October 29, 2015
Molecular Biology and Evolution (Oxford University Press)
By observing evolution’s ‘greatest hits’ (and misses) and the history of the major themes and patterns of genome conservation (and divergence) across many species, one scientist’s approach predicts probable mutations that will be found among people and the fate of human variation.
To gain a clearer picture of health and disease, scientists have now provided an independent reference for all human variation by looking through the evolutionary lens of our nearest relatives. Such a powerful approach has been developed by Temple University professor Sudhir Kumar and colleagues and was detailed in the advanced online publication of Molecular Biology and Evolution.
“There are two ways to generate a map of the human genome variation: one is to get genomes of all the humans and build a compilation as the 1,000 Genomes Project and others have undertaken,” said Kumar, a Temple University professor and director of the Institute for Genomics and Evolutionary Medicine (iGEM). “The alternative, which is the basis of our approach, is to compile all genome data from other species and predict what the human sequence reference should be.”
By observing evolution’s “greatest hits” (and misses) and the history of the major themes and patterns of genome conservation (and divergence) across many species, Kumar’s approach predicts probable mutations that will be found among people and the fate of human variation.
His research team relied on an evolutionary tree that included 46 vertebrate species spanning over 500 million years of life on Earth to predict the evolutionary probability (EP) of each possibility at each position of our genome. They applied their new method on all protein-coding genes in the human genome (more than 10 million positions). Consistent with the knowledge that most mutations are harmful, they found very low EPs (lower than 0.05) for a vast majority of potential mutations (94.4 percent).
Next, they produced a complete evolutionary catalog of all human protein variation, or evolutionary variome (eVar), that can be used to better understand human diseases and adaptations. And, it can be directly applied to the genomes of any other species. Their eVar was also compared against available human sequence data from the 1,000 Genomes Project to look at benign and disease mutations, and found that the use of EPs could correctly diagnose them. They also used a cancer benchmark dataset to show that EPs accurately predicted cancer-related mutations.
Lastly, they found a large number (36,691) of variations, that according to the EP data were evolutionarily improbable (EP less than 0.05), but were found 100 percent of the time in the 1,000 Genomes Project data — which Kumar suggests could be strong candidates for adaptive evolution — and what may make us uniquely human.
“The fascinating part of the story is that once we know what our ancient evolutionary history predicts our sequence to be, then we can compare this expectation to what we observe in human populations today. When there is a discordance such that an unlikely variant is found in many people, it directly indicates that something has changed about us or the protein,” said Kumar.
The above post is reprinted from materials provided byMolecular Biology and Evolution (Oxford University Press).Note: Materials may be edited for content and length.
- Li Liu, Koichiro Tamura, Maxwell Sanderford, Vanessa E. Gray, Sudhir Kumar. A Molecular Evolutionary Reference for the Human Variome. Molecular Biology and Evolution, 2015; msv198 DOI: 10.1093/molbev/msv198
Source: Molecular Biology and Evolution (Oxford University Press). “Predicting the human genome using evolution.” ScienceDaily. ScienceDaily, 29 October 2015. <www.sciencedaily.com/releases/2015/10/151029124542.htm>.
October 27, 2015
Ecole Polytechnique Fédérale de Lausanne
Researchers have discovered how intestinal worm infections cross-talk with gut bacteria to help the immune system. Intestinal worms infect over 2 billion people across the world, mostly children, in areas with poor sanitation. But despite causing serious health problems, worms can actually help the immune system of its host as an indirect way of protecting themselves, say authors of the new report.
EPFL researchers have discovered how intestinal worm infections cross-talk with gut bacteria to help the immune system.
Intestinal worms infect over 2 billion people across the world, mostly children, in areas with poor sanitation. But despite causing serious health problems, worms can actually help the immune system of its host as an indirect way of protecting themselves. The evidence for this is so strong that we are now testing worms for clinical benefits. However, very little is known about how worms interact with the host’s immune system. A new study by EPFL now shows that these effects go through the gut’s bacteria that help digestion. The work is published inImmunity.
Intestinal worms belong to a larger family of helminths, which are large multicellular parasites that can cause chronic infections in their hosts. Virtually eradicated in industrialized areas, helminths still infect billions of people.
But because of their long co-evolution with mammals, helminths have developed a close relationship with their host’s immune systems, to the point that they can regulate the host’s immune system in beneficial ways. For example, helminths can ameliorate diseases such as allergic asthma. However, very little is known about how helminths modulate the immune system, and whether or not we can exploit this to fight against diseases caused by inflammation.
The lab of Nicola Harris at EPFL has now shown that the anti-inflammatory activity of intestinal helminths involves “cross-talk” with an unexpected agent: the gut’s bacteria, also known as the “microbiome.” These are the bacteria that have been dominating nutritional news in recent years, as we are increasingly learning how much they influence a person’s metabolism, immunity, and health in general.
