Physiology

AJMC in the Press, August 14, 2020 – AJMC.com Managed Markets Network

Coverage of our peer-reviewed research and news reporting in the health care and mainstream press.

An article by The Doctor Weighs In spotlighted a podcast published on AJMC.com, the website of The American Journal of Managed Care (AJMC). The podcast, Cancer Care in the Age of COVID-19: Dr Patricia Salber Interviews Dr Bobby Reddy, was conducted by Salber, of The Doctor Weighs In, with Reddy, who discussed the clinical care of patients with cancer in the age of coronavirus disease 2019 (COVID-19), including how care has changed as a result of the pandemic and best practices at treatment centers to protect patients and staff.

An article by MobiHealthNews cited a study published online ahead of print in the October 2020 issue of AJMC. The study, Machine Intelligence for Early Targeted Precision Management and Response to Outbreaks of Respiratory Infections, found that precision management through personalized and predictive machine learning offers the opportunity to reduce the burden of outbreaks of respiratory infections.

A piece by ksl.com referenced an article published on AJMC.com, titled The Effects of Chronic Fear on a Person's Health. The article covered a session at the 2017 Neuroscience Education Institute Congress, presented by Mary D. Moller, PhD, DNP, ARNP, PMHCNS-BC, CPRP, FAAN, associate professor at the Pacific Lutheran University School of Nursing, which focused on the physiology of fear and its impact on wellness.

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Physiology

NAU researcher studying the mechanics of breathing in adult survivors of preterm birth – NAU News

JJ Duke, an assistant professor in Northern Arizona Universitys Department of Biological Sciences, is studying respiratory mechanicsthe how of breathing. He wants to understand the underlying reasons why exercise ability and lung function, or breathing, in general are more difficult for adults who were born prematurely. His research suggests the problem may be smaller airways.

According to the World Health Organization, 10 to 12 percent of all live births are preterm (at or before 37 weeks). However, because of medical advances, this number likely will continue to increase. Preterm birth results in an underdeveloped cardiopulmonary system and can lead to lung deficiencies that continue into adulthood and decline further with age. Researchers have found that adult survivors of preterm birth may have an atypical physiology and are functioning with 20 to 25 percent less lung and exercise ability than their counterparts who were born at full term.

With a three-year R15 grant of more than $432,000 from the National Institutes of Health, Duke is studying the underlying causes of the reduction in lung function, as well as exercise ability, in adult survivors of preterm birth. This knowledge, he believes, will assist physicians in ensuring a correct diagnosis and course of treatment for those born prematurely and suffering from respiratory problems later in life.

Duke first became interested in this population while studying determinants, or causes, of pulmonary gas exchange efficiency as a postdoctoral fellow at the University of Oregon. Given that adult survivors of preterm birth have underdeveloped lungs, it seemed likely that their gas exchangetheir bodies ability to get oxygen into the blood and carbon dioxide out of the bloodwould be impaired.

We found no differences in the gas exchange efficiency, meaning they had normal oxygen and carbon dioxide levels in their blood. The lungs were functioning just fine in that respect, which makes it unlikely that this is the cause of their lower exercise ability, Duke said. As I left my postdoc, I pivoted my focus to another area of the pulmonary system that could limit exercise abilityrespiratory mechanics, which describes pressure, airflow and volume in the system. As a result of their underdeveloped lungs, these individuals may have impaired or altered respiratory mechanics.

Duke is measuring various aspects of respiratory mechanics in the Integrative Cardiopulmonary Physiology Laboratory at NAU. To do so, he and his Ph.D. students measure esophageal pressure by having participants swallow a balloon catheter, then perform a variety of breathing tests and exercise on a stationary bike. The researchers measure the participants work of breathing, or how much energy they need to move air in and out of their lungs.

By conducting these studies, Duke can meet his objective to glean information about airway size in adults who were born prematurely by measuring esophageal pressure.

If you are drinking a milkshake through a large straw, its easier to get it through that big tube than with a small straw, he said. Similarly, if airways are smaller, there is more resistance and you have to generate enough pressure to force the air through the airways.

Because these individuals have never known anything different, they may not know it is more work for them to breathe during exercise.

What is really compelling me to try to understand how the physiology is, and isnt, different from people born at term is to help clinicians accurately target the problem and direct treatment, Duke said. Most of the time, people are aware that they were born prematurely but may not be aware that they may be more limited than their peers who were carried to term. If they report asthma-like symptoms, including chest tightness, they could be misdiagnosed and given a rescue inhaler, which might or might not help.

