A Little Furry Test for Human Toxicity

PLOS Medicine Associate Editor Laureen Connell discusses a research article from 2014 in which Gary Peltz and colleagues described a new mouse model with a humanized liver that can replicate human-specific toxicity and improve safety of clinical trials.

Image credit: Rama, Wikimedia Commons.

Image credit: Rama, Wikimedia Commons.

In 1993, fialuridine (a nucleoside analogue used to treat hepatitis B virus infection) was tested in humans in a phase II trial after earlier preclinical testing in animals suggested the drug was safe. Some participants had a variety of severe reactions to the drug, including liver failure, lactic acidosis, and steatosis, which led to the death of five participants. Human-specific drug toxicity is a potential problem that requires screening early in drug development.  The development of accurate models in the lab to test drugs for toxicity before serious side effects arise during clinical trials in humans is an important part of developing therapeutics.  Also, more nucleoside analogues are being developed as therapeutics, and therefore improved screening tools are needed for human-specific toxicity. Peltz and colleagues recently explored this problem when they investigated whether testing fialuridine in a new mouse model would have predicted the problems found in humans during clinical trials.

Chimeric TK-NOG mice with humanized livers were generated in 2011 and have been used to predict human-specific drug metabolism and interactions with other drugs. These chimeric TK-NOG mice have been transplanted with human liver cells in order to establish a long-lived mature “human organ.” Previous mouse models used for testing drug toxicity in humans had many limitations and did not accurately predict toxicity in humans. The TK-NOG chimeric mouse was generated by expressing a herpes simplex virus type 1 thymidine kinase (TK) transgene within the liver of a highly immunodeficient mouse strain (NOG).  The mouse’s liver cells expressing the transgene were ablated by exposure to an antiviral drug, allowing transplanted human liver cells to develop into a humanized liver, with a three-dimensional architecture and gene expression pattern characteristic of mature human liver and containing only a small percentage of mouse liver cells.

Continue reading »

Category: 10th Anniversary | 2 Comments

Happy Birthday to PLOS Medicine

On the 10th anniversary of our first issue, the PLOS Medicine Editors reflect on some of our most interesting and influential articles.

Image Credit: Larry Peiperl

Image Credit: Larry Peiperl

This week PLOS Medicine celebrates the 10th anniversary of our first issue. Don’t worry, you don’t need to get us a present. Instead, you can celebrate with us by taking a stroll down memory lane and reading some of the most exciting and interesting articles from the past decade.

We’ve chosen eight articles and one collection that highlight the breadth and influence of PLOS Medicine, from publishing ethics to public health policy to translational medical advances and more.

Starting today and over the next week, Speaking of Medicine will be publishing posts written by the editors of PLOS Medicine explaining what each article is about, what makes it exciting and important, and reflecting on its influence on the field since it was published.

Post 1 of 8:

A little furry test for human toxicity” by Laureen Connell, about Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing the 2014 translational study in which Gary Peltz and colleagues described how a new mouse model with a humanized liver can replicate human-specific toxicity and improve safety of clinical trials.

Post 2 of 8:

PLOS Medicine’s Big Food Series: Shining a Spotlight on Industry’s Influence on Health” by Paul Simpson, about the series of eight commissioned articles that considered the various ways food corporations influence global human health.

Post 3 of 8:

Outing Wyeth and Their Hired Ghosts” by Margaret Winker, about The Haunting of Medical Journals: How Ghostwriting Sold “HRT”, Adriane Fugh-Berman’s 2010 Policy Forum that explored a pharmaceutical company’s manipulation of the medical literature to promote a product.

Post 4 of 8:

Quantifying the dirty nature of war” by Amy Ross, about The Dirty War Index: A Public Health and Human Rights Tool for Examining and Monitoring Armed Conflict Outcomes, Madelyn Hsiao-Rei Hicks and Michael Spagat’s 2008 Policy Forum that proposed a new tool to quantify the harm done by certain weapons and warfare tactics on civilians.

