Rockefeller University Research Articles

Jacques Genest Sr

Dr Jacques Genest Sr, one of the pioneers of the hypertension research field, passed away peacefully at the age of 98 years in Montreal, Quebec, Canada, on January 5, 2018. Dr Genest is survived by his wife Estelle, his children Paul, Suzanne, Jacques Jr, Marie, and Helene, as well as 12 grandchildren and 7 great-grandchildren. Jacques Genest Sr was born in Montreal on May 29, 1919. He studied medicine at the Universite de Montreal before going on to specialize in internal medicine, endocrinology, and nephrology at Harvard Medical School, Johns Hopkins Hospital, and The Rockefeller Institute for Medical Research. Jacques Genest was one of the giants of hypertension research of the 20th century. He was also a major force in medicine, science, and education in Quebec and Canada throughout his career. His contributions to the mechanisms of hypertension were major, starting with his article in Science on the …

The discoveries of molecular mechanisms for the circadian rhythm: The 2017 Nobel Prize in Physiology or Medicine

Circadian clocks evolved to allow plants and animals to adapt their behaviors to the 24-hr change in the external environment due to the Earth's rotation. While the first scientific observation of circadian rhythm in the plant leaf movement may be dated back to the early 18th century, it took 200 years to realize that the leaf movement is controlled by an endogenous circadian clock. The cloning and characterization of the first Drosophila clock gene period in the early 1980s, independently by Jeffery C. Hall and Michael Rosbash at Brandeis University and Michael Young at Rockefeller University, paved the way for their further discoveries of additional genes and proteins, culminating in establishing the so-called transcriptional translational feedback loop (TTFL) model for the generation of autonomous oscillator with a period of ∼24 h. The 2017 Nobel Prize in Physiology or Medicine was awarded to honor their discoveries of molecular mechanisms controlling the circadian rhythm.

Martha Wollstein: A pioneer American female clinician-scientist.

Martha Wollstein was not only the first fully specialized pediatric perinatal pathologist practicing exclusively in a North America children's hospital, she also blazed another pathway as a very early pioneer female clinician-scientist. Wollstein provided patient care at Babies Hospital of New York City from 1891 until her retirement in 1935, and also simultaneously worked for many years as a basic scientist at the prestigious Rockefeller Institute for Medical Research. Wollstein published over 65 papers, many frequently cited, during her career on a wide range of topics including pediatric and infectious diseases. Wollstein was a rare female in the field of pathology in an era when just a relatively small number of women became doctors in any medical specialty. Wollstein was born into an affluent Jewish American family in New York City in 1868 and graduated from the Women's Medical College in 1889. This paper explores her family support and ethnic and religious background, which helped facilitate her professional success. During her time, she was recognized internationally for her research and was respected for her medical and scientific skills; unfortunately today her important career has been largely forgotten.

Broad and Rockefeller settle CRISPR dispute

The CRISPR patent dispute between the University of California, Berkeley, and Broad Institute of MIT & Harvard continues unabated, but a separate dispute between Broad and Rockefeller University has concluded. Rockefeller researcher Luciano Marraffini was an author on a foundational 2013 Science paper describing CRISPR gene editing along with Feng Zhang of Broad. Both scientists’ names were included on patents for using CRISPR in prokaryotes, but eukaryotic patents did not include Marraffini. Under a settlement between Broad and Rockefeller, the patents will remain unchanged.

Editorial introductions

Editorial introductions

The effects of trans-resveratrol on insulin resistance, inflammation, and microbiota in men with the metabolic syndrome: a pilot randomized, placebo controlled clinical trial

