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Top Techniques: Confocal Microscopy

by Alenka Lovy

What is confocal microscopy?

Reading and thinking about cell biology is very interesting no doubt, but I find that to be able to see biological processes by live microscopy just amplifies the questions at hand so much! Have you ever seen movies of cells dividing? I remember when I first did. It was hard to go from the picture perfect diagrams of the textbook to the real thing, but after a few times of watching the movies I saw the perfect (or not so perfect) progression through all the steps. Maybe it was the timing of it, or just being able to see the tangle of chromosomes trying to line up, and then the sudden division, I found it so breathtaking! Live cell microscopy has been my tool of preference to answer many biological research questions ever since.

Confocal microscopes in particular are powerful because they optically slice through a specimen (even live cells) and allow 3D image reconstruction in up to four different fluorescent channels. Confocals are built to scan point by point through your sample using laser light, and image just one particular plane of focus. This is very different to the standard fluorescent microscope which illuminates and images the entire sample at once, including out-of-focus light. The confocal is used to obtain clearer images of subcellular details that cannot be imaged with the fluorescent microscope and is especially useful for co-localization studies. There are many exciting techniques you can use with the confocal including fluorescence recovery after photobleaching (FRAP) with which you can observe protein mobility and recovery, fluorescence resonance energy transfer (FRET) which can show protein interactions, as well as photoactivation/uncaging studies.


BOX 1: What confocal can do for you (and your mitochondria)

Using a photoactivatable GFP targeted to the mitochondria to measure mitochondrial fusion is a nice demonstration of the precision and quantitation that can be achieved using a confocal. Mitochondria are amazingly motile and networked and look like spaghetti . They also undergo constant fission and fusion, which can be difficult to capture. The top panel in the figure below shows the mitochondrial network (z stack) labeled with TMRE in Hela cells imaged every 15 min for 1 hr. It is impossible to capture which mitochondria are fusing.

red

green

However, if a small portion of the network is photoactivatedand then imaged in z stacks over time, the signal can be monitored over time (bottom panel in the above figure). As the mitochondria fuse, the GFP protein becomes diluted in the larger volume of the network that has not been photoactivated, and the extent of dilution can be quantified and used as a measure of mitochondrial fusion.


What facilities does Tufts have for confocal microscopy and other imaging techniques?

The Tufts Imaging Facility has four confocal microscopes and most are equipped with the standard 405nm, 488nm, 561nm and 633nm laser lines, which is important to know when choosing fluorophores. Using the Fluorescence SpectraViewer online will help you determine if the emission spectra of your fluorophores overlap such that crosstalk between them can be minimized. We have two inverted microscopes equipped for live cell imaging, and two upright microscopes that are usually used for fixed samples and 3D reconstructions. While imaging living cells, you can use an automated focusing mechanism which employs an infrared laser that keeps track of the coverslip, and therefore your sample. If you’ve ever had to adjust the focus yourself over several hours, you know just how powerful this feature is!

The Nikon A1R inverted confocal has a resonant scanner capable of high speed imaging (500 frames/sec at 512×512 pixel resolution) suitable for ion imaging and is being used for calcium imaging in cardiomyocytes. It also comes in handy during very long tiled scans with z-stacks, and although the image quality is slightly sacrificed, depending on the resolution needed, the gain in speed may well be worth it.

The Leica SP8 inverted confocal has a HyD sensitive detector and can be used with very low laser powers allowing longer imaging of easily bleached samples. For example, measuring how quickly a photoactivated GFP spreads within the mitochondrial network every minute over an hour would bleach the signal before all the information was collected on a regular detector compared to a HyD detector.

Another good technique to avoid bleaching in live cell imaging is to use the total internal reflection microscope (TIRFM). On this microscope, you can adjust the angle of laser light with which you illuminate your sample. There is a particular angle at which all the laser light is internally reflected, except for a 100nm evanescent wave. With this you can then image processes close to the membrane, such as receptor insertion/cycling. Very often you can image a little bit deeper than the 100nm, and because the laser is at an angle, you will not bleach your specimen as fast. As opposed to confocal, the TIRF system has a sensitive EMCCD camera, enabling faster imaging (I have been looking at calcium sparks at 50 ms/frame).

The Leica upright microscope has water immersion objectives that have a large working distance and work well for thick cleared samples such as mouse brains or zebrafish embryos.

Finally, in addition to standard fluorescent microscopes, we also have the automated Keyence fluorescence microscope which can scan up to 3 slides and stitch large images together in four channels as well as in brightfield. If large tiled scans are needed, this may be the instrument of choice due to the speed and ease of use.

For more information about the instruments in the Tufts Imaging Facility, please visit our website. If you would like to use an instrument or need help planning an experiment please email me at:

Alenka.Lovy@tufts.edu.

If you’d like to learn more about microscopy in general, the Molecular Expressions Microscopy Primer is a great resource.

