Category Archives: Michigan Stem Cells

A research team led by Francesca Luca, Ph.D., associate professor of Wayne State Universitys Center for Molecular Medicine and Genetics, has published a study that annotated environmental components that can increase or decrease disease risk through changes in gene expression in 43 genes that could exacerbate or buffer the genetic risk for cardiovascular disease. Their results highlight the importance of evaluating genetic risk in the context of gene-environment interactions to improve precision medicine.

Interpreting Coronary Artery Disease Risk Through GeneEnvironment Interactions in Gene Regulation was published in Genetics, the journal of the Genetics Society of America.

The study, said Dr. Luca, also of the WSU Department of Obstetrics and Gynecology, illustrates that combining genome-wide molecular data with large-scale population-based studies is a powerful approach to investigate how genes and the environment interact to influence risk of cardiovascular disease.

By identifying regions of DNA important for endothelial cell response to different common environmental exposures, the researchers discovered that caffeine can influence the risk of cardiovascular disease. The study demonstrates the potentially beneficial and/or detrimental effects of certain environmental exposures on the cardiovascular disease risk differ depending on individual DNA sequence.

The study focused on cardiovascular disease, Dr. Luca said, because it is the leading cause of death, both in the United States and worldwide. Also, the disease is highly multifactorial, with large contributions from both environmental and genetic risk factors. By treating endothelial cells under a controlled environment, we can discover how these genetic and environmental risk factors influence each other at the molecular level, she said. Our lab has developed expertise in cardiovascular research, with additional projects using endothelial cells to develop new assays to test the regulatory activity of genetic variants. The approach outlined in this paper can be applied to many different diseases; for example, our lab has also focused on how bacteria in the human gut affect gene expression in the colon, and also on the effect of psychosocial stress on asthma.

While the work identified regions of the genome important for how endothelial cells respond to the environment and can influence the risk of cardiovascular disease, the researchers do not yet know exactly which genetic variants are directly responsible. A former graduate student, Cynthia Kalita, developed an assay to test thousands of genetic variants for gene regulatory activity. The researchers can test the variants discovered in their study using that assay to validate and explore the mechanisms by which they exert their effects, Dr. Luca said. They also are developing computational/statistical methods that can yield better personalized risk scores.

We have extended our approach to study cardiomyocytes, which are the muscle cells of the heart. Healthy heart tissue is difficult to obtain, so we have collaborated with researchers at the University of Chicago to derive cardiomyocytes from stem cells, Dr. Luca said. This will allow us to shift our focus from the vasculature to the heart itself, where we can study diseases like cardiomyopathies and arrhythmias.

As the cost of DNA sequencing continues to decrease, Dr. Luca expects that genetic testing will play a greater role in preventive health care. To fully realize the potential of precision medicine, we need to consider both genetic and environmental risk factors of disease, and how they interact. While there are already direct-to-consumer tests that prescribe an individualized diet based on DNA, these products currently offer no demonstrated clinical value. However, with very large numbers of individuals for whom we have both DNA sequencing and information on diet and lifestyle, we may one day be able to offer better recommendations.

Others involved in the study included Anthony Findley, an M.D./Ph.D. student; Allison Richards, Ph.D., a research scientist; Cristiano Petrini, of the Center for Molecular Medicine and Genetics; Adnan Alazizi, lab manager; Elizabeth Doman, of the Center for Molecular Medicine and Genetics; Alexander Shanku, Ph.D., research scientist; Gordon Davis, of the Center for Molecular Medicine and Genetics; Nancy Hauff, Department of Obstetrics and Gynecology; Yoram Sorokin, M.D., professor of Obstetrics and Gynecology; Xiaoquan Wen, of the Department of Biostatistics at the University of Michigan; and Roger Pique-Regi, Ph.D., associate professor of the Center for Molecular Medicine and Genetics, and of the Department of Obstetrics and Gynecology.

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Researchers identify environmental components that affect gene expression in cardiovascular disease - The South End

Hesperos haveannounced a new peer-reviewed publication that describes how the companys functional Human-on-a-Chip system can be used as a drug discovery platform to identify therapeutic interventions targeting the preclinical stages of Alzheimers disease (AD) and mild cognitive impairment (MCI). The manuscript, titled A human induced pluripotent stem cell-derived cortical neuron human-on-a-chip system to study A42 and tau-induced pathophysiological effects on long-term potentiation, was published this week in Alzheimer's & Dementia: Translational Research & Clinical Interventions. The work was conducted in collaboration with the University of Central Florida and with David G. Morgan, Ph.D., Professor of Translational Neuroscience at Michigan State University, and expert in AD pathology.

To date, more than 100 potential therapeutics in development for AD have been abandoned or failed during clinical trials. These therapeutics relied on research conducted in preclinical animal studies, which often are unable to accurately capture the full spectrum of the human disease phenotype, including differences in drug metabolism and excretion between humans and animals. Therefore, there is a need for human models, especially those that accurately recapitulate the functional impairments during the preclinical phases of AD and MCI.

Hesperos offers a breakthrough technology that provides a human cell-based assay based on cognitive function metrics to evaluate drugs designed to restore cognition at early stages of the Alzheimers continuum, said Dr. Morgan. This system can serve as a novel drug discovery platform to identify compounds that rescue or alleviate the initial neuronal deficits caused by A1-42 and/or tau oligomers, which is a main focus of clinical trials.

In 2018, Hesperos received a Phase I Small Business Innovation Research (SBIR) grant from the National Institute on Aging (NIA) division within the US National Institutes of Health (NIH) to help create a new multi-organ human-on-a-chip model for testing AD drugs. Research conducted under this grant included a study to assess therapeutic interventions based on functional changes in neurons, not neuronal death.

