Developing a culture of safety in biomedical research training

The National Institute of General Medical Sciences (NIGMS) at the U.S. National Institutes of Health (NIH) is committed to supporting the safety of the nation’s biomedical research and training environments. Institutional training grants affect many trainees and can have a broad influence across their parent institutions, making them good starting points for our initial efforts to promote the development and maintenance of robust cultures of safety at U.S. academic institutions. In this Perspective, we focus on laboratory safety, although many of the strategies we describe for improving laboratory safety are also applicable to other forms of safety including the prevention of harassment, intimidation, and discrimination. We frame the problem of laboratory safety using a number of recent examples of tragic accidents, highlight some of the lessons that have been learned from these and other events, discuss what NIGMS is doing to address problems related to laboratory safety, and outline steps that institutions can take to improve their safety cultures.

All new funding opportunity announcements (FOAs) for training programs supported by the National Institute of General Medical Sciences (NIGMS) contain the expectation that the programs will promote “inclusive, safe and supportive scientific and training environments.” In this context, the word “safe” refers to several aspects of safety. First, we mean an environment free from harassment and intimidation, in which everyone participating is treated in a respectful and supportive manner, optimized for productive learning and research. We also mean that institutions should ensure that their campuses are as safe as possible so that individuals can focus on their studies and research. Finally, we mean safety in the laboratory and clinical spaces. In this Perspective, we focus on this last issue and describe some of the approaches NIGMS is taking to help the biomedical research community move toward an enhanced culture of safety in which core values and the behaviors of leadership, principal investigators (PIs), research staff, and trainees emphasize safety over competing goals.     

Association of biochemistry grades with performance in pharmacology and anatomy in a Saudi Arabian medical college

The College of Medicine, King Khalid University of Abha, Saudi Arabia currently accepts 100 students a year, up from 50 to 70 students four years ago. The first-year students take four science courses (Biology,Chemistry, Physics, and Statistics) in addition to some general university requirement courses. Biochemistry is offered in the second year, Anatomy in the second and third year and Pharmacology in the fourth year. This study was carried out to determine the correlation between the performance of medical students in Biochemistry and their performance in Anatomy and Pharmacology. Data were obtained from two groups of students (Group 22 and 23) of the years 1995 and 1996 who had already taken Biochemistry, Anatomy and Pharmacology. Performance was equal in Pharmacology but in biochemistry performance of group 23 was clearly lower than group 22. Scores of students in Biochemistry course strongly correlated with the basic Pharmacology course (r=0.714, P<0.0001). Scores in Anatomy also correlated with those in Biochemistry (r=0.616, P<0.001) but much less with scores in Pharmacology (r=0.345, P<0.01).     

20 years of the bioengineering Department at the Politecnico, Milano, and beyond..

To celebrate the 20th anniversary of the first Bioengineering Department in Italy at the Politecnico di Milano, a number of articles in this issue highlight the department's achievements. The department was eventually founded in 1990 after many years of research and didactic activity in the area that officially began in 1969 when the first teaching course, called biological electronics, was offered in the electronic engineering specialization.     

A great adventure: from quantitative metabolism to the revelation of Chinese science

By the end of the 1930s, Frederick Gowland Hopkins had built his Cambridge laboratory into the pre-eminent institute of biochemistry that was a magnet for scientists from all over the world. Even so, it was an exceptional event that saw a young Chinese student leave a homeland at that time relatively isolated from the West and embark on a research career in his department. Within 2?years, she had published a highly influential set of papers on metabolism in the Biochemical Journal, a field that some 70?years on has once again become a major focus as its role in cancer is dissected. From the outset, however, she had come under the spell of the legendary polymath Joseph Needham to whom she would dedicate the rest of her life in a partnership that would unveil the astounding history of Chinese science to the world.     

Why a Symposium on Biology at Johns Hopkins?

From its inception in 1876, Johns Hopkins University has stoodout as an institution where the laboratory and experimentationhave been accorded the highest respect and priority, and wherethe most capable people have been chosen to occupy positionsof authority. The first president of the University, DanielGilman, was able to guide and shape the university unencumberedby outside influences and began the tradition of hiring thebest men to work with him. H. N. Martin and W. K. Brooks inbiology were two of these leaders in the early period of theuniversity (1876–1908). During the middle years (1909–1939), expansion dilutedfaculty and diverted them away from research and toward teaching.Herbert Spencer Jennings headed the Zoology Department duringthis middle period and in spite of the general trend away fromquality research activities, maintained a standard of excellencein his department. Another leader during this period and onewhom some consider more influential than Jennings was BurtonE. Livingston, chairman ofthe Plant Physiology Department. The modern period began in 1939 and saw some rebuilding of thebiological sciences after World War II, combining of the Zoology,Botany, and Plant Physiology Departments into one Biology Department,the building of the Mergenthaler Laboratory for Biology, themodernization of the department into one oriented toward molecularbiology, and a host of quality appointments. Most of these accomplishmentscan be attributed to H. B. Willier who headed the departmentfrom 1940 to 1955. Presently the Department of Biology at Johns Hopkins Universityis one of this country's leading centers of molecular biology.     

