Fixing 'leaky' blood vessels to combat severe respiratory ailments and, perhaps, Ebola

When you get an infection, your immune system responds with an influx of inflammatory cells that target the underlying bacteria or viruses. These immune cells migrate from your blood into the infected tissue in order to release a cocktail of pro-inflammatory proteins and help eliminate the infectious threat. During this inflammatory response, the blood vessel barrier becomes “leaky.” This allows for an even more rapid influx of additional immune cells. Once the infection resolves, the response cools off, the entry of immune cells gradually wanes and the integrity of the blood vessel barrier is restored.

But if the infection is so severe that it overwhelms the immune response or if the patient is unable to restore the blood vessel barrier, fluid moves out of the blood vessels and begins pouring into the tissue. This “leakiness” is what can make pneumonia turn into acute respiratory distress syndrome. ARDS, by my estimate affects hundreds of thousands of people each year worldwide. In the US around 190,000 people develop ARDS each year and it has a mortality rate of up to 40%. In people with Ebola, this leakiness is also often deadly, causing severe blood pressure drops and shock.
New therapies to fix the leakiness of blood vessels in patients suffering from life-threatening illnesses, such as acute respiratory distress syndrome and Ebola virus infections, have the potential to save many lives.

What is ARDS?

Severe pneumonia can lead to acute respiratory distress syndrome (ARDS), a complication in which the massive leakiness of blood vessels in the lung leads to the fluid build-up, which covers the cells that exchange oxygen and carbon dioxide. Patients usually require mechanical ventilators to force oxygen into the lungs in order to survive.
Pneumonia is one of the most common causes of ARDS but any generalized infection and inflammation that is severe enough to cause massive leakiness of lung blood vessels can cause the syndrome.
For people with ARDS treatment, options other than ventilators and treating the underlying infection are limited. And suppressing the immune system to treat this leakiness can leave patients vulnerable to infection.

A new treatment option

But what if we specifically target the leakiness of the blood vessels? Our research has identified an oxygen-sensitive pathway in the endothelial cells which line the blood vessels of the lungs. The leakiness or tightness of the blood vessel barrier depends on the presence of junctions between these cells. These junctions need two particular proteins to work properly. One is called VE-cadherin and is a key building block of the junctions. The other is called VE-PTP and helps ensure that VE-cadherin stays at the cell surface where it can form the junctions with neighboring cells.
When the endothelial cells are inflamed, these junctions break down and the blood vessels become leaky. This prompts the cells to activate a pathway via Hypoxia Inducible Factors (HIFs), which are usually mobilized in response to low oxygen stress. In the heart, HIF pathways are activated during a heart attack or long-standing narrowing of the heart blood vessels to improve the survival of heart cells and initiate the growth of new blood vessels.

We found that a kind of HIF (called HIF2α) was protective in lung blood vessel cells. When it was activated, it increased levels of the proteins that support the junctions between lung cells and strengthened the blood vessel barrier. But in many patients, this activation may not start soon enough to prevent ARDS.

The good news is that we can activate this factor before the lung fluid accumulates and before low oxygen levels set in. Using a drug, we activated HIF2α under normal oxygen conditions, which “tricked” cells into initiating their protective low-oxygen response and tightening the blood vessel barrier. Mice treated with a HIF2α activation drug had substantially higher survival rates when exposed to bacterial toxins or bacteria which cause ARDS.

Similar drugs have already been used in small clinical trials to increase the production of red blood cells in anemic patients. This means that activating HIF2α is probably safe for human use and may indeed become a viable strategy in ARDS. However, the efficacy and safety of drugs which activate HIF2α still have to be tested in humans with proper placebo control groups.

Could this treat Ebola?

The Ebola virus is a hemorrhagic virus and is also known to induce the breakdown of blood vessel barriers. In fact, it is these leaks in the blood vessels that make the disease so deadly. Due to the leakage of fluid and blood from the blood vessels into the tissue, the levels of fluid and blood inside the blood vessels decrease to critically low levels, causing blood pressure drops and ultimately shock. A group of researchers in Germany recently reported the use of an experimental drug (a peptide) developed for the treatment of vascular leakage in a 38-year-old doctor who had contracted Ebola in Sierra Leone and was airlifted to Germany. The researchers received a compassionate-use exemption for the drug and the patient recovered.

This is just a single case report and it is impossible to know whether the patient would have recovered similarly well without the experimental vascular leakage treatment, but it does highlight the potential role of drugs which treat blood vessel leakiness in Ebola patients.



