Opening Remarks & "Shooting Science”
By Amanda M. Dettmer, PhD
The retreat began with welcoming remarks by the Scientific Director, Dr. Constantine Stratakis, who focused on “moving forward.” He emphasized the role of the “DIR Interactome,” a reorganization of the Division of Intramural Research to foster collaborations among intramural laboratories. He also highlighted the NICHD Intramural program’s potential for meeting the Precision Medicine Initiative, a new approach to medicine that takes into account genetic, environment, and lifestyle variability. Dr. Stratakis concluded with remarks on the NICHD DIR’s public outreach efforts through diversity initiatives and the Three-minute-Talks (TmT) Competition—a nice transition into the morning keynote speaker.
Professor Graham Chedd, an acclaimed science documentary film producer, editor, writer, and visiting professor at the Alan Alda Center for Communication Science, kicked off the retreat with his talk, “Shooting Science.” Chedd captivated the audience with a decade-old story of his time working with Alan Alda, star of the hit TV show M*A*S*H. They were at an observatory in Chile filming the opening for an episode of Scientific American Frontiers (SAF) called “The Dark Side of the Universe.” In the middle of shooting, they had to abort the trip as Alda had developed an erupted intestine that required immediate—and, ultimately, life-saving—surgery.
Chedd told the audience that this event drove Alda to his numerous achievements over the past decade: documentaries, films, series, books, and awards, all dedicated to his passion for communicating science. “All of us have had some personal event that put us on our current track,” Chedd said.
For Chedd, the event was receiving the book “One, Two, Three, Infinity” by George Gamow at the age of 16 as an academic prize. This book, Chedd said, described how science was full of big ideas that kids don’t get exposed to in school. The book inspired Chedd to learn—and eventually communicate—these big ideas. “I pursued a career in the nascent field of science journalism.”
Chedd then described some of the most memorable experiences of his career. One of these was sitting down with James Watson and Francis Crick to talk about their research discovering the structure of DNA. Another was founding the show SAF, dedicated to communicating science to the public in a similar fashion to Scientific American magazine. Of the 20 people the SAF staff contacted about hosting the show, Alan Alda was the only one to respond, but with the stipulation that, “If it’s not going to emulate the magazine, I’m not going to do it. I’m a big fan of the magazine.”
Alda further insisted on being as hands-on as possible, coming to all the shoots, meeting all the scientists, and talking to them himself. Alda took the reins in these interviews: rather than adhering to scripted conversation, he would be briefed ahead of time about the importance of the scientist’s work, and once on site, he would have long, in-depth conversations with the scientist to develop his own understanding of the subject. Through his getting that understanding, Alda knew the audience would, too.
Alda’s method of interacting on a personal level with scientists to tell their story really transformed how science is communicated, Chedd explained. He showed a beautiful example of Alda “at work” with a clip from a 2001 episode of SAF about the Human Genome Project, featuring NIH’s own Dr. Francis Collins, along with Dr. Eric Lander. In this clip, Dr. Lander described the technology to Alda as “highly automated toothpicks” collecting bacterial samples for later genetic analysis.
Chedd finished his talk with a personal story, that of his daughter, born with cerebral palsy, now 24 and at the Massachusetts Hospital School Foundation. This school is dedicated to providing services and education for children with all manner of disabilities. Chedd showed a clip from a documentary of the school that he and Alda created, depicting the highlight of the year: Prom Day. Chedd described the hospital as “an opportunity of a lifetime,” giving these kids independence, friends, and social opportunities. As the audience watched the video of these exuberant children, oblivious to their developmental disabilities, Chedd concluded, with a teary, wavering voice, “These are the people that your research is going to help.”
Morning Fellow Talks
The “Handed” Fish
By Cathy Ramos, PhD
Ninety-nine percent of the human population shows asymmetric locomotor preference that is independent of age, race, and gender. This lateralized preference is also described for other vertebrates and invertebrates. Dr. Eric Horstick from the Burgess laboratory began the morning fellow session by describing the first fish model of innate lateralized locomotor behavior—a “handed” fish, so to speak. Dr. Horstick takes advantage of the stereotyped zebrafish neuronal connections, the transparency of zebrafish larvae, and computational analyses to study primary behaviors.