In the recent Alzheimer's & Dementia publication, Hesperos describes its in vitro human induced pluripotent stem cell (iPSC)-derived cortical neuron human-on-a-chip system for the evaluation of neuron morphology and function after exposure to toxic A and tau oligomers as well as brain extracts from AD transgenic mouse models.

Researchers are now focusing on biomarker development and therapeutic intervention before symptoms arise in AD and MCI, said James Hickman, Ph.D., Chief Scientist at Hesperos and Professor at the University of Central Florida. By studying functional disruption without extensive cell loss, we now have a screening methodology for drugs that could potentially evaluate therapeutic efficacy even before the neurodegeneration in MCI and AD occurs.

The researchers found that compared to controls, treatment with toxic A and tau oligomers or brain extracts on the iPSC cortical neurons significantly impaired information processing as demonstrated by reduction in high-frequency stimulation-induced long-term potentiation (LTP), a process that is thought to underlie memory formation and learning. Additionally, oligomer and brain extract exposure led to dysfunction in iPSC cortical neuron electrophysiological activity, including decreases in ion current and action potential firing.

While exposure to the toxic oligomers and brain extracts caused morphological defects in the iPSC cortical neurons, there was no significant loss in cell viability.

Clinical success for AD therapies has been challenging since preclinical animal studies often do not translate to humans, said Michael L. Shuler, Ph.D., Chief Executive Officer of Hesperos. With our recent study, we are now one step closer in developing an AD multi-organ model to better evaluate drug metabolism in the liver, penetration through the blood-brain barrier and the effects on neuronal cells.

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Hesperos Human-on-a-Chip used to model Alzheimer's and MCI - SelectScience

One of the few bright spots in the Covid-19 pandemic has been the perception that children are mostly spared from its worst effects. But what about kids already at risk of contracting serious infections due to a compromised immune system? Do they have the same protection?

"One group we always worry about when it comes to viral illnesses is immunocompromised children," said Dr Reggie Duerst, director of the stem cell transplant programme at Children's Hospital of Chicago. These kids are typically more at risk of known viral illnesses, such as chickenpox, common cold viruses and flu.

But, he said, because there's so little information available on Covid-19 infections, it's hard to know how much higher the risk might be for children with compromised immune systems.

So far, he said, the incidence of Covid-19 infections in his hospital is very low.

Dr Basim Asmar, chief of infectious disease at Children's Hospital of Michigan, said it's just not clear yet whether or not children with compromised immune systems are more likely to get Covid-19 infections. It's also unclear if they would have more severe complications if they got an infection.

"We're not really sure right now. We're still learning, and every day we're learning something new. But with other viral infections, immunocompromised children tend to have a more prolonged course," Asmar said.

Dr Mehreen Arshad, a member of the Infectious Diseases Society of America and an assistant professor of paediatrics at Northwestern University in Chicago, agreed that there's just not a lot of data on children and Covid-19 yet, especially kids with compromised immune systems. She said that immunocompromised children likely have less risk from Covid-19 than older adults do, but they may have more risk than children with healthy immune systems. She added it's important to "take all precautions" to lessen the risk of infection for these children.

Which kids have a compromised immune system?

Duerst said many children who are being treated for cancer and those receiving stem cell transplants or organ transplants tend to have compromised immune systems. There are also inherited immune deficiency conditions. Children who have certain autoimmune diseases, such as rheumatoid arthritis or lupus, may take medications that dampen their immune system's response.

Other children who might be at a higher risk include those with cystic fibrosis and other lung diseases because their lung capacity is already compromised.

Among children who've received a stem cell transplant, the immune systems of those who get their own cells back (autologous transplant) are close to normal after a year or two, Duerst said. In kids who get stem cells from a donor (allogeneic transplant), "they are on ongoing immune suppression for three to six months, and often longer. If they have a smooth course, by two years they begin to return to normal," he said.

Kids who've had an organ transplant may remain on immune-suppressing drugs for a long time, often for life.

So, what steps do parents need to take to keep these youngsters safe?

Arshad said, "I would be a little more stringent for children with compromised immunity. Stay inside as much as possible. Don't have contact with anyone at higher risk, like grandparents, or anyone with symptoms. Don't go to stores. Avoid crowds."

She noted that "these families are used to taking precautions already. They may be more aware of the potential dangers."

Asmar agreed that it's important to follow common-sense infection prevention. And, he added, "If someone is ill within the family, even the mother or father, they should try to avoid coming in contact with the child, and should stay in a separate room."

In addition, Asmar said that children with compromised immune systems should be as up-to-date on immunisations as possible.

If your child has a compromised immune system and gets sick, Duerst said to call the physician treating the immune-compromising condition to get instructions. "There are multiple reasons you do not want to enter just any emergency room entrance," he said. But with a number of precautions and screening in place, hospitals are "still a relatively safe place to be," he added.

Arshad said that for more routine visits, kids can often be seen via telehealth. And if there's something a doctor needs to see your child for, the doctor might have your child stay in the car and come out to you.

"While we're not seeing immune-compromised children get an overwhelming number of infections, there's no reason to be complacent," she noted.

READ | Coronavirus hitting younger children harder than we thought

READ | Keep TB vaccine for babies, implore experts

READ | Up 50 000 US kids may be hospitalised with Covid-19 by year's end

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Are immune-compromised kids at greater risk from Covid-19? - Health24

Increasing amounts of nitrogen and phosphorus in terrestrial ecosystems lead to decreasing biodiversity, not only among plant species, but in herbivores and pollinators as well.

Globally, ecosystems change as the climate does, responding to shifts in temperature and the availability of water and nutrients such as nitrogen and phosphorus. These shifts affect plant community productivity and diversity. However, in general we know very little about how these changes happen.

