IHS Library celebrates our first year in our 2018-2019 Annual Report

The IHS librarians are delighted to share our IHS 2018-2019 Annual Report. The report highlights our accomplishments in our first year serving the IHS community, including:

  • Collaborating on teaching and learning with the 3 schools we serve;
  • Heavy usage of the databases, journals, and textbooks we license for IHS, as well as the website and online toolkits we’ve developed;
  • Offering reserved study spaces, which were booked 15,000 times in FY2018-2019; and
  • A myriad of interprofessional collaborations across the campus community.

We are happy to call the IHS campus home, and we are proud to be your library!

A Bioethicist’s Response to “When is a Brain Really Dead?”

Today’s post is a response by Dr. Bryan Pilkington to Dr. Stan Terlecky’s July 15, 2019 Terlecky’s Corner post entitled, “When is a Brain Really Dead?” Dr. Pilkington is an Associate Professor at Seton Hall University.

Last month’s Terlecky’s Corner post raises the question, “When is a brain really dead?” The reanimation – to borrow Terlecky’s phrase and his caution about its use – of porcine brains is both exciting and concerning. The excitement is due, as Terlecky notes well, to the possible benefits of such work: “potentially impacting several health scourges of our time including Alzheimer’s disease, Parkinson’s disease, and other age-related neurodegenerative disorders.”[1] He also notices that ethicists will be busy sorting through these and future studies, especially if the human brain gets involved.

Brain

This is how the usual dialectic goes when addressing ethical questions about emerging medical technologies. Undoubtedly, there will be lectures and papers from ethicists raising the usual kinds of questions, many titled with some version of, “We can, but should we?” These are not endeavors without merit; ethical analysis often lags behind research; in many cases, something has to be created in order to have something about which to raise questions. In fact, one of the important tasks of ethicists in this realm is to serve as watchdogs: to give caution, to aid researchers in thinking through possible concerns, and in some instances – at least with respect to IRB oversight – to say “no.”[2] However, though this is a useful and important role, it comes at a cost. Many times, those raising these kinds of concerns are termed “the ethics police”[3] and this image has hurt collaboration on research and made more challenging the necessary interprofessional tasks that medical research and healthcare practices are.

So what should be said in response to this kind of research? What are the answers to Terlecky’s list of ethical questions? The questions require longer answers than the space of a blog post admits, but I’ll take a shot at two sets of questions, suggesting a model for answering them and those remaining.

The first set comprises a list of real and immediate questions about one of the practical consequences of this research: organ donation. Will donation rates plummet? Will the organ shortage increase because there will be hold outs who think reanimation is possible? Will public trust diminish as this research moves forward?[4] Will families request that additional healthcare resources be spent on loved ones who meet the legal definition of brain death? An answer which avoids the problematic policing approach but takes seriously the importance of these questions is to engage in an extended conversation with researchers, ethicists, healthcare practitioners and administrators, and members of their communities about new technology, how it might be used, and its far-reaching implications. We must not shy away from these hard questions nor from recognizing the potential value of certain kinds of research, but we must also keep in mind the possible negative externalities that could result. This approach raises more questions. Should this research be halted if it damages public trust? Should it be stopped if fewer organs are donated? These questions lead to further questions. If the organ shortage is a primary concern, is it appropriate to connect it to this research? The conversation I am suggesting must consider that, as well. Some have argued that the sale of organs should be allowed and that this would alleviate the shortage[5], others have raised concerns about the commodification of human beings if such sale is legalized[6] – the breadth of the needed conversation is wide, as answers to questions about organ sale are connected to ethical concerns raised about porcine brain experimentation.

A second set of questions hover around the definition of death and the sources upon which we rely to answer those questions. Terlecky helpfully asks about the legal, ethical, and spiritual determinations of death. From where or in what do we root our conceptions of life, of human flourishing, and of death? Are they religious? Are they legalistic? Are they rooted in metaphysical conceptions of the person that we learned in our undergraduate philosophy courses? The kind of conversation I am suggesting is most effectively held when we bring the deep and rich traditions that inform our thought to bear on the subject matter under discussion. It is not a simple task to work through various traditions and try to understand how others think about reanimated porcine brains, human brains, and death, but that is what is needed. As physician and ethicist Lauris Kaldjian recently asked of his colleagues,[7] did you take a course about the existential questions in medical school? Though rhetorical, the suggestion is powerful. How should we respond to this research? In the same way we should respond to all research that raises significant ethical questions, by practically reasoning together.

