Category Archives: Transhuman News

By C.A. Wolski | Photography by Bryce Vickmark

If the decades of research to which Susan Redline, MD, MPH, has devoted her life has a recurring themeits making connections.

Her training in pulmonology and public health and her work in epidemiology were all about making connections. Her interest in sleep medicine, awakened in the 1980s while doing research on black lung disease at Ohios MetroHealth Medical Center and learning about the advances in CPAP, was a natural segue for someone who naturally made connections.

There are so many crossovers, she observes. Sleep disorders have numerous dimensionssocial, economic, health. Theres a potential to impact and reflect so many processes.

Redline, now a senior physician at Brigham and Womens Hospital and the Peter C. Farrell Professor of Sleep Medicine at Harvard Medical School, will be honored at SLEEP 2017 with the American Academy of Sleep Medicines William C. Dement Award for her research on the influence of genomics and the environment on sleep apnea. The research by Redline, who is also now a senior physician at Beth Israel Deaconess Medical Center, has spanned decades making the connection between various environmental and family factors and genetics with sleep disorders (particularly sleep apnea) and their role in influencing susceptibility to a wide range of health problems. Her work is being used by physicians in other disciplines to understand how sleep apnea may be a predictor of other health problems, such as heart disease in women.

Redlines initial research into sleep apneaa cohort she recruited in the early 1990scontinues to serve at the heart of her (and a growing number of her colleagues) research.

In my early research at the Case Western Reserve University in Cleveland, I started a family-based longitudinal cohort because there was a dearth of information on risk factors and outcomes of sleep disorders in the general population, she says. Sleep apnea was more common than we thought, and I was finding there were many intersections with social, environmental, and health factors.

This early research built on Redlines clinical and public health training. The Cleveland Family Study looked at how prevalent sleep disorders were, if they ran in families, and what some of the factors werefrom air pollution to geneticsthat influenced their development.

Because of its large sampling, Redline and her team were able to determine sleep apnea was more prevalent in African-American children than white children. Of adults who had sleep apnea, about 20% to 40% werent obese and the disorder affected both men and women.

Even more significant, thanks to Redlines forward thinking, this research data continues to be as valuable today as it was 25-plus years ago. While there was little immediate value in collecting DNA samples from participants, Redline collected and stored it anyway. It was the early days of genetic research, so there was limited enthusiasm for genetic analyses, she says. There was no way we could have foreseen the ability of using DNA to identify common and rare genetic variants and change in gene structure that influence disease, as we are today. Research has moved from descriptive epidemiology to studies that integrate physiology and molecular and genetic medicine.

Today, researchers are using genetic data from the Cleveland Family Study to further their own research, adding it to other cohorts to improve statistical power. Now we have the level of resolution to identify how variation in gene structure and function influences many aspects of sleep apneasuch as susceptibility to frequent apneas to degree of hypoxemia experienced during sleep. Furthermore, by collaborating with many others, we are preparing a foundation for sleep precision health. This is an exciting direction that we hope will inform how we can personalize diagnosis and treatment of sleep apnea, she says.

This has allowed for other intersections in Redlines research. For instance, she has worked with circadian biologists who are researching diabetes connection to melatonin receptor levels and circadian rhythms and with psychiatrists who are researching ways that disturbed sleep influences brain function.

Unsurprisingly, Redline is an advocate of the use of Big Data in clinical research. Big Data for her can mean, simply, lots of datasuch as the tens of thousands of research records she has collected over many years of collaborating with large cohort studies, including leading a national Sleep Reading Center, and which she has aggregated in the National Sleep Research Resource, a repository she developed to facilitate large data collaborations. Or it can be what she calls high dimensionality data, that is, data that is detailed, diverse, and complex.

Today, researchers need a wider range of dataenvironmental, biological, geneticto make breakthroughs, according to Redline. For her own research, this has motivated Redline to work with more researchers.

And she has seen data she has collected through her early cohort studies and later collaborations with national cohorts put to good use to help make further connections with sleep and other health factors. Researchers are using these data to query and reanalyze, generating new sources of Big Data, she says.

Redline adds that Big Data has created wonderful opportunities to expand knowledge of sleep apnea susceptibility. For instance, she has helped to make potential breakthroughs in cardiology. Whats been exciting to us in our cardiology study outcomes of sleep apnea patients with women is discovering that older women with sleep apnea are at risk for heart failure, likely due to susceptibility to cardiac ischemia occurring with sleep apnea, she says, and that is opening the way for more treatments.

