All posts by Nafis Hasan

Precision Medicine: Too Big to Fail?

In January 2015, President Obama announced the launch of the “Precision Medicine Initiative”, proclaiming it to usher in “a new era of medicine that makes sure new jobs and new industries and new lifesaving treatments for diseases are created right here in the United States.” In addition, he remarked that the promise of this initiative laid in “delivering the right treatments, at the right time, every time to the right person”. This initiative, with bipartisan support in the Congress, provided a total of $215 million investment in 2016 for the NIH, along with the FDA and the Office of the National Coordinator for Health Information Technology (ONC), with a large portion of the money ($70 million) awarded to NCI to “scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment”. The initiative doesn’t stop at the genome level, as Dr. Francis Collins, Director of the NIH, pointed out in an interview with PBS News Hour, and is meant to provide information about environmental exposures, lifestyle choices and habits and pretty much everything that can affect one’s health. Given the mass of information that will be generated (the initiative aims to enlist 1 million volunteers for its cohort), it is no surprise that patient privacy issues, as well as database infrastructure, are major concerns in this mammoth undertaking.

In addition to this initiative, the US government also launched its “Cancer Moonshot Program” a year later in January 2016. This program, under the leadership of Vice President Joe Biden, and with the help of an expert panel, the “Cancer Moonshot Task Force”, aims to “make more therapies available to more patients, while also improving our ability to prevent cancer and detect it at an early stage.” Since cancer is widely accepted to be a genetic disease, it seems fitting to serve as the poster child for an initiative that aims to cure and prevent diseases based on tailoring therapy for an individual using personal genetic information.

Tied to these two initiatives is also the latest approach to clinical trials at the NCI, commonly termed as “basket trials”. Based on findings from exceptional case reports where patients treated with drugs not commonly used for that type of cancer, the NCI was encouraged to try out drugs traditionally reserved for particular types of cancer for the ones that they weren’t developed for; thus, the Molecular Analysis for Therapy Choice (MATCH) and the Molecular Profiling-Based Assignment of Cancer Therapy (MPACT) trials were incorporated into the Precision Medicine initiative.  The NCI-MATCH trial aims to sequence tumor biopsy specimens from ~6,000 patients to identify mutations that will respond to targeted drugs selected for the trial; these drugs are already approved by the FDA for certain cancer types or are being tested in other clinical trials. On the other hand, the MPACT trial will compare whether patients with solid tumors fare better with targeted therapy vs non-targeted therapy.

The NCI-MATCH trial explained. Source: National Cancer Institute website.

Despite the initial fanfare, the recently released NCI-MATCH major interim analysis report does not paint a pretty picture for the trial’s outcome. While the enrollment was higher than expected (795 people registered in first 3 months compared to the projected 50 patients/month) and the labs were able to sequence most of the tumors (87%), it was also found that “most of the actual mutation prevalence rates were much lower than expected based on estimates from The Cancer Genome Atlas and other sources”. In fact, the overall expected mutation match rate was adjusted to 23% for the 24 treatment arms in the study as it continues.

While no endpoint has yet been reached to draw conclusive remarks about this trial, data available from other clinical trials that have taken a similar approach do not seem favorable. In the SHIVA trial, a randomized phase II trial carried out in France where 99 patients were treated based on identified mutation(s) compared to 96 patients treated with drugs of their physicians’ choice, median progression-free survival was 2.3 and 2 months, respectively. Current clinical data on patients with relapsed cancers, a major focus of the MATCH trial, do not seem favorable either. As Dr. Vinay Prasad, a haematologist-oncologist at Knight Cancer Institute, points out, only 30% of such patients respond to drugs based on biological markers and the median progression-free survival is 5.7 months. Based on this response rate, he estimated only 1.5% of patients with relapsed and refractory solid tumors to benefit from the precision medicine approach.

In a review of current clinical trials and past trials that have used the targeted therapy approach, Tannock & Hickman (NEJM, 2016) warn about the limitations of such an approach – heterogeneity and clonal evolution of cancer cells when challenged with targeted therapy, the inconsistency between expected and clinically achievable levels of inhibition of candidate molecules and of course, the efficacy of such therapies compared to currently available, standard but effective therapies such as aromatase inhibitors for breast cancer. While one can argue that heterogeneity in tumors can be countered with combination targeted therapy, the authors point out that “combinations of molecular targeted agents that target different pathways have often resulted in dose reduction because of toxic effects… in a review of 95 doublet combinations in 144 trials, approximately 50% of the combinations could use the full doses that were recommended for use as single agents, whereas other doublets required substantial dose reductions.” Even if it is possible that intratumoral heterogeneity can be countered with combination targeted therapy, a much-overlooked point in this initiative is the cost of such treatment strategy, considering the exorbitant costs of targeted cancer therapy. There already exists a disparity among cancer patients from a socio-economic standpoint and this initiative does little to address how to bridge such a gap. Questions such as how many drugs will a patient have to take, especially in cases of tumors that are highly heterogeneous, such as glioblastoma multiforme and how that would affect the living standard of a patient need to be considered before heralding a victory for the precision oncology approach even if the MATCH trial outcomes are favorable.

In another recent study, Dr. Victor Velculescu and his team from Johns Hopkins showed that sequencing only tumor genetic data can lead to false positives. After analyzing 815 cancer patients’ tumor sequencing data and comparing that data to the one from the patients’ healthy tissue, they found that 65% of genetic changes identified with tumor-only  sequencing data were unrelated to the cancer and therefore, “false positives”. The team also found that 33% of mutations, which are targets of currently available drugs, were also false positives when the patient’s germline genome was compared to the tumor genome; this affected 48% of the patients in their cohort.