Erika Hersch-Green, evolutionary biologist and assistant professor of biological sciences at Michigan Technological University, has received a National Science Foundation CAREER award to investigate how increased nitrogen and phosphorus availability across different temperature and water regimes alters the primary productivity of some plants, while reducing the growth of others. Hersch-Green will examine how the amounts of nutrients available to plants determine which plants thrive or wither due to their specific genome attributes.

For evolutionary biologists, one of the main goals is to match the genotype of organisms to what they look like their phenotype, Hersch-Green said. Historically, evolutionary biologists have focused on how natural selection for protein function or genetic drift has shaped evolutionary landscapes, as well as the mapping of genotype to phenotype. My research is taking a slightly different perspective, looking at how molecular attributes of organisms interact to reduce the material cost of building genomes. I am examining whether natural selection operates to reduce the cost to a plant species of building genomes, rather than how natural selection acts on proteins, which is a novel approach.

Hersch-Green is conducting her research across several grassland sites distributed across North America, focusing on two common North American grassland plants: fireweed and goldenrod.

Hersch-Greens research examines how nutrients affect plants that vary in their genome size. Genomes are made up of nucleic acids and cells, which cost plants a significant amount of nitrogen and phosphorus to build. And, some of these plants are polyploids with varying numbers of chromosomes which, in turn, affects genome size.

The cost of building genomes and a nutrient environment influence physiological tradeoffs of primary processes like photosynthesis and growth versus secondary tradeoffs like defense compounds, Hersch-Green said. My research takes a multifaceted approach. Im combining molecular cytological [chromosomal] and physiological phylogenetic [appearance] approaches.

Hersch-Green will examine mechanistic tradeoffs in 10 Nutrient Network consortium sites distributed across the American West Coast and Midwest, including a new site at Michigan Techs Ford Center and Research Forest featuring gardens planted in particular arrangements to test particular mechanisms. The sites vary in climate zones, temperature and available moisture.

Using fireweed and goldenrod, Hersch-Green will look specifically at tradeoffs in size between the plants genome their total genetic code and their transcriptome the parts of the genome transcribed into RNA molecules. RNA codes, decodes, regulates and expresses genes. Hersch-Green will use different nutrient environments with different cytotypes of each plant to measure certain functional traits. By combining data from multiple plants, the creatures that pollinate plants or eat the plants (known as consumer community assemblages), and time series phylogenetic modeling and experiments Hersch-Green hopes to gain insights into the roles of material costs and genome size in biodiversity patterns.

Her work provides a system-level understanding of how eutrophication the increasingly dense growth of particular plants at the expense of other species brought on by increasing nutrient inputs are affecting individual organisms and multi-species communities by looking at their interactions. Ultimately, this research will generate genomic tools for other species as well.

Every CAREER award features an education component. Hersch-Greens approach features multiple methods to enhance scientific literacy for middle schoolers, high schoolers and undergraduates. At Hersch-Greens Ford Center site, she is working with a STEM educator to formulate different science communication and botany modules based on photosynthesis research conducted by Hersch-Green and graduate students in her lab. She is also collaborating with Erin Smith, director of the Humanities Digital Media Zone and faculty advisor to Cin/Optic Communication and Media Enterprise students, to create a series of educational modules.

The goal of any CAREER award is to effect change beyond the field of study through novel research and education. Hersch-Greens research, through two prairie plants, examines how community diversity, from plant to pollinator to herbivore, is changing and in broad terms, how that affects biodiversity.

Michigan Technological University is a public research university, home to more than 7,000 students from 54 countries. Founded in 1885, the University offers more than 120 undergraduate and graduate degree programs in science and technology, engineering, forestry, business and economics, health professions, humanities, mathematics, and social sciences. Our campus in Michigans Upper Peninsula overlooks the Keweenaw Waterway and is just a few miles from Lake Superior.

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Erika Hersch-Green Wins CAREER Award for Biodiversity Research - Michigan Tech News

It now seems apparent that COVID-19 will dominate American life for months to come, quite possibly through the national election in November.

That means the disease, and efforts to respond to it, will likewise dominate the 2020 campaign and make it largely about something it has never been about before.

That something is science.

It is hard to think of a time when hard science biology, virology, epidemiology has been so much the core of our political conflict. Issues from evolution to stem cells to vaccination have long been a part of our political conversation, but not at the forefront of presidential elections.

This virus crisis has largely taken over the political conversation. Americans are all learning new, polysyllabic vocabulary and complex truths about threats they cannot see.

And that is likely to bring out all of the culture's ambivalence about science.

Trust in science

Last summer, a Pew Research Center survey found that 86% of Americans expressed "a fair amount or a great deal of faith" that scientists act in their best interests.

But the survey's co-author told NPR, "It tends to be kind of soft support." In fact, only 48% were willing to say that medical doctors "make fair and accurate research statements and recommendations all or most of the time." And only 32% were willing to say as much for "medical research scientists."

A YouGov poll in April 2017 found an even less sanguine attitude, as reported in Scientific American. That measure found only 35% of Americans had "a lot of confidence" in scientists. A plurality (45%) had "a little," while those with "none at all" had grown substantially since YouGov polled the same question in 2013.

Little wonder then that political figures such as Texas Lt. Gov. Dan Patrick, a Republican, and media personalities such as Fox News' Tucker Carlson pounce on the difference between various projections of deaths from COVID-19.

They interpret lower death totals (thus far) as evidence that the threat was overblown, even though public health experts consider it proof that shutdowns and social distancing are working and note that the threat is not over.

Rejecting expertise

Scientific experts, like experts in general, have fared poorly in the populist atmosphere of the past decade in Europe and the United States.

"Voters say they reject expertise because experts, whom they think of as indistinguishable from governing elites, have failed them," writes Tom Nichols, a professor of national security affairs at the U.S. Naval War College.