Normal lung function decreases after the age of about 25 in healthy adults; however, by eating well, exercising and not smoking, Duke says most people should outlive their lungs. But those who were born preterm and are operating with 20 or 30 percent less lung function in the prime of their life may experience a displaced or steeper downward slope.

Understanding the physiology of young people who were born prematurely, who do not have significant current lung function and exercise ability issues, is critical, Duke said. This research will help further the understanding of the physiology of adult survivors of preterm birth and identify potential targets for therapeutic interventions to improve and/or maintain cardiopulmonary function.

Bonnie Stevens and Kerry Bennett | Office of the Vice President for Research

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Physiology

The Week That Wasn’t: Gaiters, Chicken Wings, Nasal Spray – Medscape

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

This week in COVID-19 news, scientists tested how well various face coverings, including a neck gaiter, blocked respiratory droplets coming from the wearer's mouth and nose, authorities detected SARS-CoV-2 genetic material on frozen chicken wings, and researchers described a nasal spray they say could block viral infection. But you didn't see these headlines on Medscape. Here's why.

Researchers at Duke University developed a method to test how many respiratory droplets a person emits while wearing a face covering. The method employed a laser, a prism, a box, and a smartphone camera. They described the setup and their results from testing 14 different face coverings in the journal Science Advances. The particular tests, the authors write, "should serve only as a demonstration," because they expect different people would get different results wearing the same mask, owing to variation in factors such as their physiology, how well the mask fits, head position, and speech pattern.

But that's not what headlines said about this study. Many news outlets' coverage emphasized one of the tested face coverings: a neck fleece or gaiter. In the researchers' test, the speaker appears to have emitted slightly more droplets while wearing this face covering than when wearing no face covering, though the error bars overlap in the figure depicting the number of droplets emitted in the tests.

It takes a lot of extrapolation to make a claim about gaiters in general from the single test described in this study, and the researchers' overall point that face coverings vary in their effectiveness has been demonstrated previously. We mentioned this study and the discussion around it in our daily COVID-19 Update, but we didn't devote a full story to it because its findings are not novel.

Genetic material from SARS-CoV-2 was detected on the surface of frozen chicken wings imported to China from Brazil, local authorities said. CNN reported that the testing did not assess whether the virus was infectious. Health authorities traced people who could have been in contact with the frozen wings, and none tested positive for the virus.

This chicken report is not the first of SARS-CoV-2 genetic material apparently being found on frozen food, and it doesn't change the overall balance of evidence about how COVID-19 spreads mainly through person-to-person interaction with someone who is infected. We didn't think this story was a priority for our readers.

In a preprint posted to bioRxiv.org, scientists from the University of California, San Francisco, describe how they developed nanobodies like antibodies, but smaller that bind to the parts of SARS-CoV-2 that interact with a cell's receptors to enter and infect it. They report that the nanobodies they engineered "proved exceptionally potent" at neutralizing SARS-CoV-2 in vitro and could be aerosolized for potential delivery via a nasal spray or nebulizer.

"These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century," the researchers write.

We hope so too, but there's a long road ahead. We didn't cover this because we don't want to hype an experimental treatment that may not have been tested in animal models yet, much less in clinical trials, before it's even out of the lab or peer-reviewed for publication in a scientific journal.

Ellie Kincaid is Medscape's associate managing editor. She has previously written about healthcare for Forbes, the Wall Street Journal, and Nature Medicine. She can be reached at ekincaid@medscape.net or on Twitter @ellie_kincaid.

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Physiology

Why more heatwaves endanger our health and ability to work – ScienceBlog.com

Its actually quite easy for us to point out the problem we have increasing temperatures, increasing frequency of heatwavesit affects our physical and cognitive performance, said Lars Nybo, a professor of integrative physiology from the University of Copenhagen, Denmark. He is working on a project calledHEAT-SHIELDdesigned to examine the effects of heat exposure on worker productivity in industrial sectors that employhalf of Europes workforce: manufacturing, construction, transportation, tourism, and agriculture.

Precipitated by a series of heatwaves, 2019 was thehottest year ever recorded in Europe. Over the past five years, mean temperatures in the continent are averaging almost 2C warmer than pre-industrial figures,a worrying sign for the achievementof the Paris climateagreement to keep global mean temperatureincreases well below2C.