This is not the first study of its kind to warn against false positives when trying to identify disease-causing mutations. Findings from the Exome Aggregation Consortium (ExAC), the largest catalogue of genetic variation in the protein-coding sequence of the human genome,  show that out of the 54 (on average) “pathogenic” mutations present in an individual’s genome, 41 of them “occur so frequently in the human population that they aren’t in fact likely to cause severe disease”. This is in direct contrast with studies that seem to enforce the idea that there are many more “oncogenes” to be found that can serve as novel drug targets.

The paradigm behind the MATCH trial, and in general the Precision Medicine initiative, seems to be blind to an obvious aspect of biology – context matters, and more so, in case of mutations that are deemed to be “carcinogenic”. As outlined in a recent paper by Zhu et al (Cell, 2016) and the famous “bad luck” paper by Tomasetti and Vogelstein,  it appears that the stem cells and their differential regenerative properties in different tissue types are responsible for the differential rates of carcinogenesis in various tissue types, a finding that again, buttresses the idea that tissue specificity matters. In fact, Iorio et al (Cell, 2016) was able to show just that in the context of pharmacogenomic interactions of currently available cancer drugs with data available from patient samples in the TCGA and other databases. Using a big data and machine learning approach, the authors developed a logic-based model that would predict the efficacy of any drug that is either approved or undergoing clinical trials against the mutation it is intended for in different cancer types ,which is essentially the basis of the MATCH trial. Surprisingly, it appeared that tissue specificity determined the pharmacological agents’ effects on the intended molecular targets; more specifically, only one drug interaction (out of 265 drugs tested) was found to be significant in multiple cancer types, which may sober up the expectations from the MATCH trial outcome. Therefore, using a blanket approach to target mutations in various tissue types without consideration to their environments can seem futile in the light of such findings.

The evidence from all these basic science and clinical studies raise the question of whether precision medicine is doomed to fail. While the gene-centric view of disease etiology have deepened over the years since the completion of the Human Genome Project, does this evidence point to the necessity of another paradigm in our understanding of cancer and other complex diseases, whose cures have been presumed to lie in genetic aberrations and molecular targets? An even more concerning question, relevant in this era of big data, is whether we actually understand what the data is telling us, as the prominent cancer researcher, Dr. Robert Weinberg, admits that “while data mining, as it’s now called, occassionally flags one or another highly interesting gene or protein, the use of entire data sets to rationalize how and why a cancer cell behaves as it does is still far beyond our reach”. A strong critic of the initiative, Dr. Michael Joyner from Mayo Clinic, opines that while “hundreds of genetic risk variants with small effects have been identified…But for widespread diseases like diabetes, heart disease and most cancers, no clear genetic story has emerged for a vast majority of cases” and that “when higher-risk genetic variants are found, their predictive power is frequently dependent on environment, culture and behavior”.

The success of Precision Medicine Initiative, and in particular, the precision oncology approach, ultimately rests on whether it can stem and curb deaths resulting from cancer and other complex diseases, based on molecular targeted therapy. Unfortunately, it appears that large scale public health initiatives have done more to that end (e.g. – tobacco control has largely cut down rates of lung cancer incidence, diet and exercise can cut down the risk of converting pre-diabetes to diabetes by nearly two-thirds), compared to what targeted therapy have achieved. However, it seems that such public health success was overlooked by the Cancer Moonshot panel as in February 2016, right after the program was announced, public health researchers across the country had to urge the Vice President to make prevention a bigger focus in controlling cancer incidence in the population, rather than just trying to find a cure. This approach should have been incorporated into a billion-dollar initiative by default, one would think, but this didn’t seem to be the case and one must wonder why.

In order for this huge, publicly-funded initiative to achieve more than just lukewarm outcomes and to actually become a breakthrough it is promised to be, the Precision Medicine initiative needs to break free of the gene-centered tunnel vision and incorporate all factors that affect an individual’s health, such as lifestyle choices and environmental exposures, as Dr. Collins boasted it to be. While this initiative is only at its infantile stage, changes based on clinical trial and basic science evidence should be made early enough so that favorable outcomes can be achieved and does not require the government to stage another public bailout as it did for the failing banks and wall street corporations back in 2008 when they were deemed to be “too big to fail”.

Dr. Tyler Jacks to deliver Charlton lecture, following poster competition

The 41st annual Charlton lecture will be held on Wednesday, November 30, 4-5.30 pm, in the Sackler Auditorium. The lectureship, established in 1975 in honor of Mr. Earle P. Charlton, has since evolved to include a poster competition that serves as a platform to recognize outstanding research work performed by graduate and professional students on the medical school campus. This year, the poster competition will be held on Tuesday, November 29 and Wednesday, November 30 in Sackler 114. Details regarding participation, eligibility and review criteria can be found here – http://sackler.tufts.edu/Student-Life/Student-Awards/Charlton-Poster-Award. The deadline for submitting abstracts for the competition is Thursday, Nov. 9, 5 pm. Please submit your abstracts electronically to Rachael Bailey at Rachael.Bailey@tufts.edu.

The keynote lecture will be delivered by Dr. Tyler Jacks, Professor of Biology at Massachusetts Institute of Technology (MIT) and Director of the David H. Koch Institute for Integrative Cancer Research. His talk is titled “Engineering the Cancer Genome”. 

