Demystifying Scientific Authorship

Over the last few months, I’ve been talking quite a bit with historians. Many of them are starting to read more biology papers; some are perplexed by the format and brevity. So, I plan on occasionally writing posts that I hope will help non-science folks and students cope with science literature.

A recent question:  how can a paper have ten or more authors? Who is in charge of the project?

A science paper is not an essay like a history or literature publication. Its is a research report representing the work of a whole team. There are very few soloists in science.   In some ways “authorship” is really not the right term for the names on the report, but it is historical convention.

There are no hard and fast rules for who is named on a paper or their order. However, names can be classified in four groups in relatively this order  on papers with more than four  authors.

• First author: recognition of  the person who has done the most bench work. First authorship is important in the development of a researcher because it shows that they have accomplished new laboratory experiments and can do the daily management of experiments. The first author is usually a grad student or post-doc (post-doctoral fellow). When there are multiple authors (>4), the first author is never the project leader.

• Research contributors: other members of the team including research assistants, post-docs, and other grad students. Research assistants are finally getting recognition for what is often a career long commitment to a project.  Specialists who provide unique services like pathologists or bioinformatics/ computer specialists may also be included here. Ultimately it is the principal investigator who determines which other members of the team are recognized on the paper.

• Materials contributors: providers of unique materials that are vital to the project. Examples of material contributors include physicians who collect patient specimens, archaeologists who provide access to bones or teeth, or molecular biologists who provide a vital clone or research organism (like a specially bred rat etc).

• Principal Investigator, usually called the PI,  is the person responsible for the project on federal grants. They are the project director. Roles of the PI include research direction and administration,  recruiting, funding, and outreach to the scientific community as much as the public. They are always the last author listed on publications and usually designated as the corresponding author. When in doubt, always go with the corresponding author as the project leader.

For large multi-center studies, like some of the recent plague genetics papers, there can be multiple PIs (designated by multiple corresponding authors) and the recognition of more than one ‘first author’ (notation that multiple people contributed equally). Some newer publications will have some indication of who contributed to what. It is fairly unusual for any one person to be designated as the author (writer) of the paper, even though there is usually one primary writer.

With fewer than four authors it is nearly impossible to predict roles unless you know the individuals named. Go with the corresponding author as the project leader.

Hopefully, this has helped demystify scientific authorship. Comments and questions are always welcome!

Leptin: Linking Malnutrition and Vulnerability to Infection

The correlation between malnutrition and vulnerability to infection has been well established (discussed previously here). While the immune dysfunction could be characterized it was not until the last 10-15 years that an exact mechanism began to resolve.

It all began with the discovery of a new hormone called leptin from an unexpected place, adipose tissue (fat cells). Leptin, a product of the obese (ob) gene, was discovered while looking for factors that regulate body fat. As a consequence of manipulating this gene in an attempt to regulate body fat, it was discovered that mice deficient in leptin had profound immune deficiencies.

The amount of leptin produced by adipose cells (fat cells) is directly proportional to the amount of fat in the cells. (The number of fat cells in adults does not change,  their size just shrinks or swells.) Leptin levels drop as body fat decreases or during fasting. Once leptin levels fall below a threshold, the lack of leptin puts the mammalian body into a starvation response. Areas of leptin activity are signaled by the production of the leptin receptor (OBR gene). Tissues producing the leptin receptor include areas of the hypothalamus that regulate body weight, bone mass, and appetite; ovarian cells, beta-cells of the pancreas, endothelial cells, and bone marrow stem cells, macrophages, and lymphocytes (1). Leptin influences cellular function by directly interacting with peripheral tissues including immune cells in lymph nodes, bone marrow, pancreatic function and bone homeostasis, but also by triggering hormonal changes in the brain, specifically in the hypothalamus. Study of leptin levels has opened previously unsuspected linked between central nervous system control and the development of the immune system.

The Hormonal Trigger of the Starvation Response

Leptin’s control of metabolism and the  immune system. (Ref. 2)

As long as leptin levels stay within normal levels, all of the functions displayed above function normally. As the leptin levels drop, many of these functions are adversely effected. It is a wide-spread trigger for a starvation response.  Why cripple the immune response during starvation? My best guess would be because of the huge energy expenditure required to keep the immune response running normally, especially in cellular proliferation.

When leptin levels drop too low, physiological dysfunction occurs in haematopoiesis (blood cell production), bone metabolism, glucose metabolism and angiogenesis (blood vessel production and maintenance) and immune suppression involving both the innate (non-specific) and adaptive immune system. During malnutrition, the size of the thymus gland shrinks with diminished T cell development. This may be one of the long-term consequences of childhood malnutrition. Children with congenitally low leptin levels have a higher mortality rate due to childhood infections (2).

