importance of funding basic science

East of Eden: The Suboptimal State of Funding in the Natural Sciences

By Asu Erden

“Don’t stay here, go to the U.S. if you can.” I heard my fair share of invaluable insight into the world of scientific research during my time at the Pasteur Institute in Paris, but this one really stuck with me. “The difference between Europe and the United States is that, if there are about ten hypotheses you can formulate to address a specific question, in France we have to choose the three or four more likely ones to test. In the U.S., they can test all ten in a heartbeat without worrying about funding.” This romanticized view of scientific research in the U.S. held some truth to it when I heard it back in 2005. But while the U.S. seemed to be the Eden of scientific funding in the early 2000s, funding cuts have had a tremendous impact on the state of research in the natural sciences on this side of the pond too.

 

A historical overview of public science funding

 

The National Institutes of Health (NIH) is the United States government’s medical research agency and the largest source of funding for medical research in the world. However over the last decade, it has not been able to fund as many projects as it used to. The funding for research project grants by the NIH – including the much coveted R01 grants which determine a lot of the tenure track positions in the natural sciences – increased steadily between 1995 and 2003, but has decreased by over 20% since 2004. “With shrinking government funding (or flat-lined, which is the same as shrinking), labs have to look for alternative sources, it’s just a fact of the situation,” admitted Dr. Heather Marshall, a former postdoctoral researcher in the Immunobiology Department at Yale University.

 

The percentage of successful research grant applications to the NIH was of 26.8% in 1995, reached 32.0% in 1999, before decreasing to 17.5% by 2013. “The state of funding most definitely shifted during my postdoc and it was most evident when discussing with PIs [ED: principal investigators], successful ones at that.  The attitude was depressing and demoralizing.  The funding percentiles of postdoctoral fellowships went down each year I was a postdoc and it became evident that attaining a fellowship was mostly out of your control,” shared Dr. Marshall. The success rate for new applications, which new faculty members rely on to start up their labs and research, has fluctuated between 18.6% in 1995, reached approximately 22% by 1999, before plummeting to 13.4% in 2013. According to the latest numbers, this means that investigators are 37.8% less likely to obtain an R01 or equivalent award today than they were in 2003. This decrease is partially explained by the NIH budget being cut by over one fifth of what it was in 1995.

 

Most of the time, it is the task of PIs – i.e. the professors running labs – to write grants lauding the importance of the research carried out in their laboratories in order to ensure the future of their line of research and that of their trainees. Graduate students and postdoctoral researchers also apply for fellowships and grants but the pecuniary benefits at stake only really affect their own work, not that of the lab overall. With the success rates for grants – new or continued – decreasing over the last decade and a half, grant applications have become particularly stressful endeavors. While PIs usually serve as a protective shield from this reality, it seems to be increasingly hard to cut the stress out…”I’ve been in research since 2003. PIs are communicating their stress more,” said Dr. Smita Gopinath, a postdoctoral researcher immunology at Yale University. The situation is not as dire in Ivy League or top tier universities. But for those PIs that do not work for private universities, loss in funding means laying off personnel or closing their lab altogether. This hinders research and in the long run biomedical advances.

 

With this decrease in funding for research in the natural sciences comes a sense of lack of job security for the extremely skilled highly educated workers that scientific researchers are. “Funding directly impacts the number of jobs available, so in that sense the state of funding absolutely played a major role in my decision to leave academia,” said Dr. Marshall. “In addition to that, I was worried that I wouldn’t get enough grants to fund the projects I wanted to take on, which would also impact my ability to train students and postdocs.  That caused a lot of anxiety and I didn’t even have a job yet!”

 

The budget fluctuations in the NIH and other science funding agencies accompany political changes in the White House, the Senate, and the Congress. During the Bush presidency, the NIH funding initially increased between 2001 and 2003 but suffered a big decrease from then onwards. Entire fields of research were completely defunded such as stem cell research. In 2009, Obama refunded these fields but the NIH has not seen an increase in budget to match inflation. Over the last few years, Republicans have increasingly criticized a number of national agencies such as the National Science Foundation (NSF) and the NIH for the type of research they fund. “Sometimes these dollars they go to projects having little or nothing to do with the public good. Things like fruit fly research in Paris, France. I kid you not!” exclaimed McCain’s running buddy, ever-entertaining Sarah Palin, during the 2008 presidential campaign.

 

The importance of funding basic sciences

 

You may argue that basic research does not always lead to biomedical advances that can be translated to the treatment, cure, or prevention of infectious or non-infectious diseases in humans. “It’s like the mosquito bed net problem. I have so many friends that work on malaria but stop and think, “My stipend can buy 200 bed nets, what am I doing with my life when I could save people directly?” This is the eternal struggle,” shared Dr. Gopinath. “Why fund basic science? Because at some point bed nets will not be effective enough.” There lies the central problem of basic science funding. It can take years between the research and its putative application for humans. This time lag has affected the mentality of the funding agencies. There is a growing gap between what the NSF, which has traditionally funded more basic research in the natural sciences, and the NIH fund, which now funds more translatable research endeavors.

 

But you never know where the next thing is going to come from. The nature of basic research is that while fuelled first by scientific curiosity, it also aims to develop our understanding of the world surrounding us in order to potentially make translational contributions. Let’s take Sarah Palin’s insightful comments on fruit fly research. In 1933, Dr. Thomas Hunt Morgan received the Nobel Prize for his research on the inheritance of physical traits. His animal model? The fruit fly. Since then, fruit fly research has led to the identification of genes as the unit of biological inheritance, to understanding how organismal ontology works, and to the now growing field of epigenetics. Working on fruit flies, scientists have also been able to identify key components of the immune system, which in the long run increased our power to medically reduce human suffering. Drosophila melanogaster – one of the more studied fruit fly species – has provided much insight into the role of genes in neurological behavior including human genes involved in autism. The irony…I kid you not Mrs. Palin!