 

References:

[1] Terlecky, S. 2019, July 15. “When is a Brain Really Dead?”

[2] ​Evans, J. 2012. The History and Future of Bioethics: A Sociological Account. Oxford, United​ ​Kingdom: Oxford University Press.

[3] Klitzman, R. 2015. The Ethics Police? The Struggle to Make Human Research Safe. Oxford: Oxford University Press

[4] ​Moschella, M. 2018. Brain death and organ donation: A crisis of public trust. Christian Bioethics 24(2):133–50.

[5] ​Cherry, M. ​2005​. ​K​​idney for Sale by Owner: Human Organs, Transplantation, and the Market. Georgetown University Press.

[6] Pilkington, B. 2018. A Market in Human Flesh: Ramsey’s Argument on Organ Sale, 50 years later. Christian Bioethics 24(2):133–50.

[7] Kaldjian, L. (Personal communication during lecture in Grand Rapids, Michigan, March 25, 2019).

When is a Brain Really Dead?

When is a brain really dead? The answer to this question was made far more complicated by the recent work of Dr. Nenad Sestan and colleagues at Yale University. Their astonishing paper entitled “Restoration of brain circulation and cellular functions post-mortem,” appeared in the journal Nature[1] this April. In it, the authors were able to demonstrate that brains taken from slaughtered animals (pigs in this case), could be “reanimated” 4 hours later in the laboratory – and made at least partially functional for some 6 hours thereafter. I use the word reanimated with some trepidation – it implies the brains were dead and somehow brought back to life. That is not quite the story – rather, the organ turns out to be far more resilient than we previously realized and the research team simply identified a way to tap into that inherent resiliency.

A brief description of the research study: 32 brains from slaughtered pigs were delivered to the research team on ice. Within 4 hours, the scientists carefully perfused the brains using a proprietary surgical procedure, pumping apparatus, and oxygen and nutrient-rich solution collectively termed BrainEx. The team then analyzed the brains for specific cellular, metabolic, and electrical activities. What they found was incredible. The BrainEx perfusion system restored a number of brain functions, including glucose and O2 utilization and concomitant CO2 production (indicative of metabolic function), induced inflammatory responses (suggesting an active immune system), active microcirculation (evidence of structural integrity), and electrical activity (with neuronal firing).

Figure of porcine brain connected to perfusion system
Connection of the porcine brain to the perfusion system via arterial lines. The pulse generator (PG) transforms continuous flow to pulsatile perfusion. Source: Figure 1B, Nature 568, 336–343 (2019).

With respect to the last point, it should be noted the investigators were well aware of the ethical concern that full restoration of brain function could potentially lead to a state of “consciousness.” What it would mean for a disembodied brain to attempt to operate without peripheral sensory input, and what the organ might remember, was simply too much to consider; the brains were treated pharmacologically to assure no coordinated higher level cognitive activity was possible. Said another way, the renewed brains could not begin to think.

Overall, the results suggested to a first approximation, functional activity of the otherwise dead brain had been restored. Importantly from an experimental standpoint, control perfusates were without effect – the brains degenerated much like untreated specimens.

Against the backdrop of these remarkable results are the inevitable ethical questions that follow. Returning to the one posed above – when is a brain really dead? If our understanding of brain death requires a deeper examination, how then do we determine legally, ethically, and/or spiritually, when a person truly dies? What are the implications of this work on the issue of organ donations? Is a brain death as currently defined sufficient to permit the harvesting of a person’s organs? Will (and should) donations ebb as people begin to question the legitimacy of declarations of death. Also, could future brain reanimation experiments include restoration of conscious thought? Certainly the ability to control the brain in this manner permits the testing of drugs in new ways – potentially impacting several health scourges of our time including Alzheimer’s disease, Parkinson’s disease, and other age-related neurodegenerative disorders.

Naturally, science requires replication, expansion, and more careful delineation of what is, and is not possible with the technology described. But what enormous doors have been opened for neuroscientists, neurologists, neuropharmacologists, cognitive scientists, and the many others interested in the structure and function of the brain. I suspect ethicists will also be very busy sorting through these and the inevitable follow-up studies – especially as applications involving the human brain are contemplated.