Mr. Earle P. Charlton was a renowned entrepreneur and a social benefactor, as exemplified by his legacy, the Charlton Trust. Mr. Charlton established a chain of stores throughout Massachusetts back in 1890, before merging with the Woolworth company and expanding to the west and Canada. The Woolworth company would later go on to acquire several brands throughout the twentieth century. However, due to increased competition in the retail sector, the company chose to focus on a select brands and is today represented by the Foot Locker stores. Mr. Charlton passed away in 1930, and is commemorated by the Charlton Memorial Hospital in Fall River, MA, a town which benefitted greatly from his entrepreneurship and generosity. (Source – https://en.wikipedia.org/wiki/E._P._Charlton_%26_Company)

About the Speaker

Dr. Tyler Jacks is the Professor of Biology at MIT, the Director of the David H. Koch Institute for Integrative Cancer Research and a Howard Hughes Medical Investigator. He has served on public and private advisory panels on cancer research and also sits on the board of directors for Aveo Oncology and Thermo Fisher, Inc. His expertise in the field is of no surprise given his pedigree – Dr. Jacks completed his PhD under the guidance of Nobel Laureate Dr. Harold Varmus at University of California, San Francisco, and went on to do his postdoctoral work with Dr. Robert Weinberg at the Whitehead Institute, both of whom were pioneers of the field. His work has earned him prestigious awards including the Paul Marks Prize for Cancer Research and other accolades.

Dr. Jacks’ research focuses on the “genetic events contributing to the development of cancer” using mouse models that have been engineered to carry clinically relevant mutations. His lab works on a number of different cancers that range from lung, pancreatic and ovarian cancers to peripheral nervous system tumors, astrocytoma and retinoblastoma. A major focus of his current research is to develop more powerful and accurate mouse models of cancer using cutting edge genetic technology.

More detailed information regarding his work can be found on his lab website.

Harold F. Dvorak, M.D., invited to deliver 11th Annual Jeffrey Isner Lecture

The 11th Annual Isner Lecture is scheduled to be held on Wednesday, November 2, 2016, 4 pm at Behrakis Auditorium in the first floor of the Jaharis building. In keeping with the tradition of inviting speakers who have made significant contributions to the field of angiogenesis-related research, this year’s speaker will be Harold F. Dvorak, M.D., credited with the discovery of the Vascular Endothelial Growth Factor (VEGF). Dr Dvorak’s talk is titled “VPF/VEGF, Angiogenesis and Stroma Formation: The Tumor Vasculature as Therapeutic Target”.

 

About the lectureship & Dr. Jeffrey M. Isner

The Jeffrey M. Isner, M.D. Endowed Memorial Lectureship was established in 2007, in honor of Dr. Jeffrey Isner, a graduate, and later, a faculty member, of the Tufts Medical School. This lectureship is meant to provide an opportunity to bring the Tufts medical and biomedical communities together to “ to reflect upon and consider the pioneering work of Dr Jeffrey Isner.” The lectureship also invites a keynote speaker, chosen from the internationally recognized pioneers in clinical and/or basic science research communities focusing on angiogenesis-related research, vascular biology and cardiovascular medicine.

Dr. Jeffrey M. Isner, Source - Tufts Medical School website
Dr. Jeffrey M. Isner, Source – Tufts Medical School website

Dr. Isner was a pioneer himself, as evidenced by his profession as an interventional cardiologist, a nascent medical field at that time. He is also known for his novel therapeutic approaches, such as combining gene therapy and angioplasty to treat blocked blood vessels in patients. While treating a patient in 1994 for a blocked vessel in the leg, Dr. Isner and his team coated the angioplasty balloon with genes to express VEGF in an attempt to observe whether the VEGF protein would be able to promote the growth of new blood vessels that would bypass the blocked artery. While clinical gene therapy applications were still years away, his attempts and results were deemed promising by his peers. Dr. Isner was also actively involved in bringing his approach to the market – he was a founder and a major stockholder in the company Vascular Genetics, based in North Carolina. Not surprisingly, his involvement in the industry resulted in some critics to suggest that this could affect his medical judgement, suggestions that were rejected by Dr. isner. In 2000, the FDA suspended research carried out by the company and St. Elizabeth’s on the grounds of possible improper reporting on death of patients enrolled in the trial. However, in Spring of 2011, his research was allowed to resume and he was additionally awarded a $10 million dollar grant. (Nagourney 2001)

 

Dr. Isner, who passed away at the age of 53 from a cardiac arrest in 2001, is survived by his wife, Linda Hajjar, and his three children – Joshua, Jessica and Matthew. His motivation to bring novel therapies for cardiovascular diseases from the lab to the clinic stemmed from his will to make a difference, as he said in an interview in 1998 – “… the thing that really motivated me more than anything else is a sense that I don’t want to feel that I was just kind of passing through during this lifetime. I do not want to be just one more person that came and left. I always wanted to do something that could make a little difference.” (Ferguson 2001).

 

Fun fact – Dr. Isner had a walk-on role in “Seinfeld”, thanks to his friendship with Larry David, the show’s co-director, co-producer and a chief writer.

