Target Health at the UN
This past week, it was an honor for Dr. Jules Mitchel to be part of a panel at the 65th Annual UN DPI/NGO Conference on the topic of Antibiotic Resistance and Obsolescence: Meeting The Major Infectious Disease Challenge For Post-2015. Dr. Mitchel is an Advisor to The Institute for Life Sciences Collaboration (ILSC), one of the co-Sponsors of the panel. The Moderator of the panel was Ambassador John E. Lange (retired), Senior Fellow of Global Health and Diplomacy, United Nations Foundation.
The panel discussed the global challenges and possible solutions to the lack of new antibiotics. Topics included the history of antibiotic research and discovery, new FDA rules to speed the delivery of antibiotics, antibiotics in the course of pediatric care, global perspectives and proposed new guidelines by the White House.
Mitchel’s View from the Podium Dr. Chu, Dr. Mitchel, AMB. Lange (retired) Dr. Chu, AMB. Lange (retired)
Panel participants included:
1. Dr. May C. Chu, Assistant Director of Public Health in the Office for Science and Technology Policy(OSTP)/Executive Office of the President of the United States
2. Dr. Allan R. Goldberg, President and CEO, Avacyn Pharmaceuticals, Inc.
3. Jonathan Lourie, Esq., Partner in the law firm of Duane Morris LLP and intellectual property expert
4. Dr. Jules T. Mitchel, President of Target Health Inc.
5. Dr. Elijah Paintsil, Associate Professor of Pediatrics Infectious Diseases and Pharmacology at Yale School of Medicine
6. Dr. Pilar Ramon-Pardo, Regional Advisor on Clinical Management of Infectious Diseases and Antimicrobial Resistance Surveillance at the Pan American Health Organization (PAHO)
7. Dr. Eric A. Utt, Director in the Pfizer Global Policy Center of Excellence
Discussant/Rapporteur: Dr. Reza Naghavi, Medical Director and Board Member of Global Associates for Health Development
Bee Pollinating Hybrid Zinnia
Our friend and colleague, James Farley, Clinical Data Manager at TransTech Pharma LLC and subscriber to ON TARGET newsletter, has shared another fantastic photo with us! He tells us, The bees were covering these Hybrid Zinnias and I couldn’t resist capturing the beauty! When our CEO, Joyce Hays, saw this photo, she exclaimed, This is beyond beautiful!
Bee pollinating Hybrid Zinnia, Greensboro, NC ©JFarleyPhotography.com
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
Your Second Brain
Underlying the sensation of butterflies in the stomach or a gut feeling about something, is an often-overlooked network of 1) ___ lining our guts that is so extensive some scientists have nicknamed it our second brain. A deeper understanding of this mass of neural tissue, filled with important neurotransmitters, is revealing that it does much more than merely handle digestion or inflict the occasional nervous pang. The brain in our innards, in connection with the big one in our skulls, partly determines our mental state and plays key roles in certain diseases throughout the 2) ___.
Although its influence is far-reaching, the second brain is not the seat of any conscious thoughts or decision-making. Or, at least at this time, it’s not thought to. So far, the second brain doesn’t help with the great thought processes: religion, philosophy and poetry is left to the brain in the head, says Michael Gershon, chairman of the Department of Anatomy and Cell Biology at New York-Presbyterian Hospital/Columbia University Medical Center, an expert in the nascent field of neurogastroenterology and author of The Second Brain (HarperCollins).
Technically known as the enteric nervous 3) ___, the second brain consists of sheaths of neurons embedded in the walls of the long tube of our gut, or alimentary canal, which measures about nine meters end to end from the esophagus to the anus. The second brain contains some 100 million neurons, more than in either the spinal cord or the peripheral nervous system, Gershon says. This multitude of neurons in the enteric 4) ___ system enables us to feel the inner world of our gut and its contents. Much of this neural firepower comes to bear in the elaborate daily grind of digestion. Breaking down food, absorbing nutrients, and expelling of waste requires chemical processing, mechanical mixing and rhythmic muscle contractions that move everything on down the line. Thus equipped with its own reflexes and senses, the second brain can control gut behavior independently of the brain, Gershon says. We likely evolved this intricate web of nerves to perform digestion and excretion on site, rather than remotely from our brains through the middleman of the spinal cord. The brain in the head doesn’t need to get its hands dirty with the messy business of digestion, which is delegated to the brain in the 5) ___, Gershon says. He and other researchers explain, however, that the second brain’s complexity likely cannot be interpreted through this process alone.