SRT – July 2019

[1] Vrselja Z, et al., Nature 568, 336-343 (2019). PMID: 30996318

Faster and easier article PDFs in PubMed

We’re pleased to announce another enhancement to the user experience for IHS students, faculty, and staff: Libkey Link for PubMed. To quote Third Iron, the vendor we’ve partnered with for this feature, Libkey Link “brings one-click access to PDF articles in PubMed, dramatically simplifying workflow and improving user experience. No more confusion over what full text source to pick, no more waiting for different pages to load hunting for the PDF button.” We’ve implemented LibKey Link to cut out a couple of steps in the old process, making it easier and faster for you to get the article PDF you’re looking for. As always, if you need any help with this feature (or anything else information-related), contact your IHS librarian.

Improvements to the SHUhealth search tool

SHU Health is a tool that allows IHS Library users to search both the catalog (books, videos, CDs, etc.) and articles simultaneously. We are excited to announce a number of improvements to the interface to streamline the experience for you.

You can search SHUhealth from the library homepage
Getting to SHUhealth from the library homepage

The updated interface is significantly simpler, reducing clutter by removing little-used and unnecessary features. IHS librarians reached out to our partner EBSCO, which manages the interface, to suggest the changes.

Updated and simplified SHUhealth interface
The updated and streamlined SHUhealth interface

We’re interested in continually improving your experience with IHS Library website and other library interfaces. If you have an improvement to suggest or notice a bug we need to fix, email me at andrew.hickner AT shu.edu.

Cardiac Exosomes to the Rescue

In an extremely exciting study that appeared last month in the journal Nature Communications[1], scientists from the University of Alabama at Birmingham, and Huazhong University of Science and Technology in Wuhan, China, showed that after myocardial infarction (~heart attack), heart tissue release tiny membrane-bound vesicles called exosomes, specifically loaded with genetic material designed to promote cardiac tissue repair. Such restoration is mediated by bone marrow progenitor cells that have been released from their sequestered bone-specific existence by the information carried in the newly arrived exosomes.

Several hundred thousand Americans suffer heart attacks each year, making it critical for the medical and scientific communities to understand this potentially transformative study. To begin our analysis, let’s begin with exosomes – tiny membrane-enclosed vesicles released from many cell types. Thought to mediate communication/cell-cell signaling activities, exosomes leave cells loaded with proteins, lipids, DNA, mRNA, and microRNAs among other potentially bioactive molecules. Exosomes are synthesized within the endosome-lysosome system of cells – emerging cargo loaded and poised to deliver their contents locally, or at a distance. It is perhaps not surprising that several pharmaceutical companies – recognizing the potential drug delivery platform that exosomes represent, are pursuing the tiny vesicles in several biomedical contexts.

Once released, how the nascent exosomes hone to specific target tissues and cells is unclear. Perhaps the proteins assembled into their membranes – distinct to each type of exosome – play a role in this discrimination. Also not well understood is the nature of the exosome-target cell interaction. Is it a receptor-ligand-like binding event that triggers signaling events and results in fusion and integration of exosomal contents? Or is it a more basic fusion of two membranes held in close apposition? What about a straightforward endocytic process whereby the exosome is taken up and released within the newly formed endosome?

Back to the study at hand – the investigative team identified the exosomes released from damaged heart muscle as containing specific microRNAs (called myocardial microRNAs or myo-miRs). Recall microRNAs are short, non-coding RNAs with the capacity to (negatively) regulate gene expression. The myo-miRs under consideration here do just that – they very effectively block activity of the chemokine receptor, CXCR4 in bone marrow progenitor cells. Such inhibition allows such stem-like cells to escape their seclusion, enter the bloodstream, and travel to the injured heart…“exosomes to the rescue.” There, repair processes are initiated.

Knowing this cell biology, there must be ways to better harness exosomes to improve cardiac repair. Investigators are sure to pursue this quickly. Almost as assuredly, scientists will also be looking for other examples of exosomes and their bioactive contents as biomarkers for pathology, and as potential rescue mechanisms for disease’s damaging wrath.

SRT – April 2019

[1]Cheng M, et al., Nat Commun. (2019) doi: 10.1038/s41467-019-08895-

My Professional Journey: Dr. Heather Frimmer

On March 13, Hackensack Meridian School of Medicine at SHU students, faculty, and staff gathered over lunch to hear Dr. Heather Frimmer discuss her unique career trajectory from medical trainee to radiologist and published author. This engaging event was part of the “My Professional Journey” series sponsored by Student Affairs and Wellbeing “Careers in Medicine,” the OME Professionalism Committee, and the IHS Library.