GSC holds first advertised open meeting in 3 years

On March 3, 2016, the Sackler Graduate Student Council (GSC) held an advertised open meeting and invited the Sackler student body to attend. While all GSC meetings are open, according to the bylaws, and club/organization leaders attend the first meeting of academic year, this was the first time in 3 years that the GSC meeting was publicly advertised. When asked about the motive behind this action, Michaela Tolman, current GSC President, stated “we serve the students, so we wanted to offer a way in which they could express their opinions while also giving them a flavor of what GSC does and how it is run.” While the turnout was modest, she did mention that it was more than what she had expected.

Traditionally, GSC meetings  mostly comprise of financial updates from the treasurer, different committees (career paths, social, newsletter, etc.) reporting on their previous events and discussing their future plans and setting up action items to be completed before the following meeting. This meeting  followed the same pattern and after the committee updates, the floor was opened up to the non-GSC attendees.

Most of the non-GSC attendees shared that they were curious about the inner workings of the GSC and had either been invited to the meeting by a GSC member to the meeting or attended on their own initiative; some of them were also interested in joining the council the next academic year. Almost all class years and programs were represented in the attendee group.

Given that a major focus of the GSC is to organize and hold events focusing on career building and networking, it was no surprise that most of the suggestions from attendees were focused on that topic. Suggestions were made for events to improve social media networking, seminars on data management and presentation skills and early stage career development, and most emphasis was placed on the interactive nature of the events and their diverse nature. Other suggestions included a consolidation of seminar schedule, especially student talks, across programs and departments, including the hospital seminars.

GSC’s commitment on serving students manifests itself in it’s quick response to the students’ feedback at the meeting. CMP rep Dan Wong, has already put together a google calendar program that allows consolidation of all seminars that are listed on the Sackler calendar and can be easily integrated with an individual’s calendar (here is how to do it).  When asked about the outcome of the meeting, Tolman mentioned “I had no idea what people would bring up – which shows that we always need to seek student input. Some things were helpful for directing our current efforts – career paths heard positive things about diversifying the type of events that they hold while also focusing more on skills. The coordination between programs was discussed, and I am really excited to put into action the student suggestions.” She also hoped that some of the attendees would join the GSC in the future, and that most, if not all, attendees would see GSC as “a fun and an exciting opportunity to take part in”.

Overall, the open meeting seemed to have served its purpose in getting student feedback. The necessity of such a meeting, at least once a year, was echoed by both the GSC President and the attendees; Tolman believes that a town hall style meeting will be more effective in increasing student engagement and getting more input from students as “it would help better direct what we do and better serve the students’ needs”. Attendees who were contacted as a followup of the GSC meeting agreed that this year the GSC has become more interactive and applauded the various efforts GSC has undertaken to integrate students better and become more interactive, such as through The Goods email format, the Instagram account and voting on the location for Relays.

The bylaws of the Sackler GSC clearly show that this organization is for the students and by the students, and therefore, there should be no doubt that increasing student engagement in not only its events, but also its governance should be made a priority. In the past, there have been GSC events where student attendance and engagement have fallen short of expectation, whether it be due to lack of advertising or a distancing of the GSC from the student body it represents. This publicly advertised open meeting is, in my opinion, a definite right step towards the actual fulfillment of this organization’s mission.

Versatile PhD – a Non Academic Career Resource for Doctoral Students

Guest Post by Christina McGuire, CMP

Versatile PhD, a tool for graduate students to explore non-academic careers, began as a listserv while Founder and CEO Paula Chambers was finishing her dissertation at Ohio State University. Her goal was to create a safe space where PhD students could discuss non-academic career options without feeling pressured to go into academia. From this original idea, the company has blossomed into an active resource where PhD’s from all backgrounds can come together in a supportive environment to learn, discuss, and network based on their interest.

While most of the website content is unavailable without a subscription, the website still has much to offer for those beginning to explore career options outside of academia. The PhD Career Finder lists many career opportunities available to STEM and Humanities PhD’s with information about what the career entails, how to advance, what background is best suited for the career, and how best to prepare yourself and your resume for following that path. It is an excellent resource for those who are interested in exploring what their future options are.

Additionally, with a paid subscription you gain access to resumes and cover letters and narratives from of the hiring process from real PhDs. You can post questions to any of the Forums, and network with members within the Versatile PhD network. While Versatile PhD is a national business, they also run regional meetups, where you can network in person.

So how can this site help you as a Tufts student or postdoc? Come to hear Paula herself speak about the mission, founding, and resources that Versatile PhD has to offer on March 16. Additionally, we will be hearing from Tufts post-doc and Versatile PhD Volunteer Sarah Dykstra on how she uses and benefits from Versatile PhD.

Notes from the North – Reporting at the Molecular Level

March’s Notes from the North article is written by guest writer Spencer Scott, a current member of the Liaw Lab at MMCRI and recent transplant to the field of molecular medicine. He worked for seven years in New York as a producer for NPR, CNN, and ABC and is now a pre-med post-baccalaureate studying Biochemistry at the University of Southern Maine. Spencer will be applying to M.D. programs this spring.
Spencer CNN

CNN cameraman Spencer Scott reporting on the blackout in Manhattan following Hurricane Sandy in 2012.