 

 

Many of the drugs and treatments we use today are derived from such discoveries in the basic natural sciences. 40% of the medical drugs we use target a protein family known as G protein-coupled receptors (GPCRs), which translate signals external to the cell into intracellular signaling. Hormones, neurotransmitters in the brain, and even light can activate these receptors leading to biological processes such as vision, taste, smell, mood regulation, and that of the immune system. Drs. Brian Kobilka and Robert Lefkowitz won the Nobel Prize in Chemistry – not Physiology and Medicine – for solving the crystal structure of this class of transmembrane proteins. Their work focused on the chemical structure of GPCRs. This had immense ramifications in understanding how these receptors transduce signal from outside the cell by interacting with components inside the cell. Eventually, it led to the better understanding of the cellular and physiological processes these receptors are involved in which allowed the scientific community to recognize their central importance in drug targeting. From crystals we reached therapy.

 

Other examples of basic science research leading to translational advances abound. Dr. Jennifer Doudna moved to the University of California Berkeley in 2002 where she started studying how bacteria can defend themselves against viruses that infect them, also known as bacteriophages. In particular, she was interested in the clustered regularly interspaced short palindromic repeats – CRISPR – in bacterial genomes that enable these microbes to kill off bacteriophages that previously infected them. With help from collaborators, Dr. Doudna was able to identify Cas9 as the protein allowing for this viral DNA editing. Thus was born the CRISPR-Cas9 system. Since its discovery in 2012, this system has allowed the genome editing of multiple cell lines commonly used in research, but also organ-specific genetic editing in mice. The method allows scientists to make mouse lines with permanent gene silencing – also known as knock-outs – in a matter of a few weeks where it previously took them years to breed the gene of interest out.  Moreover, CRISPR-Cas9 allows researchers to delete genes of interest in fully developed mice, as opposed to embryonic deletions of genes, which can prove fatal if they are required during development. The technique is set to allow for great medical advances especially if applied to the genome editing of hematopoietic cells to cure blood disorders such as sickle cell anemia, primary immunodeficiencies (such as AIDS), and cancer. When Dr. Doudna’s research was funded, no one knew the implications it would have. It took over ten years to go from better understanding bacterial defenses against viruses to developing an incredibly potent tool that will potentiate the cure of many human woes.

 

Better tailored funding for the natural sciences involves better communication

 

There is a mismatch between the public’s understanding of the importance their taxes play in funding fundamental scientific advances and scientists pleading for politicians not to further cut their funding. As Dr. Marshall pointed out “We can’t really expect all government officials to have strong science backgrounds if they are also expected to have strong backgrounds in law, history, economics etc., but we absolutely need to have our representatives surrounded by scientists.  So from that perspective, [better science funding] does start with the general public.” The nature of scientific funding, as with all funding, is that it is limited. “We can’t rely on our achievements alone. We need to put it out there and communicate the importance of scientific research,” shared Dr. Gopinath. “We need to be managers and communicators. We do get training to collaborate with other scientists and communicate on that level. Communicating science to non-scientists is not at all on our radar!”

 

It is usually the University Office, which is in charge of what gets or does not get communicated about the scientific research carried out on campuses. While the impetus should not be on scientists to carry out science communication by themselves, additional training of PhD students, postdoctoral fellows, and PIs is required. When a journalist picks up the phone to talk about the latest advance in stem cell research, she should not face a public relations wall. Perhaps unbeknownst to the public, researchers have to meet an astounding number of training requirements annually to be able to continue carrying out their research: radiation safety, animal care and use, biosafety, laboratory chemical safety, medical surveillance for animal handlers, blood-borne pathogens and so on and so forth. To these requirements we should add science communication.  The ramifications are countless!


HPV vaccine now covers 9 strains

Extra Protection: New HPV Vaccine Extends Protection to Nine Strains of The Virus

 

By Asu Erden

The human papillomavirus (HPV) is responsible for 5% of all cancers. Until, 2006 there were no commercially available vaccines against the virus. That year, the Food and Drug Administration (FDA) approved the first preventive HPV vaccine, Gardasil (qHPV). This vaccine conveys protection against strains 6, 11, 16, and 18 of the virus and demonstrates remarkable efficacy. The Centers for Disease Control (CDC) estimates that this quadrivalent vaccine prevents 100% of genital pre-cancers and warts in previously unexposed women and 90% of genital warts and 75% of anal cancers in men. While this qHPV protects against 70% of HPV strains, there remains a number of high-risk strains such as HPV 31, 35, 39, 45, 51, 52, 58 for which we do not yet have prophylactic vaccines.

 

In February of this year, a study by an international team spanning five continents changed this state of affairs. The team led by Dr. Elmar A. Joura, Associate Professor of Gynecology and Obstetrics at the Medical University, published its study in the New England Journal of Medicine. It details a phase 2b-3 clinical study of a novel nine-valent HPV (9vHPV) vaccine that targets the four HPV strains included in Gardasil as well as strains 31, 33, 45, 52, and 58. The 9vHPV vaccine was tested side-by-side with the qHPV vaccine in an international cohort of 14, 215 women. Each participant received three doses of either vaccine, the first on day one, the second dose two months later, and the final dose six months after the first dose. Neither groups differed in their basal health or sexual behavior. This is the immunization regimen currently implemented for the Gardasil vaccine.