The system is way too complicated to have evolved only to make sure things move out of your colon, says Emeran Mayer, professor of physiology, psychiatry and biobehavioral sciences at the David Geffen School of Medicine at the University of California, Los Angeles (U.C.L.A.). For example, scientists were shocked to learn that about 90% of the fibers in the primary visceral nerve, the 6) ___, carry information from the gut to the brain and not the other way around. Some of that info is decidedly unpleasant, Gershon says.
The second brain informs our state of mind in other more obscure ways, as well. A big part of our emotions are probably influenced by the 7) ___ in our gut, Mayer says. Butterflies in the stomach – signaling in the gut as part of our physiological stress response, Gershon says – is but one example. Although gastrointestinal (GI) turmoil can sour one’s moods, everyday emotional well-being may rely on messages from the brain below to the brain above. For example, electrical stimulation of the vagus nerve – a useful treatment for depression – may mimic these signals, Gershon says.
Given the two brains’ commonalities, other depression treatments that target the mind can unintentionally impact the gut. The enteric nervous system uses more than 30 neurotransmitters, just like the brain, and in fact 95% of the body’s serotonin is found in the bowels. Because antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels, it’s little wonder that meds meant to cause chemical changes in the mind often provoke GI issues as a side effect. Irritable bowel syndrome – which afflicts more than two million Americans – also arises in part from too much serotonin in our entrails, and could perhaps be regarded as a mental illness of the second 8) ___. Scientists are learning that the serotonin made by the enteric nervous system might also play a role in more surprising diseases: In a medical study a drug that inhibited the release of serotonin from the gut counteracted the bone-deteriorating disease osteoporosis in postmenopausal rodents. It was totally unexpected that the gut would regulate bone mass to the extent that one could use this regulation to cure?at least in rodents?osteoporosis, says Gerard Karsenty, lead scientist of the study and chair of the Department of Genetics and Development at Columbia University Medical Center.
9) ___ seeping from the second brain might even play some part in autism, the developmental disorder often first noticed in early childhood. Gershon has discovered that the same genes involved in synapse formation between neurons in the brain are involved in the alimentary synapse formation. If these genes are affected in autism, he says, it could explain why so many kids with autism have GI motor abnormalities in addition to elevated levels of gut-produced serotonin in their blood. Down the road, the blossoming field of neurogastroenterology will likely offer some new insight into the workings of the second brain – and its impact on the body and mind. We have never systematically looked at [the enteric nervous system] in relating lesions in it to diseases like they have for the central nervous system, Gershon says. One day, perhaps there will be well-known connections between diseases and lesions in the gut’s nervous system as some in the brain and spinal cord today indicate multiple sclerosis.
Cutting-edge research is currently investigating how the second brain mediates the body’s immune response; after all, at least 70% of our immune system is aimed at the gut to expel and kill foreign invaders. U.C.L.A.’s Mayer is doing work on how the trillions of bacteria in the gut communicate with 10) ___ nervous system cells (which they greatly outnumber). His work with the gut’s nervous system has led him to think that in coming years psychiatry will need to expand to treat the second brain in addition to the one atop the shoulders.
ANSWERS: 1) neurons; 2) body; 3) system; 4) nervous; 5) gut; 6) vagus; 7) nerves; 8) brain; 9) Serotonin; 10) enteric
Otto Loewi MD (1873-1961)
Otto Loewi was a German-born pharmacologist whose discovery of acetylcholine helped enhance medical therapy. The discovery earned for him the Nobel Prize in Physiology or Medicine in 1936 which he shared with Sir Henry Dale, whom he met in 1902 when spending some months in Ernest Starling’s laboratory at University College, London. He has been referred to as the Father of Neuroscience.
Born in Frankfurt, Germany on June 3, 1873, Otto Loewi studied medicine at the University of Strasbourg (then part of Germany) in 1891, where he attended courses by famous professors Gustav Schwalbe, Oswald Schmiedeberg, and Bernhard Naunyn among others. He received his medical doctoral degree in 1896. He also was a member of the fraternity Burschenschaft Germania Strassburg. During 1897-1898 he was assistant to Carl von Noorden, clinician at the City Hospital in Frankfurt. Soon, however, after seeing the high mortality in countless cases of far-advanced tuberculosis and pneumonia, left without any treatment because of lack of therapy, he decided to drop his intention to become a clinician and instead to carry out research in basic medical science, in particular pharmacology.