Redline also continues to examine both environmental and socioeconomic issues related to sleep apnea. For example, shes been doing research about sleep apnea and how its affecting minority communities. She has been a leader in a large study of sleep apnea in 16,000 Hispanic American individuals and is actively working with low-income communities in Boston to identify strategies for improving sleep in people at high risk for sleep apnea and insomnia.

She is also collaborating with pediatricians across the United States to better understand how to treat children with sleep disorders. Her studies have identified suboptimal responses to tonsillectomy in African-American children. Redline has hypothesized this could be due to environmental factors that cause chronic inflammation and continuing symptoms and will soon begin a study examining the specific household and neighborhood triggers for airway inflammation.

Again reflecting her public health background, Redline has gone beyond the lab (or the computer screen) and engaged patients directly via the Internet with the Sleep Apnea Patient-Centered Outcomes Network (SAPCON). The patient-centered research network went live in 2013. Its goal is to empower patients and inform researchers to treat and research sleep.

With the patient-centered network, I have seen really involved, motivated patients who are breaking down the stereotypes of what patients look like, and are eager to lend new perspectives to efforts at improving sleep apnea recognition and treatment, Redline says.

Taken together, all of Redlines research has one ultimate goal. I want to utilize rigorous data to help design approaches for preventing sleep disorders and for improving the treatment of all patients with sleep disorders, including those from disadvantaged communities.

Redlines own contribution to making an impact on sleep medicine and medicine in general has been the involvement in numerous large-scale research studies and authoring more than 400 peer-reviewed articles. But its not her own research she is most proud of. Its the impact shes made on fellow researchers.

My proudest moments have been seeing junior colleagues and trainees get excited about sleep, and get grants and succeed, she says.

For their part, junior colleagues and mentees agree that Redline has been instrumental in their clinical and research success both when they were starting out and through to today.

Reena Mehra, MD, MS, FCCP, FAASM, director of sleep disorders research, Neurologic Institute, and associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, has known Redline for more than 15 years, first working under her via a T32 NIH Training Grant in Sleep Medicine Neurobiology and Epidemiology at Case Western Reserve University. It was a transformative experience.

Mehra says that Redline has provided me with the skill set in sleep medicine epidemiology needed to develop a research career in sleep medicine funded by the NIH and foundation grants. In my early career, not only was she a mentor to me and others, but very importantly she has been our sponsor by facilitating national and international connections and collaborations. She is truly an amazing role model for so many, and I am honored to say that she has been a key, steadfast mentor in my career.

Sanjay Patel, MD, MS, visiting professor of medicine, director of the Sleep and Cardiovascular Outcomes Center, and the medical director of the University of Pittsburgh Medical Center (UPMC) Sleep Laboratory, credits his early and ongoing success to Redline. Dr Redline has mentored me in epidemiologic sleep research for over 15 years. I have learned how to design both observational and interventional studies, collect high-quality data, and use state-of-the-art analytic techniques to make novel insights in sleep medicine, he says. She has pushed me to think critically, to be open to completely new ideas and hypotheses, and to build collaborations with experts in other fields in order to move understanding of sleep medicine forward. Although I now direct my own center, I still touch base with Dr Redline regularly to pick her brain and get advice and feedback.

While Mehra and Patel were nurtured by Redline during their early training, Neomi Shah, MD, met Redline when she was a researcher at Albert Einstein College of Medicine in New York. There Shah began her work on the connection of coronary artery disease and sleep apnea, which is ongoing.

Redline has been instrumental in helping not only junior colleagues but women in particular, Shah says, and credits Redline with helping to secure several foundation grants for her sleep research. She has been monumental in my career, Shah says. I didnt know her and she had no reason to help promote me.

Redline not only has influenced peers and those shes mentored, but also has inspired her son who works helping the homeless (and is not a sleep researcher). Her son suggested to his superiors that they do research on sleep in transitional-age homeless youth. He just picked up on my research and my interest in public healththats made me very proud, Redline says.

Redline continues to be busy doing research. And that means building another cohort. Shes currently setting up a research group in urban Boston looking at sleep apnea in a low-income minority community. She is also continuing her research into the connection between heart disease and sleep disorders and hopes to test new interventions to reduce heart disease in sleep apnea patients.

While Redline sees the interest in sleep by the public and media encouraging, she also observes that in terms of personal behavior many Americans dont make sleep a priority. It also concerns her that many patients are still underdiagnosed.