 

Blood samples as well as local tissue swabs were collected for analysis of antibody responses and HPV infection, respectively. They revealed the same low percentage of high-grade cervical, vulvar, or vaginal. Antibody responses against the four HPV strains included in the Gardasil vaccine were similar in both treatment groups. Of note is that participants in the 9vHPV vaccine group experienced more mild to moderate adverse events at the site of injection. Dr. Elmar A. Joura explained that these effects are due to the fact that the “[new] vaccine contains more antigen, hence more local reactions are expected. The amount of aluminium [editor’s note: the adjuvant used in the vaccine] was adapted to fit with the amount of antigen. It is the same amount of aluminium as used in the Hepatitis B vaccine.”

 

These results confirm that the novel 9vHPV vaccine raises antibody responses against HPV strains 6, 11, 16, 18 that are as efficacious as the original Gardasil vaccine. In addition, the novel vaccine also raises protection against HPV strains 31, 33, 45, 52, and 58. Importantly, the immune responses triggered by the 9vHPV vaccine are as protective against HPV disease as those raised by the qHPV vaccine.

 

Yet we are all too familiar with the contention surrounding the original qHPV vaccine. And no doubt, this new 9vHPV vaccine will reignite the debate. Those who specifically oppose the HPV vaccine question its safety and usefulness. In terms of its safety, the HPV vaccine has been tested for over a decade prior to becoming commercially available and has been proven completely safe since its introduction a decade ago. Adverse effects include muscle soreness at the site of injection, which is expected for a vaccine delivered into the muscle…

 

As for its usefulness, don’t make me drag the Surgeon General and Elmo onto the stage. The qHPV vaccine has been shown to be safe and to significantly impact HPV-related genital warts, HPV infection, and cervical complications, “as early as three years after the introduction of [the vaccine]” in terms of curtailing the transmission and public health costs of HPV infections and related cancers.   “HPV related disease and cancer is common. It pays off to get vaccinated and even more importantly to protect the children,” noted Dr Elmar A. Joura.

 

Other opponents to the HPV vaccines raise concerns regarding the use of aluminium as the adjuvant in the formulation of the vaccine. This inorganic compound is necessary to increase the immunogenicity of the vaccine and for the appropriate immune response to be raised against HPV. Common vaccines that include this adjuvant include the hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTP), Haemophilus influenzae type b, as well as pneumococcal vaccines.

 

The only question we face is that given the availability of Gardasil, why do we need a nine-valent vaccine? In order to achieve even greater levels of protection in the population at large, extending coverage to additional high-risk HPV strains is of central importance for public health. The team of international scientists that contributed to the study underlined that the 9vHPV vaccine “offers the potential to increase overall prevention of cervical cancer from approximately 70% to approximately 90%.” Thus the novel 9vHPV vaccine offers hope in bringing us even closer to achieving this epidemiological goal. “With this vaccine cervical and other HPV-related cancers could potentially get eliminated, if a good coverage could be achieved. This has not only an impact on treatment costs but also on cervical screening algorithms and long-term costs,” highlighted Dr. Elmar A Joura.


Dengue It: Dengue-Specific Immune Response Offers Hope for Vaccine Design

 

By Asu Erden

The dengue virus is a mosquito-borne pathogen that infects between 50 and 100 million people every year. Furthermore, the World Health Organization estimates that approximately half of the global population is at risk. Yet there are currently neither vaccines nor medicines available against this disease, whose symptoms range from mild flu-like illness to severe hemorrhagic fever. The central challenge in designing a vaccine against dengue is that infection can be caused by any of four antigenically related viruses, also called serotypes. Moreover, prior infection with one serotype does not protect against the other three. In fact, such heterotypic exposure can result in much more severe secondary infections – a phenomenon called antibody-dependent enhancement. The lack of knowledge about naturally occurring neutralizing antibodies against dengue viruses has hindered the development of an efficient vaccine. A new study published in the journal Nature Immunology by Professor Screaton’s team at Imperial College, London, may allow the field to overcome this barrier.

 

In this month’s issue of Nature Immunology, Dejnirattisai and colleagues present their characterization of novel antibodies identified from seven hospitalized dengue patients. They first isolated monoclonal antibodies – antibodies made by identical immune cells derived from the same parent cell – from immune cells in the blood of these patients. Among the isolated antibodies, a group emerged that recognized a key component of the dengue virus envelope known as dengue E protein. But unlike previously identified antibodies, this group specifically recognized the envelope dimer epitope (EDE) of dengue, which results from the coming together of two envelope protein subunits on the mature virion rather than a single E protein.

 

The novelty of the study lies in its identification of a novel epitope – EDE – a potent immunogen capable of eliciting highly neutralizing antibodies against dengue. Previously identified antibodies did not show great efficacy against the virus. Antibodies that do not bind dengue antigens sufficiently strongly or are not present at a high enough concentration end up coating the virus through a process named opsonization. This is believed to lead to a more efficient uptake of the virus by immune cells thus fostering a more severe infection by infectious and sometimes also by non-infectious viral particles. This is the issue facing the field. An effective dengue vaccine would have to elicit a potent antibody response able to neutralize the virus while circumventing antibody-dependent enhancement. The antibodies characterized in this study present the peculiarity of efficiently neutralizing dengue virus produced in both insect cells and human cells – both relevant for the lifecycle of the virus – and being fully cross-reactive against the four serotypes.

 

The identification of highly neutralizing antibodies with an efficiency of 80-100%, cross-reactive against the dengue virus serocomplex, and able to bind both partially and fully mature viral particles offers hope for the design of a putative subunit vaccine. Mimicking potent immune responses seen in patients facilitates the process of vaccine development since it removes the need for identifying viral antigens relevant for protection not seen in nature. The naturally occurring responses already point in the right direction. Of the two dengue vaccine trials, neither relied on insight from such immune responses in patients infected with the virus. Based on the present study, it seems that the next step facing the field is to efficiently elicit an immune response that specifically targets EDE. If the antibodies identified here are shown to initiate protection in vivo, Dejnirattisai et al.’s study will have brought the field forward incommensurably.