In 1898, he became an assistant of Professor Hans Horst Meyer, the renowned pharmacologist at the University of Marburg. During his first years in Marburg, Loewi’s studies were in the field of metabolism. As a result of his work on the action of phlorhizin, a glucoside provoking glycosuria, and another one on nuclein metabolism in man, he was appointed Privatdozent (Lecturer) in 1900. Two years later he published his paper Uber Eiweisssynthese im Tierkorper (On protein synthesis in the animal body), proving that animals are able to rebuild their proteins from their degradation products, the amino acids – an essential discovery with regard to nutrition.
In 1902 Loewi was a guest researcher in Ernest Starling’s laboratory in London, where he met his lifelong friend Henry Dale. In 1903, he accepted an appointment at the University of Graz in Austria, where he would remain until being forced out of the country in 1938. In 1905, Loewi became Associate Professor at Meyer’s laboratory and received Austrian citizenship. In 1909 he was appointed to the Chair of Pharmacology in Graz.
Loewi married Guida Goldschmiedt in 1908. They had three sons and a daughter. He was the last Jew hired by the University between 1903 and the end of the war.
In 1921, Loewi investigated how vital organs respond to chemical and electrical stimulation. He also established their relative dependence on epinephrine for proper function. Consequently, he learnt how nerve impulses are transmitted by chemical messengers. The first chemical neurotransmitter that he identified was acetylcholine.
After being arrested, along with two of his sons, on the night of the German invasion of Austria, March 11, 1938, Loewi was released on condition that he voluntarily relinquish all his possessions, including his research, to the Nazis. Loewi moved to the United States in 1940, where he became a research professor at the New York University College of Medicine. In 1946, he became a naturalized citizen of the United States. In 1954, he became a Foreign Member of the Royal Society. He died in New York City on December 25, 1961.
Shortly after Loewi’s death in late 1961, his youngest son bestowed the gold Nobel medal on the Royal Society in London. He gave the Nobel diploma to the University of Graz in Austria in 1983, where it currently resides, along with a bronze copy of a bust of Loewi. The original of the bust is at the Marine Biological Laboratory in Woods Hole, Massachusetts, Loewi’s summer home from his arrival in the US until his death.
Before Loewi’s experiments, it was unclear whether signalling across the synapse was bioelectrical or chemical. Loewi’s famous experiment, published in 1921, largely answered this question. According to Loewi, the idea for his key experiment came to him in his sleep. He dissected out of frogs two beating hearts: one with the vagus nerve which controls heart rate attached, the other heart on its own. Both hearts were bathed in a saline solution (i.e. Ringer’s solution). By electrically stimulating the vagus nerve, Loewi made the first heart beat slower. Then, Loewi took some of the liquid bathing the first heart and applied it to the second heart. The application of the liquid made the second heart also beat slower, proving that some soluble chemical released by the vagus nerve was controlling the heart rate. He called the unknown chemical Vagusstoff. It was later found that this chemical corresponded to Acetylcholine (Kandel, et al. 2000).
Loewi’s investigations On an augmentation of adrenaline release by cocaine and On the connection between digitalis and the action of calcium were profound concepts and were studied relentlessly by others decades later. He also clarified two mechanisms of eminent therapeutic importance: the blockade and the augmentation of nerve action by certain drugs. He is almost as famous for the means by which the idea for his experiment came to him as he is for the experiment itself. On Easter Saturday 1921, he dreamed of an experiment that would prove once and for all that transmission of nerve impulses was chemical, not electrical. He woke up, scribbled the experiment onto a scrap of paper on his night-stand, and went back to sleep. The next morning he arose very excited because he knew this dream had been very important. But he found, to his horror, that he couldn’t read hismidnight scribbles. That day, he said, was the longest day of his life, as he could not remember his dream. That night, however, he had the same dream. This time, he immediately went to his lab to perform the experiment. From that point on, the consensus was that the Nobel was not a matter of if but of when.
A little over a decade later, in 1936, Loewi was awarded the Nobel Prize in Physiology or Medicine, which he shared with Sir Henry Hallett Dale.