Spencer Scott

Tom McCarthey’s brilliant film Spotlight took best picture at the Oscars this year. In an age when news has become synonymous with 24-hour cable networks plastered with pundits and steadily declining newspaper readerships, Spotlight is an important homage to the important role of real journalism in American society. For over seven years I worked as an aspiring producer for outlets including NPR, CNN, and ABC. While I would never dream of comparing my young career to the work of the incredible reporters at the Globe’s investigative unit, there is still a common aspiration amongst all those who enter the field. As their name, “Spotlight,” implies, we wish to shine light where there once was darkness, to illuminate the unknown for the betterment of our society.

A little more than a year ago, I left the craft to which I had thought I would devote my life. I spent the final four months of my career in television news shooting a medical documentary series for ABC in three of Boston’s Level I trauma centers. It was there in those halls that I finally decided to follow in the foot steps of my mother, father, and brother, and pursue medicine. I left my work in television and returned to my home state to begin a post-baccalaureate pre-medical program at University of Southern Maine, which I will finish in May.

It may seem odd that the child of an orthopedic surgeon and emergency room physician grew up shying, if not flat out running, away from the sciences. I still struggle to answer that for myself. But the only answer I can give is that I didn’t think my mind was wired in that way. I loved history and language and stories, and when I thought I could help people by telling their stories, I believed I’d found my calling. I sold my first story to NPR when I was seventeen, an interview with an Iraq war veteran, only three years older than I was. He had nearly lost his life in an IED explosion in Fallujah, the shrapnel of which had torn through his throat, rendering his voice a quiet rasp. Because of my reporting, millions of “All Things Considered” listeners heard Cpl. Chris Kotch tell his story. It was a feeling that inspired the pursuits of the next decade of my life.

In fact, after all of my years working in the field, I’m still proudest of the reporting I did when I was just a kid in high school. None of the stories I told in my professional career carried the weight that my earliest, self-directed work did. Working for big networks, the feeling that you had helped someone share something vital, that you had illuminated what was once shrouded in darkness, became rare, especially for a young producer. But in Boston, as I watched the doctors in my camera’s viewfinder treating their patients I saw something so exhilarating. It may sound cliché, or like a line from “We Are the World,” but I saw people helping people, through my lens and live before my eyes. I do not mean to discount the importance of journalism, I believe steadfastly in the critical role it plays in our society. But for me, witnessing those human connections made walking away from the field easy. I knew my place lay on the other side of the lens where the help was delivered every day directly and in real time.

Back in Maine, I threw myself headlong into my studies. When I walked into my first class at USM (BIO 105 Cell & Molecular Biology) I didn’t yet know if I had a mind for science, but I was willing to do whatever it took. Fortunately, I soon learned that in academia, you can do whatever you set your mind to, as long as you are willing to put in the work and the passion is genuine. Finding science has been the most fulfilling and gratifying experience of my life and I have been rewarded for the work I’ve put into it. When I started my program a little over a year ago, I never could have dreamed that I would be interning at a place like Maine Medical Center Research Institute, involved in the incredible work its investigators perform every day. In one sense, my work at the Institute is the farthest I have yet strayed from the newsroom. Whether it is furiously scribbling down names of promoters or genes or antibodies to google, or looking at slides of fluoresced cells and western blots, every Monday lab meeting reminds me that I am not in Kansas anymore. But in another sense, the work of the researchers at MMCRI is akin to that original creed of the aspirant journalist. Science and research, like journalism, work to shed light where there once was darkness. Both disciplines endeavor to peer into the unknown and learn what lies within. Whether it be learning the struggle of an American veteran who can no longer sleep through the night, or learning the process by which the notch signaling pathway impacts the function of endothelial cells in vasculature, science and journalism share the understanding that we are all better off for knowing.

Zika: Coming This Summer to a Mosquito Near You

Guest Post by Ila Anand, Micro

A startling number of viral epidemics have made major media headlines in recent years. In 2014, the Middle Eastern Respiratory syndrome coronavirus (MERS-CoV) was quickly brought to America’s attention after two reported cases in Indiana and Florida. 2015 was the year the world went into Ebola frenzy and U.S. hospitals took extreme precautions to manage suspected infected patients. This year, the Zika virus has caught the CDC’s eye and for good reason. As Zika continues to spread from Brazil through the Americas, its arrival in the U.S. this summer is inevitable. Although no vector-borne cases have been reported inside the U.S. yet, over 150 travel-associated cases have been reported. Public health departments across the U.S. should brace for the next likely step: the moment when Zika passes from traveler-infected blood to a local mosquito and then to another person.