How Our Environment Affects the Development of Autoimmune Diseases

 

By Asu Erden

In the past fifty years, there has been a significant increase in the incidence of autoimmune diseases, such as type 1 diabetes and lupus, in the West and in countries adopting western lifestyles. Given that half a century is too small a time scale for human evolution to occur, what exactly is contributing to this increase? Recent studies have been highlighting the role of environmental factors.

 

If the age-old debate regarding the relative importance of nature versus nurture taught us anything, it is that the more apt position lies somewhere in the middle. Both our genetic makeup and the environment in which we live affect our phenotype. However, the study of autoimmune diseases has often focused on the contribution of genetic factors. The etiology of these diseases relies on recognizing one’s own proteins – also called self-antigens – and on triggering an immune response against them. For such a response to occur, these antigens need to be presented to the immune system by genetically encoded molecules called human leukocyte antigen (HLA) molecules. They constitute the most highly associated factor with autoimmune diseases. It is therefore easy to overlook the role of the environment.

 

Two seminal studies have contributed to shifting this bias. The first by Mahdi and colleagues at the Karolinska Institute in Stockholm, Sweden, looks at the impact of smoking on the development of rheumatoid arthritis (RA). The other by Dr. David Hafler’s team at Yale University, in New Haven, Connecticut, dissects the role of our diet in the etiology of multiple sclerosis (MS).

 

In their study published in the scientific journal Nature Genetics, Mahdi’s group carried out a population study based on three RA cohorts from the UK and Sweden. Comparing RA patients and healthy individuals, they identified that smoking contributes to RA development by increasing an individual’s immune response to the self-antigen citrullinated α-enolase. Importantly, the association that they found between smoking and RA requires a susceptible genetic background (e.g. HLA-DRB1*0401, HLA-DRB1*0404). This means that smoking alone cannot cause RA in a person that does not have the “right” genes.

 

The increasingly high salt content of Western diets led Dr. Hafler’s group to investigate the effect of these recent dietary changes on autoimmunity. In their study published in the journal Nature, they observed that a high sodium chloride diet results in a high concentration of this mineral in organs. In turn, this results in an increased number of activated CD4+ T cells – a subset of immune cells that participate in the adaptive immune response – that become helper T 17 cells (Th17 cells). These Th17 cells are responsible for inflammatory conditions that promote MS as shown in mouse models of the disease. Thus high salt intake primes the immune system to respond to self-antigens in the context of MS.

 

Despite great advances in our understanding of the mechanisms through which environmental factors contribute to the development of autoimmune diseases, challenges remain. A given environmental factor does not affect the development of all autoimmune diseases in the same way. Smoking may increase the risk of RA onset in patients with genetic predispositions. However, nicotine is also known to alleviate symptoms of ulcerative colitis, a type of inflammatory bowel disease (IBD) closely related to the autoimmune condition Crohn’s disease. Overall, the fact remains that the incidence of autoimmune diseases has increased greatly in the last half century. And, to some extent, it seems that we are doing it to ourselves…


A new HIV Model Could Help Shed Light on Mechanisms of Viral Host Tropism

 

By Asu Erden

 

To better understand the epidemiology of human diseases, we must identify the immunological mechanisms that govern their transmission and enable their jumping from one reservoir to the next. In this regard, animal models have proven useful. Yet the pathogenic mechanisms enabling the interspecies transmission of many diseases remain elusive. This is the case for the Human Immunodeficiency Virus (HIV). Primate and humanized mouse models have helped shed light on the viral mechanisms of HIV. As far as primate models go, pigtailed macaques have been particularly useful since they present the advantage of better mimicking the pathogenesis of AIDS as seen in humans. However, these macaques are not susceptible to HIV-1 since the virus does not normally cause AIDS in this host species. But Hatziioannou et al. recently provided a new stepping-stone to the field when they published their findings of an HIV-1 infection leading to AIDS in pigtailed macaques in the journal Science.

The team of researchers used a modified HIV-1 that encodes Simian Immunodeficiency Virus (SIV) Vif. The latter protein prevents the action of host-specific antiviral enzymes. By passaging this virus and taking advantage of the lack of key antiviral proteins (e.g. TRIM5) in pigtailed macaques, Hatziioannou and her colleagues were able to successfully infect these animals. In one of them, the virus replicated to reach stable high titers. The team decided to deplete this animal of circulating CD8+ T cells to alleviate immune pressure and allow for higher viral titers, since these cells are believed to contribute to the initial control of viremia. By the fourth passage (P4) of this virus in CD8-depleted macaques, AIDS-like pathogenesis became apparent (e.g. sustained high viremia, immune activation in the gut) and eventually animals fully developed the disease (stark loss of CD4+ T cells).

Hatziioannou et al. confirmed that they had obtained a virus capable of causing AIDS in pigtailed macaques by isolating it from P4 animals and inoculating new CD8-depleted animals. The infected macaques developed AIDS confirming that the researchers had developed a virus capable of triggering a pathogenesis similar to what is seen in humans. Moreover, the key time period for CD8+ T cell-depletion was identified to be the acute phase of infection since depletion at the chronic stage did not yield AIDS-like symptoms.