This article was originally published on The Conversation. Read the original article.


Gong, H., Rehman, J., Tang, H., Wary, K., Mittal, M., Chatturvedi, P., Zhao, Y., Komorova, Y., Vogel, S., & Malik, A. (2015). HIF2α signaling inhibits adherens junctional disruption in acute lung injury Journal of Clinical Investigation, 125 (2), 652-664 DOI: 10.1172/JCI77701

Physician-Scientists: An Endangered Species?

Can excellent scientists be excellent physicians at the same time?

“I would like to ask you about a trip to Thailand.”

This is not the kind of question I expected from a patient in my cardiology clinic at the Veterans Administration hospital in Indianapolis. Especially since this patient lived in rural Indiana and did not strike me as the adventurous type.

“A trip to Thailand?”, I mumbled, “Well, ummm…I am sure……ummm…I guess the trip will be ok. Just take your heart medications regularly, avoid getting dehydrated and I hope you have a great vacation there. I am just a cardiologist and if you want to know more about the country you ought to talk to a travel agent.”

I realized that I didn’t even know whether travel agents still existed in the interwebclickopedia world, so I hastily added “Or just use a travel website. With photos. Lots of photos. And videos. Lots of videos.”

Now it was the patient’s turn to look confused.

“Doctor, I didn’t want to ask you about the country. I wanted to know whether you thought it was a good idea for me to travel there to receive stem cell injections for my heart.”

I was thrilled because for the first time in my work as a cardiologist, a patient had asked me a question which directly pertained to my research. My laboratory’s focus was studying the release of growth factors fromstem cells and whether they could help improve cardiovascular function. But my excitement was short-lived and gradually gave way to horror when the patient explained the details of the plan. A private clinic in Thailand was marketing bone marrow cell injections to treat heart patients with advanced heart disease. The patient would have to use nearly all his life savings to travel to Thailand and stay at this clinic, have his bone marrow extracted and processed, and then re-injected back into his heart in order to cure his heart disease.

Much to the chagrin of the other patients in the waiting room, I spent the next half hour summarizing the current literature on cardiovascular cell therapies for the patient. I explained that most bone marrow cells were not stem cells and that there was no solid evidence that he would benefit from the injections. He was about to undergo a high-risk procedure with questionable benefits and lose a substantial amount of money. I pleaded with him to avoid such a procedure, and was finally able to convince him.

I remember this anecdote so well because in my career as a physician-scientist, the two worlds of science and clinical medicine rarely overlap and this was one of the few exceptions. Most of my time is spent in my stem cell biology laboratory, studying basic mechanisms of stem cell metabolism and molecular signaling pathways. Roughly twenty percent of my time is devoted to patient care, treating patients with known cardiovascular disease in clinics, inpatient wards and coronary care units.

“Portrait of Dr. Gachet” – Painting by Vincent van Gogh (Public Domain via Wikimedia)

As scientists, we want to move beyond the current boundaries of knowledge, explore creative ideas and test hypotheses. As physicians, we rely on empathy to communicate with the patient and his or her family, we apply established guidelines of what treatments to use and our patient’s comfort takes precedence over satisfying our intellectual curiosity. The mystique of the physician-scientist suggests that those of us who actively work in both worlds are able to synergize our experiences from scientific work and clinical practice. Being a scientist indeed has some impact on my clinical work, because it makes me evaluate clinical data on a patient and published papers more critically. My clinical work helps me identify areas of research which in the long-run may be most relevant to patient care. But these rather broad forms of crosstalk have little bearing on my day-to-day work, which characterized by mode-switching, vacillating back and forth between my two roles.

Dr. J. Michael Bishop, who received the Nobel Prize in 1989 with Dr. Harold Varmus for their work on retroviral cancer genes (oncogenes), spoke at panel discussion at the 64th Lindau Nobel Laureate Meeting (2014) about the career paths of physician-scientists in the United States. Narrating his own background, he said that after he completed medical school, he began his clinical postgraduate training but then exclusively focused on his research. Dr. Bishop elaborated how physician-scientists in the United States are often given ample opportunities and support to train in both medicine and science, but many eventually drop out from the dual career path and decide to actively pursue only one or the other. The demands of both professions and the financial pressures of having to bring in clinical revenue as well as research grants are among the major reasons for why it is so difficult to remain active as a scientist and a clinician.