In this study, the researchers looked at the effects of helminths that infect pigs. After chronic infection with the helminths, they discovered that the animals’ metabolism had been changed drastically; specifically, they produced increased levels of a class of fats in the gut called “short-chain fatty acids.” These fatty acids are produced by the microbiome, and can activate a family of receptors that in turn influence the immune system. The receptors are also known to contribute to certain functions — and malfunctions — of the colon, and are even involved in modulating allergic airway disease.
This is exactly what the researchers found when they also monitored cells in the immune system of mice that had been infected with a helminth. Like the pigs, the mice showed an increased production of short-chain fatty acids. Further testing showed that these acted on the same receptors to influence specific immune cells. In short, the researchers uncovered a clear link between worm infection, microbiome, and the immune system.
The work highlights the microbiome as a new pathway through which helminths could influence the immune function of the host. “It’s not the whole story,” says Nicola Harris. “But it opens up an additional, intriguing way to explain — and perhaps exploit — the strategy with which intestinal worms communicate with the host’s immune system.”
- Nicola L. Harris et al. The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity, October 2015 DOI:10.1016/j.immuni.2015.09.012
Source: Ecole Polytechnique Fédérale de Lausanne. “Intestinal worms ‘talk’ to gut bacteria to boost immune system.” ScienceDaily. ScienceDaily, 27 October 2015. <www.sciencedaily.com/releases/2015/10/151027132835.htm>.
Findings establish critical link between structural and functional brain changes during learning
October 27, 2015
Carnegie Mellon University
Fifteen years ago, a study showed that the brains of London cab drivers had an enlargement in the hippocampus, a brain area associated with navigation. But questions remained: Did the experience of navigating London’s complex system of streets change their brains, or did only the people with larger hippocampi succeed in becoming cab drivers? Now, scientists have determined that learning detailed navigation information causes the hippocampal brain changes. The findings establish a critical link between structural and functional brain alteration.
Fifteen years ago, a study showed that the brains of London cab drivers had an enlargement in the hippocampus, a brain area associated with navigation. But questions remained: Did the experience of navigating London’s complex system of streets change their brains, or did only the people with larger hippocampi succeed in becoming cab drivers?
Now, Carnegie Mellon University scientists have determined that learning detailed navigation information causes the hippocampal brain changes. Published in NeuroImage, Tim Keller and Marcel Just show that brief navigation training changes a person’s brain tissue and improves how that changed tissue communicates with other brain areas involved with navigation. The findings establish a critical link between structural and functional brain alterations that happen during spatial learning. They also illustrate that the changes are related to how neural activity synchronizes — or communicates — between the hippocampus and other regions that are important for navigation understanding and learning.
“The hippocampus has long been known to be involved in spatial learning, but only recently has it been possible to measure changes in human brain tissues as synapses become modified during learning,” said Keller, a senior research scientist in CMU’s Department of Psychology and Center for Cognitive Brain Imaging (CCBI). “Our findings provide a better understanding of what causes the hippocampal changes and how they are related to communication across a network of areas involved in learning and representing cognitive maps of the world around us.”
To examine how the hippocampus changes, Keller and Just recruited 28 young adults with little experience playing action video games. For 45 minutes, the participants played a driving simulation game. One group practiced maneuvering along the same route 20 times. The control group drove for the same amount of time, but along 20 different routes. Before and after each training session, each participant’s brain was scanned using diffusion-weighted imaging (DWI), which measures water molecule movement in the brain, and functional magnetic resonance imaging (fMRI), which analyzes brain activity.
The researchers found that the group that practiced the same route over and over — the spatial learning group — increased their speed at completing the driving task more than the group practicing on different routes, indicating that they learned something specific about the spatial layout of the virtual environment. The spatial learning group also improved their ability to order a sequence of random pictures taken along the route and to draw a 2-D map representing the route.
Importantly, only the spatial learning group showed brain structural changes in a key spatial learning part of the hippocampus, the left posterior dentate gyrus. There also were increases in the synchronization of activity — or functional connectivity — between this region and other cortical areas in the network of brain regions responsible for spatial cognition. And, the amount of the structural change was directly related to the amount of behavioral improvement each person showed on the task.
“The new discovery is that microscopic changes in the hippocampus are accompanied by rapid changes in the way the structure communicates with the rest of the brain,” said Just, the D.O. Hebb University Professor of Psychology in the Dietrich College of Humanities and Social Sciences and director of the CCBI. “We’re excited that these results show what re-wiring as a result of learning might refer to. We now know, at least for this type of spatial learning, which area changes its structure and how it changes its communication with the rest of the brain.”