Several signature mutations in the passaged virus’ genome also reflected that Hatziioannou et al. had successfully adapted the virus to acquire characteristics seen in human HIV-1 infection. Single viral genome sequencing revealed that envelope mutations were essential for the aforementioned adaptation in pigtailed macaques. Of specific interest was a deletion in one of the loops of the envelope protein, which is typical of human lentiviral infections but much more rarely observed in non-human primates. Additionally, an insertion mutation in the transmembrane domain of the HIV-1 Vpu immune evasion protein enabled it to immunologically outcompete macaque tetherin, which normally prevents virions from budding from the host cells.

HIV-1 causes AIDS in humans and chimpanzees. The fact that Hatziioannou et al. were able to develop a model of HIV-1-induced AIDS in pigtailed macaques promises to shed light on the key immunological factors at play in the epidemiology of HIV. Their protocol also reinforces the idea that CD8+ T cells play an essential role in the early stages of the pathogenesis, since macaques had to be depleted of this cell subtype during the acute phase of infection to progress to AIDS. Overall, these results highlight the importance of the arms race between the virus and the host. In four passages, Hatziioannou et al.’s modified HIV-1 virus developed the ability to counteract macaque tetherin. Such evolution is required for the virus to spread to new hosts. In the future, studies of HIV-1 in this pigtail macaque model have the potential to provide insight about new prophylactic vaccines and therapeutic drugs against the virus.


Why knowing how to communicate science is so important

The Language of Scientific Discovery

 

By Asu Erden

Most of us are aware of the political controversies surrounding the human papillomavirus (HPV) vaccine. Some of us even have personal anecdotes relating to this highly charged subject. “I remember my aunt calling me to ask me about the vaccine. She was worried about what it meant for her children’s health and why her son should get an immunization aimed at preventing cervical cancer,” said Dr. Heather Marshall, a postdoctoral fellow at the Yale Department of Immunology. The confusion is all too common. As scientists, we have failed Dr. Marshall’s aunt and millions like her. In fact, the HPV vaccine has been extremely poorly marketed despite its astounding efficacy. The Centers for Disease Control (CDC) estimates that the quadrivalent vaccine offered in the US has an efficacy against genital pre-cancers and warts of nearly 100% in previously unexposed women, as well as 90% against genital warts and 75% against anal cancer in men. Despite the remarkable efficacy of the vaccine, not all parents in the US want to have their sons and daughters vaccinated. The scientific achievement that a vaccine embodies is not enough. This is one of the tragedies brought about by the failure of science communication. The HPV vaccine has been marketed towards young girls. Why has it not been made clear that both women and men should get the vaccine and that the early age of vaccination is only meant to increase vaccine efficacy? Men and women can actually be immunized up until the age of 26, after which it is assumed that you have most likely been exposed to one or more of the HPV strains that the vaccine protects against. In reality, you can still get the vaccine after this age. It will just not be as efficacious.

 

“The contribution of science is to have enlarged beyond all former bounds the evidence we must take account of before forming our opinions” wrote British biologist Sir Peter Medawar in Pluto’s Republic. In this day and age, the Internet provides readers around the world with a spate of resources – most of which not peer-reviewed – on just about anything. Unlike newspapers and books, blogs are most often not fact-checked. Just have a look at the Natural News blog and you’ll see how harmful misinformation disguised in a professional layout can be. As Dr. Marshall notes “a hundred years ago, it took weeks or months for a piece of scientific news to reach the other end of the country or the other side of the Atlantic. Fifty years ago it took a few hours or days. Twenty years ago it became one second but that sort of news still had a very narrow audience. Today you can literally reach 100 million people within a few seconds, which is really scary.” It is scary because it comes with a duty to inform that too many scientists choose to ignore out of frustration and because of the lack of any tangible benefits to their career. Dr. Schatz, professor of Immunobiology and Molecular Biophysics and Biochemistry at Yale, deplored that the connection is very tenuous between talking to students at local high schools and increasing interest and funding for scientific research. It inevitably comes down to scientists’ intrinsic motivations to go out there and share their research with the public.

 

As a graduate student at Yale and as a scientist, I find these realities challenging. I am unsure as to when I first came to realize the widening mismatch between how scientists talk to the public about their research and how they should talk about it. But this is something that every budding and established scientist is aware of. Yet we are seldom taught how to translate scientific concepts back into the vernacular. Science truly has a separate language that facilitates talking about complex concepts with peers that share the same premises. It is easy to forget that this has been taught to us and does not come naturally. I discussed this with Will Khoury-Hanold, a graduate student in my lab. His involvement with the Science in the News initiative – which trains Yale graduate students to give talks to high school students about a broad range of current scientific topics – taught him a lot in this regard. He described science as requiring a greater leap than other disciplines. “Anyone can pick up a history book and read about the elements that led to the Civil War. It’s not the same with science. […] With science, it’s about translating it back to English.” This is hard to do, and we often shy away from talking to the public. But in a world where Jenny McCarthy is hired by The View and has access to a 3 million viewer platform to spread her anti-vaccine views, scientists have to speak up and as loudly as they can to provide the public with fact-checked truths. Of course entertainers can aptly serve the cause: if you have not seen this vaccine-related video by Penn & Teller I strongly encourage you to do so. Nevertheless, the duty to inform the public about these matters should fall on scientists.