During the 90-minute program, Dr. Frimmer spoke of the path that led to her current position as Diagnostic Radiologist in Breast and Emergency Radiology. Once established in her medical career, she would then follow an altogether different path and write her first novel, Bedside Manners, published by SparkPress in 2018.

After her talk, those in attendance were treated to a reading of two passages from Bedside Manners, followed by small-group discussion and reflection of the passages’ themes. Students were then invited to do a bit of their own creative writing based on their personal clinical experiences thus far.

On behalf of everyone who attended, the sponsors of the “My Professional Journey” series would like to thank Dr. Frimmer for joining us and speaking about her medical and writing career.

Dr. Heather Frimmer (left) with former medical school classmate, Dr. Miriam Hoffman, Associate Dean of Medical Education.
From left to right: Dr. Miriam Hoffman (Associate Dean of Medical Education), Janae Moment (MS1), Raquel Cancho Otero (MS1), Dr. Heather Frimmer, Candace Pallitto (MS1), Caryn Katz Loffman (Human Dimension Assistant Course Director), Katherine Veltri (MS1), and Allison Piazza (Health Sciences Librarian).
Medical students and faculty discussing Bedside Manners by Dr. Heather Frimmer.

Unexpected Role for Mitochondria in Bacterial Killing

Just when we thought we understood the cell biology of antimicrobial resistance in macrophages, a study like the one detailed by Abuaita and colleagues in their Cell Host & Microbe article comes along.[1] Not only are the molecular mechanisms of pathogen metabolism updated, but new cellular signaling and trafficking pathways are implicated. There is a lot of new and important science included in this exciting paper.

Let’s begin by remembering that macrophages are immune cells whose role is to internalize and degrade invading microorganisms. They do so by endocytosing the pathogenic microbes and sequestering them in a newly developed phagosome. It is there that the destructive processes are initiated; final elimination of residual components occurs in the lysosome – a related degradative organelle that works in close concert with the nascent phagosome.

Graphical abstract of Abuaita et al, 2018.

What Abuaita and co-authors describe is a process by which certain bacteria, including the potentially dangerous methicillin-resistant Staphylococcus aureus, trigger more than simply a phagocytic event. Rather, it is clear that the phagosome somehow recognizes the microorganism within its midst, and launches a far more lethal and complex biochemical reaction. The cascade begins with the infected macrophage mounting a stress response – one initiated by the phagosome but further elaborated by the endoplasmic reticulum. Specifically, the endoplasmic reticulum turns on one of the most elegantly choreographed and well-described quality-control systems in the cell, called the unfolded protein response, or UPR. The critical sensor that needs to be tripped to turn on the pathway is the endoplasmic reticulum membrane protein, IRE1a. It is at this point that the cell biology really gets exciting.

The response is not confined to the endoplasmic reticulum and well understood downstream nuclear effector pathways; rather, the signal is somehow transmitted to mitochondria. In response, the organelle is prompted to produce reactive oxygen species – hydrogen peroxide in particular. Mitochondria are known to produce reactive oxygen species, including hydrogen peroxide, as part of their normal energy-generating metabolism. What is different here is that a defense mechanism initiated in the phagosome, signals the endoplasmic reticulum, which then communicates to the mitochondria; a truly elegant and previously unrecognized relay system.

As interesting as the new interorganellar signaling events are – there is more. Specifically, the fascinatingly novel trafficking pathways identified.

The newly synthesized mitochondrial hydrogen peroxide is packaged in vesicles which are shed from the organelle. The authors even identify a critical component of this release step – the ubiquitin ligase, Parkin. These newly created, hydrogen peroxide-loaded mitochondrial vesicles then migrate through the cell, destined to fuse with pathogen-infected phagosomes – releasing their toxic contents and supplementing the already initiated bacterial killing process. Just in case the newly delivered hydrogen peroxide does not provide a sufficient amount of toxic reactive oxygen, some mitochondrial vesicles actually encapsulate the hydrogen peroxide-synthesizing enzyme, superoxide dismutase-2.

What we have here is the cell marshalling its degradative armamentarium in a manner we never imagined to help fight methicillin-resistant Staphylococcus aureus and other invading pathogens. It seems clear that this is only the tip of the iceberg – interorganelle communication/signaling networks and elaborately coordinated effector apparatuses in cells are certain to exist in ways we can only begin to imagine. In this case, the goal is to fight infection; in others, it may very well be to thwart the effects of aging, to counter disease, or neutralize the effects of mutations, toxins, or other environmental insults. The more we know about cell biology, the more we realize how much we do not know; it is amazing how the field continues to captivate our attention.