 

About the Speaker

Dr. Harold F. Dvorak. Source - www.bidmc.org
Dr. Harold F. Dvorak. Source – www.bidmc.org

This year the Isner Lectureship steering committee has invited Dr. Harold F. Dvorak, MD, Professor of Pathology, Beth Israel Deaconess Medical Center,  to deliver the keynote lecture, a choice that is befitting to honor Dr. Isner’s memory given that Dr Dvorak is internationally recognized for his discovery of VPF in 1983, later known as VEGF, and his contributions on understanding tumor vasculature. His work on the role of VEGF secreted by tumors led us to the understanding of tumors as wounds that cannot heal, but are able to sustain themselves by promoting growth of blood vessels (Ribatti 2007). This discovery opened up a whole new facet of tumor biology and a host of potential new avenues for cancer therapeutics. To this date, Dr. Dvorak and his team are working on understanding angiogenesis in tumors to the greatest detail and developing anti-angiogenic therapy for cancer treatment.

 

Sources –

Tufts Advisory Partners mean business

Guest Post by Jen Shih, writer for TBBC

From Left to Right (Alexandra Taracanova, Ji Kang, Christina Hao, Valerie Larriau, Maddy Das, Mike Pereria, Michaela Tolman, Farrah Roy, Wendi Ni, Mike Jager, Geoff Gonzalez
From Left to Right (Alexandra Taracanova, Ji Kang, Christina Hao, Valerie Larriau, Maddy Das, Mike Pereria, Michaela Tolman, Farrah Roy, Wendi Ni, Mike Jager, Geoff Gonzalez

 

April 2016: The excitement is palpable as the three co-founders sat around the table and planned out their first session as part of the inaugural Tufts Advisory Partners (TAP), a pro bono consulting group made up of Boston-area graduate students and postdocs. Alexandra Taracanova, Michaela Tolman, and Ji-Yong Kang were meeting to plan out their first engagement, or client relationship. They had selected a team of consultants, and now it was time to get to work. Tufts was about to be put on the map as an institution with high interests and talents for consulting and business development.

TAP was largely inspired by the sudden explosion in interest for the Case Study Group at Tufts. Students at Tufts, as well as institutions in the area, were becoming aware that career choice options were growing, make it an ideal time for TAP to emerge. Realizing the unmet need for hands-on opportunities in life sciences consulting, the founders of TAP got together in January 2016 and came up with a solution. TAP provides strategy services to biotechnology companies to develop their business. In working with a potential client, TAP will consult on how to set up the business, help them expand, or provide market research and due diligence. What makes this new consulting group unique is the ability to build an organization from the ground up, recruit clients, make their own rules, and pick projects to work on–in other words, they are essentially a fully functioning, autonomous firm that will provide a real product that will impact the biotechnology market. However, another integral goal in creating TAP was to connect enthusiastic and committed grad students and postdocs with the opportunity to use their talents.

For their first engagement, TAP selected a mid-sized medical devices company from several options. They planned to spend six weeks on the engagement, working with two teams. Of the three partners, Ms. Taracanova would work primarily with the client, and Ms. Tolman and Ms. Kang would each lead one of the teams as an engagement manager. Before the engagement began, and even before they could release the identity of the client, the eagerness and enthusiasm from the TAP partners was obvious. In particular, Ms. Taracanova was excited by the prospect of teamwork in the engagement teams and “seeing the two teams work together and move forward to deliver the end product.”

The team members for this first engagement hailed from three institutions: Tufts University, Boston University, and Harvard University. Throughout the engagement, team members collected information from key opinion leaders, analyzed the data, and presented recommendations on business strategy for the company. Both teams worked to develop market entry strategies for one of the company’s assets. As the members were from different institutions and departments, there was ample opportunity to network and get to know other students and postdocs who were interested in the consulting field. However, after completion of the engagement, it was clear that the team members first and foremost gained a valuable and rewarding experience. Christina Hao, a team member from Boston University, said of her experience: “I worked with TAP for six intense weeks on a consulting project, where I was able to gain hands on experience with solving business problems in a hypothesis-driven, structured manner, as well as honing my presentation and leadership skills.  The level of teamwork was incredible, and the engagement manager was very professional and genuinely cared about our learning goals.  TAP is hands down the most enriching, rigorous and fulfilling business experience I have experienced so far as a graduate student.” What was perhaps key to the consultants who participated in this engagement was the learning experience, and Michael Pereira, from Tufts University, reports that “as a first-time consultant, TAP exceeded all of my expectations. I learned more about the consulting profession in those six weeks than any number of books or classes could possibly teach me. It is an absolute must for anyone seeking a career in life sciences consulting!”

The team members were not the only people who had positive reviews for the first TAP engagement; the client, now revealed to be SteadMed Medical, also had encouraging comments. The CEO disclosed that “[he] was very pleased with the personal engagement and passion the entire team embraced throughout the project. The final report was clear, concise and supported with facts and data. [They were] excited to execute on the recommendations made.” The marketing manager of the company describes the TAP engagement with the following: “The quick uptake of our industry, its challenges, and our visions were outstanding.  From the first week, we felt there was a deep understanding of how to take our questions and deliver them back with tangible perceptions and directions for us to move forward.  At the next given opportunity, we will engage with TAP again to leverage their passion, knowledge, and ability to deliver promising direction with a message tailored to a market we thought only we knew so well.”

With the first engagement behind them and with success, no less, the TAP team is looking forward. They are looking to begin a second engagement in August, and to build upon this first experience to improve, further engage, and delve deeper. With the growing interest in life science consulting, they should have no problem recruiting more team members who are interested in venture capital, life science investing, and the life science business in general. And if the initial reviews are any hint to the future, the next client they select from their list of options will benefit enormously as well.