The Zika virus was first isolated in Uganda in 1947 from the Zika Forest, where researchers from the Rockefeller Foundation were studying yellow fever. These researchers experimentally used rhesus monkeys that were set out in cages in treetops as bait for mosquitos carrying yellow fever virus. Ironically, instead of yielding yellow fever virus from the blood of these monkeys, the researchers discovered Zika and speculated the virus had been lurking chronically in African monkeys for millennia. The virus was later isolated from mosquitoes of the Aedes genus in the same Zika forest and Aedes has since been identified as the vector of Zika. Eventually, Zika virus was discovered to infect humans across the African continent as well as in South Asia and Southeast Asia. More recently, circa April 2015, the virus has spread to the South America.

In humans, the virus manifests infection known as Zika fever, which often produces no symptoms to mild symptoms, such as headache, fever, rash, bloodshot eyes, and joint pain. Recently, the spread of Zika in South America has been linked to the growing number of infants born with microcephaly in Brazil. Microcephaly is a neurological condition in which the brain and skull fail to grow at a normal pace, resulting in a significantly smaller head size. At first the link to Zika was purely correlation, however, a recent report published in Cell Stem Cell directly demonstrated that Zika is able to infect and kill lab-cultured human neural progenitor cells. These neural progenitor cells were derived from induced pluripotent stem cells (iPSCs) and scientists tested Zika’s “tropism” by comparing percent infection across four cell types: neural progenitor cells, immature neurons, embryonic stem cells, and human iPSCs. While less than 20% of iPSCs, embryonic stem cells and neurons became infected, up to 90% of neural progenitor cells contained the virus and Zika either killed these cells or slowed their proliferation significantly. These findings may begin to unearth some possible mechanisms to how Zika infects and damages fetal brain tissue. Since neural progenitor cells give rise to a larger population of neurons and glial cells in the brain, infection of these cells could impact the neurons they produce and possibly affect brain development. In addition to microcephaly, Zika has also been linked Guillain-Barré syndrome, a sickness in which the person’s own immune system damages nerve cells, causing muscle weakness and sometimes paralysis. However, clinical findings from Brazil are still preliminary and there’s a need for more compelling evidence.

Sources –

 

Sackler website calendar now available in iCal format

The Sackler calendar is a great resource for the community, but its current form does not follow Internet calendar format standards, which limits its utility.  A majority of Tufts community members utilize digital calendar packages like Google Calendar, Apple Calendar, Microsoft Outlook, Mozilla Thunderbird, and others, to keep track of their schedules and subscribe to shared calendars, but the Sackler calendar cannot be used with these programs because it is served as an RSS feed and not an iCal one. The RSS standard was designed for syndication of articles and other news-like data, while iCal is the standard for Internet calendars. Fixing this mismatch will require structural changes to the Sackler website, but the timeline for such changes is not known.

To solve this problem, I have written a script that automatically retrieves the publicly available event information from the Sackler calendar and presents it in a format that calendar programs can utilize. I’ve also made some improvements to the presentation of events, so seminar title will now appear in the event name if it is available. Additionally, the room number will appear alongside the building address in the location field of the event, and has been formatted in a way that allows mapping programs to ignore the room and focus on the address if directions are needed. This code will work until the Sackler calendar URL or the event information formats change, but my hope is that the script will no longer be necessary once that happens. The iCal feed is available at http://sackler.danielsenhwong.com/calendar.ics, and can be imported as a calendar subscription in most calendar software packages. This feed is set to automatically update every morning at 4 AM, but the refresh frequency of common calendar programs varies. Instructions for some of the most popular applications are included below. This calendar is not compatible with either Outlook 2011 for Mac or the Outlook Web App (2010) available from Tufts at http://exchange.tufts.edu for reasons that are beyond my control, but should work with Outlook 2007 and newer versions for Windows.

The Sackler calendar is only as useful as the information that is provided to it, so individuals responsible for planning and scheduling events should continue to submit their event information to it by using the website form: http://sackler.tufts.edu/Calendar/Submit-an-Event

 

Google Calendar (calendar.google.com)

Adding an iCal feed to Google Calendar To add the Sackler calendar to your list of calendars, open Google Calendar. Click the downward-pointing triangle to the right of “Other Calendars” that appears along the left side of the page, and select “Add by URL” from the menu. Enter the URL http://sackler.danielsenhwong.com/calendar.ics in the text box and click “Add Calendar”.  The new calendar should appear in the list, and the events will populate your calendar in a few seconds. Google Calendar will refresh this feed every few hours. The iCal feed can only be added to Google Calendar from a computer, and not the Android mobile phone application.

 

Apple Calendar (Apple OS X)

Adding an iCal feed to Apple CalendarTo add the Sackler calendar to your list of calendars, open Apple Calendar, and select “New Calendar Subscription…” from the “File” menu. Enter http://sackler.danielsenhwong.com/calendar.ics as the Calendar URL in the text box and click “Subscribe”. The new calendar should appear in the list, and the events will populate your calendar in a few seconds. By default, Apple Calendar only updates calendar subscriptions once per week. To change the update frequency, right-click (Control+click) the “Sackler Website Calendar” entry in the list of calendars and select “Get Info”. The update frequency can be changed by selecting a different interval from the “Auto-refresh” option list.