This is not the first brain research breakthrough to happen at Carnegie Mellon. CMU is the birthplace of artificial intelligence and cognitive psychology and has been a leader in the study of brain and behavior for more than 50 years. University researchers have performed some of the first mind-reading studies using fMRI, they created some of the first cognitive tutors, helped to develop the Jeopardy-winning Watson, founded a groundbreaking doctoral program in neural computation, and completed cutting-edge work in understanding the biological basis of autism. Building on its strengths in biology, computer science, psychology, statistics and engineering, CMU launched BrainHub, an initiative that focuses on how the structure and activity of the brain give rise to complex behaviors.
- Timothy A. Keller, Marcel Adam Just. Structural and functional neuroplasticity in human learning of spatial routes. NeuroImage, 2015; DOI: 10.1016/j.neuroimage.2015.10.015
Source: Carnegie Mellon University. “Mental maps: Route-learning changes brain tissue: Findings establish critical link between structural and functional brain changes during learning.” ScienceDaily. ScienceDaily, 27 October 2015. <www.sciencedaily.com/releases/2015/10/151027123859.htm>.
October 26, 2015
University of Vermont
In the past, whales, giant land mammals, and other animals played a vital role in keeping the planet fertile by transporting nutrients via their feces. However, massive declines and extinctions of many of these animals has deeply damaged this planetary nutrient recycling system, threatening fisheries and ecosystems on land, a team of scientists reports.
Giants once roamed the earth. Oceans teemed with ninety-foot-long whales. Huge land animals–like truck-sized sloths and ten-ton mammoths–ate vast quantities of food, and, yes, deposited vast quantities of poop.
A new study shows that these whales and outsized land mammals–as well as seabirds and migrating fish–played a vital role in keeping the planet fertile by transporting nutrients from ocean depths and spreading them across seas, up rivers, and deep inland, even to mountaintops.
However, massive declines and extinctions of many of these animals has deeply damaged this planetary nutrient recycling system, a team of scientists reported October 26 in theProceedings of the National Academy of Sciences.
“This broken global cycle may weaken ecosystem health, fisheries, and agriculture,” says Joe Roman, a biologist at the University of Vermont and co-author on the new study.
On land, the capacity of animals to carry nutrients away from concentrated “hotspots,” the team writes, has plummeted to eight percent of what it was in the past–before the extinction of some 150 species of mammal “megafauna” at the end of the last ice age.
And, largely because of human hunting over the last few centuries, the capacity of whales, and other marine mammals, to move one vital nutrient–phosphorus–from deep ocean waters to the surface has been reduced by more than seventy-five percent, the new study shows.
“Previously, animals were not thought to play an important role in nutrient movement,” said lead author Christopher Doughty, an ecologist at the University of Oxford.
But the new study shows that animals are a crucial “distribution pump,” the scientists write, transporting masses of fecal matter to fertilize many places that would otherwise be less productive, including ocean surface waters and the interior of continents.
These fertilized ecosystems, in turn, maintain natural functions vital to people. For example, the new study notes that restoring whale populations could help increase the ocean’s capacity to absorb climate-warming carbon dioxide.
Traditionally, scientists studying nutrient cycling have focused on weathering of rocks and nitrogen collection by bacteria–largely ignoring animals. This view assumed that the role of animals was minor, and mostly that of a passive consumer of nutrients. “However, this notion may be a peculiar world view that comes from living in an age where the number and size of animals have been drastically reduced from their former bounty,” the team of nine scientists write.
“This study challenges the bottom-up bias that some scientists have–that microbes are running the show, and phytoplankton and plants are all that matter,” says Joe Roman, a whale expert in UVM’s Rubenstein School of Environment and Natural Resources and the Gund Institute for Ecological Economics.
“This once was a world that had ten times more whales; twenty times more anadromous fish, like salmon; double the number of seabirds; and ten times more large herbivores–giant sloths and mastodons and mammoths,” says Roman.
On land, before the rise of modern humans, there were elephant-like gomphotheres the size of a backhoe, deer with twelve-foot wide antlers, and bison herds to the horizon. These were just a few of the huge animals that could eat huge amounts of plant matter, accelerating the release of nutrients through digestion and carrying these nutrients away from feeding areas to higher ground through their deposit of feces, urine and, upon death, decomposing bodies.
Overall, the scientists calculate that this animal-powered, planetary pump may have dropped to just six percent of its former capacity to spread nutrients away from concentrated sources on both land and sea.
A series of recent studies show that large animals appear to disproportionately drive nutrient movements. To make their new study, the team–including scientists from University of Oxford, University of Vermont, Harvard University, Aarhus University in Denmark, Princeton University, Netherlands Institute of Ecology, and Purdue University–used these findings and other existing data about historic and current animal populations. Then they applied a set of mathematical models to estimate the movement of nutrients vertically in the oceans and across the land–and how this movement changed with extinctions and declining animal populations.