To learn more about physician-scientist careers in Germany, I also spoke to Dr. Christiane Opitz who heads a cancer metabolism group at the German Cancer Research Center, DKFZ, in Heidelberg and is an active clinician. She was a Lindau attendee as a young scientist in 2011 and this year has returned as a discussant.

JR: You embody the physician-scientist role, by actively managing neuro-oncology patients at the university hospital in Heidelberg as well as heading your own tumor metabolism research group at the German Cancer Research Center (Deutsches Krebsforschungszentrum or DKFZ in Heidelberg). Is there a lot of crosstalk between these two roles? Does treating patients have a significant influence on your work as a scientist? Does your work as cancer cell biologist affect how you evaluate and treat patients?

CO: In my experience, my being a physician influences me on a personal level and my character but not so much my work as a scientist. Of course I am more aware of patients’ needs when I design scientific experiments but there is not a lot of crosstalk between me as a physician and me as a scientist. I treat patients with malignant brain tumors which is a fatal disease, despite chemotherapy and radiation therapy. We unfortunately have very little to offer these patients. So as a physician, I see my role as being there for the patients, taking time to talk to them, provide comfort, counseling their families because we do not have any definitive therapies. This is very different from my research where my aim is to study basic mechanisms of tumor metabolism.

There are many days when I am forced to tell a patient that his or her tumor has relapsed and that we have no more treatments to offer. Of course these experiences do motivate me to study brain tumor metabolism with the hope that one day my work might help develop a new treatment. But I also know that even if we were lucky enough to uncover a new mechanism, it is very difficult to predict if and when it would contribute to a new treatment. This is why my scientific work is primarily driven by scientific curiosity and guided by the experimental results, whereas the long-term hope for new therapies is part of the bigger picture.

JR: Is it possible that medical thinking doesn’t only help science but can also be problematic for science?

CO: I think in general there is increasing focus on translational science from bench-to-bedside, the aim to develop new treatments. This application-oriented approach may bear the risk of not adequately valuing basic science. We definitely need translational science, because we want patients to benefit from our work in the basic sciences. On the other hand, it is very important to engage in basic science research because that is where – often by serendipity – the real breakthroughs occur. When we conduct basic science experiments, we do not think about applications. Instead, we primarily explore biological mechanisms.

Physicians and scientists have always conducted “translational research”, but it has now become a very popular buzzword. For that reason, I am a bit concerned when too much focus and funding is shifted towards application-oriented science at the expense of basic science, because then we might lose the basis for future scientific breakthroughs. We need a healthy balance of both.

JR: Does the medical training of a physician draw them towards application-oriented translational science and perhaps limit their ability to address the more fundamental mechanistic questions?

CO: In general, I would say it is true that people who were trained purely as scientists are more interested in addressing basic mechanisms and people who were trained as physicians are more interested in understanding applications such as therapies, therapeutic targets and resistance to therapies.

They are exceptions, of course, and it is ultimately dependent on the individual. I have met physicians who are very interested in basic sciences. I also know researchers who were trained in the basic sciences but have now become interested in therapeutic applications.

JR: When physicians decide to engage in basic science, do you think they have to perhaps partially “unlearn” their natural tendency of framing their scientific experiments in terms of therapeutic applications because of their exposure to clinical problems?

CO: We obviously need application-oriented science, too. It is important to encourage physicians who want to pursue translational research in the quest of new therapies, but we should not regard that as superior to basic science. As a physician who is primarily working in the basic sciences, I make a conscious effort to focus on mechanisms instead of pre-defined therapeutic goals.

Looking to the future

Dr. Opitz’s description of how challenging it is to navigate between her clinical work in neuro-oncology and her research mirrors my own experience. I have often heard that the physician-scientist is becoming an “endangered species”, implying that perhaps we used to roam the earth in large numbers and have now become rather rare. I am not sure this is an accurate portrayal. It is true that current financial pressures at research funding agencies and academic institutions are placing increased demands on physician-scientists and make it harder to actively pursue both lines of work. However, independent of these more recent financial pressures, it has always been extremely challenging to concomitantly work in two professions and be good at what you do. Dr. Bishop decided to forsake a clinical career and only focus on his molecular research because he was passionate about the research. His tremendous success as a scientist shows that this was probably a good decision.