Post 5 of 8:

Pulling back the curtain on lethal injection” by Thomas McBride, about Lethal Injection for Execution: Chemical Asphyxiation? the 2007 research article by Leonidas Koniaris and colleagues that investigated whether lethal injection actually produces a consistently painless death.

Post 6 of 8:

The truth about standardized packaging? Blow some my way” by Linda Nevin, about Representation and Misrepresentation of Scientific Evidence in Contemporary Tobacco Regulation: A Review of Tobacco Industry Submissions to the UK Government Consultation on Standardised Packaging, in which Selda Ulucanlar and colleagues deconstructed advocacy documents submitted to the UK and demonstrated a meaningful distinction between scientist and advocate.

Post 7 of 8:

Voluntary Male Circumcision as HIV Prevention in Africa” by Linda Nevin, about the first randomized controlled trial of voluntary medical male circumcision.

Post 8 of 8:

I’ve got a (lot of) little (check)lists” by Virginia Barbour, about CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials and Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. This pair of guidelines, published in 2009 and 2010, presented medical researchers and publishers with standards for reporting to improve the way we read, assess, test, and reproduce science.


Category: 10th Anniversary | 3 Comments

Improving the health of pre-adolescent children: The latest update to the Pediatric Medicine Collection

In celebration of PLOS Medicine’s 10th birthday, we announce an exciting update to the Pediatric Medicine Collection, highlighting new articles focusing on the health needs of 5 to 10 year old children globally.

In January 2014 PLOS Medicine launched a call requesting papers on the Health of Pre-Adolescent Children, and in light of PLOS Medicine’s own 10 year anniversary, the theme of the call was chosen with the aim to contribute to a better understanding of children who live beyond their 5th birthday but aren’t yet at adolescence. This resulting collection has brought together a broad range of research and commentary.

pediatric_medicineFeatured work in this latest update

Authors Angela Donin and colleagues invited 9-10 year old children to participate in a study examining risk factors for type 2 diabetes. By measuring the levels of insulin, glucose, and other markers, participants reported how often they ate breakfast. It was concluded that children who ate breakfast infrequently had higher fasting insulin levels and increased insulin resistance than children who ate breakfast every day who displayed a favourable type 2 diabetes profile in comparison.

A recent policy forum by Sumit Gupta and co-authors drew attention to the growing need for national childhood cancer strategies in low- and middle-income countries. Amongst severe resource constraints, deficits in infrastructure and other pressing health needs, pediatric oncology resourcing has yet to be translated through from high-income countries. The authors outline why pediatric cancer should now be considered a global child health priority.

Researchers from New Zealand attempted to evaluate the importance of using hand sanitizer for reducing illness in school children. Following a parallel-group cluster randomised trial across 68 primary schools, Patricia Priest and Joanne E McKenzie and colleagues discovered that the provision of hand sanitizer did not reduce the number of school absences due to a specific illness.


Through this collection we hope to provide a broad platform for the dissemination of new high-quality evidence and analysis of conditions that affect pre-adolescent children from around the world.


Please visit the collection at: www.ploscollections.org/pediatricmedicine

Or read the Flipboard version: http://flip.it/SzfOB

Category: 10th Anniversary, Collections | 2 Comments

Global Health Security and the NTDs

Peter Hotez, co-Editor in Chief of PLOS NTDs, comments on President Obama’s call for global action to prepare for future disease outbreaks and to treat biological threats as issues of national and global security.

globe light

Glyn Lowe

In a landmark White House summit last week President Barack Obama addressed health ministers from more than 40 countries, in addition to leaders from several international health organizations.  His welcomed message was that highly lethal and widespread epidemics such as the West African Ebola outbreak are more than public health threats.  Instead these devastating infections when they affect or threaten large populations also have dire economic consequences and themselves are highly destabilizing leading to further breakdowns in already fragile systems and infrastructures.  In this sense Ebola is a direct and serious threat to national and global securities.