Scientists are partly responsible for the failures of science communication. Clearly, we have a tendency to revel in esoteric statements about our research and about science more generally. If you take the word “theory” for instance, its scientific meaning widely differs from its colloquial understanding. For non-scientists, a theory is something that has yet to be proven. For scientists, a theory is “a well-substantiated explanation of some aspect of the natural world that can incorporate facts, laws, inferences, and tested hypotheses […] theories do not turn into facts through the accumulation of evidence. Rather, theories are the end points of science. They are understandings that develop from extensive observation, experimentation, and creative reflection,” as pointed out by the National Academy of Sciences. Our arcane vocabulary makes it seem as though understanding science were a luxury. We need to use more accessible language so that such misrepresentations of scientific truths do not happen. Is it the fault of scientists that the HPV vaccine was poorly marketed? Perhaps not directly but we should have made it clearer to journalists why the vaccine is so important and how it is significantly reducing the incidence of cervical cancer. Another infamous example is that of the alleged correlation found between the measles, mumps, and rubella (MMR) vaccine and autism. While the study published by Mr. Wakefield in 1998 has been debunked and his medical license was stripped, most people still don’t know why his results were wrong. Not only did he not comply with the clinical trial rules for his study, the putative correlation he claimed to have found was based on a confounding factor. What is that you say? That would be an example of scientific jargon but what it really means is this: the MMR vaccine usually gets administered around the age of 2, which is also the age at which most children start speaking. One of the clearer symptoms of autism is to not start speaking when you are supposed to. Thus, autism inherently gets diagnosed around the age of 2. This is what underlines the correlation Wakefield reported. The confounding factor was the age of the children. When it comes down to their kids’ health, reminding parents that “correlation is not causation” achieves little. Having the population actually exposed to that concept more generally would achieve much more.

 

As Dr. Marshall emphasized, “a lot of the time it can come down to the scientist. If you had asked me [about it] a couple of years ago, I might not have said this as easily.” As scientists we never get properly trained to know how to answer that phone call we might get from journalists who under the pressure of publication might perform less than optimal fact-checking. By not being as clear as possible we inadvertently provide ground for sensationalism. But this reflects a broader failure to communicate science to the public. We live in a world where it is acceptable not to know what a gene is or how evolution actually works. To remedy this, scientists need to make concepts they are familiar with more accessible and report their research aptly.

 

 

But the language of scientific discovery and science communication is not solely beneficial to the public. It can help scientists better share their research with people beyond the realm of their own department. A good talk fosters cross-fertilization between fields. Scientists have a tendency to narrowly focus on their thought-processes and dig a deeper and deeper hole to burrow themselves into. As a result, we lose the forest for the trees. Many graduate students, postdoctoral fellows, professors, and department chairs have encountered this somewhere along the line. Insufficient training in writing and in giving public speeches results in science talks that fail to convey their points across. The problem is that scientists are asked to give many talks and presentations. What happens most often is that they regurgitate PowerPoints they prepared for specialists in their field and use them to give talks to an unspecialized audience.

 

The challenge and art of giving a good talk is to know your audience and to aptly choose the level of detail versus abstraction that suits said audience. “We as a species – by which I mean scientists –,” added Professor Schatz “are so programmed to show the data that it takes effort not to.” That skill is not just useful when communicating science to a lay audience. It fosters collaborations and thus important breakthroughs within the field of scientific research. Professor Schatz recalled an immunology meeting organized by the Federation of American Societies for Experimental Biology he was at a few months ago. One of the speakers at that conference was Dr. Margaret Goodell who specializes in the field of stem cell research and therefore stood out as not being an immunology-related speaker. She gave such an inspiring and thought-provoking talk that immunology professors were lining up to discuss potential collaborations with her lab. This does not happen when content prevails over format. At a time when knowledge within the sciences has become so specialized, collaborations become a necessity. If as scientists we are unable to communicate our research to people outside our field – whether they are scientists or not – we prevent such collaborations from budding. It also prevents good scientists from getting grants because they are unable to write well enough about their research.

 

Most scientists get into their field with the hope to increase the spectrum of human knowledge about the world surrounding us, even if only by a little bit. And most of us thrive on the possibility of understanding something about nature that no one had understood previously and of sharing it with the rest of the world. But somewhere along the line, this humanistic ideal wanes or at least no longer suffices. “You make a scientific discovery and you can’t wait to share it with your peers” said Will. Why this does not necessarily translate into a desire to talk about your research to the public remains somewhat elusive. So to those scientists out there, I must ask: do you remember your personal statement for college and for graduate school? You meant it when you said that you wanted to save the world by increasing our understanding of worm neurobiology or by curing cancer. Don’t forget it!


New Insight Into Breast Cancer Offers Therapeutic Hope

 

By Asu Erden

Triple negative breast cancers are highly aggressive malignancies. They do not express any of the hormone receptors usually used to target chemotherapies to treat this type of cancer and have a high relapse rate after treatment. As such, these cancers can come with a very poor prognosis and insight into their development is therefore direly needed. A study published this month by Chen et al. in the scientific journal Nature dissects the role of the XBP1 protein in the development of triple negative breast cancers. The team of scientists from Weill Cornell Medical College observed that XBP1 levels are higher in triple negative breast cancer cell lines. Of particular therapeutic relevance is their finding that depleting XBP1 leads to reduced tumor metastasis in both a mouse model of triple negative breast cancer and human cell lines derived from such cancers. These findings offer hope for the development of therapies aimed at treating this highly challenging cancer.

 

Cancers have high proliferative rates. This incurs a high energetic cost on cells by requiring the rapid synthesis of proteins. The resulting accumulation of unfolded proteins can in time lead to cellular stress. Studies have shown that the unfolded protein response (UPR) is activated in most breast cancers. The UPR is a cellular stress response mediated by the enzyme IRE1. The role of this enzyme is to cut up the Xbp1 mRNA into its mature form and allow the activated XBP1 protein to translocate to the nucleus. There, XBP1 acts as a transcription factor and allows the expression of a host of genes involved in the UPR.