Leptin modulates immune function (ref. 1)

With all the functions illustrated above, it’s not very surprising that malnutrition is the second most common cause of secondary immune suppression today (2). Alternatively, high leptin levels in obese people have also been linked with increased vulnerability to infection possibly through the development of leptin resistance due to prolonged exposure to excessively high levels of leptin (2). Food for thought considering that obesity was one of the only risk factors for a poor outcome during the recent H1N1 influenza pandemic. We have come to expect malnutrition induced immune suppression, but we may also have to consider over-nutrition induced immune suppression and/or autoimmunity as outcomes of immune dysregulation due to leptin resistance.

References:

[1] La Cava, A., & Matarese, G. (2004). The weight of leptin in immunity Nature Reviews Immunology, 4 (5), 371-379 DOI: 10.1038/nri1350

[2] Procaccini C, Jirillo E, & Matarese G (2012). Leptin as an immunomodulator. Molecular aspects of medicine, 33 (1), 35-45 PMID: 22040697

What makes a Super-Spreader?

Parameters that should be theoretically equal often aren’t so in the real world. Ideally everyone should have the same potential to transmit an infection during a given outbreak, but it has long been observed that this isn’t true. Super-spreaders play an extraordinary role in driving outbreaks of infectious disease. A super-spreader is a person who transmits an infection to a significantly greater number of other people than the average infected person. The occurrence of a super spreader early in an outbreak can be the difference between a local outbreak that fizzles out and a regional epidemic.

Super-spreaders have been known since infamous Typhoid Mary spread typhoid fever to 51 people over seven years with just an asymptomatic infection [1]. For much of the time since then, they have been treated as oddities, puzzles that could be cracked as if there was necessarily something intrinsically wrong with them. It turns out that its a lot more complicated than personal immunity or genetics. Eventually new models arose like the “20/80″ rule that says that 20% of cases are responsible for 80% of the transmission and formed a core ‘high risk’ group [2,3]. This model works well for some diseases but not all.

For pathogens that do rely on super-spreaders, the majority of cases will not transmit the infection to anyone [3]. This can lead to a sense of false security because it seems poorly communicated. As Galvani and May assert, “heterogeneously infectious emerging disease will be less likely to generate an epidemic, but if sustained, the resulting epidemic is more likely to be explosive”[3].  Super-spreaders tend to beget more super-spreaders, although most of the cases they generate will still not transmit the infection to anyone. For example, a super-spreader begets 30 cases, 3 (10%) of which become new super spreaders.  The rest may transmit to 0-1 people.  Even with super-spreaders it superficially doesn’t look very efficient but it can create an explosive epidemic.

Super-spreading has been documented for HIV, SARS (Sudden Acute Respiratory Syndrome), measles, malaria, smallpox and monkeypox, pneumonic plague, tuberculosis, Staphylococcus aureus, typhoid fever, and a variety bacterial sexually transmitted diseases [1,2,3]. For the sexually transmitted diseases (STDs) we tend to talk more about risk groups than super-spreaders but this still what they are. Case studies are easily found for most of the diseases listed above, including measles super-spreaders who infect known vaccinated children [1].

So what makes a super-spreader? Richard Stein recently summarized what we know so far. Some pathogens have virulence factors that have been associated with super-spreading. I am not aware of many pathogen genes or genotypes associated with super-spreading. So far predominantly extra-pathogen factors have been associated with super-spreading.

Co-infection is turning out to be the most interesting factor in producing super-spreaders. Consider Typhoid Mary, her normal flora may have kept her both asymptomatic and promoted her super-spreader activity. Its been known for some time that co-infection with another sexually transmitted disease increases transmission of HIV. There are less obvious co-infections. It has been shown that a rhinovirus, a common cold virus, infection dramatically increases the airborne spread of Staphylococcus aureus, producing ‘cloud-adults’ or ‘cloud-babies’ [1].

Immunological factors are often suspected in super-spreaders. People with a decreased immunity for any reason may carry a higher pathogen load that can increase environmental pathogen shedding. It has also been suspected that conditions that cause sneezing like seasonal allergies could spread pathogens colonizing the respiratory system[1].

Host behavior is a known factor in some super-spreading events. Transmission of STDs depends on contact rates and so contact frequency and length matters, [1]. People who ignore instructions like wearing a condom or not working in food service can become super-spreaders.  Education aimed at high risk groups (potential super-spreaders) seeks to alleviate this risk. There are also a number of laws that have been on the books many years that make it illegal to intentionally spread disease and force compliance with some public health mandates. These laws and mandates work pretty well considering people with life threatening infections are not too concerned with trouble in the seemingly distant future, or who like Typhoid Mary simply don’t believe they are a threat.