Dr. Horstick was first interested in why asymmetric locomotor preference exists and how it works. He described a simple experiment in which he tracked larvae in a water bath in the presence or absence of light. While light evokes larvae movements, the loss of illumination induces territory exploration. The tracking record revealed that the first turn of the larva was in the same direction in both cases (light ON or OFF). These results strongly suggest a turn behavior bias.
By performing a recording paradigm to separate “lefties” from “righties,” Dr. Horstick showed that larvae have an innate preference that does not change from day to day. But how does that bias develop?
Dr. Horstick examined sensory development, genetics, asymmetric retinal sensitivity, and structural asymmetry. First, when he mated lefties with righties, the larvae did not show a selection for directional bias in the first generation—indicating the trait is not inherited in a Mendelian manner. Second, Dr. Horstick studied blinded larva and observed a progressive loss of directional bias without retinal input. Thus, visual input potentiates the bias, although asymmetric retinal input does not appear to be the driving factor. Future directions include studying the role of deep brain photoreceptors and examining asymmetric brain structures.
But maybe the most important question for Dr. Horstick, as asked by one of the fellows, is: “Do you plan to perform the same experiments in the southern hemisphere?”
A New Way to Look at the Brain
By Joanna Cross
Due to the brain’s sheer intricacy, understanding cognitive variations in neurodevelopmental disorders is a daunting task. Afrouz Anderson has risen to the challenge with a novel approach to analyze cognitive function associated with Autism Spectrum Disorder (ASD).
ASD is characterized by problems with social interaction and communication skills. Its specific cause is unknown, but the disorder usually appears within the first few years of life. Currently, the earliest ASD detection relies on psychological evaluations of the child, but it is likely that there are changes within the brain much earlier.
Two common methods to evaluate brain function include Functional Magnetic Resonance Imaging (fMRI) and Positron Emission Tomography (PET). Because fMRI and PET scans require a patient to be still for extended periods of time, patient movement during examination presents a major challenge in ASD research.
Ms. Anderson is using her background in electrical engineering to develop a more convenient brain imaging method using functional near-infrared spectroscopy (fNIRS). This noninvasive method uses the absorption wavelengths of oxy- and deoxy-haemoglobin to evaluate oxygen flow to the pre-frontal cortex of the brain.
In order to evaluate the oxygen saturation in the brain efficiently, Ms. Anderson and her group have designed a new metric, the Oxygen Variability (OV) Index. Because the OV index varies among different physiological processes, the team can use OV index information derived from fNIRS measurements as a novel way to analyse brain development.
Ms. Anderson’s first fNIRS study on 17 typically developing children ranging from four to eight years old showed that brain development relating to cerebral autoregulation (the process of maintaining cerebral blood flow) increases up to a peak at six years old, followed by a subsequent decrease. In a second pilot study, she compared four subjects with language delay to five age-matched typical controls. She discovered a smaller OV index in the language delay subjects with unilateral brain activation. In contrast, the typical subjects showed activation in both hemispheres.
Although a penetration depth of 2.5 cm limits fNIRS, these experiments show the promise of using the OV index to monitor brain development and detect impairments of cerebral autoregulation.
The Weaker Sex?
By Emily Mitchell, PhD
In the third fellow talk of the morning, Dr. Rose Radin explained the biological underpinnings of conception and implantation of a human embryo. The endometrium, which lines the uterus, has the capacity to reject recently fertilized embryos if they are deemed unviable. The likelihood of an embryo being rejected has been linked to an inflammatory response in women, where a heightened inflammatory status is more likely to result in a rejected embryo.