This is not the first time we have seen epidemics threaten global security. We saw such connections during the SARS pandemic in 2002-03, again with the emergence of avian influenza, and especially during the H1N1 influenza pandemic of 2009.  These outbreaks together with concerns about bioterrorism were underlying reasons why BARDA (The Biomedical Advanced Research and Development Authority) was established within the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (DHHS).
Continue reading »

Category: General | 4 Comments

PLOS Medicine launches a new Collection on Universal Health Coverage

A new PLOS Medicine collection, Monitoring Universal Health Coverage, provides technical details and country-level experience of the implementation, monitoring, and evaluation of Universal Health Coverage, adding much needed insight to the global conversation on this topic.

Universal Health Coverage (UHC) is the desired outcome for health system performance, whereby all people who need the full spectrum of health services – promotion, prevention, treatment, rehabilitation and palliation – receive them according to need and without resulting in financial hardship.

Image Credit: PLOS

Image Credit: PLOS

The high-profile nature of the event held at The Rockefeller Center (more information here) at which the Collection will launch is fitting for the topic that has emerged as front-runner of the post-2015 development agenda. UHC has been the focus of much work and effort by the international community in order to turn its broad aims into an actionable framework.
Continue reading »

Category: General | 1 Comment

Ebola: a Blind Outbreak

Grazia Caleo of Médecins Sans Frontières (MSF) UK describes her experiences as a medical epidemiologist during the Ebola outbreak in Kailhun, Sierra Leone.

In José Saramago’s book, Blindness, he describes an epidemic of an unknown infection that causes people to lose their sight; a single person remains uninfected to bear witness to the anger, chaos, violence and death generated by the spread of disease.

In the novel, humanity’s descent into blindness represents the loss of reason, and shows how fear can cause dramatic social breakdown; at the same time, the clear vision of one person represents the opportunity to restore light.

What I saw in Sierra Leone as a medical epidemiologist reminded me of Saramago’s book.

I saw ‘blindness’ circulating in villages and amongst local and international Ebola ‘experts’; I saw wisdom among the patients who survived and the doctors and nurses who cared for them.

I saw the under-estimation of the risk and consequences of Ebola in an area bordering three countries; the fear caused by rumours; the late communication with villagers about Ebola and its spread; the huge numbers of patients dying in front of us without our being able to provide them with treatment; the missed opportunity to trace contacts and to apply the simple rule of previous outbreaks: ‘time, place, person’. All of these contributed to a blind response.

Image credit: MSF

Image credit: MSF

Continue reading »

Category: General, MSF | Tagged | 2 Comments

In Honor of Dr. Elisabetta Ullu

Kasturi Haldar, PLOS Pathogens Editor-in-Chief, reflects on Elisabetta Ullu’s pioneering contributions to the understanding of molecular mechanisms of RNAi in T. brucei.

Dr. Elisabetta Ullu.  Image credit: Yale

On the eve of 25th anniversary of the premier Molecular Parasitology Meeting (MPM) held at the Marine Biological laboratory at Woods Hole MA, we reflect on the tremendous accomplishments of the field presented at this meeting, ranging from leading therapeutics in global parasitic diseases as well as fundamental mechanisms enabling development of treatments in seemingly disparate disease states, like tumor biology and autoimmunity.  But the excitement is burdened with hearts full of sadness that Dr. Elisabetta Ullu, a beacon in the field and past MPM organizer, passed away on September 8, 2014 after a heroic battle against cancer.

Dr. Ullu joined the faculty of Yale University School of Medicine as an Assistant Professor in 1984, where she rose through the ranks to Professor of Medicine and Cell Biology.  Her laboratory pioneered in molecular mechanisms of RNA biology in the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness and a portal for RNA based mechanisms at cellular and organismal levels.  Professor Ullu and Prof. Chris Tschudi (her partner in science and life) discovered the novel mechanism of ‘RNA interference’ (RNAi) by which T. brucei blocks the expression of its genes.   Broad acceptance of the central role of RNAi for cells in general, was a 2006 Nobel Prize shared by Andrew Fire and Craig Mello, for their work in nematodes.  Ullu’s findings were transformational to determine functions of proteins encoded by parasite genes, which is key to the discovery of new therapies urgently needed for sleeping sickness. She received many honors and accolades for her work, the most recent being the American Society for Biochemistry and Molecular Biology’s inaugural Alice and C. C. Wang award in 2012, for seminal contribution to the field of Molecular Parasitology.
Continue reading »