The metabolic syndrome (MetS) is a pathological condition comprised of abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. It has become a major threat globally, resulting in rapidly increasing rates of diabetes, coronary heart disease, and stroke. The polyphenol resveratrol (RES) is believed to improve glucose homeostasis and insulin resistance by activating sirtuin, which acetylates and coactivates downstream targets and affects glucose and lipid homeostasis in the liver, insulin secretion in the pancreas, and glucose uptake in skeletal muscle. We studied the effects of RES on insulin resistance, glucose homeostasis, and concomitant effects on adipose tissue metabolism and fecal microbiota in insulin-resistant subjects with the MetS. A total of 28 obese men with the MetS were studied during a 35-day stay in the Rockefeller University Hospital metabolic unit. Subjects were randomized to receive RES 1 g orally twice daily or placebo while kept weight stable and consuming a western-style diet. At baseline, and after 30 days of RES or placebo administration, subjects underwent testing that included a euglycemic, hyperinsulinemic clamp, 2-h oral glucose tolerance test (GTT), resting energy expenditure, daily blood pressure monitoring, abdominal adipose tissue biopsy, and fecal and blood collections. RES induced no changes in insulin resistance but reduced the 120-min time point and the area under the curve for glucose concentration in the 2-h GTT. In post-hoc analysis, Caucasian subjects showed a significant improvement in insulin sensitivity and glucose homeostasis after GTT, whereas non-Caucasians showed no similar effects. Levels of fasting plasma RES and its primary metabolite dihydroresveratrol were variable and did not explain the racial differences in glucose homeostasis. RES administration to Caucasian subjects leads to an increase in several taxa including Akkermansia muciniphila. RES 2 g administered orally to obese men with MetS and insulin resistance marginally altered glucose homeostasis. However, in a small group of Caucasians, insulin resistance and glucose homeostasis improved. No concomitant changes in adipose tissue metabolism occurred, but fecal microbiota showed RES-induced changes. The MetS increases the risk of diabetes, heart disease, and stroke. A major component of the syndrome is insulin resistance, resulting in systemic inflammation and hyperinsulinemia. The primary treatment consists of lifestyle changes, improved diet, and increased physical activity. This is often unsuccessful. In this study, RES was well tolerated. In Caucasian men, it significantly improved insulin sensitivity and glucose homeostasis. Similar results were found in studies that consisted exclusively of Caucasian men. However, RES presents a novel addition to the current treatment of the MetS and its sequelae.

Changing the Treatment Direction for Opiate Addiction: Dr. Dole's Research

ABSTRACTUnder the leadership of Drs. Vincent P. Dole, Marie Nyswander, and Mary Jeanne Kreek, in collaboration with the psychologist, Norman Gordon and sociologist, Herman Joseph at The Rockefeller University beginning in the 1960s, the first medical treatment for heroin addiction was developed. Drs. Dole, Nyswander and Kreek also developed the first hypothesis of opiate addiction as a metabolic disease. This biological revolution challenged beliefs about addiction, spurred further research and challenged legal positions of the judiciary and the broader criminal justice system (Dole & Nyswander, 1967).

BIOBOARD

ASIA – Gene mutation discovered to cause severe growth retardation in newly discovered disease. ASIA – Singapore scientists make major breakthrough to treat fibrotic diseases that cause organ impairment and failure. ASIA – DcR3 is the key factor of endometriosis. ASIA – Singapore Volition signs MOU with National Taiwan University to conduct two large clinical studies. EUROPE & CIS – NPL relaunches to accelerate access to new health innovations. EUROPE & CIS – The hard truth about Eczema: It’s something in the water. EUROPE & CIS – Gastric acid suppressant lansoprazole may target tuberculosis. EUROPE & CIS – Long-term aspirin use reduces incidence of digestive cancers by up to 47 per cent. AMERICAS – Rockefeller University biologist Michael W. Young honored with Nobel Prize for pioneering studies on circadian rhythm. AMERICAS – Ohio physicians contribute to groundbreaking stroke research. AMERICAS – A poorly explored immune cell may impact cancer immunity and immunotherapy. AMERICAS – Superbugs have a new foe. AMERICAS – Approved drug or herbal treatment: How to choose?

Blavatnik Foundation presents regional awards

Two chemical scientists are among the winners of the 2017 Blavatnik Regional Awards for Young Scientists, given annually by the Blavatnik Family Foundation to outstanding postdoctoral scientists from institutions in New York, New Jersey, or Connecticut. Chao Lu of Rockefeller University is being honored for his work in identifying chromosomal modifications leading to tumor formation. Andrew Ilott of New York University is being honored for his development of magnetic resonance imaging techniques to better understand mechanisms of battery failure. Each winner will receive $30,000 in unrestricted funds. Please send announcements of awards to l_wang@acs.org.