Nichols published a book in 2017 called The Death of Expertise: The Campaign Against Established Knowledge and Why It Matters. Summing up his argument for Politico, Nichols observed that Americans have always had a healthy skepticism about "eggheads" of various kinds.

He says that skepticism renewed itself in the "social and political traumas" of the 1960s and 1970s. But since then, he argues, "Globalization and technological advances have created a gulf between people with enough knowledge and education to cope with these changes and people who feel threatened and left behind in the new world of the 21st century."

Lacking "scientific merit"

The plain fact is that for many, science is a source of wisdom but by no means the only one. There can be a "balancing" of science with religious teaching or humanistic ethics or what people may regard as their own common sense.

That is why so many Americans may identify with President Trump's overeagerness about potential drug therapies for COVID-19 that have worked on other diseases.

Trump's hopefulness for the antimalarial hydroxychloroquine, for example, was apparently not shared by one of the administration's own leading vaccine scientists, Richard Bright. Bright tried to limit broad use of the drug because its application lacked "scientific merit." As a result, he says, he was removed as director of the Biomedical Advanced Research and Development Authority.

In a statement released by his attorneys last week, Bright sounded the alarm: "To combat this deadly virus, science, not politics or cronyism, has to lead the way."

Also this past week, the president stood at the podium of the White House briefing room and cast doubt on the survival of the coronavirus in the fall. He then deferred to his top scientific adviser on the question.

"We will have the virus in the fall," said Dr. Anthony Fauci of the National Institutes of Health.

Trump also insisted the head of the Centers for Disease Control and Prevention had been misquoted about the difficulties of managing COVID-19 in the fall. Dr. Robert Redfield took the lectern to say he had not been misquoted.

But all this was prelude to the Thursday night stunner, when the president extended his embrace of "game-changer" therapy ideas to raising the question of whether injecting a disinfectant (which can kill the coronavirus on a surface) into a person could kill the virus (in reality, doing so would be toxic).

This prompted such immediate blowback from scientists, hospital personnel and even the makers of Lysol that the president later insisted he had made the comment sarcastically. And the next evening's briefing was cut off at just 22 minutes, with the president taking no questions.

A long-term struggle

The crisis is spreading through the body politic even as it spreads through the human population. It will stress both in myriad ways. Americans' conflicted relationship with science will play a role in how they deal with that stress.

For the moment, most are accepting the scientific approach of social distancing in service of a greater good. But there are rejections of stay-at-home orders in street protests and in some statehouses.

Saturday night, Trump repeated a line used to argue for reopening the country sooner rather than later: "Remember, the Cure can't be worse than the problem itself." He added, "Be careful, be safe, use common sense!"

The struggle has been joined, and it will likely outlast both this one campaign season and this one pandemic.

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Science Becomes A Dividing Issue In Year Of Election And Pandemic - Michigan Radio

For the first time, doctors have used a CRISPR gene editing therapy in an attempt to fix broken genes within the body, marking another step forward for a technology that promises to change how some inherited diseases are treated.

Clinicians at Oregon Health and Science University recently injected the therapy, developed by biotech Editas Medicine and partner Allergan, into the eye of a patient with a type of severe blindness, the companies confirmed Wednesday.

A study last year tested another CRISPR medicine in stem cells extracted from patients' blood, while a third trial previously used a different type of gene editing technology called zinc finger nucleases inside the body. But the patient recently given Editas and Allergan's therapy is the first to be treated using a CRISPR therapy that works in vivo.

The eye disease the companies hope to correct, called Leber cogenital amaurosis, is caused by mutations in any of at least a dozen genes. Editas and Allergan are focusing on just one particular type, known as LCA10. Between 2,000 and 5,000 patients in the U.S. and Europe have it, according to the companies.

"Half of the patients who have this disease are born essentially with light perception vision. They can tell that the room is dark or light," said Mark Pennesi, an associate professor of ophthalmology who is leading OHSU's involvement in the study, in an interview.

"The other half start at legal blindness and then will degrade over the first two decades of life."

Pennesi and his colleagues hope Editas and Allergan's medicine could restore vision by deleting the mutation that prevents the eye from making a protein critical to light-detecting cells.

If that protein is made again, the damaged segment of those photoreceptors should be able to regenerate, said Charles Albright, chief scientific officer at Editas, in an interview last month.

Editas and Allergan plan to enroll 18 adults and children into the study, which is currently being conducted at OHSU as well as centers in Miami, Boston and Ann Arbor, Michigan.

The initial focus will be on safety, as researchers gauge whether the CRISPR medicine being tested causes any side effects or toxicities. Should all go well with the first few adults given a low dose, Editas and Allergan will test four higher doses and potentially try the therapy in children.

Enrolling patients into the study, dubbed BRILLIANCE, has taken longer than the companies first expected when they opened the trial last July.

"Getting patients enrolled and recruiting has taken longer than planned," said Albright, noting there were prospective study participants who came in but ultimately weren't eligible for dosing.

Moving forward, Albright said enrollment should proceed more smoothly.

Whether the treatment helps improve vision will be measured using eye charts and a "mobility maze" similar to one used by Spark Therapeutics for its gene therapy Luxturna, approved in late 2017 for a different type of inherited blindness.

Luxturna works not by editing DNA, but rather by inserting a functional copy of a defective gene directly into the eye. That approach wasn't possible with LCA10, Pennesi said, because the gene in question is too large to fit into the inactivated viruses companies are using as delivery vehicles.

Editing DNA holds potential risks, however the greatest being that the CRISPR therapy inadvertently cuts DNA in places the companies and researchers don't intend and makes irreversible changes.

As with all firsts, the long-term effects of gene editing aren't known either, although Albright noted that photoreceptor cells in the eye no longer divide, potentially making the results of Editas and Allergan's therapy more predictable.

While Editas and Allergan are first to the milestone of in vivo CRISPR editing, the field around them is quickly advancing.