 

Microsoft Outlook 2013

Adding an iCal feed to Microsoft OutlookTo add the Sackler calendar to your list of calendars, open Outlook and go to the Calendar pane. Select “Open Calendar” and “From Internet…”  from the middle of the “Home” ribbon across the top of the screen. Enter http://sackler.danielsenhwong.com/calendar.ics as the Calendar location in the text box and click “OK”. The “Advanced…” button will open a menu allowing you to change the name of the Calendar and the description I have provided. Click “Yes” to subscribe to the calendar. The new calendar should appear in the list, and the events will populate your calendar in a few seconds, after Outlook finishes processing the feed.

Mozilla Thunderbird (mozilla.org/thunderbird)

To add the Sackler calendar to your list of calendars, open Thunderbird and go to the Calendar view. Select “New…” then “Calendar…” from the “File” menu. Select “On the Network” as the location for the calendar, and then click “Continue”. Select “iCalendar (ICS)” as the format, and enter http://sackler.danielsenhwong.com/calendar.ics as the location in the text box and click “Continue”. Thunderbird doesn’t read the given calendar name, “Sackler Website Calendar”, from the iCal feed, so give the calendar a name of your choice and click “Continue” to complete the process.

Contributing to the Healthcare Ecosystem through Evidence-based Investing

In an effort to continually explore the interface between science and business, Tufts Biomedical Business Club recently caught up with Dr. Zach Scheiner, an Associate at RA Capital Management, for a discussion about his experience in the healthcare investment industry.

RA Capital Management is a crossover fund manager dedicated to evidence-based investing in public and private healthcare and life science companies. Prior to his current role at RA Capital, Zach worked as a Science Officer at the California Institute for Regenerative Medicine, where he managed a portfolio of research programs concentrated in translational neuroscience. He holds a BS in Molecular Biophysics and Biochemistry from Yale University, and a PhD in Neurobiology and Behavior from the University of Washington.

RA Capital Management
Zach Scheiner, PhD

As an Associate for RA Capital, Zach’s efforts are realized through the team’s core research division, TechAtlas. This division is a scientifically trained team that maps out competitive landscapes in a continual effort to survey the landscape and identify emerging therapeutics and technologies that will reshape how physicians treat disease. The interview is edited for brevity and clarity.

 

Tell me about the career path that led you to your job. How did you become involved with RA Capital Management?

My interest in biomedical science and research began as an undergrad, when I had several summer research internships and was exposed to a few different fields of research. At the same time I had my first opportunity to teach science classes at a local high school and quickly realized that I also had a passion for teaching. After graduating, I decided to teach middle school science and math for a year (which turned into three) before returning to research and going to grad school.

I attended the Neurobiology & Behavior graduate program at The University of Washington in Seattle. My thesis work focused on the molecular basis of memory and drug addiction. Though I enjoyed my time as a graduate student, by my fourth year I began to realize that the academic career path and spending more years at the lab bench were not for me. I really enjoyed reading primary literature, planning experiments, and reviewing/analyzing data, so as I finished up graduate school I began looking at alternatives where I might be able to incorporate these interests as well as leverage my scientific background in a non-research capacity.

I found a great opportunity at the California Institute for Regenerative Medicine (CIRM) in San Francisco. CIRM funds stem cell research at institutions throughout California with the goal of advancing promising stem cell based therapies into clinical trials and ultimately to patients. I began as a science writer and quickly moved to a position managing a portfolio of translational research programs. In this position, I worked closely with funded scientists to help set milestones and success criteria, assess progress, and, however possible, facilitate success. In my six years at CIRM I learned a tremendous amount about the drug development process, gained experience reviewing and analyzing data, and developed management skills, all of which have been invaluable in my current role at RA Capital.

My move to RA Capital was the result of my wife being offered an assistant professorship at Brown University. In preparation for the move from one coast to the other I reached out to everyone in my network, including an old lab-mate I had stayed in touch with from graduate school who was now an Associate for RA Capital. I had a long-time interest in biotech investing, nurtured by my dad, and had been learning about this part of the industry in my spare time. Luckily, RA was hiring and the rest is history. For me, RA Capital was a perfect fit. I can put my communication and analytical skills from teaching, grad school and CIRM to good use and I love staying immersed in cutting-edge science while learning more about the investment side of the biotech industry.

 

What are the duties/functions/responsibilities of your job?

As an Associate with RA Capital, my primary role involves creating dendrograms (mind-maps) of specific diseases or capabilities within the healthcare industry. These comprehensive landscape maps take all the available drugs, both on the market and still in development, and put them into the context of current standard of care and unmet needs. They help our team fully appreciate and contextualize the market potential of assets and companies before making investments. Mapping out a disease landscape is a research-intensive process that involves surveying the literature, meeting with companies with assets in the space, speaking directly to physicians, attending scientific conferences, and analyzing data. The process can take several months to complete but the maps are never truly finished. Therapeutic landscapes are constantly evolving, new data are released and new licensing and acquisition deals are made. Our maps are equally dynamic and a lot of my time is spent staying up to date with the latest news and data coming out in the areas I cover.