It’s About Time! Three Researchers Win Nobel for Circadian Clock Discoveries

It’s About Time! Three Researchers Win Nobel for Circadian Clock Discoveries

As Time Flew By

Most of my research support has come from the National Institutes of Health. In fact, NIH has supported me continuously since 1971. I was a pre-doctoral NIH trainee from 1971–1975 and had a postdoctoral fellowship from NIH at Stanford, and my first NIH R01 grant arrived shortly after moving to Rockefeller in 1978. This whole pathway of research opportunities was not uncommon in the 1970s. During my time at Rockefeller, I have had unwavering interest and encouragement from many of my colleagues, but especially Norton Zinder, Jim Darnell, Gunter Blobel, and Torsten Wiesel. I also had the good fortune to marry an immunologist in the 1970s, Laurel Eckhardt, now Hesselbach Professor at Hunter College, who has loved discussing the “clock problem” as it unfolds almost as much as I have. This work was supported in part by a grant from Calico Life Sciences.

Cell scientist to watch – Gregory Alushin

ABSTRACT Gregory Alushin received his bachelor degree in biochemistry from Columbia University in 2006. He then joined the laboratory of Eva Nogales to work on structural aspects of microtubules and kinetochores for his PhD in biophysics, and graduated from the University of California, Berkeley in 2012. Greg then moved to the National Heart, Lung and Blood Institute, NIH, Bethesda, as a postdoctoral fellow with Clare Waterman. In 2013, he received an Early Independence Award from the NIH, enabling him to establish his own laboratory. Greg has been an Assistant Professor at Rockefeller University, New York, since 2017. He has received the Norton B. Gilula Award from the American Society for Cell Biology, the Presidential Early Career Award for Scientists and Engineers, and was named one of Forbes' ‘30 under 30 in science and healthcare’ in 2014. Research in his laboratory focuses on understanding how actin responds to mechanical forces and how this response affects cellular signalling.

Profile of Charles D. Gilbert

Neuroscientists once thought that the brain’s wiring was fixed in early life, but the pioneering research of National Academy of Sciences member Charles Gilbert continues to show that the adult brain is remarkably dynamic. Evidence supporting that view is presented in Gilbert and colleagues’ studies of the neural mechanisms underlying visual perception, learning, and memory. Gilbert, the Arthur and Janet Ross Professor of Neuroscience at The Rockefeller University, and his team have discovered long-range, lateral neuronal connections within the visual cortex and have determined that this region of cells at the back of the brain is capable of altering its functional properties and circuitry. Gilbert and colleagues’ latest work strengthens evidence for a new general theory of brain function that helps explain the brain’s plasticity and provides insight into how recovery may occur following certain lesions and neurodegenerative disease, such as macular degeneration. Charles Gilbert. Image courtesy of The Rockefeller University. Gilbert’s parents were both academics who imparted their interest in science to their three sons. His father, a Chairman of the Psychology Department of Long Island University, served as a prison psychologist during the Nuremberg, Germany, war crime tribunal of 1945–1946 and was interested in the factors that influence human behavior. Gilbert was inspired by his father’s work, but from a young age he forged his own path in the sciences. “I was always drawn to biology, but not so much psychology, so it’s therefore interesting that my own work has migrated in the direction of perception and brain function in general, though coming from a biological perspective,” he says. Gilbert attended Amherst College, where he earned a B.A. in biophysics in …