We need to improve efficiency in diagnosis; 80% of sleep disorders are undiagnosed in the general population, she says. For Chinese and Hispanic communities, its about 90%.

The good news for sleep medicine is that CPAP has become one of the most effective ways to treat sleep apnea, but it isnt a panacea. Many patients arent adherent to it, because they need better education or they need different therapies, says Redline.

While this is a challenge, Redlines research is making an impact and will continue likely making the connections that have been the hallmark of her career, improving sleep health and health in general. With all of her relentless research, she admits, It seems like I never catch my breath and there are more questions than answers.

While writing his profile on Susan Redlines research for Sleep Review, C.A. Wolski was inspired to make connections throughout his daily life, including his own sleep habits and his day-to-day health and moodhis wife was grateful.

Visit link:
Big Data Hits the Big Time: Susan Redline, MD, MPH - Sleep Review

8 October 2007

The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2007 jointly to

Mario R. Capecchi, Martin J. Evans and Oliver Smithies

for their discoveries of "principles for introducing specific gene modifications in mice by the use of embryonic stem cells"

This year's Nobel Laureates have made a series of ground-breaking discoveries concerning embryonic stem cells and DNA recombination in mammals. Their discoveries led to the creation of an immensely powerful technology referred to as gene targeting in mice. It is now being applied to virtually all areas of biomedicine from basic research to the development of new therapies.

Gene targeting is often used to inactivate single genes. Such gene "knockout" experiments have elucidated the roles of numerous genes in embryonic development, adult physiology, aging and disease. To date, more than ten thousand mouse genes (approximately half of the genes in the mammalian genome) have been knocked out. Ongoing international efforts will make "knockout mice" for all genes available within the near future.

With gene targeting it is now possible to produce almost any type of DNA modification in the mouse genome, allowing scientists to establish the roles of individual genes in health and disease. Gene targeting has already produced more than five hundred different mouse models of human disorders, including cardiovascular and neuro-degenerative diseases, diabetes and cancer.

Information about the development and function of our bodies throughout life is carried within the DNA. Our DNA is packaged in chromosomes, which occur in pairs one inherited from the father and one from the mother. Exchange of DNA sequences within such chromosome pairs increases genetic variation in the population and occurs by a process called homologous recombination. This process is conserved throughout evolution and was demonstrated in bacteria more than 50 years ago by the 1958 Nobel Laureate Joshua Lederberg.

Mario Capecchi and Oliver Smithies both had the vision that homologous recombination could be used to specifically modify genes in mammalian cells and they worked consistently towards this goal.

Capecchi demonstrated that homologous recombination could take place between introduced DNA and the chromosomes in mammalian cells. He showed that defective genes could be repaired by homologous recombination with the incoming DNA. Smithies initially tried to repair mutated genes in human cells. He thought that certain inherited blood diseases could be treated by correcting the disease-causing mutations in bone marrow stem cells. In these attempts Smithies discovered that endogenous genes could be targeted irrespective of their activity. This suggested that all genes may be accessible to modification by homologous recombination.

The cell types initially studied by Capecchi and Smithies could not be used to create gene-targeted animals. This required another type of cell, one which could give rise to germ cells. Only then could the DNA modifications be inherited.

Martin Evans had worked with mouse embryonal carcinoma (EC) cells, which although they came from tumors could give rise to almost any cell type. He had the vision to use EC cells as vehicles to introduce genetic material into the mouse germ line. His attempts were initially unsuccessful because EC cells carried abnormal chromosomes and could not therefore contribute to germ cell formation. Looking for alternatives Evans discovered that chromosomally normal cell cultures could be established directly from early mouse embryos. These cells are now referred to as embryonic stem (ES) cells.

The next step was to show that ES cells could contribute to the germ line (see Figure). Embryos from one mouse strain were injected with ES cells from another mouse strain. These mosaic embryos (i.e. composed of cells from both strains) were then carried to term by surrogate mothers. The mosaic offspring was subsequently mated, and the presence of ES cell-derived genes detected in the pups. These genes would now be inherited according to Mendels laws.

Evans now began to modify the ES cells genetically and for this purpose chose retroviruses, which integrate their genes into the chromosomes. He demonstrated transfer of such retroviral DNA from ES cells, through mosaic mice, into the mouse germ line. Evans had used the ES cells to generate mice that carried new genetic material.