In addition to mapping, Associates also join the investment team in diligence projects on specific investment opportunities. Our maps are a great way of contextualizing drugs and their competitors and can help our team identify potential new opportunities but it’s always critical to dig deeper before making an investment. One of the most rewarding parts of my job is seeing all the work I’ve put in researching and understanding a therapeutic space pay off with insights that are potentially investable, or that directly benefit a diligence project.

On a day-to-day basis I also survey industry news and the scientific literature not only to keep up with the science but to search for new investment opportunities that could be licensable for an RA Capital portfolio company or even form the basis for a new company. I also enjoy being involved in the recruiting process at RA and playing a small role in shaping the future of the company.

 

What is the most rewarding part about your job?

Personally, the most rewarding part of my work is knowing that we are investing in companies that are developing therapies for patients that really need them! These companies often have no marketed drugs and need capital to advance their assets through clinical trials and into the hands of patients. When I think about the work that I do, I know I am helping to identify great science, underappreciated drugs, and promising new opportunities. And I hope that by influencing where RA Capital’s dollars are invested, I’m impacting the whole healthcare ecosystem in a positive way.

 


 

What experiences best prepared you for your job?

I think all of my previous work experiences helped prepare me for RA Capital, the first of which was teaching. Communication is such an essential skill and getting an opportunity to develop this early in my career has been a huge benefit. Having controlled a classroom every day for three years definitely makes communicating with colleagues, companies and scientific experts a little easier. Effective communication is a vital part of this job.

The second experience is my time spent as a graduate student. In graduate school I learned how to rigorously analyze data, both my own and from the literature. I developed my critical thinking and analytical skills and the ability to quickly identify key questions, design key experiments, and understand the limitations of a study.

Lastly, at CIRM I learned the process of moving a drug from the lab to the market and everything in between. I also regularly participated in grant review meetings with panels of scientists, clinicians, and patient advocates. These meetings gave me the opportunity to learn what was truly important to each group. While the views and opinions would often vary between the groups, one key takeaway was that for a drug to succeed, doctors have to want to prescribe it and patients have to want to use it. My experience at CIRM taught me to evaluate drugs with the patient perspective in mind; new therapies are worthless unless patients will use them, and sometimes improvements that appear marginal can be very meaningful to patients.

 

What skills or personal characteristics do you feel contribute most to success in this industry?

Very often, investment firms require that applicants have a background in finance, an MBA, or prior experience in the industry. That is not the case at RA Capital. I wouldn’t say any particular background or degree is required, but there are certainly skills that are critical. Analytical skills, for example. The ability to rigorously analyze data and quickly get to the “meat” of primary literature or a clinical data set is invaluable. Another key skill is effective writing and communication. Much of my day is spent writing and talking. I am continuously expressing my thoughts and providing analysis and it is important to do so concisely and effectively.

In terms of personal characteristics, I would highlight skepticism. Being skeptical is a common trait among scientists due to the nature of research, but this skill is especially important when meeting with companies. Every company is trying to convince us that their assets or data are the best. Skepticism is required to separate the pitch from the quality of the science.

Humility is another important personal characteristic. To put it simply, in something as complicated as drug development, it’s easy to be wrong! There are so many variables to consider, and science changes so quickly; it’s essential to have an open mind and be humble about everything you do not know.

 

What are the biggest challenges you face as an associate for RA Capital Management?

I think the largest challenge I face is simply the pace of the industry and science itself. There is new data coming out all the time; from company press releases, new primary literature, scientific conferences—the amount of information can be overwhelming. Developing the ability to quickly assimilate and analyze new information is the biggest challenge. But it’s also one of the things I enjoy most about my job. In this field you have to enjoy constant learning and also get good at processing information quickly enough to inform an investment decision. The fast pace is challenging but exciting.

 

What are some other opportunities within RA Capital Management for scientists aside from the TechAtlas Research Division?

Most opportunities for PhD trained scientists are within our TechAtlas research team. This team is made up primarily of PhD trained scientists in either Associate or Scientific Writer positions. The Science Writers work closely with the Associates as they build the story of their map, acting as a thought partner to develop the key insights for standard of care, unmet needs, and investable opportunities for each disease. As members of the research team gain experience, they can specialize in one of several areas, including early-stage assets, strategic analysis of licensing and partnerships, and equity analysis.

 

For somebody interested in pursuing this career, what would be your advice to best prepare them?

I would highly recommend that PhD candidates supplement their education in three areas: biostatistics, clinical trials, and FDA regulatory pathways. These topics are not always emphasized or even addressed in many graduate programs. A working knowledge of biostatistics goes a long way; being able to understand statistical pitfalls and the pros and cons of different analyses is invaluable. I would also recommend becoming familiar with clinical trials: the general FDA requirements for advancing drugs into Phase 1 trials and the typical development path for new therapies in your field of interest. Few graduate students get exposed to these areas. I would strongly suggest looking beyond the specific questions of own research project to get an understanding of the broader context: the standard of care for the disease, unmet needs, and competing approaches. If your research isn’t disease or therapy focused, choose a disease of interest or imagine potential applications of your work and research those. Putting new research and data into a broad context is a lot of what we do, so the earlier you can start practicing, the better prepared you will be.