For example, whale densities are estimated to have declined by between 66% and 90% over the last three centuries due to commercial hunting, the study notes. Most grievously, 350,000 blue whales, many over one hundred tons, used to inhabit oceans around the globe. Only a few thousand now remain. These and other great whales feed in the depths–and then defecate at the sun-lit surface “in a flocculent, liquidy cloud,” says Roman.
In particular, the new study examined phosphorus, a nutrient critical for plant growth. Prior to the era of commercial hunting, the scientists estimate that whales and other marine mammals annually moved around 750 million pounds of phosphorus from the depths to the surface. Now that figure is about 165 million pounds–some 23% of former capacity.
The team also gathered data on seabird and fish populations that feed in the sea and then come onto land–like ocean-going salmon that move up rivers to defecate, spawn, and die. Movements by these birds and fish once carried more than 300 million pounds of phosphorus onto land each year, but that number has declined to less than four percent of past values as a result of destroyed seabird colonies, habitat loss, and overfishing.
“Phosphorus is a key element in fertilizers and easily accessible phosphate supplies may run out in as little as fifty years,” says Oxford’s Chris Doughty. “Restoring populations of animals to their former bounty could help to recycle phosphorus from the sea to land, increasing global stocks of available phosphorus in the future.”
The world of giants came to an end on land after the megafauna extinctions that began some 12,000 years ago–driven by a complex array of forces including climate change and Neolithic hunters. And it ended in the oceans in the wake of whale and other mammal hunting in the industrial era of humans.
“But recovery is possible and important,” says UVM’s Roman. He points to bison as an example. “That’s achievable. It might be a challenge policy-wise, but it’s certainly within our power to bring back herds of bison to North America. That’s one way we could restore an essential nutrient pathway.”
And many whale and marine mammal populations are also recovering, Roman notes. “We can imagine a world with relatively abundant whale populations again,” he says.
But have domestic animals, like cows, taken over the nutrient distribution role of now-extinct large land animals? No, the new study shows. Though there are many cows, fences constrain the movement of domestic animals and their nutrients. “Future pastures could be set up with fewer fences and with a wider range of species,” the team writes.
“The typical flow of nutrients is down mountains to the oceans,” says Joe Roman. “We are looking at ways that nutrients can go in the other direction–and that’s largely through foraging animals. They’re bringing nutrients from the deep sea that could eventually reach a mountain in British Columbia.”
- Christopher E. Doughty, Joe Roman, Søren Faurby, Adam Wolf, Alifa Haque, Elisabeth S. Bakker, Yadvinder Malhi, John B. Dunning Jr., and Jens-Christian Svenning. Global nutrient transport in a world of giants. PNAS, October 26, 2015 DOI: 10.1073/pnas.1502549112
Source: University of Vermont. “Declines in whales, fish, seabirds and large animals disrupt Earth’s nutrient cycle.” ScienceDaily. ScienceDaily, 26 October 2015. <www.sciencedaily.com/releases/2015/10/151026172050.htm>.
2015 NORD Meeting
Last week, Target Health attended the NORD annual meeting, held in Crystal City, VA and participated on a Panel entitled The Path to Progress – Rise in Orphan Drug Approvals and Breakthrough Designations. The Panel was chaired by Dr. Gayatri Rao, Director Office of Orphan Products Development and Panel members included, in addition to Dr. Jules Mitchel, President of Target Health, Dr. Peter Marks, Deputy Director, CBER; Dr. Jeff Allen, Executive Director, Friends of Cancer Research and Dr. Amit Sachdev, Executive Vice President, Policy, Access and Value, Vertex Pharmaceuticals.
The meeting was attended by over 400 participants with a major presence by patients, patient advocates and FDA and was inspirational.
Quality by Design (QbD) and Risk-based Monitoring Presentation at CBI Conference
On November 5-6, 2015, at Hilton Philadelphia City Avenue, Dr. Jules Mitchel, President of Target Health will be presenting a Case Study on Risk-Based Approaches to Clinical Trial Management. Here is a summary:
The best risk-based clinical monitoring plan starts with a well-designed protocol and if followed properly, assures patient safety and data quality. Monitoring of a trial includes risk-mitigation strategies with the understanding that not all risks have equal weight. The FDA wants to know if informed consent was obtained properly. Was the protocol followed? How was the protocol monitored? Were critical safety issues reported? Was the investigational product used as instructed? This case study will show: how risk-based trial management (and monitoring) begins with the protocol and underscores the definition of quality as the absence of errors that matter and are the data fit for purpose. The case study will also analyze metrics derived from actual studies ranging from small single center studies to studies as large as 1,000 subjects at 40 clinical sites. Dr. Mitchel will present results from a recent FDA inspection of a study using RBM where sites entered data in real time into EDC, with no paper records.