Recently, the NICHD conducted a randomized, placebo-controlled trial evaluating the effect of low-dose aspirin on live birth rate among women with a history of pregnancy loss. The research team found that aspirin, an anti-inflammatory agent, is associated with an increased probability of a live birth among women with one pregnancy loss in the past 12 months. Unexpectedly, this increase was mostly due to an increase in male live births, while there was no effect on the likelihood of a female live birth. Investigating this phenomenon, Dr. Radin discovered that women taking aspirin were 30 percent more likely to have a male baby than those taking placebo.
To better understand the potential biological mechanisms underlying this association, Dr. Radin looked into the relationship between C-reactive protein, a biomarker of inflammation, and sex ratio, the ratio of male babies to female babies. In the placebo group, women with higher inflammation were 40 percent less likely to have a male baby than those with lower inflammatory levels. However, there was no difference by inflammatory status among women taking aspirin.
Dr. Radin hypothesized that male embryos may be more vulnerable to higher inflammation, which previous studies have shown could be a factor in embryo rejection. Therefore, taking aspirin, an anti-inflammatory agent, could reduce the number of male embryos that are rejected.
Afternoon Fellow Talks
An Ongoing Arms Race
By Torie Comeaux Plowden, MD, MPH
Endogenous retroviruses (ERVs) have integrated into mammalian DNA and comprise almost one-tenth of the human genome. ERVs are known to change host gene expression and have been associated with human disease. In order to protect the genome, humans had to develop a defense mechanism. Dr. Gernot Wolf, a member of Dr. Todd Macfarlan’s lab since 2013, presented new work on this very interesting topic. In his presentation, he discussed “an ongoing arms race between KRAB zinc finger proteins and endogenous retroviruses.”
KRAB zinc finger proteins (ZFP) work to epigenetically repress the expression of ERVs in mammals. Dr. Wolf found that one such protein, ZFP809, binds to a specific sequence of the ERVs. When conducting experiments involving ZFP809 knockout mice, he found an increase in ZFP809-targeted ERVs, although the mice had normal development. In another series of experiments, Dr. Wolf determined that not only is ZFP809 necessary to initiate ERV silencing, it also actually silences a few non-viral host genes that acquired ZFP809 binding sites secondary to ERVs. Additionally, he characterized several murine KRAB-ZFPs and demonstrated that they only bind to specific ERVs. His group concluded, “ERVs drive evolution and diversification of mammalian KRAB-ZFP.” Future experiments are planned to further study KRAB-ZFPs using CRISPR* technology.
Editor’s Note: To learn more about CRISPR technology, check out the article “Earning Your Stripes as a Scientist-in-Training” from this year’s April issue.
Putting the Brakes on Inflammation
By Cathy Ramos, PhD
Dr. Alex Szatmary from the Nossal laboratory continued the afternoon fellow session with a peek into the regulation of inflammation.
Inflammation is an innate immunity response to cell injury, Dr. Szatmary explained. In the case of an endothelial inflammation (the type seen with cells lining the inside of blood and lymphatic vessels), circulating neutrophils (an abundant white blood cell) roll along inflamed tissue and bind the endothelium via membrane surface proteins that are differentially expressed.
Dr. Szatmary focuses his work on two mechanisms: 1) chemotaxis used by neutrophils to detect the inflammation site and 2) the physical force mediated by cell surface molecules to stop the neutrophil at the right place, a process he terms “braking.” In particular, Dr. Szatmary studies P-Selectin proteins expressed on neutrophil membranes. These proteins belong to the cell adhesion molecule family of proteins and are crucial for the initial recruitment of neutrophils to the inflamed endothelium.
Dr. Szatmary showed that P-Selectin proteins function as a monomer or a homodimer. The monomeric P-Selectin allows a slow brake, while the dimeric form triggers a stronger one. He demonstrated that the neutrophil rolling velocity is inversely proportional to the dimerized fraction of P-Selectin. Thus, the P-Selectin dimerization rate is more significant than the concentration of P-Selectin itself. If you have any questions, Dr. Szatmary would be delighted to meet you over a cup of coffee.