As physician-scientists, we are plagued by gnawing self-doubts about the quality of our work. Can we be excellent scientists and excellent physicians at the same time? Even if, for example, the number of days we see patients are reduced to a minimum, can we stay up-to-date in two professions in which a huge amount of new knowledge is produced and published on a daily basis? And even though the reduction in clinical time allows us to develop great research programs, does it compromise our clinical skills to a point where we may not make the best decisions for our patients?

We are often forced to sacrifice our week-ends, the hours we sleep and the time we spend with our families or loved ones so that we can cope with the demands of the two professions. This is probably also valid for other dual professions. Physician-scientists are a rare breed, but so are physician-novelists, banker-poets or philosopher-scientists who try to remain actively engaged in both of their professions.

There will always be a rare population of physician-scientists who are willing to take on the challenge. They need all the available help from academic institutions and research organizations to ensure that they have the research funds, infrastructure and optimized work schedules which allow them to pursue this extremely demanding dual career path. It should not come as a surprise that, despite the best support structure, a substantial proportion of physician-scientists will at some point feel overwhelmed by the demands and personal sacrifices and opt for one or the other career. Even though they may choose drop out, the small pool of physician-scientists will likely be replenished by a fresh batch of younger colleagues, attracted by the prospect of concomitantly working in and bridging these two worlds.

Instead of lamenting the purported demise of physician-scientists, we should also think about alternate ways to improve the dialogue and synergy between cutting-edge science and clinical medicine. A physician can practice science-based medicine without having to actively work as a scientist in a science laboratory. A scientist can be inspired or informed by clinical needs of patients without having to become a practicing physician. Creating routine formalized exchange opportunities such fellowships or sabbaticals which allow scientists and clinicians to spend defined periods of time in each other’s work environments may be much more feasible approach to help bridge the gap and engender mutual understanding or respect.

Originally published as “Physician Scientists: An Endangered Species?“ in the Lindau Nobel Laureates Meeting blog.

Moral Time: Does Our Internal Clock Influence Moral Judgments?

Does morality depend on the time of the day? The study "The Morning Morality Effect: The Influence of Time of Day on Unethical Behavior" published in October of 2013 by Maryam Kouchaki and Isaac Smith suggested that people are more honest in the mornings, and that their ability to resist the temptation of lying and cheating wears off as the day progresses. In a series of experiments, Kouchaki and Smith found that moral awareness and self-control in their study subjects decreased in the late afternoon or early evening.  The researchers also assessed the degree of "moral disengagement", i.e. the willingness to lie or cheat without feeling much personal remorse or responsibility, by asking the study subjects to respond to questions such as "Considering the ways people grossly misrepresent themselves, it's hardly a sin to inflate your own credentials a bit" or "People shouldn't be held accountable for doing questionable things when they were just doing what an authority figure told them to do" on a scale from 1 (strongly disagree) to 7 (strongly agree). Interestingly, the subjects who strongly disagreed with such statements were the most susceptible to the morning morality effect. They were quite honest in the mornings but significantly more likely to cheat in the afternoons. On the other hand, moral disengagers, i.e. subjects who did not think that inflating credentials or following questionable orders was a big deal, were just as likely to cheat in the morning as they were in the afternoons.

Understandably, the study caused quite a bit of ruckus and became one of the most widely discussed psychology research studies in 2013, covered widely by blogs and newspapers such as the Guardian "Keep the mornings honest, the afternoons for lying and cheating" or the German Süddeutsche Zeitung "Lügen erst nach 17 Uhr" (Lying starts at 5 pm). And the findings of the study also raised important questions: Should organizations and businesses take the time of day into account when assigning tasks to employees which require high levels of moral awareness?  How can one prevent the "moral exhaustion" in the late afternoon and the concomitant rise in the willingness to cheat?  Should the time of the day be factored into punishments for unethical behavior? 

One question not addressed by Kouchaki and Smith was whether the propensity to become dishonest in the afternoons or evenings could be generalized to all subjects or whether the internal time in the subjects was also a factor. All humans have an internal body clock – the circadian clock- which runs with a period of approximately 24 hours. The circadian clock controls a wide variety of physical and mental functions such as our body temperature, the release of hormones or our levels of alertness. The internal clock can vary between individuals, but external cues such as sunlight or the social constraints of our society force our internal clocks to be synchronized to a pre-defined external time which may be quite distinct from what our internal clock would choose if it were to "run free". Free-running internal clocks of individuals can differ in terms of their period (for example 23.5 hours versus 24.4 hours) as well as the phases of when individuals would preferably engage in certain behaviors. 