ON TARGET is the newsletter of Target Health Inc., a NYC – based, full – service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.
For more information about Target Health contact Warren Pearlson (212 – 681 – 2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Parkinson’s Disease: The Nose Knows – (fill in the blanks)
Dr. Les Milne and his wife Joy
Smelling Parkinson’s disease before symptoms appear
A Scottish anesthesiologist, Les Milne, who worked long hours, began emitting a subtle musky 1) ___. His wife with a keen sense of smell, Joy Milne, assumed the smell was just sweat. But with the change in scent came a growing tiredness that was explained by a devastating diagnosis six years later, of Parkinson’s disease. When Joy Milne attended a meeting for the charity, Parkinson’s UK, attended by doctors and Parkinson’s patients, she noticed that the patients in the audience, shared her husband’s musky scent, and realized that the odor might be tied to the 2) ___. She mentioned this observation to a few scientists and they decided to investigate, on new skin odor tests to detect Parkinson’s disease (PD). As a result, Parkinson’s UK and the Manchester Institute of Biotechnology are investigating new 3) ___ odor tests to diagnose Parkinson’s disease earlier.
Researchers at the University of Edinburgh gave T-shirts to six people with Parkinson’s and six people without the disease. After the subjects wore the shirts, they were passed on to Joy Milne, who then had to determine by 4) ___ whether each wearer had Parkinson’s. Her diagnoses were eerily accurate – and have potentially groundbreaking implications for people living with 5) ___ disease (PD). Milne made correct assessments for 11 out of the 12 cases. In the one case she got wrong, she insisted that a T-shirt worn by a member of the control group had the warning scent. Eight months after the study was conducted, she was proven right, bringing her accuracy rate up to one hundred. The supposedly healthy individual contacted one of the doctors and informed him that he had, in fact, just been diagnosed with Parkinson’s.
That really impressed us, said, Edinburgh University scientist Tilo Kunath, We had to dig further into this phenomenon. Intrigued by Joy Milne’s abilities as a super-smeller, scientists at the universities of Manchester, Edinburgh and London are undertaking a project to identify differences in the skin 6) ___ of people with Parkinson’s, study sponsor Parkinson’s UK announced this week. Scientists believe that people with early Parkinson’s, experience skin changes that produce a particular odor. If they find the molecular signature responsible for the smell, it may be possible to develop a diagnostic test for Parkinson’s as simple as swabbing a person’s forehead. As our understanding of it stands now, the disease is incredibly difficult to diagnose. Doctors still rely on an observational technique developed in the early 1800s. There is currently no cure for Parkinson’s, a degenerative disorder of the central 7) ___ system which causes shaking, slowness of movement and difficult walking as well as behavioral problems like dementia and depression.
Arthur Roach, the director of research at Parkinson’s UK, said in a BBC announcement this week, that in addition to having a huge impact on diagnostic procedures, The research would also make it a lot easier to identify people with the disease and to test drugs that may have the potential to slow, or even stop Parkinson’s, something no current 8) ___ can achieve. Source: The Washington Post, October 2015, by Yanan Wang
ANSWERS: 1) odor; 2) disease; 3) skin; 4) smell; 5) Parkinson’s; 6) chemicals; 7) nervous; 8) drug
James Parkinson MD (1755-1824)
Illustration of Parkinson’s disease by William Richard Gowers, which was first published in A Manual of Diseases of the Nervous System (1886)
Several early sources, including an Egyptian papyrus, an Ayurvedic medical treatise, the Bible, and Galen’s writings, describe symptoms resembling those of Parkinson’s disease (PD). After Galen there are no references unambiguously related to PD until the 17th century. In the 17th and 18th centuries, several authors wrote about elements of the disease, including Sylvius, Gaubius, Hunter and Chomel.
In 1817 an English doctor, James Parkinson, published his essay reporting six cases of paralysis agitans. An Essay on the Shaking Palsy described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time. Early neurologists who made further additions to the knowledge of the disease include Trousseau, Gowers, Kinnier, Wilson and Erb, and most notably Jean-Martin Charcot, whose studies between 1868 and 1881 were a landmark in the understanding of the disease. Among other advances, he made the distinction between rigidity, weakness and bradykinesia. He also championed the renaming of the disease in honor of James Parkinson.
In 1912 Frederic Lewy described microscopic particles in affected brains, later named Lewy bodies. In 1919 Konstantin Tretiakoff reported that the substantia nigra was the main cerebral structure affected, but this finding was not widely accepted until it was confirmed by further studies published by Rolf Hassler in 1938. The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Arvid Carlsson on the neurotransmitter dopamine and Oleh Hornykiewicz on its role on PD. In 1997, alpha-synuclein was found to be the main component of Lewy bodies by Spillantini, Trojanowski, Goedert and others.