Category: General, Trypanosomiasis | Tagged , , , , , , | 1 Comment

When Implementing Universal Health Coverage, Context Matters

As the WHO’s Millennium Development Goals reach their final phase, Sara Gorman reflects on what we have learned about how political, cultural and financial contexts impact the success of universal health coverage systems. 

Image Credit: Edith Soto, Flickr

Image Credit: Edith Soto, Flickr

In May of 2013, Margaret Chan affirmed the WHO’s commitment to achieving universal health coverage worldwide, proclaiming “universal health coverage is the single most powerful concept that public health has to offer”. For Chan, public health measures such as universal health coverage represent a key component of development work in the 21st century. As the Millennium Development Goals (MDGs) begin to wind down with their 2015 expiration date looming, the WHO has turned its attention toward the next set of goals for world health. With statistics revealing that more than 100 million are pushed into poverty each year due to excessive health care costs, it seems ever more urgent to advocate for universal health coverage, spreading the costs across entire populations.
Continue reading »

Category: General | 5 Comments

When Retroviral Research Goes Viral

The PLOS Pathogens team reflects on their most widely shared article and the benefits and pitfalls of sharing science research on social media.


Image credit: Pixabay

Social media has taken the science world by storm. Or maybe it’s the other way around; but regardless, if you are reading this, you are likely a scientist engaging in social media (this is a science blog). Scientists are participating in all types of social media— blogs, Facebook, Twitter, reddit, Tumblr, Flipboard — showing that science discourse is not limited to conference rooms and laboratories.

Prominent and famous scientists from the Nobel prize winning climatologist Dr. Michael Mann to television-show sensation Bill Nye use social media (see famous scientists on Twitter at Business Insider as well as  scientists on the reddit Ask Me Anything Series). However, social media isn’t just for Principle Investigators in the public eye or distinguished science journalists. Scientists in any field can and are using social media on a daily, even hourly, basis— just check out Vincent Racaniello, the host of the TWiV podcast and an active twitter user. PLOS Biology has even published An Introduction to Social Media for Scientists instructing scientists why and how to showcase their research using social media and PLOS Computational Biology more recently published Ten Simple Rules of Live Tweeting at Scientific Conferences.
Continue reading »

Category: General | 1 Comment

Further Integration: The latest update to the MHTF & PLOS Maternal Health Collection

In November 2013, PLOS Medicine and the Maternal Health Task Force (MHTF) called for submissions to the third year of the MHTF-PLOS Collection on Maternal Health. Today we announce an exciting new update to the Year 3 Collection, including original 11 research articles and a policy forum, all recently published in PLOS.

This continued collaboration between the MHTF at Harvard School of Public Health and PLOS Medicine is reflected in this latest collection update, highlighting recently published work that ties in with the current theme, “Integrating Health Care to Meet the Needs of the Mother–Infant Pair”. 

Image credit: Jack Zalium, Flickr

Image credit: Jack Zalium, Flickr

Chosen with the aim to contribute to a better understanding of how and when to comprehensively integrate maternal and infant health care, this year’s theme includes work on conditions such as HIV, malaria, exposure to environmental risks, and other situations that have a significant impact on both maternal and infant health.

Featured work in this latest update

A policy forum by Jenny Hill and colleagues highlights the importance of prioritizing pregnant women, as a high risk group, for delivery of long lasting insecticide treated nets through antenatal clinics. Delivering free or subsidized long-lasting insecticide treated nets (or vouchers) to pregnant women is a key approach for controlling malaria and increases coverage and use by both pregnant women and their infants.
Continue reading »

Category: General | 2 Comments