The Nobel Prize diploma of Otto Loewi, housed at the University of Graz
Single Animal to Human Transmission Event Responsible For 2014 Ebola Outbreak
According to the World Health Organization, the 2014 Ebola outbreak is now the largest outbreak in history, with current estimates of 2,473 infections and 1350 deaths since it began in late December 2013. This outbreak is also the first in West Africa and the first to affect urban areas. There are no approved drugs for Ebola virus disease, though prompt diagnosis and aggressive supportive care can improve survival. The disease is characterized by high fever, headache, body aches, intense weakness, stomach pain, and lack of appetite. This is followed by vomiting, diarrhea, rash, impaired kidney and liver function and in some cases, internal and external bleeding.
According to the NIH, advanced genomic sequencing technology was used to identify a single point of infection from an animal reservoir to a human in the current Ebola outbreak in West Africa. This research has also revealed the dynamics of how the Ebola virus has been transmitted from human to human, and traces how the genetic code of the virus is changing over time to adapt to human hosts. Pardis Sabeti, M.D., Ph.D, a 2009 National Institutes of Health Director’s New Innovator awardee and her team carried out the research.
To better understand why this outbreak is larger than previous outbreaks, an extensive analysis was performed of the genetic makeup of Ebola samples from patients living in affected regions. The analysis pinpointed a single late 2013 introduction from an unspecified animal reservoir into humans and showed that the strain responsible for the West African outbreak separated from a closely related strain found in Central Africa as early as 2004. This indicated movement from Central to West Africa over the span of a decade. Studying RNA changes occurring over the span of the outbreak suggests that the first human infection of the outbreak was followed by exclusive human to human transmissions.
While analyzing the genetic makeup of the Ebola samples, a number of mutations were discovered that arose as the outbreak spread. Some of these mutations, termed nonsynonymous mutations, alter the biological state of the virus and may allow it to continually and rapidly adapt to human immune defenses as the outbreak continues. This feature points to the need for improved methods that will allow for close monitoring of changes in the viral genome and the impact on vaccine targets. Such monitoring, called genomic surveillance, can provide important insights into the biology of how the Ebola virus spreads and evolves. It may also allow scientists to develop improved methods to detect infection, and point the way to new and improved drug and vaccines.
Vitamin D and the Risk of Dementia and Alzheimer Disease
According to a study published online in Neurology (6 August 2014), a study was performed to determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.
For the study, 1,658 elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were then assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria.
Results showed that during a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (>25 to <50 nmol/L) were 2.25 and 1.53 (more likely to be affected) compared to participants with sufficient concentrations (>50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 and 1.69. In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.
According to the authors, the results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease and this adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.
FDA Approves Pediatric Indication for ELELYSO™ for the Treatment of Type 1 Gaucher Disease
Target Health is pleased to share this good news with our friends and colleagues at Protalix and Pfizer. We have been providing full CRO and eCRO services for this program since 2004, starting with the pre-IND meeting with FDA, with the initial NDA approval in 2012.
Pfizer Inc. and Protalix BioTherapeutics, Inc. have announced that the U.S. Food and Drug Administration (FDA) approved ELELYSO™ (taliglucerase alfa) for injection for pediatric patients. ELELYSO is therefore now indicated for long-term enzyme replacement therapy (ERT) for adult and pediatric patients with a confirmed diagnosis of Type 1 Gaucher disease.
“The approval of ELELYSO to treat pediatric patients with Type 1 Gaucher disease provides physicians another treatment option for this rare and potentially debilitating disease, said Rory O’Connor, Senior Vice President, Global Medical Affairs, Global Innovative Pharma Business, Pfizer Inc. This pediatric indication, along with the recent announcement that ELELYSO received kosher certification by the Orthodox Union (OU), reinforces the ongoing commitment of Pfizer to addressing the needs of the Gaucher community.
The safety and efficacy of ELELYSO were assessed in fourteen pediatric patients with Type 1 Gaucher disease in two clinical trials. The first trial consisted of nine patients in a 12-month, multi-center, double-blind, randomized study in treatment-naive patients aged two to 13 years. At the end of the 12-month study, therapeutic efficacy of ELELYSO was demonstrated, as measured by a decrease in spleen and liver volume and an increase in platelet count. A second trial consisted of 5 pediatric patients aged 6 to 16 years who were switched from imiglucerase to ELELYSO. The trial was a 9-month, multi-center, open-label, single-arm study in patients who had been receiving treatment with imiglucerase at dosages ranging from 9.5 units/kg to 60 units/kg every other week for a minimum of 2 years. ELELYSO was administered for 9 months at the same dose as each patient’s previous imiglucerase dose. If needed, adjustment of dosage was allowed during the study in order to maintain stability of clinical parameters. Mean spleen and liver volume, platelet count and hemoglobin value remained stable through 9 months of ELELYSO treatment.