SRT – February 2019

[1]B.H. Abuaita et al., Cell Host and Microbe (2018) doi: 10.1016/j.chom.2018.10.005. PMID: 30449314 (Request article via ILL).

Get all the data you need with PolicyMap

As their website states, PolicyMap is “All the data you need.  All in one place.”  In just a few clicks you can access authoritative data from public and private sources to create highly detailed maps.  As a user you can find data on demographics, housing, health, education and more in communities across the nation.

PolicyMap is an excellent resource for both students and faculty to use to find data on specific areas.  It provides up-to-date demographic data that allows users to become research producers.  PolicyMap has many options based on what you want to create including: maps, tables, reports and 3-layer maps.  The maps option allows users to create maps based on data for a geographical region for a single variable while the 3-layer maps allows you to find places that match one or up to three variables.

Check out the PolicyMap toolkit https://library.shu.edu/policymapgs for more information on how to use PolicyMap.  And keep an eye out for PolicyMap session here on the IHS campus!

Kyle Downey, 12/5/2018

The Value of Negative Results

Every investigator hopes the results they obtain support the hypothesis they put forth. However, more often than not, this does not happen – the data acquired do not conform to what was expected. What to do then with the “negative” results?

To be clear, the results we are talking about were obtained through carefully considered, well executed, and appropriately controlled (read: presence of positive and negative controls) experiments. They simply do not extend that which was predicted; in some cases, they may even call into question the underlying – often already published – results that led to the hypothesis guiding the study.

Of course, it may be that the work that was to be extended was never solid in the first place. That is, it is possible that the prevailing view in a field is based on incorrect and/or irreproducible results. Indeed, a number of studies are showing an alarmingly large percentage of high-profile published results are not reproducible [1],[2]. In the field of cancer – the pharmaceutical giants Amgen and Bayer Healthcare were unable to replicate the findings included in a large number of studies published in elite journals. The implications are profound; how can companies which rely on such research published in the scientific literature to define molecular targets and develop therapeutic drugs, do so against a backdrop of irreproducibility?

Source: Baker M. 1,500 scientists lift the lid on reproducibility. Nature; 2016.

Why is this happening? Explanations offered include – among others, pressures to publish, financial considerations, poor statistical analyses, insufficiently detailed protocols/technical complexity, selective reporting, and inadequate reagent authentication. The National Institutes of Health is aware of these problems and is calling on investigators seeking support to include in their proposals detailed descriptions of i. the scientific premise of the proposal; ii. experimental design specifications; iii. how biological variability will be considered; and iv. how biological and chemical reagents will be authenticated[3]. This is in addition to newly required statements regarding evidence that a detailed plan for data analysis is in place.

Although the (negative) results obtained do not confirm or extend other studies, the point here is that they are still very much of value. Other scientists in the field would welcome knowing what was done, and what was observed. The obvious benefit is that it will prevent others from wasting time, energy, and resources on approaches that are not fruitful, and would help focus the field by better defining what are, and what are not reliable results/models.

Despite the inherent value of such results, there is the perception of publication bias – the belief that only positive data is worthy of publication. Non-confirmatory or negative results are often not disseminated, at great cost to the scientific community.

One approach to assuring sufficient promulgation of the conclusions of a study is for appropriate journals to agree, in advance, to publish the results regardless of whether they confirm or refute the underlying hypotheses that initiated the study. This would provide a mechanism for a field to enjoy a wealth of otherwise unreported information about what works, and what does not – in particular investigators’ laboratories. Many clinical trials operate this way, with final results disseminated regardless of the effects seen on patients. A second approach would be to develop journals that will consider negative, confirmatory, and non-confirmatory results, data notes, and virtually any valid scientific or technical finding in a particular field. F1000Research is a journal that adheres to just such guidelines. The idea that all results are embraced is extremely attractive; after all, science is, at its core, simply a search for the truth.

SRT – November 2018

[1] M. Baker, Nature (2016) doi: 10.1038/533452a. PMID: 27225100 (article)
[2] C.G. Begley and L.M. Ellis, Nature (2012) doi: 10.1038/483531a. PMID: 22460880 (article)
[3] National Institutes of Health – New Grant Guidelines; what you need to know. https://grants.nih.gov/reproducibility/documents/grant-guideline.pdf