Applications for TAP’s second engagement open August 1st, 2016. If you are interested in applying or have a business that would benefit from TAP’s services, please contact tuftsadvisorypartners@gmail.com.

 

Editorial: Career Development Survey Results

In the April issue of the Sackler Insight, we published an editorial discussing the career development resources available for Sackler students, their effectiveness and how they could be better suited to the dynamic landscape of a post-PhD worklife. As a follow-up, the Graduate Student Council (GSC), in collaboration with the Dean’s office, developed a survey to hear from students about their needs. This editorial will focus on the outcomes and suggest recommendations to be implemented by the GSC and the Dean’s office.

The survey was conducted over a period of 2 weeks, and around 1/3rd of all Sackler students responded, with representation from all class years and programs. Majority of the respondents had either prior research experience in an academic setting or had come straight from their undergraduate institutions, as shown in the pie chart below. While career development opportunities were of varying degrees of priority among the respondents at their time of graduate school interviews, almost all respondents, regardless of class year, considered these opportunities as a high priority at the time of the survey.

The survey also asked the students to indicate how many career development events at Sackler they had participated in over the last 2 years and to rate their usefulness. This data has been summarized in the bar graphs below. The same was asked for any career development opportunities outside Sackler the students had participated in. The students were also asked to indicate reasons they were unable to attend the events at Sackler and what kind of events they would like to see more. Lastly, an open-ended question was posed to gather additional comments from respondents. After analyzing the data, we identified 3 premises that were prevalent among the responses.

 

 

1. Alumni network building

 

Majority of respondents to the survey advocated for more networking opportunities and information regarding alumni’s current jobs. The comments section also focused on the disconnect between alumni and the current students. While there are no Sackler specific alumni databases, as is true for other Tufts schools, it should be noted that Tufts does maintain a database of all alumni through the Advancement office. Individual schools can request alumni information through the advancement office and vice versa. There is already an existing network of Tufts alumni called Tufts Online Community (OLC) that allows Tufts alumni and students to establish and maintain connections. More info on the OLC and how to register for it can be found here – http://tuftsalumni.org/who-we-are/faqs/#community-what-is. Additionally, the Dean’s office, who keeps track of the Sackler alumni through social media services such as LinkedIn for training grant application purposes, also update the alumni information on the Sackler website (can be found here – http://sackler.tufts.edu/Student-Life/Career-and-Professional-Development/Career-Outcomes). Given that this existing database can be effectively used for networking, we urge the Sackler students to utilize this resource for their benefit. We also urge the GSC and the Dean’s office to hold a workshop to showcase this resource and guide the students on how to use it most effectively. A stronger alumni network can also be made possible through student organizations such as TBBC, who have been able to form a tight-knit group of peers across programs and class years.

  1. Full-time Career Development Office

There have been requests for a full-time career development resource to be made available for the Sackler students. However, due to the small size of the school, and the cost associated with hiring new employees and setup, it is difficult to be justified considering that PhD-track Sackler students do not pay tuition. However, if there could be a collaboration between the PHPD programs in the TUSM and the Sackler school, it could potentially provide a critical mass to warrant a full-time career office to serve all the schools on the Boston campus, albeit for broader services such as resume reviews. The changing landscape of the post-graduate work opportunities also indicate that there is a need for alternative career options, related to the healthcare and biomedical professions, which can be addressed through collaborative efforts between the various schools on the Boston campus. For example, last year the Sackler GSC collaborated with the Friedman nutrition school to host a career fair. Even if a full-time career resource center on the Boston campus is not possible, it’d serve the students well if the GSC, the PDA, and the Dean’s office could organize a few resume review workshops for students and post-docs throughout the year.

  1. Career Development Events & Resources

The bar graph showing the usefulness of the various career development events and resources indicates that most respondents find the seminars organized by Career Paths, TBBC and PDA to be most useful. However, some respondents commented on the focus of these seminars to be heavily biotech or industry-centric, which could undermine the needs of students who are not looking into get into such fields. While in general there might have been an increased number of events with such a focus, it should be noted that the GSC have sought to put out a diverse group of seminars, panels and workshops to help students pursuing any non-academic career path. Historically, the career paths committee of the GSC have focused on non-academic careers since that was the gap that needed to be filled – the Sackler faculty are well-equipped to provide advice on academic career paths, but that is not necessarily true for non-academic ones. In addition, a clear distinction needs to be made between the seminars organized by the various student groups – TBBC seminars will be focused on the biotech industry whereas the GSC seminars are more likely to include a diverse group of topics, based on their mission statements. This being said, it would also serve the GSC well to have a standardized version of event flyers for easy recognition. It would also help to showcase their previous events through the blog so students unable to attend such events can follow-up on what was discussed and presented.

In the last year, the PDA, GSC and TBBC have all worked closely together to host events that have been well-attended and lauded, and this is a trend that should continue to aid students and post-docs alike. However, more visibility and promotion of these events are required for a well-rounded attendance, as indicated by some survey respondents.

MyIDP was indicated to be really useful by the respondents who had used it, although this resources was not used by majority of the survey users. This shows that there is a need for a myIDP workshop that would help guide the students on using the valuable resource, which was deemed to be more useful than talking with thesis advisory committees. This workshop can potentially be done at the beginning of the academic year in September, to help the incoming and the rising students. Recent graduates should also be invited to a panel on different careers as mentioned in myIDP. This would further aid to establish connections between current students and alumni. Additionally, grant writing workshops should also be organized for both students and post-docs, as requested in the survey.