Data from the project suggestthat exposure to external heat in combination with physical activity, which elevates the bodys production of heat, can result in physiological changes that can diminish occupational performance, via reduced working endurance, vision, motor coordination and concentration. This can lead to more mistakes as well as injuries.

Roughly 70% of all European workers, at some time during the working day, are not optimally hydrated, Prof. Nybo said. The solution to the problem, he adds, is intuitive: drink water, replace electrolytes and reduce physical activity, but implementing these measures whilst maintaining productivity is where things get tricky.

You could just say to the worker stay at home and drink cold margaritas in the shadow to prevent heat stress, he joked. But that will not help productivity.

Productivity

As coordinator of HEAT-SHIELD, Prof. Nybo and his team are tasked with not just assessing the extent of the problem modelling the expected rise in temperature in Europe in the coming years and its impact on worker productivity but also devising and implementing solutions that are location and vocation specific to adjust to the inevitable increases in temperature.

A construction worker wears a safety helmet, which impairs the bodys ability to purge heat, but the worker thinks this problem cannot be solved because it is intrinsic to their work, Prof. Nybo notes.

Surmounting challenges like this is one of the key objectives of the project conceiving ways to weave in heat mitigation strategies alongside the practicalities of the job.

For instance, outdoor workers should be vigilant of weather patterns and plan work earlier in the day during periods of extreme heat, take a short break every hour and secure easy access to water. Similar remedies for workers in enclosed settings could mean a combination of air conditioning, working in shade and improving ventilation keeping in mind the ecological footprint of such measures.

But on a macro level, for climate change policymakers to take concrete action here and now the numbers are key, Prof. Nybo says.

In Europe, agricultural and construction workers for instance, lose some 15% of effective working time when the temperature goes beyond 30C, which works out to almost one working day per week, he notes, citing HEAT-SHIELD analyses.

If you are a policymaker, he says, the numbers show that theres an incentive to act now: if you mitigate the problem the cost will stabilise at a lower level in the long run than if you dont.

Excessive heat

Diminished worker productivity and the downstream economic damage are prominent impacts of rising temperatures caused by climate change. But to get a full picture of the consequences, its necessary to understand what excessive heat does to the human body.

It can damage organs such as the heart and the lungs, exacerbate a range of diseases, and increase the risk of death.

Extreme heat can increasethe occurrence of heart attacksand strokes in susceptible patients due to increased blood viscosity, and raise the risk of cardiovascular death in vulnerable patients. Hot, humid days can also triggerasthma symptomsand have been shown to increase airway resistance, while warmer climates tend to extend the pollen season.

Another side effect of rising temperatures is the association with air pollution the largest environmental killer in Europe,causing roughly 500,000 premature deaths annually.

Observational data and modelling suggest that as it gets warmer, air pollution levels particularly surface ozone gas (O3) and fine particulate matter (PM2.5) increase in some populated regions, even whenemissions of air pollutants have not risen, as well as create conditions favourable for forest fires.

Both extreme heat and air pollution raise the risk of cardiovascular and respiratory disease, which currently costs the European Union anestimated 600bna year.If these environmental stressors continue to accumulate unabated, these costs could jump.

We think there are reasons to believe that being able to comply with a Paris agreement will save very many lives and reduce human suffering.

-Dr Kristin Aunan, Center for International Climate Research, Norway

Projections

But the synergistic relationship between air pollutants and rising temperatures is not well understood and existing health-risk projections in Europe do not properly account for adaptive measures that can be taken to ameliorate associated health risks, according to Dr Kristin Aunan, a senior researcher at the Norway-based Center for International Climate Research.

Theres quite a lot of literature on short-term impact in terms of the day-to-day variation on the impact of heat stress on mortality but when it comes to long-term impact, there is not a lot of information, she said.

As part of a project calledEXHAUSTIONthat kicked off last year, researchers including project coordinator Dr Aunan, are focused on quantifying the risks of cardiopulmonary disease in different temperatures.

The project is also working on identifying interventions to minimise the risks to health sparked by environmental stressors and demystifying the link between air pollution and temperature hikes.

Quantifying the cascading effect of cardiopulmonary diseases on the economy is key to affecting action on climate change, she suggests.

EXHAUSTION researchers, for instance, are devising a macro-economic model that tracks increased hospitalisation and mortality in different age groups to measure the impact on the broader economy in different European countries. We also have a bottom-up model where you put a price on every premature death or hospital admission and add up to estimate the economic cost.