CRISPR Therapeutics and Vertex, which are running the study that used a CRISPR therapy on extracted stem cells, already have initial data, while rival Intellia Therapeutics plans to begin this year a study of in vivo CRISPR editing in a rare disease known as transtheyretin amyloidosis.

Other, newer companies, meanwhile, are working to move past CRISPR and into more specific types of gene editing. One, the Cambridge, Massachusetts-based Beam Therapeutics, recently raised $207 million on the promise of its base-editing platform.

But the studies run by CRISPR Therapeutics and Editas, being the first in their respective settings, will be watched close.

"These are setting precedent," said Albright. "You're going to be seeing a lot more gene editing."

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In a CRISPR first, Editas therapy used to fix genes in the body - BioPharma Dive

New research results reinforce the benefits of quitting smoking.

Not only does it stop further damage to the lungs, it appears that it also allows new, healthy cells to actively replenish the lining of the airways. This shift in the proportion of healthy cells to damaged cells could reduce the risk for lung cancer, say researchers.

The findings were published online January 29 in Nature.

The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.

The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of "driver" mutations, which increase the potential of cells to become cancerous.

However, they also found that in ex-smokers but not in current smokers up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.

"People who have smoked heavily for 30, 40 or more years often say to me that it's too late to stop smoking the damage is already done," commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

"What is so exciting about our study is that it shows that it's never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco," he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.

This study has "broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung," writes Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writing in an accompanying comment.

"It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation," he added.

Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, United Kingdom, added that the study has "an important public health message.

"Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices," he said.

"Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics," James added.

In an interview with Medscape Medical News, Campbell said that the team would next like to try "to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly."

He continued: "If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.

"Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways."

Campbell concluded that they are "a long way away yet, but the toolkit exists for getting there."

In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.

However, this does not explain why individuals who stop smoking in middle age or earlier "avoid most of the risk of tobacco-associated lung cancer."

They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they mused.

To investigate further, the team set out to examine the "landscape" of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.

All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.

The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.

The results showed there was "considerable heterogeneity" in mutational burden both between patients and in individual patients.

Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10-8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2330 per cell in ex-smokers and 5300 per cell in current smokers.

The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, "even within the same individual."

They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2350 per cell in ex-smokers and 2100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P < 10-16 for within-subject heterogeneity).

Between individuals, the mean substitution burden was 1200 per cell in ex-smokers, 1260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10-8 for heterogeneity).

Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells, vs 4%14% of cells from adult never-smokers and none of the cells from children.

It was calculated that current smokers had a 2.1-fold increase in the number driver mutations per cell in comparison with never-smokers (P = .04).

In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5000 extra somatic mutations per cell (P = .0003).

However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.

Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.

Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.

"Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation," the team writes.

They argue that the presence of longer telomeres suggests they are "recent descendants of quiescent stem cells," which have been found in mice but "remain elusive" in human lungs.

"The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens," they suggest.

"Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface," they add.

However, in his commentary, Pfeifer highlights that a "potential caveat" of the study is the small number of individuals (n = 16) from whom cells were taken.

In addition, Pfiefer notes that the "lack of knowledge" about the suggested "long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers' cells with few mutations."

The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Campbell and Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.

Nature. Published online January 29, 2020. Abstract, Comment

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Stopping Smoking Allows Healthy Lung Cells to Proliferate - Medscape

ANN ARBORConventional thinking is that bone regeneration is left to a small number of mighty cells called skeletal stem cells, which reside within larger groups of bone marrow stromal cells.

But new findings from the University of Michigan recasts that thinking.

In a recent study, Noriaki Ono, assistant professor at the U-M School of Dentistry, and colleagues report that mature bone marrow stromal cells metamorphosed to perform in ways similar to their bone-healing stem cell cousinsbut only after an injury.

Bone fracture is an emergency for humans and all vertebrates, so the sooner cells start the business of healing damaged boneand the more cells there are to do itthe better.

Our study shows that other cells besides skeletal stem cells can do this job as well, Ono said.

In the mouse study, inert Cxcl12 cells in bone marrow responded to post-injury cellular cues by converting into regenerative cells, much like skeletal stem cells. Normally, the main job of these Cxcl12-expressing cells, widely known as CAR cells, is to secrete cytokines, which help regulate neighboring blood cells. They were recruited for healing only after an injury.

The surprise in our study is that these cells essentially did nothing in terms of making bones, when bones grow longer, Ono said. Its only when bones are injured that these cells start rushing to repair the defect.

This is important because the remarkable regenerative potential of bones is generally attributed to rare skeletal stem cells, Ono says. These new findings raise the possibility that these mighty skeletal stem cells could be generated through the transformation of the more available mature stromal cells.

These mature stromal cells are malleable and readily available throughout life, and could potentially provide an excellent cellular source for bone and tissue regeneration, Ono says.

The study appears in the journal Nature Communications.

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After a bone injury, shape-shifting cells rush to the rescue - University of Michigan News

Technological advancements have paved the way for many important breakthroughs in biomedical engineering. New methods are being developed, as are our understanding, diagnosing and treating of medical conditions.

Unsurprisingly, the job outlook for biomedical engineers looks promising. The US Bureau of Labor Statistics notes that employment of biomedical engineers is projected to grow four percent from 2018 to 2028, about as fast as the average for all occupations. It adds that the increasing number of technologies and applications to medical equipment and devices, along with the medical needs of a growing and ageing population, will further require the services of biomedical engineers.

If youre trained in biomedical engineering or are a graduate in a related field looking to enhance your qualifications or progress into a leadership role, you may want to consider enroling in doctoral studies in biomedical engineering.

A good place to start is Michigan State University (MSU), which has carved itself a strong reputation in the field.