TUSM Faculty takes steps to unionize

On December 11, 2014, tenured and tenure-track faculty members of the Tufts University School of Medicine (TUSM) filed a petition to the National Labor Relations Board (NLRB) to hold on-campus union elections. If this election is allowed by NLRB, then the 70 members of the TUSM faculty will join the ranks of their Medford colleagues in the Faculty Forward union at Tufts, a division of the Service Employees’ International Union (SEIU) Local 509 (1). As mentioned, this is not the first time Tufts-affiliated faculty have filed for unionizing.  In February 2015, majority of the Medford/Somerville campus faculty had voted in favor of unionizing in an effort to improve working conditions (2). And even before that  in 2014, adjunct faculty members on the Medford campus, rallying under the Adjunct Action division of SEIU, negotiated a significant raise in their pay (3) that is set to be completely in effect by September 2016 (4).

http://www.seiu509.org/files/2015/02/IMG_0487_580p.jpg
Tufts University Medford Faculty vote to unionize. Source – SEIU Local 509

The TUSM faculty appears to be motivated for similar reasons; in a joint email to Tufts Daily, Dr. Karina Meiri, Professor of Developmental, Chemical & Molecular Biology (DMCB), and Dr. Henry Wortis, Professor of Integrated Physiology & Pathobiology (IPP), mentioned issues regarding salary and research funding as major sources of motivation. They elaborated in the letter that while faculty members are trying to get funding in an increasingly competitive environment with diminishing sources, the university is putting on additional pressure on them by providing “negative incentives”. Drs. Meiri and Wortis mentioned, “If faculty were unsuccessful, [in their application] as they were pretty much bound to be, given the odds, their salaries would immediately be cut, often by very significant amounts.” They also pointed out that many faculty felt that their ability to speak their minds on administrative decisions was being limited. Drs. Meiri and Wortis believe that through unionization, financial transparency and partial restoration of decision-making ability, job security and stability can be achieved for the faculty. To quote, “Our strong belief is that the educators and researchers at a university need to be deeply involved in decisions that shape its mission and that unionization will provide a path towards…the return of collegiality”.  It seems that majority of the TUSM faculty are in favor of unionizing, as almost 60% of them had voted in favor of holding on-campus elections. The ones who did not vote, either did not do so because they do not want a union or they do not feel strongly enough for the need of one, as Drs. Meiri & Wortis explained in their letter.

Faculty unions are not new in this part of the country – if the TUSM faculty are allowed to hold elections on campus, they will join their colleagues at Northeastern, BU, Lesley and Bentley Universities (5). There is also an increasing trend of faculty unionization throughout the country, and Drs. Meiri & Wortis believe it to be a reactionary movement to the increasing adaption of a for-profit model by universities. They explained in their letter, “Many universities have chosen to save money by shifting the burden of teaching to part-time untenured…adjunct faculty members. Others have increased the cost of enrollment to plug financial holes. University priorities are increasingly being set by financial rather than academic agenda. Across the country whenever universities are being managed as corporations rather than collegial institutions faculty are increasingly looking towards unionization as a means to re-assert the original model of shared decision-making.”

While it may seem reasonable to allow tenured and tenure-track faculty to unionize, it is not the case. The legal precedent set by the 1980 ruling in the NLRB v. Yeshiva University, which found the tenured faculty not eligible for unionization for their significant influence on administrative decisions, stacks the odds against the TUSM faculty’s hopes of holding on-campus elections. This precedent is also partially responsible for the opposition of the TUSM administration to the faculty’s petition at the NLRB. As the Executive Director of Public Relations, Kim Thurler, told Tufts Daily “that 1980 Supreme Court ruling … recognizes the substantial authority faculty members hold and their significant voice in determining curriculum, academic standards and policies. Many NLRB decisions since 1980 have followed this Supreme Court precedent.” (1)

Currently, the TUSM faculty waits on the NLRB’s decision on whether they will be allowed to hold elections or not. Regardless of this decision, the fact that this has become a trend across universities, institutions founded on principles of non-profit due to their increasing profiteering nature, is a great cause of concern indeed.

 

Drs. Meiri & Wortis’ quotes have been reproduced from their letter to Tufts Daily with their permission. The Tufts Daily article was published on Jan 29, 2016, and can be found here

 

Qualifying Exam Survival Toolkit: Faith, Trust, & Post-Its

I read my drafted email with the attached qualifying exam proposal for the fifteenth time, hit send, and then I felt like I was going to throw up.