By 1986 all the pieces were at hand to begin generating the first gene targeted ES cells. Capecchi and Smithies had demonstrated that genes could be targeted by homologous recombination in cultured cells, and Evans had contributed the necessary vehicle to the mouse germ line the ES-cells. The next step was to combine the two.

For their initial experiments both Smithies and Capecchi chose a gene (hprt) that was easily identified. This gene is involved in a rare inherited human disease (Lesch-Nyhan syndrome). Capecchi refined the strategies for targeting genes and developed a new method (positive-negative selection, see Figure) that could be generally applied.

The first reports in which homologous recombination in ES cells was used to generate gene-targeted mice were published in 1989. Since then, the number of reported knockout mouse strains has risen exponentially. Gene targeting has developed into a highly versatile technology. It is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal.

Almost every aspect of mammalian physiology can be studied by gene targeting. We have consequently witnessed an explosion of research activities applying the technology. Gene targeting has now been used by so many research groups and in so many contexts that it is impossible to make a brief summary of the results. Some of the later contributions of this year's Nobel Laureates are presented below.

Gene targeting has helped us understand the roles of many hundreds of genes in mammalian fetal development. Capecchis research has uncovered the roles of genes involved in mammalian organ development and in the establishment of the body plan. His work has shed light on the causes of several human inborn malformations.

Evans applied gene targeting to develop mouse models for human diseases. He developed several models for the inherited human disease cystic fibrosis and has used these models to study disease mechanisms and to test the effects of gene therapy.

Smithies also used gene targeting to develop mouse models for inherited diseases such as cystic fibrosis and the blood disease thalassemia. He has also developed numerous mouse models for common human diseases such as hypertension and atherosclerosis.

In summary, gene targeting in mice has pervaded all fields of biomedicine. Its impact on the understanding of gene function and its benefits to mankind will continue to increase over many years to come.

Mario R. Capecchi, born 1937 in Italy, US citizen, PhD in Biophysics 1967, Harvard University, Cambridge, MA, USA. Howard Hughes Medical Institute Investigator and Distinguished Professor of Human Genetics and Biology at the University of Utah, Salt Lake City, UT, USA.

Sir Martin J. Evans, born 1941 in Great Britain, British citizen, PhD in Anatomy and Embryology 1969, University College, London, UK. Director of the School of Biosciences and Professor of Mammalian Genetics, Cardiff University, UK.

Oliver Smithies, born 1925 in Great Britain, US citizen, PhD in Biochemistry 1951, Oxford University, UK. Excellence Professor of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA.

High resolution image (pdf 900 kb)

To cite this page MLA style: "The 2007 Nobel Prize in Physiology or Medicine - Press Release". Nobelprize.org. Nobel Media AB 2014. Web. 1 May 2017. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2007/press.html>

See the original post:
The 2007 Nobel Prize in Physiology or Medicine - Press Release

Researchers from RCSI (Royal College of Surgeons in Ireland) and the University of Nice, France, may have discovered a gene, KCNQ1, that is associated with the survival of patients who have colon cancer.

The gene creates pore-forming proteins in cell membranes, known as ion channels. This could be an important breakthrough in the development of increasingly effective colon cancer therapies and new diagnostics that will provide an improved accuracy in the prognosis for colon cancer patients.

The research team, led by Professor Brian Harvey, Department of Molecular Medicine, RCSI, published their findings in the journal Proceedings of the National Academy of Sciences of the USA (PNAS). They identified the molecular mechanisms by which the KCNQ1 gene suppresses both the growth and spread of colon cancer cells.The gene functions by producing an ion channel protein, trapping a tumour promoting protein (beta-catenin) in the cell membranes before it can enter the nucleus of the cell to cause the growth of more cancer cells.

In over 300 colon cancer patients, those who had higher expressions of the KCNQ1 gene were found not only to have a longer survival but also less chance of relapse. Commenting on the significance of the discovery, Professor Harvey said:

It could open up the possibility of developing new drug treatments that will be able harness the suppressive properties of the gene to target the colon specifically, without exposing other tissues in the body to unnecessary chemotherapy. The development of more targeted treatments for colon cancer is vital to improve the prognosis and quality of life for colon cancer patients.In Ireland, bowel cancer is the second most common cause of cancer death as almost 2,500 Irish people are diagnosed with the cancer annually.

Read the original post:
RCSI scientists discover gene that blocks spread of colon cancer - Irish Medical News