Fifty-eight years in science--a commentary

After 58 years in science, mostly in pharmacology, one gains perspective. Mine is that there have been important changes over this time, some good and some questionable. In this commentary, I try to reveal how I got to this stage, partially explaining my biases, and possibly helping others learn from my experiences including mistakes. Changing from seeking an M.D. to cellular biology and then to pharmacology early in my career were the best moves I made. The next best move was migration to Canada, away from the McCarthy-McCarran hysteria. Arriving at a time after the end of World War II when science in Canada was expanding was very good luck. I had an excellent opportunity to enjoy both the administration (as Chair of the first independent Department of Pharmacology at the University of Alberta) and the practice of pharmacology (as a practitioner of research on smooth muscle in health and disease). For me, the practice of research has always won over administration when a choice had to be made. Early on, I began to ask questions about educational practices and tried to evaluate them. This led me to initiate changes in laboratories and to seek nondidactic educational approaches such as problem-based learning. I also developed questions about the practice of anonymous peer review. After moving to McMaster in 1975, I was compelled to find a solution for a failed "Pharmacology Program" and eventually developed the first "Smooth Muscle Research Program". Although that was a good solution for the research component, it did not solve the educational needs. This led to the development of "therapeutic problems", which were used to help McMaster medical students educate themselves about applied pharmacology. Now these problems are being used to educate pharmacology honours and graduate students at the University of Alberta. The best part of all these activities is the colleagues and friends that I have interacted with and learned from over the years, and the realization that many of them have collaborated with me again in this volume.     

Tuberculous orchiepididymitis, meningoencephalitis and hydrocephalus

Tuberculous meningoencephalitis (TBM) is a rare and serious, often fatal presentation of active tuberculosis and account for about 1% of cases. Early diagnosis and prompt treatment of TBM is essential to reduce morbidity and mortality. Here, we report a case of TBM in 60-year-old man. TBM was considered on the basis of clinical presentation, laboratory findings (hyponatraemia), cerebrospinal fluid studies, radiological findings (hydrocephalus on multi-slice computed tomography), and history of orchiepididymitis of unknown origin one year earlier, together with information that the patient originated from Kosovo where incidence of tuberculosis is still high. Mycobacterium tuberculosis was cultured from cerebrospinal fluid on Lowenstein-Jensen medium confirming diagnosis of TBM. Subsequently, acid-fast bacilli (AFB) staining on samples obtained after orchiectomy a year ago was performed, revealing AFB. Anti-tuberculosis therapy is still in course. This is the second case of tuberculous meningoencephalitis with the same disease pattern (i.e. tuberculous orchiepididymitis - meningoencephalitis) in our Department, and this fact was crucial for the presumptive diagnosis and urgent treatment of TBM. The former case was described five years ago.     

Profiles of Pioneer Women Scientists: Katherine Esau

“Profiles of Pioneer Women Scientists: Katherine Esau” tells the story of a noted botanist, plant anatomist, and electron microscopist who was born in the Russian Ukraine (in 1898), forced to flee the Bolshevik Revolution with her family—her father a mayor of Ekaterinoslav under the Czar—to Germany, where she received a bachelor’s degree in agriculture, education she put to good use in America. Beginning in a sugarbeet field in Salinas, California, she progressed through the doctoral degree at the University of California at Davis (UC Davis) and there began her exceptional research on plant anatomy and plant viral diseases. Her textbookPlant Anatomy became known among college students as “Aunt Kitty’s Bible,” and all of her textbooks have gone into second, and some to third, editions. Transferring to the University of California at Santa Barbara (with its new Chancellor, V. I. Cheadle) only two years before retirement, she blossomed anew, producing some of her best work there and obtaining National Science Foundation support for a new electron microscope and other research funds through her 89th year. Katherine Esau started accruing awards and honors at a relatively early age (Faculty Research Lecturer at age 50, election to the National Academy of Sciences at 59) and has never stopped (the President’s Medal of Science at age 91, a UC Santa Barbara building named for her at age 93). It has been her good fortune to live to enjoy these honors. The short autobiography of her father, a truly enterprising engineer, is included here, as are the recollections of Celeste Turner Wright. Celeste, who arrived at UC Davis the same year as Katherine Esau, became an acclaimed poet, and chaired the English Department for many years. She has added a lively reminiscence of the days she and Katherine spent at UC Davis. The introduction to the book by one of Esau’s former graduate students, Ray Franklin Evert, himself a renowned plant pathologist, provides a heartfelt tribute to his greatly admired professor.     