 

To investigate the effects of anti-XBP1 treatment on cancer relapse, Chen et al. treated a breast cancer mouse model with a combination of XBP1 short-hairpin RNA (shRNA) and doxorubicin (a chemotherapeutic drug). XBP1 shRNA prevent the expression of the XBP1 gene. This combination therapy prevented tumor growth and relapse. Further probing revealed that XBP1 shRNA acts by targeting a specific tumor cell subset – human breast cancer stem cells – known to be involved in tumor relapse. Isolation of this cell population from triple negative breast cancer patients revealed increased levels of activated XBP1. Moreover, the silencing of XBP1 in these mammary gland cells resulted in reduced cell clumps, while overexpression of this gene resulted in increased cell clump formation and resistance to chemotherapeutic drugs.

 

Chen’s team also further dissected the mechanism allowing XBP1 to promote the development of triple negative breast cancers. They unraveled the protein’s involvement in the hypoxia-induced cellular stress response. Hypoxia – a condition characterized by a deficiency in the amount of oxygen reaching cells – is a potent cellular stressor. It is also a central feature of many tumors. The hypoxia-induced factor 1a (HIF1a) is activated during the cellular response to hypoxia and is known to be upregulated in triple negative breast cancers. Chen et al. shed light on the interplay between XBP1 and HIF1a, which was hitherto unknown. They revealed that the two proteins cooperate in targeting specific DNA sequences and that XBP1 increases HIF1a activity. XBP1 therefore allows the hypoxia response, characteristic of cancers, to take place by promoting the cellular responses mediated by HIF1a.

 

The results from this study shed light on the mechanism through which XBP1 contributes to the development of triple negative breast cancers. Of particular note is Chen et al.’s silencing data. Therapies utilizing XBP1 silencing techniques, such as shRNAs, combined with chemotherapies could result in highly successful clearance of these cancers and significantly reduced chances of relapse.

 


It's Alive!

 

How the largest virus ever discovered rose from the dead and taught us a few a lessons about viral latency

By Asu Erden

The first giant DNA virus was discovered only 10 years ago and astounded the scientific community due to its implications for viral biology. How could a virus that lied dormant for thousands of years still be infectious? Last week, scientists from the National Centre of Scientific Research (CNRS) in France published their findings in the Proceedings of the National Academy of Sciences about the 30,000 year-old virus they uncovered from the deeper layers of the Siberian soil. This giant DNA virus, called Pithovirus sibericum, is the largest one ever found. It does not infect humans but Legendre et al. have shown that it can parasitise amoebae.

It was hitherto believed that giant DNA viruses belonged to two widely different families: the Megaviridiae and the Pandoraviruses. The former have smaller particle sizes and genomes and replicate in the host cell’s cytoplasm, which means that they do not need to hijack the cell machinery to make copies of themselves. The Pandoraviruses, on the other hand, have larger particle sizes and genomes and need to enter the host nucleus to replicate. The newly discovered Siberian virus belongs to a new category, called Pithoviruses, that combines features from both of the formerly described giant virus families. It exhibits a large particle size, a small genome, and has entirely cytoplasmic replication. This means that the biology of giant viruses is much more diverse than previously imagined. It seems that many different features can allow a virus to survive freezing temperatures and to rise still fully functional after thirty millennia of hibernation.

While scientists keep virus stocks at freezing temperature for long-term storage, the idea that viruses can survive for tens or hundreds of millennia in ice remains a contentious issue in the field. In their study, Legendre et al. combined microscopy techniques and infection assays in amoebae to identify putative DNA viruses from Siberian deep soil samples. Using amoebae as bait for putative pathogens from soil samples, they observed that these eukaryotic organisms started to die. This is when Legendre et al. knew they were onto something. The infection assay allowed them to identify and characterise Pithovirus sibericum as a rod-shaped virus of approximately 1.5 μm making it bigger than many bacteria. Infection “symptoms” within the amoebae appeared after 4 to 6 hours. A few hours later, viral particles were ready to bud out of their host cells and continue their infectious cycle.

The French team was somewhat helped by the geochemical and geophysical properties of the Siberian deep soil, also called permafrost. Indeed, this frozen soil layer has a neutral pH and provides an anaerobic environment to the organisms it imprisons. Previous studies have shown that these non-fluctuating frozen conditions are ideal for long-term DNA preservation. As such, the credible threat posed by the thawing of such viruses remains unclear. However, it seems like this undead prehistoric pathogen can teach us a few lessons about viruses of current relevance to public health.

Many of the viruses infecting humans have a latent phase during which they continue to infect cells but do not replicate and therefore do not circulate within their hosts. They therefore remain invisible to our immune system and are extremely difficult to monitor. Such viruses include the varicella zoster virus (VZV) responsible for chicken pox during childhood and shingles later in life, cytomegalovirus, which infects over 60% of us, and most infamously the human immunodeficiency virus (HIV).

While the discovery of P. sibericum from thawed Siberian permafrost is a relevant harbinger of the many long-term destructive effects of global warming, it should also be lauded as a reminder of the ongoing scientific challenge that viral latency poses to researchers, physicians, and most importantly patients. Just like the features that allow some pathogens to survive for thousands of years in the ice before they are unleashed into the wild, the precise factors that lead to the reactivation of a latent virus remain elusive. As Legendre et al. put it, “an entire world of viruses [remains] to be unraveled.” Let this new viral discovery be a humbling memo that there is still plenty that we do not understand about these microorganisms and that they will continue to fascinate and challenge us for years to come.