A Stressful Start for Yeast
By Megan Sampley, PhD
Dr. Shardul Kulkarni, a postdoctoral fellow in Dr. Jon Lorsch’s laboratory in the Section on the Mechanism and Regulation of Protein Synthesis, shared his recent findings regarding how environmental stress affects the ability of yeast to properly translate mRNA into protein. Specifically, Dr. Kulkarni is interested in the effects of temperature on start codon fidelity during translation initiation.
In normal translation initiation, the ribosome starts translation at a canonical start codon, AUG, which is most often preceded by a 5’ untranslated region. In Dr. Kulkarni’s work, he found that hot or cold stresses in yeast cause a decrease in start codon fidelity and that alternative codons are used to start translation. In order to address possible regulators of this process, Dr. Kulkarni performed a screen of yeast kinase deletions to determine particular kinases that play a role in this process. He identified several candidate kinases that may play a role in elevated temperature stresses on translation initiation—most notably a casein kinase 2 subunit called CKB1.
Dr. Kulkarni also used a bioinformatics approach to establish a list of mRNA candidates whose translation is affected by temperature stresses. Further characterization of these results will add to our understanding of translation initiation, which will aid in understanding and potentially treating genetic diseases caused by point mutations in start codons.
Afternoon Career Keynote
How to Be Career Savvy
By Alex Szatmary, PhD
The formal activities for this year’s retreat concluded with the career keynote, entitled “Careers in the Life Sciences: Finding Your Way,” delivered by Dr. Toby Freedman, the founder and president of Synapsis Search and author of Career Opportunities in Biotechnology and Drug Development. Dr. Freedman energized our fatigued fellows with a lively and inspiring talk—she offered gold coins (chocolate) for audience members who participated in discussions and had fellows practice networking conversations and shaking hands. During her keynote, Dr. Freedman offered various tips on being career savvy.
First impressions and networking
Regarding initial networking conversations, Dr. Freedman explained that novices often offer too much or too little information. She recommended being brief and focusing on what people want to hear: your subdiscipline, your model organism, and unique techniques you have mastered. To wind down lengthy conversations, Dr. Freedman jokingly suggested looking at your watch, and if that doesn’t work, saying, “I’m sorry, I have to move on.” She did get a chuckle from the audience. In all seriousness, though, it’s important to gauge the level of interest of others during conversation and to end conversations at an appropriate time.
Networking is especially important when one is entering a new field. Often researchers lack contacts in a field other than their own. Dr. Freedman recommended attending the new field’s professional meetings to make those contacts.
Seeking and applying for a job
Calling it “the new resumé,” Dr. Freedman gave special advice on how to use LinkedIn when seeking a job:
- Provide as much information as possible. This makes you more likely to appear in searches.
- Post your email address. It costs recruiters five dollars per person to contact individuals via LinkedIn, but they can reach those who post their email address on their profiles for free.
- Don’t link to profiles that are likely fake.
- Link to everyone you know. This makes it easier for you and them to make contacts on LinkedIn.
Dr. Freedman also offered a few tips regarding job applications. When applying for a job, especially at a large organization, indicate the requisition number (found in the job posting) in the cover letter and put an objective in the resumé to help your application get to the right place.
Not only did Dr. Freedman offer practical tips, she also provided inspiration. During her talk, she reviewed several cases in which individuals brought about beneficial innovations to humanity. Dr. Freeman talked about Elizabeth Holmes (Theranos), Anne Wojcicki (23andMe), and Bill Gates (Microsoft), to name a few revolutionary individuals. Dr. Freeman closed her talk with these words of wisdom: “If you truly believe in your vision, you can make a big difference.”
You can find out more about Dr. Freedman’s recruiting services at www.synapsissearch.com. Information about her book, Career Opportunities in Biotechnology and Drug Development, is at www.careersbiotech.com. Dr. Yvette Pittman has several copies for fellows to borrow.