One of the main questions the researchers hope to answer is the magnitude of impact limiting temperature spikes to 1.5C the aim of the Paris climate agreement will have on health.

I have no answer to that today but the reason why were doing this projectis that we think there are reasons to believe that being able to comply with a Paris agreement will save very many lives and reduce human suffering, Dr Aunan said.

When you discuss climate policy and discuss the costs of it its very expensive to reduce emissions of greenhouse gases, etc. But you also need to consider the benefits and thats what we are doing with this project hoping that we can contribute to the other side of the coin.

The research in this article was funded by the EU. If you liked this article, please consider sharing it on social media.

This article was originally published on Horizon magazine.

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Physiology

How to tell if your vaginal discharge is normal: The colour, consistency and other things you need to know – Firstpost

As long as the vaginal discharge is white or clear, thick or stretchy, has no smell and causes no itchiness, it is normal

Finding a bit of discharge on your toilet paper or underwear is nothing new for most women, though it often leads to concerns about sexual and reproductive health. While this worry is absolutely natural, its important to remember that so is vaginal discharge - in most cases, at least.

Whats normal about vaginal discharge?

Vaginal discharge is a normal part of the female physiology, and experts, as well as research from around the world, underlines this fact. As a 2007 study in the British Medical Journal points out, normal discharge from the vagina is white or clear, non-offensive discharge that varies with the menstrual cycle". You might already know that the menstrual cycle has four stages which are marked by hormonal changes: menstruation, follicular phase, ovulation and luteal phase.

Each of these stages may have a different type of vaginal discharge depending on what the mucous lining of the uterus is going through and how much moisture is needed inside the vagina. The vaginal microbiome and hormones manage this discharge throughout the menstrual cycle, and other regular activities like sex and exercise can also affect it. As long as it is white or clear, thick or stretchy, has no smell and causes no itchiness, your vaginal discharge is normal.

Signs that something is wrong

While vaginal discharge may be a normal physiological process, changes in your health status can cause it to change. The study mentioned above shows that these changes in vaginal discharge could be caused by non-sexually transmitted infections like bacterial vaginosis and candida infections, or by sexually transmitted infection (STIs) like chlamydia, gonorrhea and trichomoniasis. The following are some signs you should take note of:

If you notice any of these signs, its time to consult a gynaecologist without delay to discover the underlying cause and treat it.

Types of discharge and what they say

The following are the types of vaginal discharge based on their colour, and what they say about your health.

1. White: As mentioned before, white or clear discharge thats thick and stretchy is normal. However, if the white discharge is very thick, foamy or like cottage cheese, and causes itching in the vagina, it could indicate a yeast infection.

2. Yellow: This is an abnormal type of discharge, especially when accompanied by a foul or fishy smell. It could be a sign of a bacterial infection or STI.

3. Brown: Old blood looks brown, so if this vaginal discharge occurs right before or after your period, its just a normal cleanup. If it happens in the middle of the cycle, it could indicate anything ranging between spotting due to uterine or hormonal issues like fibroids or polycystic ovary syndrome and uterine or cervical cancer. Its best to consult a doctor immediately.

4. Green: This discharge, just like the yellow one, can be a sign of infections. Its best to get treated for it sooner rather than later.

For more information, read our article on White discharge.

Health articles in Firstpost are written by myUpchar.com, Indias first and biggest resource for verified medical information. At myUpchar, researchers and journalists work with doctors to bring you information on all things health.

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Physiology

CU regents hear from DiStefano, others on move-in, testing, response, more – CU Boulder Today

In a special virtual meeting on Wednesday, Aug. 12, the University of Colorado Board of Regents heard an update from CU Boulder Chancellor Philip DiStefano about the Boulder campuss plans for a COVID-19-ready fall semester, which included student move-in and testing, as well as ongoing controls and response plans.

DiStefano reported 33,027 students have enrolled for classes; 29,310 of those students have enrolled for at least one fully in-person course or a hybrid course with an in-person component; and 3,717 students have enrolled in courses that are fully remote or fully online.

More than 7,500 students are moving into residence halls between Aug. 17 - 21.

Im very proud of what weve been able to accomplish over the last several months, DiStefano said. What our students are going to be experiencing this semester will be unlike any other semester at CU Boulder.

DiStefano reported that all first-year students living on campus will either provide proof of a recent negative COVID-19 test or will undergo testing before moving in. He explained that the RT-LAMP test that CU Boulder faculty members at the BioFrontiers Institute have developed has enabled campus to return test results rapidly as part of the move-in process.