Its Biomedical Engineering Department (BME) offers a competitive research-oriented doctoral programme with flexible and personalised curricula.

The department is housed in a state-of-the-art research facility and engages with faculty across several disciplines, departments and colleges to explore the intersection of medicine, human biology and engineering.

The BME department is housed within a new research facility, the Institute for Quantitative Health Science and Engineering (IQ). IQ consists of seven research divisions, i.e. biomedical devices, biomedical imaging, chemical biology, developmental and stem cell biology, neuroengineering, synthetic biology and systems biology.

The interdisciplinary research centre is devoted to basic and applied research at the interface of life sciences, engineering, information science and other physical and mathematical sciences.

Students have access to the stellar facilities and equipment at IQ, which foster extensive collaboration between researchers from different areas to solve some of the worlds most challenging biomedical problems.

This systems approach to biomedical research look set to lead to discoveries that are the first of their kind. IQ is connected to both the Clinical Center and Life Sciences buildings, establishing a biomedical research hub at MSU that holds the potential to transform medicine.

The BME department also boasts a range of expertise, including advanced imaging methods and nanotechnology in biomedical research.

Training PhD students in the biodesign process is a priority here whereby students identify significant needs for new biomedical technologies before developing commercialisable technologies that meet those needs.

MSU also provides a host of services to help students healthcare solutions make it to market.

The MSU Innovation Center houses MSU Technologies, Spartan Innovations and MSU Business CONNECT in support of entrepreneurship, facilitating technology transfer, and providing the educational and financial support to turn doctorate students research technologies into successful businesses.

Another major focus of the BME department is biomedical imaging, including the development of new nanoparticle-based combined imaging and therapeutic technologies. The IQ building has one of the few PET MRI systems in the world.

What differentiates MSU from other institutions is their new, two-semester course sequence on the development and translation of new biomedical technologies to meet clinical needs.

Named BioDesign IQ 1 and 2, these courses train BME PhD students and professional students from the colleges of medicine, law, and business to work together effectively in innovation teams. They shadow doctors, identify unmet medical needs that have significant market potential, prototype new technologies to meet those needs, and then develop intellectual property and a business plan to advance these new technologies towards commercialisation.

Apart from its stellar facilities, the university is also home to faculty with strong expertise.

For instance, inaugural IQ director and BME chairperson Christopher H Contag is a pioneer in molecular imaging and is developing imaging approaches aimed at revealing molecular processes in living subjects, including humans and the earliest markers of cancer. Through advances in detection, professionals in the field can greatly improve early detection of diseases and restoration of health. Contag was previously at Stanford University as a professor in the departments of Pediatrics, Radiology, Bioengineering, and Microbiology and Immunology.

Meanwhile, Dr Mark Worden, BME Associate Chair, has developed several interdisciplinary programmes that integrate research and education. His research on nanostructured biointerfaces and multiphase biocatalysis has resulted in over 10 patents issued or pending on technologies including microbiosensors, bioelectronics and multiphase bioreactors.

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Other faculty members doing trailblazing work in the field include Dr Dana Spence, who is investigating and dening new roles for red blood cells in autoimmune diseases such as Type 1 diabetes and multiple sclerosis; Dr Aitor Aguirre, whose research focuses on investigating regeneration and tissue re-modelling in health and disease; and Dr Ripla Arora, who is working on understanding how hormones influence the uterine luminal and glandular epithelium to modulate receptivity and implantation, to name a few.

In addition to insightful guidance from a faculty of this calibre, PhD students also enjoy 100 percent funding, including stipend, tuition and healthcare. As a graduate student in biomedical engineering, they will have the valuable opportunity to work alongside graduate students from different departments across campus.

Without a doubt, a PhD in biomedical engineering from MSU will prove to be fulfilling endeavour, professionally and personally.

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4 leading North American universities for biomedical engineering

Humanitas MEDTEC School: Where science and biomedical engineering meet

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Engineer the future of human health with a PhD in biomedical engineering - Study International News

The first squeeze of my left thumb is gentle, almost reassuring. I rate it as 0 out of 100 on the pain scale.

But as a technician ramps up pressure on the custom-made thumb-squeezing device, it becomes less pleasant. I give ratings of 2, 6 then 36. A few squeezes later, Im at 79.

At 84, Im glad the test is over as I put my tender thumb to my lips.

Ive offered myself up for a pain study at the University of Michigan, in a long, low-slung building northeast of the universitys main campus in Ann Arbor. As the day wears on, Ill undergo needle pokes, leg squeezes and an MRI scanall part of a grand bid to better understand the root cause of an individuals pain, and point to the best solutions.

Its an understanding thats sorely needed. Lucky for me, Im just a control in this experiment, and I can cry for mercy whenever I want. Thats not the case for the multitudes of people50 million in the US alonewho have ongoing, chronic pain, for whom the medical pause buttons are far from adequate.

Our treatments for chronic pain are very bad, says Richard E. Harris, a neuroscientist at the University of Michigans Chronic Pain and Fatigue Research Center and a co-researcher on the study, which should ultimately help to improve diagnoses and therapies. Today, doctors mostly define pain by where it is: the abdomen, the lower back, the joints. Then they offer up treatments, usually anti-inflammatories or opioids, that too often do nothing to the cells and molecules causing a person to hurt. A recent analysis in the Journal of the American Medical Association found that opioids reduced pain by an average of less than one point on a 10-point scale, across a variety of chronic conditions.

As part of the precision medicine movement and thanks to modern brain-imaging technology, scientists are starting to puzzle out the different types of pain: what causes them, how to diagnose them and how to prescribe treatments to match. Its an area that is far from settled. As recently as 2017, the International Association for the Study of Pain defined a new pain type, called nociplastic. Its characterized by the absence of any nerve or tissue damage in the parts that hurt.