Stentless aortic valve implantation through an upper manubrium-limited V-type ministernotomy

In this piece of work, we attempt to highlight our approach and early experience with minimally invasive aortic valve replacement with aortic Freedom Solo stentless bioprosthesis performed through an upper manubrium-limited ministernotomy in the second intercostal space. The novel suturing technique is required for stentless aortic bioprosthesis implantation, and this, in its turn, will predetermine and influence the surgeon's choice for operative access. In our department, the feasibility of the approach was first assessed; aortic valve was replaced by stentless bioprosthesis in a total of 23 patients (mean age 57 ± 12 years). In all cases, a cardiopulmonary bypass was established by a central ascending aorta cannulation and peripheral percutaneous venous cannula insertion. This approach was found to be technically reproducible and safe. The surgical technique used is described in this article.     

Cross talk: interview with Al Gilman

Alfred Goodman Gilman was born in the same year (1941) that his father and Louis Goodman published the first edition of The Pharmacological Basis of Therapeutics. Pharmacology has thus always been part of his life, and in his own career he has focused primarily on cell signaling. For the past twenty years, he has chaired the Department of Pharmacology at UT Southwestern, and his long list of accomplishments includes a Nobel Prize (1994) for his work on G proteins. In 1998, Gilman embarked on his most ambitious program of research yet, bringing dozens of leading investigators from the cell signaling community to Dallas in order to plan out a ten-year project aiming "to understand as completely as possible the relationships between sets of inputs and outputs in signaling cells." Now directing the full-fledged, federally funded Alliance for Cellular Signaling, Gilman stresses that a solid database for constructing a "virtual cell" will depend on extensive collaboration from the entire signaling community. (For a complete Program Summary, and to register for membership in the Alliance, consult www.cellularsignaling.org.) The luminaries that were invited to the Dallas planning meeting, in fact, were greeted at the door with a note from Gilman exhorting them: please check EGO at door.     

生物多样性与传染性疾病的关系: 进展、挑战与展望

在全球生物多样性快速丧失的背景下, 理解生物多样性如何影响传染性疾病风险具有重要意义。大量研究表明, 宿主多样性对传染性疾病可能存在稀释效应(即疾病风险随宿主生物多样性的增加而降低), 但是也有放大效应或者没有影响的证据。本文首先介绍了关于生物多样性与传染性疾病关系的研究进展, 以及该领域的热点研究问题, 包括宿主多样性-疾病关系的格局和空间依赖性、稀释效应的体系依赖性和系统发育稀释效应等。随后,介绍了相关研究伴随的争议和批判, 主要集中在: 稀释效应发生的普遍性、生物多样性-疾病关系实验研究的发表偏好性以及部分疾病生态学家对生物多样性和传染性疾病之间简单数字关系的过分关注。最后指出稀释效应与物种共存、全球变化对稀释效应的影响、进化与稀释效应、稀释效应在政策制定中的应用等领域可能是今后的主要研究方向。     

An interview with Dr. Paolo Sassone-Corsi on his highly cited paper published in Cell Cycle

Paolo Sassone-Corsi graduated in genetics at the University of Naples, Italy, and then conducted post-doctoral studies at the CNRS in Strasbourg, France, and at The Salk Institute, San Diego California. After being Directeur de Recherche at the CNRS in France from 1990 to 2006, he moved to the University of California, Irvine, where he is Distinguished Professor and Chair of the Department of Pharmacology. His research focuses on the mechanisms of gene expression, including chromatin remodeling, circadian rhythms and germ cells.     

Improving the efficiency of a hospital emergency department: a simulation study with indirectly imputed service-time distributions

This paper presents a case study which uses simulation to analyze patient flows in a hospital emergency department in Hong Kong. We first analyze the impact of the enhancements made to the system after the relocation of the Emergency Department. After that, we developed a simulation model (using ARENA) to capture all the key relevant processes of the department. When developing the simulation model, we faced the challenge that the data kept by the Emergency Department were incomplete so that the service-time distributions were not directly obtainable. We propose a simulation–optimization approach (integrating simulation with meta-heuristics) to obtain a good set of estimate of input parameters of our simulation model. Using the simulation model, we evaluated the impact of possible changes to the system by running different scenarios. This provides a tool for the operations manager in the Emergency Department to “foresee” the impact on the daily operations when making possible changes (such as, adjusting staffing levels or shift times), and consequently make much better decisions.     