Tomato Vidalia Salad with Basil and Romaine
Unbelievably easy salad for four
2 ripe Beefsteak tomatoes, cut into bite size pieces (see above)
1/2 Vidalia onion, chopped well
1 bunch basil, washed dried and cut into thin ribbons
3 Romaine leaves, washed dried and cut into thin ribbons
2 Tablespoons sunflower oil (second choice, sesame oil)
Pinch black pepper (or grind to your taste)
1. Cut the basil and romaine leaves: Place one basil leaf on top of the other. Next, roll these basil leaves up, as best you can, into a tube shape. Now, cut the roll of basil leaves, like slicing a cucumber. Do the same with the romaine leaves.
2. Put the ribbons of basil and romaine into a salad bowl.
3. Add the cut up tomatoes and chopped Vidalia onion
4. Add the sunflower oil, salt and pepper
5. Toss the salad and serve
When we got back from Santa Fe, a few days ago, we were so completely happy, satisfied and relaxed, that creating a recipe was the last thing on my mind. Before we left Manhattan, I had been experimenting with simple quick salads, so I simply took the easiest one, which turns out to be one of the most refreshing salads we have ever eaten.
For this recipe to work, your ingredients must be very fresh. This time of year has wonderful plump juicy tomatoes, so that’s one reason for doing this salad now. If you don’t know about Vidalia onions, these are not like regular onions. In addition to the luscious ripe tomatoes, these Vidalias really add to the freshness of this salad.
Although, this is a salad for four, take a look at our salad bowl, below, to see how fast this salad disappeared.
We had some hummus with warm flat bread and an old stand-by Pinot Grigio.
We miss Santa Fe, but this was a lovely way to get back into our New York groove.
The disappearing salad…
We hope everyone’s summer was as relaxing as ours
From Our Table to Yours!
Bon Appetit !
For the current study, researchers sequenced 99 Ebola virus genomes collected from 78 patients diagnosed with Ebola in Sierra Leone during the first 24 days of the outbreak (a portion of the patients contributed samples more than once, allowing researchers a clearer view into how the virus can change in a single individual over the course of infection). The team found more than 300 genetic changes that make the 2014 Ebola virus genomes distinct from the viral genomes tied to previous Ebola outbreaks. They also found sequence variations indicating that, from the samples sequenced, the EVD outbreak started from a single introduction into humans, subsequently spreading from person to person over many months.
The variations they identified were frequently in regions of the genome encoding proteins. Some of the genetic variation detected in these studies may affect the primers (starting points for DNA synthesis) used in PCR-based diagnostic tests, emphasizing the importance of genomic surveillance and the need for vigilance. To accelerate response efforts, the research team released the full-length sequences on National Center for Biotechnology Information’s (NCBI’s) DNA sequence database in advance of publication, making these data available to the global scientific community.
“By making the data immediately available to the community, we hope to accelerate response efforts,” said co-senior author Pardis Sabeti, a senior associate member at the Broad Institute and an associate professor at Harvard University. “Upon releasing our first batch of Ebola sequences in June, some of the world’s leading epidemic specialists contacted us, and many of them are now also actively working on the data. We were honored and encouraged. A spirit of international and multidisciplinary collaboration is needed to quickly shed light on the ongoing outbreak.”
The 2014 Zaire ebolavirus (EBOV) outbreak is unprecedented both in its size and in its emergence in multiple populated areas. Previous outbreaks had been localized mostly to sparsely populated regions of Middle Africa, with the largest outbreak in 1976 reporting 318 cases. The 2014 outbreak has manifested in the more densely-populated West Africa, and since it was first reported in Guinea in March 2014, 2,240 cases have been reported with 1,229 deaths (as of August 19).
Augustine Goba, Director of the Lassa Laboratory at the Kenema Government Hospital and a co-first author of the paper, identified the first Ebola virus disease case in Sierra Leone using PCR-based diagnostics. “We established surveillance for Ebola well ahead of the disease’s spread into Sierra Leone and began retrospective screening for the disease on samples as far back as January of this year,” said Goba. “This was possible because of our long-standing work to diagnose and study another deadly disease, Lassa fever. We could thus identify cases and trace the Ebola virus spread as soon as it entered our country.”