Some people like to go to bed early, wake up at 5 am or 6 am on their own even without an alarm clock and they experience peak levels of alertness and energy before noon. In contrast to such "larks", there are "owls" among us who prefer to go to bed late at night, wake up at 11 am, experience their peak energy levels and alertness in the evening hours and like to stay up way past midnight. It is not always easy to determine our "chronotype" – whether we are "larks", "owls" or some intermediate thereof – because our work day often imposes its demands on our internal clocks. Schools and employers have set up the typical workday in a manner which favors "larks", with work days usually starting around 7am – 9am. In 1976, the researchers Horne and Östberg developed a Morningness-Eveningness Questionnaire to investigate what time of the day individuals would prefer to wake up, work or take a test if it was entirely up to them. They found that roughly 40% of the people they surveyed had an evening chronotype! If Kouchaki and Smith's findings that cheating and dishonesty increases in the late afternoons applies to both morning and evening chronotype folks, then the evening chronotypes ("owls") are in a bit of a pickle. Their peak performance and alertness times would overlap with their propensity to be dishonest. 

The researchers Brian Gunia, Christopher Barnes and Sunita Sah therefore decided to replicate the Kouchaki and Smith study with one major modification: They not only assessed the propensity to cheat at different times of the day, they also measured the chronotypes of the study participants. Their recent paper ""The Morality of Larks and Owls: Unethical Behavior Depends on Chronotype as Well as Time of Day" confirms that Kouchaki and Smith findings that the time of the day influences honesty, but the observed effects differ among chronotypes. After assessing the chronotypes of 142 participants (72 women, 70 men; mean age 30 years), the researchers randomly assigned them to either a morning session (7:00 to 8:30 am) or an evening session (12:00 am to 1:30 am). The participants were asked to report the outcome of a die roll; the higher the reported number, the more raffle tickets they would receive for a large prize, which served as an incentive to inflate the outcome of the roll. Since a die roll is purely random, one would expect that reported average of the die roll results would be similar across all groups if all participants were honest. 

Their findings: Morning people ("larks") tended to report higher die-roll numbers in the evening than in the morning – thus supporting the Kouchaki and Smith results- but evening people tended to report higher numbers in the morning than in the evening. This means that the morning morality effect and the idea of "moral exhaustion" towards the end of the day cannot be generalized to all. In fact, evening people ("owls") are more honest in the evenings. 

 Not so fast, say Kouchaki and Smith in a commentary published to together with the new paper by Gunia and colleagues. They applaud the new study for taking the analysis of daytime effects on cheating one step further by considering the chronotypes of the participants, but they also point out some important limitations of the newer study. Gunia and colleagues only included morning and evening people in their analysis and excluded the participants who reported an intermediate chronotype, i.e. not quite early morning "larks" and not true "owls". This is a valid criticism because newer research on chronotypes by Till Roenneberg and his colleagues at the University of Munich has shown that there is a Gaussian distribution of chronotypes. Few of us are extreme larks or extreme owls, most of us lie on a continuum. Roenneberg's approach to measuring chronotypes looks at the actual hours of sleep we get and distinguishes between our behaviors on working days and weekends because the latter may provide a better insight into our endogenous clock, unencumbered by the demands of our work schedule. The second important limitation identified by Kouchaki and Smith is that Gunia and colleagues used 12 am to 1:30 am as the "evening condition". This may be the correct time to study the peak performance of extreme owls and selected night shift workers but ascertaining cheating behavior at this hour is not necessarily relevant for the general workforce. 

Neither the study by Kouchaki and Smith nor the new study by Gunia and colleagues provide us with a definitive answer as to how the external time of the day (the time according to the sun and our social environment) and the internal time (the time according to our internal circadian clock) affect moral decision-making. We need additional studies with larger sample sizes which include a broad range of participants with varying chronotypes as well as studies which assess moral decision-making not just at two time points but also include a range of time points (early morning, afternoon, late afternoon, evening, night, etc.). But the two studies have opened up a whole new area of research and their findings are quite relevant for the field of experimental philosophy, which uses psychological methods to study philosophical questions. If empirical studies are conducted with human subjects then researchers need to take into account the time of the day and the internal time and chronotype of the participants, as well as other physiological differences between individuals. 