海洋微生物宏基因组工程进展与展望

据初步统计,生活于海洋环境包括大洋深处的微生物有100万种以上,构成了一个动态的遗传基因库,其中绝大多数微生物或者从来没有经过实验室培养,或者至今无法培养,因而其分类地位及其生态学功能尚未为人类所认识。随着16S rRNA序列分析与系统分类学的广泛应用,海洋微生物多样性研究领域已经发生了很可观的改变,这些变化极大的丰富了人们对的微生物多样性及其生态功能的认识和理解。这里结合笔者近十年来的工作实践,讨论近年来在海洋微生物资源开发利用方面的研究进展,提出一个带有自动化特征的宏基因组功能表达平台,探讨海洋微生物资源利用的新途径。可以预见在不久的将来,海洋环境宏基因组工程研究将在一定程度上使得传统未培养海洋微生物基因资源及其功能产物能够为人类所开发和利用。     

Familial lethal sleep apnea

Summary Three of six siblings presented with sleep apnea between 18 and 26 months of age. Twin females and a male had normal growth and development without antecedent neurologic or apparent metabolic disorder. The females presented at 25 and 27 months respectively with irregular respiration and episodes of apnea. Twin A succumbed to an apneic episode while sleeping. Central sleep apnea was diagnosed in twin B at the Stanford Sleep Clinic. She died following an apneic episode three months after evaluation. The male presented at 18 months with fatal sleep apnea. A fourth child was evaluated for sleep apnea at 7 weeks of age with several hospitalizations before her death at 31 months. She and remaining family members were extensively studied for inherited neurologic disorders including subacute necrotizing encephalomyopathy (SANE, Leigh disease). This family with lethal sleep apnea presents an association with SANE with minimal neurologic signs and symptoms and neuropathologic involvement. Lesions were conined to the respiratory centers of the lower brain stem, making sleep apnea explicable. This child and family members tested positive or borderline for inhibitor substance thiamine triphosphate (TTP). All testing for TTP inhibitor substance was performed in Professor Jack R. Cooper's laboratory, Department of Pharmacology, Yale University School of Medicine, New Haven, Conn. These cases present an interesting and instructive lesson emphasizing the need for extensive evaluation of children with unsuspected sleep apnea with early demise.     

Lipid Signaling in Experimental Epilepsy

Glutamate release activates signaling pathways important for learning and memory, and over-stimulation of these pathways during seizures leads to aberrant synaptic plasticity associated with hyper-excitable, seizure-prone states. Seizures induce rapid accumulation of membrane lipid-derived fatty acids at the synapses which, evidence suggests, regulate maladaptive connectivity. Here we give an overview of the significance of the arachidonyl- and inositol-derived messengers, prostaglandins (PGs) and diacylglycerol (DAG), in experimental models of epilepsy. We use studies conducted in our own laboratory to highlight the pro-epileptogenic role of cyclooxygenase-2 (COX-2) and its products, the PGs, and we discuss the possible mechanisms by which PGs may regulate membrane excitability and synaptic transmission at the cellular level. We conclude with a discussion of AA-DAG signaling in synaptic plasticity and seizure susceptibility with an emphasis on recent studies in our laboratory involving DAG kinase ε (DGKε)-knockout mice.     

Common to both academia and industry: the challenge of discovery. An interview with Perry Molinoff

Perry Molinoff recognizes the distinctions between basic and applied science, between academic and industrial research, and between the preclinical and clinical realities of drug development. But he generally discusses these categories in fluid, practical terms, having throughout his career crossed the lines of distinction that have sometimes been rather heavily drawn among pharmacologists. As a third-year medical student at Harvard, he decided "to take a year off" to conduct laboratory research. After receiving his MD and pursuing further clinical and postdoctoral work, he enjoyed an academic career that included fourteen years as the A.N. Richards Professor and Chair of Pharmacology at the University of Pennsylvania School of Medicine. He has just completed six years as Vice President of Neuroscience and Genitourinary Drug Discovery for Bristol-Myers Squibb and will soon return to teaching, in the Departments of Psychiatry and Pharmacology at Yale University. Referring to himself as either pharmacologist or neuroscientist, depending on context, he has made fundamental discoveries in receptor biology, has overseen the discovery and development of drugs and their subsequent clinical trials, and has mentored a host of pharmacologists and neuroscientists who themselves have established careers in industry and academia. The pursuit of discovery as its own reward emerges as a theme that has marked his professional life (and is perhaps reflected also in the images displayed in his office of the Himalayan mountains, photographed by Molinoff himself from the Everest base camp last year).