Last but not least, the environment can be a key factor in super-spreading events. Crowding, poor ventilation, improper isolation procedures, unnecessary movement of the infectious, and misdiagnosis have all been identified as factors during the SARS pandemic [1]. For fairly unusual diseases like plague, misdiagnosis is likely to happen frequently in the early phase of an outbreak. Crowding and ventilation are probably significant reasons why ships have been so frequently associated with explosive historic epidemics.  A super-spreading event has already happened before the ship pulls into the dock releasing a new set of super-spreaders in the port. The same could be said for clustering together in buildings during cold weather.

To make things even more complicated, super-spreading goes down the animal chain for zoonotic diseases.  Mosquitoes infected with West Nile Virus preferentially feed on the American Robin, 17 times more likely than by chance in one study [1]. The super-spreading phenomenon could extend to transmission of the pathogen by vectors and among reservoir hosts. Cattle have been documented as being super-spreaders of brucellosis and E. coli O157. In one UK study, 9% of cattle accounted for 96% all bacteria detected in fecal specimens and were high shedders of E. coli O157 [1].

The super-spreading phenomenon is not new but it is only now that our epidemiological models are beginning to seriously wrestle with its implications. These events introduce more uncertainty into our predictions and analyses than we are often comfortable with. We crave certainty in an uncertain world. As difficult as super-spreaders will make the lives of public health professionals preparing for future threats and coping with ongoing outbreaks, they may be the key to understanding many historical mysteries.

References:

[1] Stein RA (2011). Super-spreaders in infectious diseases. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 15 (8) PMID: 21737332

[2] Lloyd-Smith JO, Schreiber SJ, Kopp PE, & Getz WM (2005). Superspreading and the effect of individual variation on disease emergence. Nature, 438 (7066), 355-9 PMID: 16292310

[3] Galvani AP, & May RM (2005). Epidemiology: dimensions of superspreading. Nature, 438 (7066), 293-5 PMID: 16292292

Historic Meanings of “Cholera”

Today the term cholera is restricted to suspected infections caused by Vibrio cholerae, sometimes called Asiatic cholera. Vibrio cholerae produces a very characteristic watery diarrhea sometimes described as ‘rice water’. This narrow definition wasn’t always so.

Since antiquity, cholera could refer to any diarrhea or dysentery. The term cholera comes from the Greek word cholē meaning bile. Cholera then was a flushing of bile from the body in an attempt to rebalance Galen’s four humors of the body (blood, bile, black bile, and phlegm) [1].

In 19th century American medical records,  it is common to see three types of cholera reported: cholera morbus, cholera infantum, and Asiatic cholera. Cholera morbus and cholera infantum were both terms for non-specific diarrhea and/or dysentery in adults and children under age five respectively.  Cholera morbus was sometimes called the summer complaint and was usually found in older children and adults from July to September [2]. It was caused by a variety of gastrointestinal pathogens with a significant contribution from contaminated food. Cholera infantum was given as the primary cause of death in children under age five in 19th century Illinois [2]. Physicians specifically associated it with the ages of teething and finger foods. Even given its non-specific definition, it was still probably over diagnosed due to paradigms of childhood illness. For example, early Illinois physicians  did not believe that children could contract malaria, then endemic in Illinois. Asiatic cholera is caused by Vibrio cholerae, epidemic in Illinois in 1832-1834, 1838, 1849-1852, 1866-1867, and 1892 [2]. Apart from discrete epidemic waves, Asiatic cholera was uncommon in America.

References:

[1] Männikkö, N. (Ed) (2011). Etymologia: Cholera. Emerging Infectious Disease, 17 (11) http://dx.doi.org/10.3201/eid1711.ET1711

[2]  Rawlings, Issac D. et al. (1927).The Rise and Fall of Disease in Illinois. State Department of Health.

Defining pandemic

Spanish Flu patients

Defining a pandemic is not an easy thing to do. It turns out that there has never really been much consensus about what constitutes a pandemic. The term pandemic has been used almost interchangeably with epidemic since the beginning of its usage. In the midst of responding to last year’s H1N1 influenza outbreak public health officials found themselves debating if and when they should call it a pandemic. Although there had been about a decade worth of pandemic planning and preparedness going on to get ready for the next pandemic, officials couldn’t agree on what a pandemic actually is when challenged by an outbreak that met some but not all of their criteria. Ironic considering that the term pandemic entered general usage to characterize the explosive spread of influenza. The term was “rescued from near obscurity” during the Russian flu of 1889 and became “virtually a household word” in 1918 (Morens, Folkers, & Fauci, 2009). It was then applied retrospectively to major historical events like bubonic plague and major smallpox outbreaks.