It was March, the snow outside was half-melted and tinged gray with grime, and I had just submitted my qualifying exam proposal. Three weeks of carrying highlighters in my pockets, drinking tea morning to night, and rarely parting from my computer, and it all came down to the click of a button. At the time, it felt like the most deciding thing I would ever do during my PhD, and that was terrifying. Looking back, it was probably just the irregular sleep hours and too much takeout that had me feeling slightly nauseous.

So, my advice, first and foremost: buy a lot of groceries and do your laundry ahead of time. I sound like a parent, I know, but still: do it. Good food and clean clothes–as well as having those tasks checked off your list in advance–really can save you in the midst of spirals of self-doubt or experimental design frustration. And you will have those moments, but it is important to know they will either pass eventually, or you will beat it by finding a way to prove yourself wrong.

Everyone–and I do mean everyone–told me, with fond amusement: you’ll be fine, it won’t be that bad, no one is out to get you. And I can tell you, with complete certainty, that is true in retrospect. I have become the older student whom I regarded with respectful but extreme skepticism this time last year. Like they said, I ended up being just fine. Still, I remember the stress and the worry, the cycle of figuring out a problem in my proposal to only have that create yet another problem, and so it went, on and on. So I will avoid telling you what most others will and instead advise this: trust your knowledge and your intuition, even if you try to convince yourself otherwise, because you do know what you are talking about. Have faith. You are going to be your own worst enemy in this four weeks of research and writing, planning and designing, but at least it is an enemy you know well. Use that to your benefit: trust your doubt, because it will help you find holes in your work where others will as well.

And there will be holes; you can’t catch them all. This is where help from older students comes in. Your practice talk with them will be one of the most valuable experiences in this process. Be prepared for your 10-15 minute talk to take an hour, or probably two, to be critiqued by your peers. You may not be able to answer all of their questions, but those are questions you then will be able to answer in your exam if they get asked. Their advice on layout and presenting style is also invaluable; they have gone through this before, and their experiences and mistakes in their own exams will be your gain. Take full advantage, even if you have to bribe them to attend with baked goods (just kidding!).

Lastly, invest in some post-its. Keep them everywhere–by your desk, by your bed, in your bag. When an idea or a question or a worry strikes, you’ll have somewhere to record it, especially if you don’t have time to deal with it at that moment.

Faith. Trust. Post-its. 

Good luck!

Notes from the North – Northern Networking

Teleconferencing from 100 miles away into classes, meetings, and extracurricular events is all well and good, but sometimes you just feel the need to practice schmoozing in person. The Sackler Graduate Student Council holds really relevant and useful networking events, and much of the content of these events can be taken advantage of through a teleconference connection, but it is hard to beat the rapport that is established when chatting, or bemoaning, face to face with colleagues over hors d’oeuvres. For anyone who does the bulk of their work away from the main campus of their organization it is imperative to find and cultivate local career enhancement resources. Not only does this give you access to opportunities in your local sphere, it also improves your connection with the members of the satellite facility.

For Sackler students studying at the Maine Medical Center Research Institute (MMCRI) in Scarborough, ME this resource is available in the form of the MMCRI Research Fellows Association (RFA). Because MMCRI is a relatively small institute, we currently have about twenty principal investigators, we have a fairly small number of postdoctoral fellows and even fewer graduate students at any given time. The RFA was originally founded to serve both groups and has recently expanded to serve non-faculty scientific staff and technicians as well. These groups share many of the same needs in terms of networking and professional development events, so the inclusiveness of the organization has worked well for us thus far.

The RFA leadership team and active members are constantly kept busy to ensure we are providing meaningful events each month. Here’s just a small taste of what we do:
• Increase MMCRI visibility in the community by sending members to participate in local career fairs and the Maine Science Festival

RFA members handing out treats at the 2015 Barbra Bush Children’s hospital costume parade
RFA members handing out treats at the 2015 Barbra Bush Children’s hospital costume parade

• Organize scientific talks from speakers suggested and voted on by RFA members
• Hold professional development workshops such as “Intro to LinkedIn” and “The Art of Schmoozing” lead by University of New England’s Career Services Coordinator, Jeff Nevers
• Maintain a library of material on resume writing, cover letter writing, grant writing, and networking advice
• Work closely with MMCRI and MMC Human Resources to utilize hospital resources such as MMC’s Training and Organizational Development department for the benefit of our members
• Poll members annually on which of their professional development needs are being met and which still need to be filled
One of our newest events is also one of my favorites. In the spirit of positive reinforcement we recognize and celebrate either a mentor or a pair of researchers (one technician and one academic) of the year. This occasion allows the RFA to show appreciation for mentors and colleagues who demonstrate superlative qualities. Appreciation in the case of researchers includes $500 from the RFA discretionary fund (supported by our fundraising efforts) to participate in further career enhancement.

Former RFA president Dave Kuhrt, PhD presenting the 2014 Mentor of the year certificate to Dr. Rob Smith
Former RFA president Dave Kuhrt, PhD presenting the 2014 Mentor of the year certificate to Dr. Rob Smith

MMCRI may be 100 miles away from the biotech hub that is Boston, but we’re no backwater slouches when it comes to career enhancement and professional development!