 The exchange between Kouchaki & Smith and Gunia & colleagues also demonstrates the strength of rigorous psychological studies. Researcher group 1 makes a highly provocative assertion based on their data, researcher group 2 partially replicates it and qualifies it by introducing one new variable (chronotypes) and researcher group 1 then analyzes strengths and weaknesses of the newer study. This type of constructive criticism and dialogue is essential for high-quality research. Hopefully, future studies will be conducted to provide more insights into this question. By using the Roenneberg approach to assess chronotypes, one could potentially assess a whole continuum of chronotypes – both on working days and weekends – and also relate moral reasoning to the amount of sleep we get. Measurements of body temperature, hormone levels, brain imaging and other biological variables may provide further insight into how the time of day affects our moral reasoning. 

 Why is this type of research important? I think that realizing how dynamic moral judgment can be is a humbling experience. It is easy to condemn the behavior of others as "immoral", "unethical" or "dishonest" as if these are absolute pronouncements. Realizing that our own judgment of what is considered ethical or acceptable can vary because of our internal clock or the external time of the day reminds us to be less judgmental and more appreciative of the complex neurobiology and physiology which influence moral decision-making. If future studies confirm that the internal time (and possibly sleep deprivation) influences moral decision-making, then we need to carefully rethink whether the status quo of forcing people with diverse chronotypes into a compulsory 9-to-5 workday is acceptable. Few, if any, employers and schools have adapted their work schedules to accommodate chronotype diversity in human society. Understanding that individualized work schedules for people with diverse chronotypes may not only increase their overall performance but also increase their honesty might serve as another incentive for employers and schools to recognize the importance of chronotype diversity among individuals. 

 References: 

 Brian C. Gunia, Christopher M. Barnes and Sunita Sah (2014) "The Morality of Larks and Owls: Unethical Behavior Depends on Chronotype as Well as Time of Day", Psychological Science (published online ahead of print on Oct 6, 2014). 

 Maryam Kouchaki and Isaac H. Smith (2014) "The Morning Morality Effect: The Influence of Time of Day on Unethical Behavior", Psychological Science 25(1) 95–102. 

Till Roenneberg, Anna Wirz-Justice and Martha Merrow. (2003) "Life between clocks: daily temporal patterns of human chronotypes." Journal of Biological Rhythms 18:1: 80-90.   

 Note: An earlier version of this article was first published on the 3Quarksdaily blog.   


Gunia, B., Barnes, C., & Sah, S. (2014). The Morality of Larks and Owls: Unethical Behavior Depends on Chronotype as Well as Time of Day Psychological Science, 25 (12), 2272-2274 DOI: 10.1177/0956797614541989

Haikus and Landays in Science

Summer grass:
That's all that remains
Of warriors' dreams.

                 --Basho

My favorite scientific experiments are those which resemble a haiku: simple and beautiful with a revelatory twist. This is why the haiku is very well suited for expressing scientific ideas in a poetic form.  Contemporary haiku poets do not necessarily abide by the rules of traditional Japanese haiku, such as including a word which implies the season of the poem or the 17 (5-7-5) syllable structure of three verses. Especially when writing in a language other than Japanese, one can easily argue that the original 5-7-5 structure was based on Japanese equivalents of syllables and that there is no need to apply this syllable count to English-language haiku. Even the reference to seasons and nature may not apply to a modern-day English haiku about urban life or, as in my case, science.

Does this mean that contemporary haiku are not subject to any rules? In the introductory essay to an excellent anthology of English-language haiku, "Haiku in English: The First Hundred Years", the poet Billy Collins describes the benefit of retaining some degree of structure while writing a haiku:

Many poets, myself included, stick to the basic form of seventeen syllables, typically arranged in three lines in a 5-7-5 order. This light harness is put on like any formal constraint in poetry so the poet can feel the comfort of its embrace while being pushed by those same limits into unexpected discoveries. Asked where he got his inspiration, Yeats answered, "in looking for the next rhyme word." To follow such rules, whether received as is the case with the sonnet or concocted on the spot, is to feel the form pushing back against one's self-expressive impulses. For the poet, this palpable resistance can be a vital part of the compositional experience. I count syllables not out of any allegiance to tradition but because I want the indifference and inflexibility of a seventeen-syllable limit to balance my self-expressive yearnings. With the form in place, the act of composition becomes a negotiation between one's subjective urges and the rules of order, which in this case could not be simpler or firmer.

The seventeen syllable limit – like any other limit or rule in poetic forms – provides the necessary constraints that channel our boundless creativity to create a finite poem. It is a daunting task to sit down with a pen and paper, and try to write a poem about a certain topic. Our minds and souls are flooded with a paralyzing plethora of images and ideas. But, as Collins suggests, if we are already aware of certain rules, it becomes much easier to start the process of poetic filtering and negotiation.