2184

OBJECTIVES/SPECIFIC AIMS: To build a multisite deidentified database of female adolescents, aged 12–21 years (January 2011–December 2012), and their subsequent offspring through 24 months of age from electronic health records (EHRs) provided by participating Community Health. METHODS/STUDY POPULATION: We created a community-academic partnership that included New York City Community Health Centers (n=4) and Hospitals (n=4), The Rockefeller University, The Sackler Institute for Nutrition Science and Clinical Directors Network (CDN). We used the Community-Engaged Research Navigation model to establish a multisite deidentified database extracted from EHRs of female adolescents aged 12–21 years (January 2011–December 2012) and their offspring through 24 months of age. These patients received their primary care between 2011 and 2015. Clinical data were used to explore possible associations among specific measures. We focused on the preconception, prenatal, postnatal periods, including pediatric visits up to 24 months of age. RESULTS/ANTICIPATED RESULTS: The preliminary analysis included all female adolescents (n=49,292) and a subset of pregnant adolescents with offspring data available (n=2917). Patients were mostly from the Bronx; 43% of all adolescent females were overweight (22%) or obese (21%) and showed higher systolic and diastolic blood pressure, blood glucose levels, hemoglobin A1c, total cholesterol, and triglycerides levels compared with normal-weight adolescent females (p<0.05). There was a statistically significant association between the BMI status of mothers and infants’ birth weight, with underweight/normal-weight mothers having more low birth weight (LBW) babies and overweight/obese mothers having more large babies. The odds of having a LBW baby was 0.61 (95% CI: 0.41, 0.89) lower in obese compared with normal-weight adolescent mothers. The risk of having a preterm birth before 37 weeks was found to be neutral in obese compared to normal-weight adolescent mothers (OR=0.81, 95% CI: 0.53, 1.25). Preliminary associations are similar to those reported in the published literature. DISCUSSION/SIGNIFICANCE OF IMPACT: This EHR database uses available measures from routine clinical care as a “rapid assay” to explore potential associations, and may be more useful to detect the presence and direction of associations than the magnitude of effects. This partnership has engaged community clinicians, laboratory and clinical investigators, and funders in study design and analysis, as demonstrated by the collaborative development and testing of hypotheses relevant to service delivery.

2348

2348

A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use

BackgroundIt has become increasingly apparent that the trophectoderm (TE) at blastocyst stage is much more mosaic than has been appreciated. Whether preimplantation genetic screening (PGS), utilizing a single TE biopsy (TEB), can reliably determine embryo ploidy has, therefore, increasingly been questioned in parallel.MethodsWe for that reason here established 2 mathematical models to assess probabilities of false-negative and false-positive results of an on average 6-cell biopsy from an approximately 300-cell TE. This study was a collaborative effort between investigators at The Center for Human Reproduction in New York City and the Center for Studies in Physics and Biology and the Brivanlou Laboratory of Stem Cell Biology and Molecular Embryology, the latter two both at Rockefeller University in New York City.ResultsBoth models revealed that even under best case scenario, assuming even distribution of mosaicism in TE (since mosaicism is usually clonal, a highly unlikely scenario), a biopsy of at least 27 TE cells would be required to reach minimal diagnostic predictability from a single TEB.ConclusionsAs currently performed, a single TEB is, therefore, mathematically incapable of reliably determining whether an embryo can be transferred or should be discarded. Since a single TEB, as currently performed, apparently is not representative of the complete TE, this study, thus, raises additional concern about the clinical utilization of PGS.

Can De‐identified Electronic Health Records Be Used to Describe Nutrition‐Related Outcomes in a Cohort of Adolescent Women Attending Primary Care Facilities?