Anticholinergics and surgery (lesioning of the corticospinal pathway or some of the basal ganglia structures) were the only treatments until the arrival of levodopa, which reduced their use dramatically. Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid-20th century. It entered clinical practice in 1967 and brought about a revolution in the management of PD. By the late 1980s deep brain stimulation introduced by Alim-Louis Benabid and colleagues at Grenoble, France, emerged as a possible treatment.
James Parkinson FGS (11 April 1755 – 21 December 1824) was an English surgeon, apothecary, geologist, paleontologist, and political activist. He is most famous for his 1817 work, An Essay on the Shaking Palsy in which he was the first to describe paralysis agitans, a condition that would later be renamed Parkinson’s disease by Jean-Martin Charcot. James Parkinson was born in Shoreditch, London, England. He was the son of John Parkinson, an apothecary and surgeon practicing in Hoxton Square in London. He was the oldest of three siblings, which included his brother William and his sister Mary Sedgewood. In 1784 Parkinson was approved by the City of London Corporation as a surgeon. On 21 May 1783, he married Mary Dale, with whom he subsequently had eight children; two did not survive past childhood. Soon after he was married, Parkinson succeeded his father in his practice in 1 Hoxton Square. He believed that any worthwhile surgeon should know shorthand, at which he was adept. In addition to his flourishing medical practice, Parkinson had an avid interest in geology and paleontology, as well as the politics of the day. Parkinson was a strong advocate for the under-privileged, and an outspoken critic of the Pitt-government. His early career was marred by his being involved in a variety of social and revolutionary causes, and some historians think it most likely that he was a strong proponent for the French Revolution. He published nearly twenty political pamphlets in the post-French Revolution period, while Britain was in political chaos. Writing under his own name and his pseudonym Old Hubert, he called for radical social reforms and universal suffrage.
Parkinson called for representation of the people in the House of Commons, the institution of annual parliaments, and universal suffrage. He was a member of several secret political societies, including the London Corresponding Society and the Society of Constitutional Information. In 1794 his membership in the organization led to his being examined under oath before William Pitt and the Privy Council to give evidence about a trumped-up plot to assassinate King George III. He refused to testify regarding his part in the popgun plot, until he was certain he would not be forced to incriminate himself. The plan was to use a poisoned dart fired from a pop-gun to bring the king’s reign to a premature conclusion. No charges were ever brought against Parkinson but several of his friends languished in prison for many months before being acquitted.
First page of Parkinson’s classical essay on shaking palsy
Parkinson turned away from his tumultuous political career, and between 1799 and 1807 published several medical works, including a work on gout in 1805. He was also responsible for early writings on ruptured appendix in English medical literature. Parkinson was also interested in improving the general health and well-being of the population. He wrote several medical doctrines that exposed a similar zeal for the health and welfare of the people that was expressed by his political activism. He was a crusader for legal protection for the mentally ill, as well as their doctors and families. In 1812 Parkinson assisted his son with the first described case of appendicitis in English, and the first instance in which perforation was shown to be the cause of death. Parkinson was the first person to systematically describe six individuals with symptoms of the disease that bears his name. In his An Essay on the Shaking Palsy, he reported on three of his own patients and three persons who he saw in the street. He referred to the disease that would later bear his name as paralysis agitans, or shaking palsy. He distinguished between resting tremors and the tremors with motion. Jean-Martin Charcot coined the term Parkinson’s disease some 60 years later. Parkinson erroneously predicted that the tremors in these patients were due to lesions in the cervical spinal cord.
Fossilized turtle, puppigerus, found in the London Clay on the Isle of Sheppey and named for Parkinson, in a collection at Teylers Museum
Parkinson’s interest gradually turned from medicine to nature, specifically the relatively new field of geology, and paleontology. He began collecting specimens and drawings of fossils in the latter part of the eighteenth century. He took his children and friends on excursions to collect and observe fossil plants and animals. His attempts to learn more about fossil identification and interpretation were frustrated by a lack of available literature in English, and so he took the decision to improve matters by writing his own introduction to the study of fossils. In 1804, the first volume of his Organic Remains of a Former World was published. Gideon Mantell praised it as the first attempt to give a familiar and scientific account of fossils. A second volume was published in 1808, and a third in 1811. Parkinson illustrated each volume and his daughter Emma colored some of the plates. The plates were later re-used by Gideon Mantell. In 1822 Parkinson published the shorter Elements of Oryctology: an Introduction to the Study of Fossil Organic Remains, especially of those found in British Strata. Parkinson also contributed several papers to William Nicholson’s A Journal of Natural Philosophy, Chemistry and the Arts, and in the first, second, and fifth volumes of the Geological Society’s Transactions. He wrote a single volume ‘Outlines of Orytology’ in 1822, a more popularized work.