 

This survey was conducted to gauge student interest in career events and resources and how the existing ones can be tailored to better fit the needs of the Sackler student population. While valuable data was obtained from this survey, it should be noted that this data is inherently biased since the respondents are more likely to seek out career development opportunities within and outside Tufts, and are likely to be more active in participating in events and workshops. Even with these limitations, it can be safely said that Sackler students have laid down a strong foundation of career development resources and events through their own enthusiasm and efforts and grassroots organization. And it is to this collaboration between student organizations and the Dean’s office that we should turn to ensure proper career development resources are made available for Sackler students and post-docs.

 

Adenine Methylation in Mammals: N6-mA is the new 5mC

Guest Post by Ila Anand, 3rd year, Micro

The advent of the epigenetics field occurred more than a decade ago and has since rapidly revolutionized our understanding of disease and inheritance. The term epigenetics encompasses any molecular switches attached to DNA that turn “on” or “off” the expression of genes. In germ cells, these molecular motifs can be passed onto the progeny. Although several types of epigenetic markers are known to exist, two types have been well characterized. The first one being histone modifications, which indirectly impact gene expression by altering nucleosome structure, and the second one being direct methylation of the DNA. The prevailing dogma in the field is that mammalian DNA methylation exclusively occurs on the fifth position of cytosine (5mC). However, the Xiao lab at Yale recently confirmed in the March issue of Nature that adenine methylation (N6-mA) can also occur in mammalian embryonic stem cells (ES cells).

Historically, adenine methylation has been known to predominantly occur in prokaryotes. Dam methylase, the bacterial enzyme responsible for methylation, has been heavily studied in E. coli since the 1970’s and controls mismatch repair of DNA, DNA replication, and gene expression. It was only until recently that several groups reported N6-mA occurring in the invertebrates, such as Drosophila, C. elegans, and green algae. Interestingly, N6-mA in these “simple” eukaryotes was implicated in activating gene expression. This is in striking contrast to 5mC, which represses gene expression in mammals. In December, a research team at the University of Cambridge published the discovery of N6-mA occurring in mouse and human cells, albeit at several orders of magnitude less frequently than cytosine methylation. However, this team was not able to identify the consequence of N6-mA on mammalian gene expression.

The Xiao lab at Yale elaborated on this discovery by finding that N6-mA represses genes on the X-chromosome of ES cells. First, the team confirmed adenine methylation was occurring in ES cells using SMRT-ChIP and mass spectrophotometry techniques. Next, they identified the demethylase enzyme Alkbh1 to be responsible for controlling N6-mA by generating a homozygous Alkbh1 knockout line. In this knockout cell line, they found increasing N6-mA levels on the X-chromosome of ES cells, indicating that adenine methylation is misregulated without Alkbh1. Intriguingly, the team found N6-mA to correlate with the silencing of LINE-1 elements. These elements are retransposons that are enriched at the X-chromosome. Although the majority of LINE-1 transposons have lost the 5’UTR and other proximal regions, several full-length “young” LINE-1 transposons exist at the X-chromosome and can be autonomously transcribed. The researchers found N6-mA to accumulate on “young” LINE-1 elements but not older, aberrant elements. Furthermore, N6-mA accumulated and silenced neighboring LINE-1 genes. These neighboring X-chromosome genes are known to play a role in cell fate decision.

The implications of the Xiao team’s findings are numerous. First, adenine methylation of LINE-1 elements appears to have evolutionary significance. N6-mA at these sites silences LINE-1 expression and neighboring gene expression and this is exactly opposite to the role N6-mA plays in invertebrates. The researchers hypothesize that controlling LINE-1 expression safeguards the active transcribed elements from reintegrating into the genome and creating genomic instability. Additionally, since neighboring genes are silenced by N6-mA, the epigenetic marker could play a salient role in embryogenesis. Although Alkbh1 cells are capable of differentiating, the Xiao team found that these knockout cells have an imbalance in cell fate decision. Another implication of N6-mA on the X-chromosome is that it could be the mechanism of X-inactivation in females and ultimately control sex ratios, since LINE-1 elements are enriched at the X-chromosome. Finally, because LINE-1 elements are also enriched in tumor cells, N6-mA sites can give us some more insight into oncogenesis. In conclusion, the Xiao lab’s findings enhance our understanding of the mammalian epigenetic repertoire and open new avenues to therapeutic design for a range of diseases.

 

References:

DNA methylation on N6-adenine in mammalian embryonic stem cells

Wu, Tao P., et. al.

Nature 532 (7599), 329-333

 

http://www.the-scientist.com/?articles.view/articleNo/45710/title/New-Epigenetic-Mark-Confirmed-in-Mammals/

 

https://www.genomeweb.com/sequencing-technology/researchers-identify-methylation-mark-previously-uncharacterized-mammalian
http://news.yale.edu/2016/03/30/sex-baby-ancient-virus-makes-call

EDITORIAL: Career development resources for non-academic paths (Part I)

This two-part editorial by the Insight team seeks to open a discussion between faculty, students, postdocs and the school administration about whether the school is prepared for meeting the changes in the future of PhD holders. The first part will address the current available resources and the unmet needs of the students/postdocs, and will also explore some possible solutions. The second part, to be published in the next issue of the InSight, will carry the opinions of all parties involved collected through a survey and communication, which will serve as a stepping stone towards meaningful changes that will benefit us all.