Dan Clauw, director of the Michigan pain center, is passionate about helping people with this kind of long-misunderstood pain, which could underpin chronic conditions, such as fibromyalgia, that afflict millions. His blue eyes flash behind spectacles as he describes crisscrossing the globe to educate other physicians about nociplastic pain. Hes wearing a navy blazer and slacks when we meet for lunch between my testing sessions, because hes just returned from giving a presentation about marijuana and pain. He jokes that his colleagues wont recognize him out of his usual jeans.

Imaging the brain, along with doing prodding and poking tests of the type I endured, is beginning to point to signatures that explain the problem and suggest solutions. Eventually, this knowledge will help scientists to develop more targeted therapies, so doctors can treat patients better.

In broad strokes, pain falls into three categories: nociceptive, neuropathic and nociplastic. (Noci- is from the Latin for to do harm.)

Nociceptive pain results from inflammation or direct damage to tissues. When that torture device squeezes my thumb, for example, pain-sensing nerves notice the pressure and spring into action. They transmit messages to my spinal cord, which sends them on to my brain, telling me Ouch!

This kind of discomfort is often short-lived; mine dissipates after Ive sucked on my thumb for a few moments. Nociceptive pain can also be chronic, thoughfor example in osteoarthritis, where the cartilage in joints wears away and causes stretching of tendons and ligaments, or through the ongoing inflammation of rheumatoid arthritis.

Neuropathic pain, in contrast, happens when the pain-sensing nerves themselves are damaged or irritated, so that they send inappropriate Ow! signals to the brain. It typically results from some injury or disease, such as diabetes or shingles. It can also happen when a nerve is pinched, as in the case of carpal tunnel syndrome, when a nerve in the wrist gets squeezed. Its often long-lasting, unless the damage is repaired.

And nociplastic, the newly named type, results from no obvious inflammation or injury. Rather, its as if the volume knob for pain is turned up way too high, not at the pain site itself but further afield. Nociplastic pain seems to arise in parts of the central nervous systemthe brain or spinal cordthat receive, transmit, or process those Ouch! signals. These nerves misfire, creating a sensation of pain even though nothing may be wrong. The location of the problem, the central nervous system, is why Clauw prefers to call it central sensitization. The classic example is fibromyalgia, which causes pain that seems to stem from muscles, tendons and joints, despite the real problems lying in the brain or spinal cord.

Complicating the picture, a person might have more than one type of pain going on at the same time. In 2012, the journal Pain published a case report of a person with burning, prickling pain on both sides of the body. Treatment with pregabalin, an epilepsy medication that can also address neuropathic pain and central sensitization, relieved pain on the right side of the body, but not the left.

All this pain classifying is more than an academic exercise: It should help guide how to treat people. For example, consider a patient with knee pain. If the issue is nociceptive, anti-inflammatories or knee surgery should help. But if the problem is central, those treatments probably wont make much difference. A better bet would be medications that can directly influence the misfiring central nervous system. Some antidepressants, for example, act on the brains chemical messengersneurotransmittersthat are involved in pain, altering their signaling to quell the Ouch message.

Nondrug treatments such as acupuncture and cognitive behavioral therapy also may help because they influence how the brain perceives pain. Acupuncture boosts availability of brain receptors that respond to the bodys natural painkillers. A recent analysis in JAMA Internal Medicine of more than 6,000 people taking opioids found that treatments such as meditation, hypnosis and cognitive behavioral therapy reduced pain and diminished the drug doses needed to control it.

Though the term nociplastic is new, Clifford Woolf, a neurobiologist at Boston Childrens Hospital and Harvard Medical School, first proposed the concept in 1983. Yet the idea has been slow to catch on. In the 1990s, when Clauw began studying fibromyalgia, it was a disease so vague, so puzzling, that some physicians simply denied its existence.

Today, fibromyalgia is more likely to be accepted as a real condition. But many doctors still dont appreciate how centralized problems might underlie pain even when the symptoms look nociceptive or neuropathic, Clauw says. The distinctions between pain types are not clean: If left untreated, nociceptive pain may sensitize the nervous system, turning a temporary problem into chronic, nociplastic pain, for example. Clauw and his Michigan colleagues believe that central sensitization shows up in myriad conditions, from irritable bowel syndrome to chronic pelvic pain to dry eye disease. And in the study Ive signed up for, they want to clarify how often this happens and how doctors might detect it in patients who show up begging for pain relief.

To that end, the team has enrolled people with three different pain disorders that seem, on the surface, to be nociceptive or neuropathic. The scientists will test their pain before and after standard treatments. If the pain is in fact central, the treatments shouldnt worka disappointment for the participants, but one that might eventually lead to better understanding and treatment for them and others like them.

Two categories of subjects have what looks like nociceptive pain: those with osteoarthritis of the hip, who will receive a hip replacement, and those with inflammatory rheumatoid arthritis, who will be treated with modern medications. A third group, people with carpal tunnel syndrome, represent neuropathic pain and will get surgery to receive the pressure on the nerve.

But if Clauw and his crew are right, then some of these people will really be suffering from central sensitization, instead of or in addition to the nociceptive or neuropathic problem. Two control groups will help tease that out: People with fibromyalgia will show the researchers what pure central sensitization looks like, and those like me, with no chronic pain, will represent the non-central state.

Once all the data are in, the researchers hope that pain features shared by the people with fibromyalgia and the others whose treatments dont work will reveal a potential signature for central sensitization.

The challenge is that theres no simple blood test or X-ray that will distinguish one type of pain from another. Theres no single measure that, by itself, will represent pain, says Woolf, author of a paper in the Annual Review of Neuroscienceabout pain caused by problems in the sensory machinery. We need a composite.

To build that composite, scientists must resort to a variety of indirect measures, including responses to the pokes and prods being inflicted on me and other subjects.