What is the essence of a haiku? In the same essay, Collins offers a very elegant answer:

Whether they are the counting or the non-counting type, poets are likely to agree that at the heart of the haiku lies something beyond counting, that is, its revelatory effect on the reader, that eye-opening moment of insight that occurs whenever a haiku succeeds in drawing us through the keyhole of its details into the infinite, or to put it more ineffably, into the "Void of the Whole." No one would argue that any tercet that mentions a cloud or a frog qualifies as a real haiku; it would be like calling an eleven-line poem about courtly love a sonnet. A true haiku contains a special uncountable feature, and every serious devotee of the form aims to achieve that with every attempt.

The revelatory surprise, the "Aha moment", is what characterizes a true haiku. I have experimented with the haiku form, trying to capture scientific concepts or the process of scientific discovery. Many poets do not give titles to their haiku, but I feel that the title can be very helpful to create a poetic tension and provide a context that may be difficult to incorporate within the haiku verses. A haiku – like every good poem – should not require explanatory lines by the poet, but I think that one can make some exceptions here in the context of experimenting with haiku.

Scientific images or phrases are not always self-evident, so I include brief annotations for the haiku I have written which may be helpful for people who are not routinely exposed to the scientific research.

Mitochondria
Grainy threads in cells,
powerhouses of life are
harbingers of death

I have been studying mitochondria for a number of years, but I still marvel at the Janus-like role of mitochondria. They are active sites of biosynthesis and produce the universal energy molecule of cells (ATP) thus ensuring the growth and survival of cells. At the same time, mitochondria can initiate a cell's suicide program (apoptosis), forcing a cell to die. You can read about some of our mitochondrial research on lung cancer here.


Pipette
Ceci n'est pas une
pipette, porting microdrops
for my macrodreams

Many of us have spent hours, days and months repetitively pipetting hundreds of samples for PCR reactions, ELISA assays or other tests, and sooner or later most of us wonder about the meaning of these Sisyphean tasks.

Progress
Most hypotheses
in science are tested only 
to be rejected

If I received a dollar for every wonderful scientific idea I have had that turned out to be wrong, I would not have to write any more grants to support my lab.

Haiku have become an integral part of English language poetry, but there is another poetic form that may soon be gaining popularity. The journalist and poet Eliza Griswold recently teamed up with the photographer Seamus Murphy, traveled to Afghanistan and collected landays that are commonly composed by Afghani women in their native language Pushto. Landays are a form of folk poetry, couplets consisting of a verse with nine syllables followed by one with thirteen syllables. Griswold worked with native Pushto speakers to translate the landays into English. In her brilliant essay published in the June 2013 issue of Poetry Magazine, Griswold provides us with glimpses into the lives of Afghani women, the hardships that they face on a daily basis. The essay also contains translations of landays, which have become a form of lyrical resistance for Afghani women, allowing them to voice their anger and frustration. Illiterate women compose, share and recite these poems, often anonymously and behind closed doors, in society that marginalizes women. The narratives about Afghani women and the translations of landays, which preserve their characteristic wit and sarcasm, are accompanied by haunting photographs that convey the beauty of war-torn Afghanistan and its people.

Here is a description of landays from Griswold's essay:

A landay has only a few formal properties. Each has twenty-two syllables: nine in the first line, thirteen in the second. The poem ends with the sound "ma" or "na." Sometimes they rhyme, but more often not. In Pashto, they lilt internally from word to word in a kind of two-line lullaby that belies the sharpness of their content, which is distinctive not only for its beauty, bawdiness, and wit, but also for the piercing ability to articulate a common truth about war, separation, homeland, grief, or love. Within these five main tropes, the couplets express a collective fury, a lament, an earthy joke, a love of home, a longing for the end of separation, a call to arms, all of which frustrate any facile image of a Pashtun woman as nothing but a mute ghost beneath a blue burqa.

Examples of landays collected by Griswold:

You sold me to an old man, father.
May God destroy your home, I was your daughter.

I tried to kiss you in secret but you're bald!
Your bare skull thumped against the wall.

I dream I am the president.
When I awake, I am the beggar of the world.

In April of 2014, Griswold and Murphy will also release the book "I Am the Beggar of the World: Landays from Contemporary Afghanistan" which will contain a more comprehensive collection of landays.