The research team increased the amount of genomic data available on the Ebola virus by four fold and used the technique of “deep sequencing” on all available samples. Deep sequencing is sequencing done enough times to generate high confidence in the results. In this study, researchers sequenced at a depth of 2,000 times on average for each Ebola genome to get an extremely close-up view of the virus genomes from 78 patients. This high-resolution view allowed the team to detect multiple mutations that alter protein sequences — potential targets for future diagnostics, vaccines, and therapies.
The Ebola strains responsible for the current outbreak likely have a common ancestor, dating back to the very first recorded outbreak in 1976. The researchers also traced the transmission path and evolutionary relationships of the samples, revealing that the lineage responsible for the current outbreak diverged from the Middle African version of the virus within the last ten years and spread from Guinea to Sierra Leone by 12 people who had attended the same funeral.
The team’s catalog of 395 mutations (over 340 that distinguish the current outbreak from previous ones, and over 50 within the West African outbreak) may serve as a starting point for other research groups. “We’ve uncovered more than 300 genetic clues about what sets this outbreak apart from previous outbreaks,” said Stephen Gire, a research scientist in the Sabeti lab at the Broad Institute and Harvard. “Although we don’t know whether these differences are related to the severity of the current outbreak, by sharing these data with the research community, we hope to speed up our understanding of this epidemic and support global efforts to contain it.”
“There is an extraordinary battle still ahead, and we have lost many friends and colleagues already like our good friend and colleague Dr. Humarr Khan, a co-senior author here,” said Sabeti. “By providing this data to the research community immediately and demonstrating that transparency and partnership is one way we hope to honor Humarr’s legacy. We are all in this fight together.”
This work was supported by Common Fund and National Institute of Allergy and Infectious Diseases in the National Institutes of Health, Department of Health and Human Services, as well as by the National Science Foundation, the European Union Seventh Framework Programme, the World Bank, and the Natural Environment Research Council.
Other researchers who contributed to this work include Augustine Goba, Kristian G. Andersen, Rachel S. G. Sealfon, Daniel J. Park, Lansana Kanneh, Simbirie Jalloh, Mambu Momoh, Mohamed Fullah, Gytis Dudas, Shirlee Wohl, Lina M. Moses, Nathan L. Yozwiak, Sarah Winnicki, Christian B. Matranga, Christine M. Malboeuf, James Qu, Adrianne D. Gladden, Stephen F. Schaffner, Xiao Yang, Pan-Pan Jiang, Mahan Nekoui, Andres Colubri, Moinya Ruth Coomber, Mbalu Fonnie, Alex Moigboi, Michael Gbakie, Fatima K. Kamara, Veronica Tucker, Edwin Konuwa, Sidiki Saffa, Josephine Sellu, Abdul Azziz Jalloh, Alice Kovoma, James Koninga, Ibrahim Mustapha, Kandeh Kargbo, Momoh Foday, Mohamed Yillah, Franklyn Kanneh, Willie Robert, James L. B. Massally, Sinéad B. Chapman, James Bochicchio, Cheryl Murphy, Chad Nusbaum, Sarah Young, Bruce W. Birren, Donald S.Grant, John S. Scheiffelin, Eric S. Lander, Christian Happi, Sahr M. Gevao, Andreas Gnirke, Andrew Rambaut, Robert F. Garry, and S. Humarr Khan.
- Gire, SK, Goba, A et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science, 2014 DOI:10.1126/science.1259657
Broad Institute of MIT and Harvard. “Genomic sequencing reveals mutations, insights into 2014 Ebola outbreak.” ScienceDaily. ScienceDaily, 28 August 2014. <www.sciencedaily.com/releases/2014/08/140828142738.htm>.
Silicon has been the most successful material of the 20th century, with major global industries and even a valley named after it. But silicon may be running out of steam for high performance/low power electronics. For example, the compound semiconductor indium gallium arsenide is known to have far superior electron mobility than silicon. As silicon strains against the physical limits of performance, could a material like InGaAs provide enough of an improvement over silicon that it would be worth the expense in new equipment lines and training to make the switch worthwhile? Samsung, one of the world’s largest electronics companies, has funded Thathachary through his adviser, professor of electrical engineering Suman Datta, in a project to help them find out.