DiStefano reported that when resident advisors returned to campus last week, all of them tested negative for COVID-19.

DiStefano told the board that the Boulder campus is monitoring many different factors, such as infection rates, hospital capacity and campus density, as the campus makes decisions about how to proceed during the course of the semester. DiStefano announced a new dashboard that will be regularly updated to provide transparency about campus data.

Professor Matt McQueen, a faculty member in the Department of Integrative Physiology and the director of the Epidemiology Laboratory, updated the board in further detail about campus plans for testing, response and environmental controls.

McQueen told the board that while CU Boulder is not planning to conduct move-in testing for off-campus students, the campus does plan to conduct surveillance testing of off-campus students throughout the semester.

McQueen explained that the campus will need to make day-to-day decisions about how to test based on campus and community needs. He said that testing resources will be used to respond to potential events on campus, such as an outbreak in a particular community, and that he hopes campus will be able to regularly test students beyond such events in order to understand how the virus is moving through the community.

McQueen emphasized to the board the need to be able to gather data that will allow the university to assess the health of the campus and the community. He told the board that because CU Boulder will be conducting surveillance testing, rather than testing symptomatic people only, there should be no surprise when positive cases start to appear.

While we will rely upon some data that is collected by other public health authorities, the campus has also built capabilities for COVID-19 testing that exceed the capabilities that exist in the community, McQueen said.

McQueen says that because the campus will be discovering asymptomatic and presymptomatic carriers, the numbers may look high.

That's a good thing because it will allow us to work to prevent the spread of disease from individuals who are infected, McQueen said.

McQueen reported that in addition to testing, CU Boulder has stood up a robust contact tracing program that involves medical staff as well as more than 50 students who are earning academic credit to support campus contract tracing efforts.

McQueen briefly highlighted work to reduce the ability of COVID-19 to spread in campus facilities, such as by evaluating each campus building to make sure the flow of air exceeds the recommended requirements. McQueen also cited other environmental controls, including following standard public health measures such as cleaning protocols. More information on these and related topics can be found on the Infrastructure Mitigation Efforts website.

McQueen also told the board that emphasizing behaviors such as social distancing and the wearing of face coverings are some of the most important strategies for mitigating the spread of COVID-19 on campus.

While testing and contact tracing are good, limiting the spread of infection is better. Social distancing and masking are the best tools in our arsenal to prevent the spread of the disease, McQueen said.

Regent Heidi Ganahl proposed a resolution that would provide a tuition discount. President Kennedy and several regents expressed concern over further budget cuts that they predicted would negatively impact the quality of education. The board voted against the resolution in a 5-4 vote.

Link:
CU regents hear from DiStefano, others on move-in, testing, response, more - CU Boulder Today

Physiology

D&E professor’s paper is published | News, Sports, Jobs – The Inter-Mountain

Stover

ELKINS An international education journal has taken notice of the Davis & Elkins College biology program for its use of clinical case studies in pre-medical curriculum.

Bioscene: Journal of College Biology Teaching recently published a paper by D&E Professor of Biology Dr. Shawn Stover detailing how the program is successfully preparing students for medical school.

In the paper, Stover explains the integration of clinical cases in human physiology, functional histology and biochemistry courses strongly recommended for pre-medical students. Each semester, students are presented with at least five clinical cases to analyze. The traditional small class sizes and strong faculty-student interactions at D&E are conducive to active learning, allowing students to work on cases in small groups as part of laboratory activities, in-class discussions and homework assignments. Clinical cases cover a range of medical conditions, including Alzheimers disease, Bells palsy and emphysema.

Small group learning has become very popular in medical schools in recent years, and the clinical case study is one of the primary teaching tools of medical education, Stover said. By providing multiple opportunities to experience clinical case teaching, D&E is preparing its pre-med students for the active learning environment associated with current medical education.

Stover points out that previous research indicates that the use of case studies is effective for promoting critical thinking, enhancing interest in curricular content, and improving student understanding of core concepts.

The Department of Biology and Environmental Science at D&E offers multiple specialization tracks for biology majors, including general biology, pre-medical, pre-veterinary and secondary education.

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Physiology

4 breathing techniques to get you through high-stress moments – Big Think

Emma Seppl, science director at Stanford Center For Compassion And Altruism Research And Education, says American culture values intensity yet undervalues calmness. We never shut off. While intensity has its place, every animal in nature inherently knows the necessity of rest in order to store up energy for when it's actually needed. Americans are careless with our energy reserves, which is why so many of us are chronically tired, overworked, and stressed out.