Space Oddity

 

By Asu Erden

How social media tools can help scientists better understand meteorite impacts

Early in the morning of February 15th 2013, a small asteroid penetrated the Earth’s atmosphere and offered the one million residents of the Chelyabinsk region in Russia a spectacle worth remembering. This rude awakening was caused by a fireball brighter than the Sun traveling at over fifty times the speed of sound. Thirty seconds after entering the atmosphere, this asteroid disintegrated, causing an airburst with an energy equivalent to more than twenty times that of the Hiroshima atomic bomb. The last comparable event occurred in 1908 near the Tunguska river in Siberia and remains elusive to this day. Unlike Tunguska, social media provided a host of information about the Chelyabinsk incident, with over four hundred YouTube videos, Dash camera records, and countless social media reports documenting this outer space intrusion. A Twitter hashtag – #RussianMeteor – even went viral.

 

A few weeks after the impact, Dr. Peter Jenniskens – a research scientist who studies interstellar and interplanetary matter at the NASA’s Carl Sagan Center in Northern California – went to Chelyabinsk where he carried out a sixteen day-long field survey with colleagues from the Russian Academy of Sciences. They wanted to collect and analyze meteorite fragments and to use social media reports to characterize the physical and material damage caused by the airburst. “To my knowledge this is the first instance YouTube videos have been used for [meteor research] purpose[s],” said Dr. Stefan Nicolescu, meteor curator at the Yale Peabody Museum.

 

When Dr. Jenniskens and his team arrived in Chelyabinsk, the ground was covered in snow, which made locating the meteorites impossible. They relied on information gathered from social media and interviews with residents in order to draw out a site distribution map. They also conducted Internet social surveys, which allowed them to better assess the types of injuries that people endured. Surprisingly, the main culprit was not glass damage but rather UV radiation from the asteroid. The majority of people reported experiencing noticeable heat, ocular damage due to the brightness of the fireball, and being sunburnt.

 

Dr. Jenniskens’ team published its findings in the journal Science last November. Their report followed two papers published in Nature earlier the same month that documented parts of the incident, focusing on the damage caused by one of the asteroid fragments and the analysis of selected video records. The key contribution of Dr. Jenniskens’ study lies in the extensive data that it made available to better understand what happens when smaller near-Earth objects penetrate the Earth’s atmosphere. The importance of the asteroid fragmentation pattern caused by the airburst and its direct implication for the damage observed on the ground are now substantiated.

 

“The assumptions when you model these sorts of things are normally 100% speculative. In this case, it was extremely well-observed,” said Dr. Jenniskens. By integrating data from social media, Dr. Jenniskens and his colleagues were able to establish the trajectory, brightness, orbit, diameter, angle of entry, UV irradiation, and speed of the asteroid. It also helped them understand how each of these parameters affected the shockwave, damage distribution on the ground, and injuries caused by the airburst.

 

Scientists will now be able to fine-tune their meteorite impact models and predict how specific characteristics of a given asteroid and its trajectory can affect the damage it will cause on Earth. This in turn will help officials respond more quickly to damage in different regions near the impact site and anticipate the sort of injuries hospitals should be ready to treat. Big Brother might be helpful after all.


One Flu Over the Cuckoo’s Nest: Has the New Avian Influenza Virus Achieved Human-to-Human Transmission?

 

By Asu Erden

Human cases of H7N9 – a new avian influenza A virus – were first reported in China between February and March 2013. It is believed that infection with this virus requires exposure to poultry but when and how the virus crossed the species barrier remains elusive. The Centers for Disease Control (CDC) originally estimated that up to 20% of the people that become infected with this virus die. There are currently no vaccines available against this avian flu virus, although clinical trials are under way with the help of the World Health Organization (WHO). The disease caused is severe and mainly affects the respiratory tract. Li et al. recently published a study in the New England Journal of Medicine that sheds light on the epidemiology of the disease caused by H7N9 and suggests that the virus might have achieved human-to-human transmission.

 

In their study, Li et al. investigated 139 confirmed cases of H7N9 from 12 different areas in China (including Shanghai and Beijing). Their aim was to better understand the epidemiology of the lower respiratory illness caused by this avian flu virus newly infecting humans. They were able to identify cases thanks to the Chinese surveillance system for pneumonia of unknown origin, which was put in place in 2004 at the time of the H5N1 avian influenza outbreak. The study confirmed that infection with H7N9 is most likely caused by exposure to live animals (poultry, birds, or swine). Most of the studied cases (77%) occurred in older individuals with the median age of patients being 61. Despite an older age distribution, the H7N9 virus seems to infect people from a broader age range than H5N1 did a decade ago.

 

This emerging zoonosis seems to be particularly virulent. After an incubation period of 7 days, H7N9 caused an acute illness characterized by severe lower respiratory symptoms – including pneumonia and respiratory failure – in all studied patients. The case fatality rate was also high, with 34% of patients dying. This rate is significantly higher than originally estimated by the WHO but remains lower than for H5N1. Further studies are required to establish the true case fatality rate of the disease caused by H7N9 in the overall population.

 

Li’s group also carried out family cluster analyses based on four families in which two or more individuals had confirmed cases of H7N9. In each cluster, one of the individuals became infected due to close contact with poultry (e.g. visits at poultry markets) but the other infected individuals never came in close contact with live animals. This suggests that the virus might have evolved to achieve human-to-human transmission. On the other hand, Li et al. also followed over 2500 close contacts of their 139 confirmed cases and only 1% developed respiratory symptoms, none of which tested positive for H7N9. Of note, however, is that these individuals were only followed for 7 days after contact and only single swabs were collected from them. This likely decreased the likeliness of detecting H7N9 cases among close contacts.

 

The most significant finding from this study also happens to be the only negative data that were presented:  Li et al. were unable to discard the possibility that H7N9 can transmit from human to human. Given the virulence, case fatality rate, and ongoing outbreak of the H7N9 avian influenza virus, the possibility of human-to-human transmission is cause for concern. The establishment of a putative human reservoir would allow for fast spread of the virus worldwide and should be scrutinized by public health officials.