David Morens, Gregory Folkers, and Anthony Fauci (2009) identified the following characteristics of outbreaks or events that have been referred to as pandemics in the past:

1. Wide geographic spread
2. Disease movement: directional movement of the pathogen to take new territory or populations
3. Explosive attack rates: transmission so rapid that widely spread cases appear simultaneously
4. Low herd immunity: relatively few members of the population have adaptive immunologic protection
5. Pathogen novelty: the disease or strain is considered new (or reemerging)
6. Infectiousness: common usage of the term can apply it to non-infectious topics that seem to spread like cigarette smoking, obesity, or suicide.
7. Contagiousness: communicable or transmitted by multiple means including person to person (ex. plague)
8. Severity: not an absolute requirement but historically the term has been applied to events with a high mortality rate (bubonic plague, cholera, smallpox).

The problem comes, as always, in the details. How severe is severe enough? Does the level of severity needed to call a pandemic vary depending on the agent? How is novelty assessed? Morens, Folker and Fauci note that “usage clearly dictates that when pandemics come and then disappear for long periods, they are still pandemics when they return.” They go so far as to say that “pandemicity can be said to be a characteristic feature of certain repeatedly reemerging diseases, such as cholera and influenza”.

This brings up the question of how long can a pandemic last? The first plague pandemic is considered to have lasted about 250 years (541- ca. 750 CE) and there seems little consensus on when to cut off the second plague pandemic (the Black Death). The current cholera pandemic has been going on for decades but the average person doesn’t link cholera outbreaks like the current one in Haiti with an ongoing pandemic. Influenza pandemics only last a couple of years. HIV has been an atypical pandemic for over 20 years. Atypical in that it didn’t spread as a wave that could be relatively easily tracked like influenza or the plague.  The longer pandemics like bubonic plague came in waves with quiet periods of a decade or more in between outbreaks.  At least a couple of cholera outbreaks occur every year but they are often geographically distant from each other. When you think that the same term is used for a 1-3 year influenza outbreak as  a disease that came in distinct waves over 250 years, it is little wonder that the public can get confused.

While I agree with Morens, Folkers and Fauci that the term pandemic should be restricted to infectious disease, now that the term is a household word that even the experts can’t agree on how to apply, I think it will continue to be used to get the public’s attention for anything that is spreading rapidly. Like any term used to get the public’s attention, it will lose its punch the more the term is used making it almost certain that the meaning of pandemic will continue to evolve.

Reference:

Morens, D., Folkers, G., & Fauci, A. (2009). What Is a Pandemic? The Journal of Infectious Diseases, 200 (7), 1018-1021 DOI: 10.1086/644537

Yersinia Etymology

The new issue of Emerging Infectious Diseases has little piece on the etymology (origins) of the genus name Yersinia. The genus Yersinia is best known for its first member, Yersinia pestis, better known as the plague or bubonic plague. The name Yerisnia is not very old. The genus was renamed Yersinia after one of its discovers Swiss microbiologist Alexandre-Émile-John Yersin (1863-1943), from its original Pasturella, in the 1970s.

Yersin lived in the great age of the microbe hunters, young men who went out into epidemics in developing countries with the primary purpose of identifying new pathogens. Yersin did his homework studying medicine in Paris and working under Robert Koch in Germany on tuberculosis, Rene Roux on rabies and rounding out his study at the Pasteur Institute in Paris. From there he took a job with at French shipping company that would bring him experience with unknown infectious diseases in southeast Asia.

Yersin was one of the microbe hunters who converged on Hong Kong during an outbreak of plague in 1894. Within a week, he had isolated the bacterium that he believed responsible for the outbreak and named it Pasteurella pestis, presumably after the Pasteur Institute. Japanese microbiologist Shibasaburo Kitasato also isolated the same bacterium during the same outbreak of the plague. Both men rapidly published their findings; Yersin in French and Kitasato in English and Japanese. There has been some tension over who actually discovered the plague bacterium.

Yersin went on to continue his study of plague in search of a vaccine for many years. Late in his life he established a laboratory in his adopted country, Vietnam, where he completed his work on a plague antiserum. Yersin’s antisera is reputed to have cut the mortality rate from 90% to about 7%.

Later at least twelve members of the Yersinia genus were discovered. It is currently believed that Yersinia pestis evolved from Yersinia pseudotuberculosis.

Reference: “Entymologia: Yersinia” Emerging Infectious Diseases, March 2010, 16 (3).