Seppl knows that breathing changes our state of mind. She recommends a popular yogic breathing technique, nadi shodhana, also known as alternate nostril breathing.

Place the index and middle fingers of your right hand on your forehead. Use your thumb to close your right nostril while inhaling through the left nostril, then close the left nostril with your ring finger and exhale through your right nostril. Repeat this for at least two minutes, then sit quietly for another minute or two, breathing normally.

There are many variations of this technique. My favorite is a four-cycle breath: inhale for a count of four through one nostril, retain your breath for a count of four, exhale for four, hold your breath out for four. If you're new to this breathing technique, retention might initially create more anxiety than it relieves, so try the basic inhale-exhale pattern until you can last for at least five minutes before moving onto breath retentions.

Game designer and author of "Superbetter," Jane McGonigal, recommends the Power Breath: exhale for twice as long as you inhale. She says this will shift your nervous system from sympathetic to a parasympathetic toneyou'll calm down. Simply sit comfortably, close your eyes, and begin by inhaling for a count of four and exhaling for a count of eight.

This is also a popular yoga breathing technique. As with nadi shodhana, it can initially kick up rather than diminish anxiety. If you find long exhales challenging, begin by inhaling and exhaling at an even rate: a count of four in both directions. Then try to slowly increase your exhale to a count of five, six, and so on. Longtime practitioners can inhale for a count of four and exhale for a count of 50. As with any muscle, you can train your breathing. The benefits are immense.

Lolly, a Mind-Body Specialist at the University of Maryland Heart Center, offers what she calls Focus Word Breathing. Traditionally, this is known as Mantra meditation. Choose a word that has meaning to youcalm, grace, easeand repeat it during every inhalation and exhalation. As your mind wanders, the word becomes a sort of flagpole that you've mentally planted to bring you back to this moment.

As a former sufferer of anxiety disorder, I remember how important my thoughts were when having a panic attack. The power of the physiological symptoms increased when I dwelled on negative thoughts. This spiral felt like being sucked into a vortex. By contrast, when I was able to redirect my thinking, the symptoms lessened.

Mantra meditation never completely worked during an attack. By that point, my physiology had been hijacked. But as a regular practice, this breathing technique is powerful. Think of it as training for the big game of life. You teach yourself to focus on beneficial words. Your attention goes where thinking leads you, but you also have control of your thoughts. By integrating a mantra with breathing, you're priming your mind to focus at will.

This exercise is commonly used by yoga instructors to bring their students into Corpse Pose (Savasana). Place your hands over your stomach while lying down and focus your attention there. Take deep, even breaths into your hands. As with the last technique, focus your mind there. Relax the muscles at your extremities: your toes, fingers, and forehead. Allow yourself to melt into the floor.

I love doing this breath while in Viparita Karani, otherwise known as Legs Up the Wall posture. The video above explains how to enter this pose; a blanket or pillow under your lower back makes the posture comfortable. Once there, I practice deep belly breathing. This technique always calms me down. I've recommended it to friends suffering from insomnia; they all responded with positive anecdotal feedback.

--

Stay in touch with Derek on Twitter, Facebook and Substack. His next book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."

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Cell Biology

Amgen : Cancer Writer and Researcher Siddartha Mukherjee Shares Novel Ideas on Battling the "Emperor" – Marketscreener.com

Siddhartha Mukherjee is best known as the author of The Emperor of All Maladies, a 'biography' of cancer that earned the Pulitzer Prize for nonfiction in 2011. But as Amgen staff who attended a recent online lecture hosted by Amgen's Global Research can tell you, Mukherjee's interest in cancer isn't confined to just writing about it. As a scientist, a physician, and an entrepreneur who has founded multiple companies, Mukherjee is advancing a host of out-of-the-box approaches for treating cancer. In many cases, these novel therapeutic ideas are informed by the love of history reflected in his books.

'There is a paper by Stephen Paget from the 1800s that I make all my students read,' said Mukherjee. 'Paget coined the term 'seed and soil,' and he wondered whether obsessing about the seed-in this case the cancer cell-was done at the cost of obsessing about the soil, or the environment in which the cancer cell flourishes and grows. What features of the environment allow certain cancers to grow, and can we change the environment of cancer rather than changing the seed?'