BackgroundElectronic health records (EHR) present a research opportunity to provide “rapid assays” for building prospective (historical cohort) studies. However, there are significant challenges to extracting and harmonizing data from different hospital and ambulatory care systems that need to be overcome before EHRs can be readily used to study nutrition‐related outcomes.Methoda community‐academic partnership with representatives from NYC Community Health Centers (n=4) and Hospitals (n=4), The Rockefeller University, The Sackler Institute for Nutrition Science and Clinical Directors Network (CDN), a primary care practice‐based research network (PBRN), was established to build a multisite de‐identified database extracted from the EHRs of female adolescents aged 12–21 years and their offspring through 24 months of age, receiving primary care between 2011 and 2015.Representatives convened through 2015 and 2016 to provide guidance on hypothesis development, variable selection, data extraction and review analyses, focusing on nutrition outcomes during pre‐conception, prenatal and postnatal periods.ResultsThe cohort included 32,030 unique female adolescents 2,291 (7.2%) of whom were pregnant adolescents. The majority were from the Bronx (60%). Keywords, ICD‐9 codes and laboratory procedure codes were provided to Health IT experts to extract clinical data on diabetes, hypertension, hyperlipidemia, gestational diabetes, and delivery and birth outcomes. Systolic blood pressure (SBP) was retrieved for 95% of the cohort (with data retrieval in each site ranging from 90% to 98%). Laboratory results for Hemoglobin A1C, total cholesterol, triglycerides, and fasting plasma glucose were retrieved for 11%, 16%, 12%, and 17% of patients respectively, with large variability among the sites (from as low as 0.4% to 50%).Data analysisAmong the cohort, 3% were underweight, 55% normal, 21% overweight and 20% obese. Higher mean SBP and a higher blood glucose levels, hemoglobin A1c, total cholesterol, and triglycerides levels were observed among overweight and obese patients compared to normal weight females (p<0.05). Obese adolescents were less likely to have low birth weight babies compared to normal weight females (OR=0.50, 95% CI: 0.29, 0.87). Underweight and normal weight mothers had significantly higher rates of low birth weight babies and overweight/obese mothers had higher rates of large babies (chi‐square p=0.01).Conclusionthe use of EHR is feasible as a rapid assay to describe nutritional outcomes in under‐studied populations. Preliminary results appear to confirm the directions and size of associations noted in large observational studies, and will help generate additional hypotheses. Taking a highly collaborative approach with clinicians, IT experts, basic science and clinical researchers has been critical to accomplish data extraction, harmonization' analysis and quality improvement.

How do mosquitoes smell us? The answers could help eradicate disease

In the coastal Rabai region of southeast Kenya, two populations of mosquitoes live within a half mile of each other but lead separate and curiously different lifestyles. Entomologists in the mid-20th century found that color distinguished the two subspecies of Aedes aegypti ( Aedes aegypti aegypti are brown and Aedes aegypti formosa are black) as well as the hosts they chose for blood meals. The “domestic” brown form frequented people’s homes, preferentially feeding on people and laying their eggs in indoor water receptacles. Meanwhile, the black-colored “forest” form roamed the nearby woods preferring to bite nonhuman animals and lay its eggs in tree trunk holes. This light sheet microscope image of an adult female Anopheles gambiae mosquito includes genetic labeling to show olfactory neurons (green). The antennae, maxillary palp, and labella on the proboscis contain many such neurons. Image courtesy of Olena Riabinina, Courtney Akitake, and Chris Potter (Johns Hopkins University School of Medicine, Baltimore). Following up on these reports some 50 years later as a postdoctoral fellow at The Rockefeller University in New York, Lindy McBride saw an opportunity to examine this natural case study with modern genetic tools. The feeding habits of Aedes aegypti aegypti make it a dangerously efficient vector for spreading yellow fever, dengue, Zika, and other diseases between humans. The other subspecies poses much less of a threat. To understand why, McBride traveled to Rabai to collect mosquito larvae and pupae from people’s homes and the nearby woods. She wanted to compare the two mosquitoes genetically and discover what changes had led the more recently evolved domestic form to hunt humans. Back at Rockefeller in the laboratory of her then-postdoctorate advisor Leslie Vosshall, McBride raised 30 strains of mosquitoes from the samples and used RNA sequencing to compare the genes expressed in their antennae (a major …

Computers predict molecules’ scents from their structures

A team of researchers and volunteers from across the globe have trained computers to predict the way a molecule will smell based on its structure. The feat may help scientists unravel the still-mysterious relationship between molecular structure and odor perception (Science 2017, DOI: 10.1126/science.aal2014). This achievement in machine learning could also be a boon to the fragrance industry, saving time and money that would otherwise be spent on laborious human sniff testing. It even suggests that computers might one day identify molecules by their odor. To tackle the complex and poorly understood phenomenon of olfaction, an international team led by Pablo Meyer at IBM and Leslie B. Voshall and Andreas Keller at Rockefeller University devised a crowdsourced project, the DREAM Olfaction Prediction Challenge. They assembled a huge set of human odor perception data by arranging for 49 people to sniff 476 molecules in separate vials. These human sniffers categorized each

The Personal Toll Of Practicing Medicine.

A physician and lifelong patient reflects on her truncated career and why the health of experienced doctors needs protection.