On 13 November 1807, Parkinson and other distinguished gentlemen met at the Freemasons’ Tavern in London. The gathering included such great names as Sir Humphry Davy, Arthur Aikin and George Bellas Greenough. This was to be the first meeting of the Geological Society of London. Parkinson belonged to a school of thought, Catastrophism, that concerned itself with the belief that the Earth’s geology and biosphere were shaped by recent large-scale cataclysms. He cited the Noachian deluge of Genesis as an example, and he firmly believed that creation and extinction were processes guided by the hand of God. His view on Creation was that each ‘day’ was actually a much longer period that lasted perhaps tens of thousands of years in length.
Parkinson died on 21 December 1824 after a stroke that interfered with his speech, bequeathing his houses in Langthorne to his sons and wife and his apothecary’s shop to his son, John. His collection of organic remains was given to his wife and much of it went on to be sold in 1827, a catalogue of the sale has never been found. He was buried at St. Leonard’s Church, Shoreditch. Parkinson’s life is commemorated with a stone tablet inside the church of St Leonard’s, Shoreditch, where he was a member of the congregation; the exact site of his grave is not known and his body may lie in the crypt or in the churchyard. In addition, a blue plaque at 1 Hoxton Square, marks the site of his home. Several fossils were also named after him. There is no known portrait of him: a photograph, sometimes published and identified as Dr. James Parkinson, is of a dentist of the same name. The better known, James Parkinson died before photography was invented. World Parkinson’s Dayis held each year on his birthday, 11 April.
A photograph of Jean-Martin Charcot, who made important contributions to the understanding of the disease and proposed its current name honoring James Parkinson.
Nuclear Transport Problems Linked to ALS and FTD
DNA is made up of building blocks called nucleotides. In the mutated C9orf72 gene, a sequence of six nucleotides is repeated many times more than are typical. These repetitive stretches of DNA produce RNA molecules that can interfere with proteins in the cell. The RNA also generates toxic proteins called dipeptide repeat proteins. However, until now, it was unknown what specific cellular systems were impaired by these two products of the mutation.
Both amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are caused by the death of specific neurons. In ALS, this leads to movement difficulties and eventually paralysis, while in FTD, patients experience problems with language and decision making. Past research has connected a specific mutation in the C9orf72 gene to 40% of inherited ALS cases and 25% of inherited FTD cases, as well as nearly 10% of non-inherited cases of each disorder. Recent experiments, conducted in yeast, fruit flies, and neurons from patients, found that the mutation prevents proteins and RNA from moving between the nucleus and the cytoplasm that surrounds it.
According to an article published in Nature (25 August 2015), 3 teams of scientists supported by the National Institutes of Health showed that a genetic mutation in the C9orf72 gene may destroy neurons by disrupting the movement of materials in and out of the cell’s nucleus. The results, provide a possible strategy for treating the two diseases. Evidence that the mutation impairs nuclear transport in neurons was derived from skin cells grown from patients. One team showed that these neurons have much more RNA in the nucleus compared to those created from healthy control cells, implying that the mutation prevents RNA from leaving the nucleus. The other two groups discovered that the patient-derived neurons had trouble bringing certain proteins into the nucleus as well. One group of investigators focused on how the abnormal RNA produced by the C9orf72 mutation affects a protein called RanGAP, which is essential for transporting materials into the nucleus. Building on previous work, the group confirmed that the RNA strands bind to RanGAP in brain tissue from patients with the mutation and stop the protein from performing its function. The team then treated those cells with compounds that prevented this interference and found that this eliminated the transport defect, allowing proteins to get inside the nucleus. Similarly, increasing production of RanGAP in fruit flies reduced neuronal deterioration and motor problems caused by the mutation.
In addition to the work with the lab-grown neurons, one team explored the mutation’s effects by inserting eight, 28, or 58 copies of the repetitive DNA sequence into fruit fly neurons. By doing this it was found that additional copies caused more harm to the cells. The group then performed a genetic screen in which they systematically mutated other fly genes to find ones that increased or decreased this damage. Many of the genes they found code for nuclear transport proteins, which regulate the movement of molecules in and out of the nucleus. The authors noted that they were amazed to find 18 genes that relate to nucleocytoplasmic trafficking, and that this indicated that they were on to something very important.
Taken together, the three studies suggest that therapies designed to increase nucleocytoplasmic transport may be effective for treating some forms of ALS and FTD.
PINK1 Protein Crucial for Removing Damaged Mitochondria
Cells are powered by tiny energy reactors called mitochondria. When damaged, they leak destructive molecules that can cause substantial harm and eventually kill brain cells. According to an article published in Nature (12 August 2015), it was shown that a protein called PINK1, that is implicated in Parkinson’s disease, is critical for helping cells get rid of dysfunctional mitochondria. According to the new research, PINK1 does this by triggering an intricate process called mitophagy that breaks down and removes damaged mitochondria from the cell.