Modern cancer research, with its focus on the genetics of tumors, is very much a seed-centric approach to disease, observed Mukherjee. He likened this focus to the famous New Yorker cartoon, 'The View from Ninth Avenue,' where Manhattan looms large in the foreground and the rest of the world looks like blips on the horizon.

'In the 1990s and 2000s, as we learned more about the cancer genome, the view of cancer biology was like that New Yorker's view,' he said. 'All we could see was the genome, and the things I was interested in-the cell biology, the microenvironment-were blips on the horizon. But cancer is not something that happens in a vacuum. What can we understand about the host?'

Deleting host antigens to make cancer stand out

Mukherjee's seed-and-soil approaches to cancer have yielded several new treatment approaches with intriguing potential. For example, one frustration in cancer drug design is the dearth of biological targets found on cancer cells but largely absent from healthy tissues. Consequently, many agents that are potent tumor killers can't be dosed as aggressively as needed due to side effects.

'Cancer is a perverted version of our normal cells,' he noted. 'So how can we attack cancer when cancer shares so many features of normalcy?' One potential solution is to remove antigens from normal cells-'in other words, change the host to make the cancer stand out. We know from genetics that some antigens are not absolutely required for survival, because there are people who are walking around without them.' Those antigens can now be deleted from normal cells using tools like CRISPR.

In AML (acute myeloid leukemia), all the cancerous cells express an antigen called CD33, but so do normal hematopoietic stem cells that give rise to mature immune cells. Experiments in mice and non-human primates have confirmed that if you delete the gene for CD33 from blood stem cells, these cells will still mature into normal, fully functioning immune cells, which are no longer susceptible to cancer therapies that target CD33.

Mukherjee is the scientific board chair of a new company that is planning to test this treatment paradigm in AML patients. 'These patients would be receiving an allogenic transplant of stem cell anyway,' he observed. 'The idea is to infuse them with CD33-deleted cells and then use a CD33 therapy to kill the cancer cells and spare the normal cells.' Several other nonessential human antigens can also be deleted to further differentiate tumor cells and reduce the risk that these cells can survive through mutations that delete a target antigen.

Asking the cancer itself what drugs would kill it

Mukherjee described several other ideas that are being advanced by biotech companies he helped to launch, including one that borrowed a page from antimicrobial therapy. 'If you get an infection in the hospital, we culture and test the bacteria to figure out what antibiotics they are sensitive to. We're doing the same with cancer by asking, 'What can the cancer tell you about its sensitivities? It sounds like a simple idea but it's quite complex to enact.'

In practice, this approach takes a biopsy from a patient with a hard-to-treat cancer and grows the tumor cell organoids, or mini tissues. The organoids are separated into hundreds of wells on plates, which are used to screen thousands of drugs to find those that are best at killing the patient's cancer. The effectiveness of treatments can vary from one patient to another with the same cancer, and the best drugs may be ones that wouldn't normally be used against that tumor type. Early and encouraging results have been seen in one patient, and a trial is being planned to evaluate this approach in more patients with metastatic disease.

In his Amgen lecture, Mukherjee described two other potential new treatment paradigms-one that treats cancer by altering the patient's immune environment and another that adjusts the metabolism to mitigate against the potential side effects that limit a promising class of cancer drugs.

Mukherjee closed his lecture by saying that he feels personally gratified that all of the ideas he discussed and several others have given rise to new companies and clinical trials. 'I like making medicines. It is one of the most profound and most beautiful things that humans do'.

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Amgen : Cancer Writer and Researcher Siddartha Mukherjee Shares Novel Ideas on Battling the "Emperor" - Marketscreener.com

Cell Biology

To Understand the Machinery of Life, a UArizona Scientist Breaks it on Purpose – UANews

By Daniel Stolte, University Communications

Today

"I'm fascinated with life, and that's why I want to break it."

This is how Betl Kaar, an assistant professor at the University of Arizona with appointments in the Department of Molecular and Cellular Biology, Department of Astronomy and the Lunar and Planetary Laboratory, describes her research. What may sound callous is a legitimate scientific approach in astrobiology. Known as ancestral sequencing, the idea is to "resurrect" genetic sequences from the dawn of life, put them to work in the cellular pathways of modern microbes think Jurassic Park but with extinct genes in place of dinosaurs, and study how the organism copes.

In a recent paper published in the Proceedings of the National Academy of Sciences, Kaar's research team reports an unexpected discovery: Evolution, it seems, is not very good at multitasking.