Editors’ Note, 4/11/16, 1:30 pm – The article has been modified to include corrected information regarding the BEST award application by Sackler. Previously it had stated that Sackler had applied for the BEST award and was not awarded due to lack of proper infrastructure. However, after communicating with the Dean’s office, we have learned that Sackler had applied in conjunction with other Tufts graduate schools and it is speculated the application was not funded partly due to complex administrative structure and evaluation and dissemination plans. The changes are reflected in the article. 

The Doctorate in Philosophy (PhD) is a degree awarded to recognize original contributions to collective human knowledge. Thus, it is no surprise that the next step after getting a PhD is to join the bastions where such knowledge is curated and cultivated, i.e., to pursue an academic career. However, given the current structure of an academic job and the nature of academic tenure, a bottleneck in academic positions have taken firm root in the last years. According to Nature, the number of postdocs have jumped by 150% between 2000 and 2012 while the number of tenured or full time faculty positions in the US has either remained stagnant or fallen. While the debate on how to improve the lives of postdocs and other non-faculty PhD holders rages on and restructuring of federal funding for scientific research is ongoing, the increasing number of PhDs leaving the traditional path and venturing into other professions is readily apparent.

Postdoctoral appointees, by field
Adapted from Powell 2015 Nature
Employment of doctorates
Adapted from Cyransoki et al 2011 Nature

In recent years, the PhD degree has been developed as a marketable asset with a accompanied with a powerful skill set — the ability to think critically, solve problems and troubleshoot, be organized and detail-oriented. The idea that the skills required for obtaining a PhD are also recognized as required to be successful in any other profession, and is now being echoed by career counselors. While industry research positions were once spoken about in hushed voices before, these positions are now not only coveted, but other non-research jobs are also becoming more prominent in seminars and career advice panels for biomedical graduate students and postdocs.

This trend is also evident within the graduate student population here at Sackler School of Biomedical Graduate Sciences, where more than half the alumni have pursued non-academic careers. As the funding climate struggles to recover and academic positions become more scarce, the question arises of whether the existing model of career development for student and postdoctoral trainees is sufficient to ensure future success and achieving their goals. It is apparent that career development training outside of academia is required, but the support for this by the curriculum and administration at the Sackler School seems to lag behind our peer institutions, and even our colleagues on the Medford campus have access to the Tufts Career Center and the students in the Fletcher School have their own Career Services office.

Resources currently available for students at Sackler interested pursuing non-academic careers are mostly driven and organized by the students themselves. These student-led initiatives have produced a full roster of seminars and workshops focusing on such career options held nearly weekly between the Career Paths Committee of the Sackler Graduate Student Council (GSC) and the Tufts Biomedical Business Club (TBBC). These groups have become increasingly active over the past few years, with their efforts growing into independent events like the Tufts New England Case Competition (TUNECC), as well as collaborations with the Tufts Postdoctoral Association and student groups in the School of Medicine. Additionally, the Tufts Mentoring Circles group has provided students peer guidance and spaces to discuss such career options among themselves. Every student initiative listed here has sought more interactions with Sackler alumni, but the information to facilitate that exchange is not readily available. Student leaders at Sackler have expended great effort to build the career resources the student body needs, but these efforts are reaching the limit of what they can achieve and will only be short term and partial solutions without additional resources and support infrastructure. Some of this could be built by students, like shared repositories for maintaining records and thus institutional memory so energy is expended solving new problems instead of rehashing old ones. The most important piece, however, cannot be done by students alone: an accurate, current database of Sackler alumni and their occupations that is accessible and searchable.

We appreciate that the Dean’s Office has recently increased its support of these student efforts, but believe that more can be done. An increased contribution to co-sponsorship from partial funding of one or two events with the GSC annually to a series of three annual workshops and career panels over the past two academic years, and the interactions between a handful of students with Sackler alumni through the new “Day in the Life” program are good starting points. However, the student body and Sackler as an institution would derive greater benefit and return on an investment in career development and advising staff, similar to those available at the Fletcher School and the Medford campus, but scaled for Sackler. It would be mutually beneficial, as it works to the advantage of a school to have an engaged student body that will recognize and appreciate the school’s support in shaping their careers as alumni. Furthermore, this infrastructure could be a common point for alumni to rely upon and connect with students and each other.

The lack of formal career development resources at Sackler has been identified by peer reviewers as an area for improvement, and puts us at a competitive disadvantage for student recruitment and securing grant funding. Prospective students actively seek graduate programs that provide career development, and among the recommendations made by the review committee for the newly-merged CMDB program were formal non-academic career training options and an expansion of extramural internships through the alumni network and faculty connections. Funding agencies such as the National Institutes of Health (NIH) evaluate grant applications on this aspect of graduate training as well. For example, F31 grant applications to support graduate students require descriptions of career training and development; the proposed changes will essentially strengthen the Sackler students’ applications and may increase the number of extramurally funded students, alleviating the pressure on the school.  A more recent example includes the NIH Broadening Experience in Scientific Training (BEST) awards, a funding opportunity established in 2013 in response to the state of the biomedical workforce and to prepare trainees for diverse career paths that utilize their PhD training. Boston University received a BEST award in 2014 for its biomedical research programs in part because of its existing career development and support infrastructure. It should be noted that Sackler, along with other graduate schools at Tufts, had applied for the BEST award. While the reviewers had found the application to be strong in certain areas and to have “potential for high impact”, they also noted weaknesses that included “complex administrative structure and the evaluation and dissemination plans”, which could partly be responsible for the award not being funded (source – email communication with Sackler Dean’s office). These issues can be addressed with the establishment of the proposed infrastructure development and can further strengthen such grant applications in the future. 