In an article in the journal Nano Letters early this year, Thathachary and his coauthors described a novel device prototype designed to test nanowires made of compound semiconductors such as InGaAs. Their goal was to see for the first time if such a compound material would retain its superior electron mobility at nanoscale dimensions in a so-called FinFET device configuration, the standard transistor architecture for sub-22 nanometer technology.
“We developed a novel test structure called a Multi-fin Hall Bar Structure. It is the first such measurement of Hall mobility in a multi-fin 3D device,” Thathachary said. “If you look at mainstream chip production today, all transistors are made in a 3D fashion, and because they are made in 3D rather than the earlier planar design, several mechanisms can degrade performance. What we looked at in that paper is how much degradation do you really suffer when going from a planar 2D surface to, in this case, 30 nm size features that are confined in 3D?”
What Thathachary and colleagues discovered was that electron mobility declined in a regular slope and that the experimental results could be modeled by a method called scattering relaxation time approximation. Using this technique they were able to predict how a compound semiconductor device would be likely to operate at the size at which this material would possibly be adopted, for example, the 7 nm technology node.
“We found that at dimensions of even 5 nm, you can still expect a 2x to 3x advantage in the mobility of these materials over silicon, which is very significant,” said Thathachary. “After we published this paper, it was clear from a fundamental physics point of view that if you engineer the device correctly you should outperform existing silicon devices. But will it really? That’s what we set out to investigate next.”
Conference paper draws interest
The VLSI Symposia is an international conference on semiconductor technology and circuits, the leading conference for discussing advances in microelectronic devices. The majority of the presenters are from industry, with only a handful of student papers picked for presentation. At this year’s VLSI, one of the papers was Thathachary’s.
“The paper in Nano Letters was a precursor to the one chosen for the conference,” Thathachary said. They had made a device with 30 nm features and measured the compound semiconductor’s electron mobility down to that scale, but now it was time to actually make nanoscale transistors out of the new materials system and understand transistor behavior in that system.
Two of the parameters that are most important in transistor technology are called “subthreshold slope” and the “on current.” Subthreshold slope indicates how efficiently you can turn the transistor on and off. While on current simply means how much current you can get out of the device. Especially for mobile devices, if the transistor can get the same amount of current with lower voltage it will extend battery life and reduce the amount of heat that has to be gotten rid of.
“In addition, it’s imperative that you increase the functionality of the computer chip,” Thathachary explained, “but that means putting more transistors inside. If you are going to put a 50 or 60 watt limit on the average power consumption of your chip, then those transistors have to require lower power than the existing devices.”
Working on his Ph.D. project and through regular consultation with the Penn State Nanofab engineering staff, Thathachary spent a year in the cleanroom optimizing the processes required to put a new material system into a state of the art 3D FinFET device. That required spending many hours tweaking the conditions, such as temperature, flow rate, types of reactant gases, as well as refining his electron beam lithography and dry etch patterning techniques.
One of the most challenging issues he overcame was etching InGaAs into dense fin arrays comprising nanoscale dimensions. Once that was accomplished, he then needed to see how the new compound semiconductor system interacted with the other materials systems, such as the high-k dielectric thin film coating that surrounded the InGaAs fin.
“If you can get that process right, then you can make a great device, and that is what we showed at the conference,” he said. “We showed that in terms of on current at lower supply voltage we are seeing very good performance compared to existing silicon devices.”
Between the time the conference paper was accepted and the June meeting in Hawaii, Thathachary had continued to refine his processes. He learned that increasing the percentage of indium in the ternary (3-part) material system increased electron mobility significantly. Another mobility boost comes from engineering the dimensions of the active material so that the electrons are forced toward the middle of the material in a process called quantum confinement. This is important because in traditional transistors the electrons move close to the surface where they are exposed to microscopic roughness that degrades their mobility.
“The paper was remarkably well received at the conference, and we had a lot of requests to share our new and improved results. We had to get permission from Samsung to share that material, and eventually we did,” Thathachary said.
Encouraged by his results, Samsung has since renewed the contract with the Datta lab and Thathachary for another year. His next challenge will be the most difficult so far. They want him to investigate the performance of a 3D transistor at the 7 nm dimension, a node that the semiconductor industry is looking at for the future. To do this in the Penn State Nanofab for the first time, means he will need to develop innovative ideas to overcome the limitations of working with limited resources in a university lab. Once a device can be made at or approaching those dimensions, Samsung will likely internalize the research and assign a large team of engineers to develop reproducible industry scale devices.
