicine applications. A profile of each individual can be made by associating their unique genetic makeup with treatments that are most likely to respond favorably to that makeup. These personalized treatments (known as targeted therapies) result in more effective treatments at lower cost and time.

A Personalized Medicine World Conference is held each year providing the latest developments in the field. Past speaker videos can be viewed at:

http://pmwcintl.com/conferences.php

Although the healthcare community recognizes that Big Data could aid in improving patient care, they often do not have the means to use it. This is where information technologies come into the picture. GNS Healthcare is an example.

http://ebdgroup.com/partneringnews/2013/07/big-data-delivers-promise-of-personalized-medicine/

their computational engine uses “ supercomputers to analyze relationships among multiple types of patient data, including patient population information, electronic medical records, images, clinical outcomes, and other data, learning as it goes.”  Personalized medicine, therefore, is going beyond application of genome analyses to include “real life” data.

Personalized medicine improves diagnostic capability and predictions of outcomes. It can aid investigators to select patients for clinical trials who are most likely to respond to the treatments. For trials in progress, biomarkers can be identified using genotype, gene expression, and patient outcome data. Big Data analytics can identify hidden drug interactions as well as patient characteristics and care processes that affect safety and efficacy.

Personalized medicine has come of age through an explosion of electronically available medical data and advances in computing technology to analyze it.