The faculty mentor plays an important role in shaping a mentee’s future career — the mentor’s support and guidance are essential for the mentee’s career development. While Sackler faculty are generally supportive of students and postdocs, it is critical for them to come forward and actively support mentees’ who choose to pursue careers outside of academia and research. The Greater Boston area is known as a hub for biotechnology research and business, with companies specializing in everything from drug development to consulting. Many recent and local alumni maintain a connection to Tufts through their faculty mentors absent a career development office at Sackler, and both students and postdocs would greatly benefit if the faculty mentors shared these connections, and offered guidance and support on leaving academia.

The current funding climate and the stagnation of academic positions, along with the burgeoning postdoc crisis, amount to conditions favorable for a paradigm shift. We cannot just keep focusing on the academic jobs traditionally held by PhDs. In order to better adapt to this changing landscape of post-doctoral work, the students, postdocs, faculty, and administration need to work together to bring about improvements to the environment at Sackler, specifically:

  1. Developing an accessible, searchable, up-to-date database of Sackler alumni that can be used by students, postdocs and faculty looking for career advice and connections.
  1. Faculty support in the form of guidance and connections in developing non-academic careers.
  1. Career development support staff for students from the Tufts and Sackler administration, so as to cultivate an engaged alumni population.

Comments, suggestions, and other feedback on this editorial can be left on either the InSight blog or via this online form: Anonymous feedback form: http://goo.gl/forms/PXEfcLfgeX

A survey to collect more detailed data from the student body will be conducted by the Sackler GSC in the coming weeks.

 

Sackler Spotlight – Wei-sheng Chen, CMDB

As part of a new endeavor to highlight exciting and groundbreaking work done at Sackler, we are now interviewing current students about their science and themselves.  

This month’s spotlight is on Wei-sheng Chen (CMDB) who earned his PhD from Sackler last year and whose dissertation work will be published in Nature Communications.  

 

What is your research focused on?

My research focused on the role of galectins, a family of carbohydrate binding proteins, in the ocular diseases. During my Ph.D., I investigated (i) the role of galectins in modulating angiogenesis and lymphangiogenesis, (ii) effect of inhibiting galectin-3 and galectin-8 on corneal and choroidal neovascularization, and (iii) therapeutic opportunities of treating glaucoma.

What are some of your major findings?

My thesis project is to study the role of galectin-8 in modulating the process of lymphangiogenesis. Compared to blood vessels, lymphatic vessels were considered less important, invisible, and thus largely neglected by scientists and clinicians. Only in recent years, subsequent to the identification of lymphatic-specific markers (such as podoplanin), it is becoming increasingly clear that lymphatic vessels do not just serve as passive conduits for interstitial fluid and cells, but is actively involved in the pathogenesis of numerous diseases. In addition, the role of carbohydrate recognition system in the regulation of lymphangiogenesis is poorly understood. For my thesis project, using the avascular cornea as a canvas, I demonstrated that galectin-8 is a key mediator of crosstalk among VEGF-C (vascular endothelial growth factor-C), podoplanin and integrin lymphangiogenic pathways. Also, this is the first report demonstrating that podoplanin is a key player in VEGF-C-induced lymphangiogenesis.

What short- and long-term implications does your research have in your field?

In this study, we demonstrated that in the mouse model of corneal allogeneic transplantation, galectin-8-induced lymphangiogenesis is associated with an increased rate of corneal graft rejection. In addition, in the mouse model of herpes simplex virus keratitis, corneal pathology and lymphangiogenesis are ameliorated in galectin-8 knockout mice. Targeting galectin-8 can be a potential novel therapy for corneal graft rejection and herpes simplex virus keratitis. In addition, these results have broad implications for developing novel therapeutic agents to treat numerous diseases, including, but are not limited to, lymphedema, tumor metastasis, cardiovascular diseases (myocardial infarction, hypercholesterolemia, and hypertension), inflammation and immunity, obesity, glaucoma, dry eye disease, and allergic eye disease.

What initially got you interested in science in general, as well as your current field, and this project(s)?

I began my scientific career as a part-time undergrad student in a cardiovascular lab in National Cheng Kung University, Taiwan. My job was to purify plasminogen from human plasma, and further process the protein enzymatically to generate different forms of anti-angiogenic angiostatins. I guess ever since then, I have been fascinated by vascular biology.

During my first year at Tufts, I was looking for a lab studying vascular biology and have done different projects related to the field. Fortunately, I joined Prof. Noorjahan Panjwani’s lab at Ophthalmology Department in 2011 to start my thesis project. During my Ph.D., I have learned a lot about the diverse functions of glycans and glycan binding proteins. In addition, I was encouraged to attend regional and international conferences and have developed great interests in pathogenesis of ocular diseases such as glaucoma and age-related macular degeneration.

Where do you see your career heading in the short or long term?

In the short term, I would like to learn more about the interaction between blood/lymphatic vessels and immune cells such as macrophages and T cells in the setting of eye diseases and/or cancers.

In the long term, I would like to become an independent scientist focusing on vascular biology in the hope to find new therapies for ocular and cardiovascular diseases.

Anything interesting that you do outside of lab or that is science-related but not connected to your research? 

I like to travel and try different cuisines. I especially like conferences that are held close to beaches. In my free time at home, I also like to watch food channel. Some of my favorite programs are “Chopped”, “Guy’s Grocery Games” and “Worst Cooks in America”.

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.