Kaar uses ancestral sequencing to find out what makes life tick and how organisms are shaped by evolutionary selection pressure. The insights gained may, in turn, offer clues as to what it takes for organic precursor molecules to give rise to life be it on Earth or faraway worlds. In her lab, Kaar specializes in designing molecules that act like tiny invisible wrenches, wreaking havoc with the delicate cellular machinery that allows organisms to eat, move and multiply in short, to live.

Kaar has focused her attention on the translation machinery, a labyrinthine molecular clockwork that translates the information encoded in the bacteria's DNA into proteins. All organisms from microbes to algae to trees to humans possess this piece of machinery in their cells.

"We approximate everything about the past based on what we have today," Kaar said. "All life needs a coding system something that takes information and turns it into molecules that can perform tasks and the translational machinery does just that. It creates life's alphabet. That's why we think of it as a fossil that has remained largely unchanged, at least at its core. If we ever find life elsewhere, you bet that the first thing we'll look at is its information processing systems, and the translational machinery is just that."

So critical is the translational machinery to life on Earth that even over the course of more than 3.5 billion years of evolution, its parts have undergone little substantial change. Scientists have referred to it as "an evolutionary accident frozen in time."

"I guess I tend to mess with things I'm not supposed to," Kaar said. "Locked in time? Let's unlock it. Breaking it would lead the cell to destruction? Let's break it."

The researchers took six different strains of Escherichia coli bacteria and genetically engineered the cells with mutated components of their translational machinery. They targeted the step that feeds the unit with genetic information by swapping the shuttle protein with evolutionary cousins taken from other microbes, including a reconstructed ancestor from about 700 million years ago.

"We get into the heart of the heart of what we think is one of the earliest machineries of life," Kaar said. "We purposely break it a little, and a lot, to see how the cells deal with this problem. In doing this, we think we create an urgent problem for the cell, and it will fix that."

Next, the team mimicked evolution by having the manipulated bacterial strains compete with each other like a microbial version of "The Hunger Games." A thousand generations later, some strains fared better than others, as was expected. But when Kaar's team analyzed exactly how the bacteria responded to perturbations in their translational components, they discovered something unexpected: Initially, natural selection improved the compromised translational machinery, but its focus shifted away to other cellular modules before the machinery's performance was fully restored.

To find out why, Kaar enlisted Sandeep Venkataram, a population genetics expert at the University of California, San Diego.

Venkataram likens the process to a game of whack-a-mole, with each mole representing a cellular module. Whenever a module experiences a mutation, it pops up. The hammer smashing it back down is the action of natural selection. Mutations are randomly spread across all modules, so that all moles pop up randomly.

"We expected that the hammer of natural selection also comes down randomly, but that is not what we found," he said. "Rather, it does not act randomly but has a strong bias, favoring those mutations that provide the largest fitness advantage while it smashes down other less beneficial mutations, even though they also provide a benefit to the organism."

In other words, evolution is not a multitasker when it comes to fixing problems.

"It seems that evolution is myopic," Venkataram said. "It focuses on the most immediate problem, puts a Band-Aid on and then it moves on to the next problem, without thoroughly finishing the problem it was working on before."

"It turns out the cells do fix their problems but not in the way we might fix them," Kaar added. "In a way, it's a bit like organizing a delivery truck as it drives down a bumpy road. You can stack and organize only so many boxes at a time before they inevitably get jumbled around. You never really get the chance to make any large, orderly arrangement."

Why natural selection acts in this way remains to be studied, but what the research showed is that, overall, the process results in what the authors call "evolutionary stalling" while evolution is busy fixing one problem, it does at the expense of all other issues that need fixing. They conclude that at least in rapidly evolving populations, such as bacteria, adaptation in some modules would stall despite the availability of beneficial mutations. This results in a situation in which organisms can never reach a fully optimized state.

"The system has to be capable of being less than optimal so that evolution has something to act on in the face of disturbance in other words, there needs to be room for improvement," Kaar said.

Kaar believes this feature of evolution may be a signature of any self-organizing system, and she suspects that this principle has counterparts at all levels of biological hierarchy, going back to life's beginnings, possibly even to prebiotic times when life had not yet materialized.

With continued funding from the John Templeton Foundation and NASA, the research group is now working on using ancestral sequencing to go back even further in time, Kaar said.

"We want to strip things down even more and create systems that start out as what we would consider pre-life and then transition into what we consider life."

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To Understand the Machinery of Life, a UArizona Scientist Breaks it on Purpose - UANews