This particular piece of the picture, called quantitative sensory testing or QST, measures the threshold at which a person can feel a given sensationsuch as pressure, heat or coldand when that sensation becomes painful. This can reveal how a persons nervous system deals with pain, and how that system might be off-kilter. Specific defects in nerves lead to specific changes in pain responses, helping scientists to distinguish one pain type from another.

Its simple, but revealing. For example, in the case of the thumb-press test, a person with fibromyalgia would probably start to feel pain at around four pounds of pressure. Clauw, who has no chronic pain of any stripe and is relatively pain-insensitive, says that he can handle up to about 18 pounds of pressure before it becomes uncomfortable. The average person would probably start to feel bothered at around eight pounds.

Or take a test where Im poked in the forearm with a needle. The device retracts into the handle like a Hollywood special-effects knife, so it doesnt pierce my skin, but it doesnt feel greatI rate it a 7 out of 100. Then I get 10 pokes in quick succession. That hurts more, at 32. This is a normal response, but if I had central sensitization, I would likely have found the 10-poke series much more painful.

In addition to sorting out nociceptive or neuropathic from centralized pain, QST also seems able to reveal subtypes. In research published in 2017, three European consortia performed QST on 900 people with diverse pain conditions, all considered to be neuropathic. The testing separated the subjects into three clusters, and the study authors predicted that each would be suited to different treatments.

The first cluster was characterized by deficits in sensation to touch, heat, or pokes that would normally be painful. This suggests that central sensitization might be behind the pain in some of these people, says study coauthor Nadine Attal, a pain specialist at the Assistance Publique-Hpitaux de Paris. Opioids, antiepileptics or antidepressants (used for their effects on pain nerves, not mood) might help, because they act in the brain.

The second group was defined by extreme sensitivity to hot and coldlike skin when its sunburned, which puts pain-sensing nerves on high alert. For this kind of neuropathic pain, local, numbing medications such as lidocaine, Botox or capsaicin (a therapeutic substance from hot peppers) might be the right choice.

People in the third group were particularly sensitive to pressure and pinpricks, and its members often reported pain akin to burning or electrical shock. This was a more complex group, Attal says; she thinks topical medications or antiepileptics might help. But now that researchers have the categories better defined, they can directly test medications to find what truly works best for each.

Looking at the brain in pain also can help scientists distinguish pain types, although the answers arent clear-cut. Theres no one, lone spot where pain lights up the brain, says Sean Mackey, chief of the division of pain medicine at Stanford University in California. Rather, the pain response is distributed across a circuit that encompasses several brain areas.

In the afternoon of my day as a pain-study subject, Im led to the universitys North Campus for an MRI. The technician slides me into a gray, General Electric-branded, upright donut about the size of a golf cart. The outside is festooned with frolicsome animal stickers (many subjects from other studies are children), but these do nothing to allay the discomfort of lying perfectly still with my head in a vise for an hour and a half.

As I lie there, listening to the scanners inharmonious beeps, rumbles and alien-laser-gun sounds, Im not thinking of anything in particular. Nonetheless, certain parts of my brain tend to draw blood at the same time, suggesting that theyre acting in sync. These are called networks.

One that Harris and colleagues are particularly interested in is called the default mode network. It turns on when Im at rest and my mind wanders to topics involving myself: what I had for breakfast, perhaps, or what Im planning for tonight once my day of pain is over.

Another network theyre watching is the salience network, which lights up when a person notices a new sensationsay, the squeezing of their thumbto determine which sensations are worth responding to. It includes the insula, a pyramid-shaped bit of brain that Mackey and others have linked to pain.

Normally, the insula and the default mode network are unlikely to act at the same time. But Harris and colleagues discovered that in people with fibromyalgia, they were much more likely to flash in synchrony.

That makes sense, says Rob Edwards, a pain psychologist at Harvard Medical School and Brigham and Womens Hospital in Boston. For someone living with chronic pain, the pain can become a core part of their identity. The salience-related threat intrudes on, and even takes over, the way that you think about yourself, he says.

It may be possible to undo that intrusion, though. Edwards is currently testing cognitive behavioral therapy, or CBT, in people with fibromyalgia. In no way is he suggesting that their pain, or any pain, is imaginary, but therapy can help people deal with pain better and even reduce it. Its all about enforcing a sense of control and mastery, says Bob Kerns, a pain psychologist at Yale University in New Haven, Connecticut, who coauthored a paper in the Annual Review of Clinical Psychology on psychological treatment for chronic pain.

In the study so far, CBT seems to be disentangling the salience and default mode networks in some people with fibromyalgia. Edwards predicts those people will also experience pain relief.

Being able to forecast who will benefit from a given treatment could make a huge difference not just for individual patients, but also in clinical trials for new pain-relief drugs. If scientists test a pain drug on 100 people, but only a fraction of those subjects actually have the pain mechanism the drug can treat, the medicine will look like a flopeven if its a superstar for a particular subset of patients. This has almost certainly happened in past trials, Woolf says.

Mackey envisions a future in which pain patients can be tested for the underlying problem, perhaps with the same kinds of tests I underwent at the University of Michigan, plus many more assessments. For example, scientists are analyzing nerve endings in small skin samples from pain patients, and others aim to tease out the role of genetics in chronic pain. Simple questionnaires can also help to identify pain types, all with this goal of prescribing medications tailored for a persons specific flavor of misery.

Medicine isnt quite there yetin fact, only 10 years ago Mackey would have called that scenario science fiction. Stay tuned, he says, because its no longer science fiction. . . . Were going to get there.

As required by the University of Michigan Institutional Review Board, Amber Dance was compensated $275 for her participation in the study at the Chronic Pain and Fatigue Research Center. She donated that amount to the American Chronic Pain Association.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.

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The Unexpected Diversity of Pain - Scientific American