Mutations in PINK1 and its partner molecule Parkin cause hereditary forms of Parkinson’s disease (PD). Moreover, the inability to remove defective mitochondria from nerve cells has been linked to numerous neurodegenerative diseases, including the more common forms of PD and amyotrophic lateral sclerosis (ALS). It was previously considered that Parkin was essential to destroy damaged mitochondria, but the new research discovered that PINK1 can initiate this process without Parkin.
Study results showed that PINK1 recruits two proteins called Optineurin and NDP52 to the surface of mitochondria. These proteins, in turn, recruit a variety of other protein molecules that mark the mitochondria for degradation. Optineurin and NDP52 are members of a group of proteins called autophagy receptors. When cells were created that contained no autophagy receptors, it was found that the cells could not dispose of malfunctioning mitochondria. However, when the function of either Optineurin or NDP52 was restored, the cells regained this ability. Reinstating other autophagy receptors had little or no effect.
According to the authors, knowing that Optineurin and NDP52 are the primary autophagy receptors involved in this process can inform about the cause of different human diseases. For example, Optineurin is mutated in ALS and also in certain forms of glaucoma, whereas NDP52 is known to be mutated in Crohn’s disease. This suggests that problems with mitophagy may be involved in those diseases.
When PINK1 accumulates on the surface of defective mitochondria, it alters a molecule called ubiquitin. The modified ubiquitin then recruits autophagy receptors as well as Parkin. Parkin promotes mitophagy by bringing more ubiquitin to the mitochondria to form long chains that flag damaged mitochondria for removal. Since PINK1 is needed to start building these ubiquitin chains, the current observations suggest a new avenue for creating drugs that treat disease by boosting the disposal of damaged mitochondria.
A number of companies are trying to develop drugs to activate this pathway and some are trying to find drugs that activate Parkin. However, this new model might suggest a different strategy where it may not be so important to activate Parkin, but more important to activate PINK1.”
FDA Approves Drug for Perinatal, Infantile and Juvenile-Onset Hypophosphatasia (HPP)
Perinatal, infantile and juvenile-onset hypophosphatasia (HPP) is a rare, genetic, progressive, metabolic disease in which patients experience devastating effects on multiple systems of the body, leading to severe disability and life-threatening complications. It is characterized by defective bone mineralization that can lead to rickets and softening of the bones that result in skeletal abnormalities. It can also cause complications such as profound muscle weakness with loss of mobility, seizures, pain, respiratory failure and premature death. Severe forms of HPP affect an estimated one in 100,000 newborns, but milder cases, such as those that appear in childhood or adulthood, may occur more frequently.
The FDA this past week approved Strensiq (asfotase alfa) as the first approved treatment for perinatal, infantile and juvenile-onset HPP. According to FDA, for the first time, the HPP community will have access to an approved therapy for this rare disease. Strensiq’s approval is an example of how the Breakthrough Therapy Designation program can bring new and needed treatments to people with rare diseases. Strensiq received a breakthrough therapy designation as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. The Breakthrough Therapy Designation program encourages the FDA to work collaboratively with sponsors, by providing timely advice and interactive communications, to help expedite the development and review of important new drugs for serious or life-threatening conditions. In addition to designation as a breakthrough therapy, the FDA granted Strensiq orphan drug designation because it treats a disease affecting fewer than 200,000 patients in the United States. Orphan drug designation provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Strensiq was also granted priority review, which is granted to drug applications that show a significant improvement in safety or effectiveness in the treatment of a serious condition. In addition, the manufacturer of Strensiq was granted a rare pediatric disease priority review voucher – a provision intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. Development of this drug was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.
Strensiq is administered via injection three or six times per week and works by replacing the enzyme (known as tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes. The safety and efficacy of Strensiq were established in 99 patients with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that patients with perinatal- and infantile-onset HPP treated with Strensiq had improved overall survival and survival without the need for a ventilator (ventilator-free survival). 97% of treated patients were alive at one year of age compared to 42% of control patients selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85% for treated patients compared to less than 50% for the natural history control patients.
In the clinical trial, patients with juvenile-onset HPP treated with Strensiq showed improvements in growth and bone health compared to control patients selected from a natural history database. All treated patients had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20% of control patients had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. Juvenile-onset patients also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. All treated patients demonstrated substantial healing of rickets on x-rays while some natural history control patients showed increasing signs of rickets over time. The most common side effects in patients treated with Strensiq include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.
Strensiq is manufactured by Alexion Pharmaceuticals Inc., based in Cheshire, Connecticut