“If we can show that at those dimensions, these III-V compound semiconductor systems can still beat silicon, that is when it makes sense for industry to move in and invest the billions of dollars required for the new technology generation,” Thathachary concluded.
- Arun V. Thathachary, Nidhi Agrawal, Lu Liu, Suman Datta. Electron Transport in Multigate InxGa1–xAs Nanowire FETs: From Diffusive to Ballistic Regimes at Room Temperature. Nano Letters, 2014; 14 (2): 626 DOI: 10.1021/nl4038399
Penn State Materials Research Institute. “Materials Other Than Silicon for Next Generation Electronic Devices.” ScienceDaily. ScienceDaily, 27 August 2014. <www.sciencedaily.com/releases/2014/08/140827122509.htm>.
The study, reported in Environmental Science and Technology, recalculates the theoretical limit of terrestrial plant productivity, and finds that it is much higher than many current estimates allow.
“When you try to estimate something over the whole planet, you have to make some simplifying assumptions,” said University of Illinois plant biology professor Evan DeLucia, who led the new analysis. “And most previous research assumes that the maximum productivity you could get out of a landscape is what the natural ecosystem would have produced. But it turns out that in nature very few plants have evolved to maximize their growth rates.”
DeLucia directs the Institute for Sustainability, Energy, and Environment at the U. of I. He also is an affiliate of the Energy Biosciences Institute, which funded the research through the Institute for Genomic Biology at Illinois.
Estimates derived from satellite images of vegetation and modeling suggest that about 54 gigatons of carbon is converted into terrestrial plant biomass each year, the researchers report.
“This value has remained stable for the past several decades, leading to the conclusion that it represents a planetary boundary — an upper limit on global biomass production,” the researchers wrote.
But these assumptions don’t take into consideration human efforts to boost plant productivity through genetic manipulation, plant breeding and land management, DeLucia said. Such efforts have already yielded some extremely productive plants.
For example, in Illinois a hybrid grass, Miscanthus x giganteus, without fertilizer or irrigation produced 10 to 16 tons of above-ground biomass per acre, more than double the productivity of native prairie vegetation or corn. And genetically modified no-till corn is more than five times as productive — in terms of total biomass generated per acre — as restored prairie in Wisconsin.
Some non-native species also outcompete native species; this is what makes many of them invasive, DeLucia said. In Iceland, for example, an introduced species, the nootka lupine, produces four times as much biomass as the native boreal dwarf birch species it displaces. And in India bamboo plantations produce about 40 percent more biomass than dry, deciduous tropical forests.
Some of these plants would not be desirable additions to native or managed ecosystems, DeLucia said, but they represent the untapped potential productivity of plants in general.
“We’re saying this is what’s possible,” he said.
The team used a model of light-use efficiency and the theoretical maximum efficiency with which plant canopies convert solar radiation to biomass to estimate the theoretical limit of net primary production (NPP) on a global scale. This newly calculated limit was “roughly two orders of magnitude higher than the productivity of most current managed or natural ecosystems,” the authors wrote.
“We’re not saying that this is even approachable, but the theory tells us that what is possible on the planet is much, much higher than what current estimates are,” DeLucia said.
Taking into account global water limitations reduced this theoretical limit by more than 20 percent in all parts of the terrestrial landscape except the tropics, DeLucia said. “But even that water-limited NPP is many times higher than we see in our current agricultural systems.”
DeLucia cautions that scientists and agronomists have a long way to go to boost plant productivity beyond current limits, and the new analysis does not suggest that shortages of food or other plant-based resources will cease to be a problem.
“I don’t want to be the guy that says science is going to save the planet and we shouldn’t worry about the environmental consequences of agriculture, we shouldn’t worry about runaway population growth,” he said. “All I’m saying is that we’re underestimating the productive capacity of plants in managed ecosystems.”
- Evan H. DeLucia, Nuria Gomez-Casanovas, Jonathan A. Greenberg, Tara W. Hudiburg, Ilsa B. Kantola, Stephen P. Long, Adam D. Miller, Donald R. Ort, William J. Parton. The Theoretical Limit to Plant Productivity. Environmental Science & Technology, 2014; 48 (16): 9471 DOI: 10.1021/es502348e
University of Illinois at Urbana-Champaign. “Earth can sustain more terrestrial plant growth than previously thought, analysis shows.” ScienceDaily. ScienceDaily, 26 August 2014. <www.sciencedaily.com/releases/2014/08/140826100855.htm>.