Landays have not yet caught on as a poetic form in the English-language, but this landmark work by Griswold might change that. I think that landays might be a great opportunity for scientists to describe their experiences with the scientific enterprise.

My landays revolve around the work and lives of academic scientists:

A-Team
I work alone in the lab each night,
conducting all our experiments for your career.

Tenure Trek
Sirens of tenure captivate us,
chained to hallowed halls of academic freedom.

Glamour
Journals can make or break our careers,
careers can make or break us, we can make or break journals.

These landays attempt to approximate the 9-13 syllable count in the couplets but as with haiku, the nature, structure and themes of landays written in English will likely be different from the original Pushto landays.
It does not really matter what poetic form or structure scientists choose to express themselves, but my personal experience has been that poetry is a wonderful way to share science.  Writing haiku or landays about science has forced me to think about what aspects of my scientific work I really treasure. What started as a playful exercise with words has become a journey.

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Note: An earlier version of this article was first published on 3quarksdaily.com.

Image Credits: 1) Basho's Flowers (by Adam Shaw via Wikimedia Commons). 2) La trahison des images (by René Magritte via Wikimedia Commons). 3) Micropipettes - public domain image

The Road to Bad Science Is Paved with Obedience and Secrecy

We often laud intellectual diversity of a scientific research group because we hope that the multitude of opinions can help point out flaws and improve the quality of research long before it is finalized and written up as a manuscript. The recent events surrounding the research in one of the world's most famous stem cell research laboratories at Harvard shows us the disastrous effects of suppressing diverse and dissenting opinions.
The infamous "Orlic paper" was a landmark research article published in the prestigious scientific journal Nature in 2001, which showed that stem cells contained in the bone marrow could be converted into functional heart cells. After a heart attack, injections of bone marrow cells reversed much of the heart attack damage by creating new heart cells and restoring heart function. It was called the "Orlic paper" because the first author of the paper was Donald Orlic, but the lead investigator of the study was Piero Anversa, a professor and highly respected scientist at New York Medical College.

#94119222 / gettyimages.com

Anversa had established himself as one of the world's leading experts on the survival and death of heart muscle cells in the 1980s and 1990s, but with the start of the new millennium, Anversa shifted his laboratory's focus towards the emerging field of stem cell biology and its role in cardiovascular regeneration. The Orlic paper was just one of several highly influential stem cell papers to come out of Anversa's lab at the onset of the new millenium. A 2002 Anversa paper in the New England Journal of Medicine – the world's most highly cited academic journal –investigated the hearts of human organ transplant recipients. This study showed that up to 10% of the cells in the transplanted heart were derived from the recipient's own body. The only conceivable explanation was that after a patient received another person's heart, the recipient's own cells began maintaining the health of the transplanted organ. The Orlic paper had shown the regenerative power of bone marrow cells in mouse hearts, but this new paper now offered the more tantalizing suggestion that even human hearts could be regenerated by circulating stem cells in their blood stream.


A 2003 publication in Cell by the Anversa group described another ground-breaking discovery, identifying a reservoir of stem cells contained within the heart itself. This latest coup de force found that the newly uncovered heart stem cell population resembled the bone marrow stem cells because both groups of cells bore the same stem cell protein called c-kit and both were able to make new heart muscle cells. According to Anversa, c-kit cells extracted from a heart could be re-injected back into a heart after a heart attack and regenerate more than half of the damaged heart!

These Anversa papers revolutionized cardiovascular research. Prior to 2001, most cardiovascular researchers believed that the cell turnover in the adult mammalian heart was minimal because soon after birth, heart cells stopped dividing. Some organs or tissues such as the skin contained stem cells which could divide and continuously give rise to new cells as needed. When skin is scraped during a fall from a bike, it only takes a few days for new skin cells to coat the area of injury and heal the wound. Unfortunately, the heart was not one of those self-regenerating organs. The number of heart cells was thought to be more or less fixed in adults. If heart cells were damaged by a heart attack, then the affected area was replaced by rigid scar tissue, not new heart muscle cells. If the area of damage was large, then the heart's pump function was severely compromised and patients developed the chronic and ultimately fatal disease known as "heart failure".

Anversa's work challenged this dogma by putting forward a bold new theory: the adult heart was highly regenerative, its regeneration was driven by c-kit stem cells, which could be isolated and used to treat injured hearts. All one had to do was harness the regenerative potential of c-kit cells in the bone marrow and the heart, and millions of patients all over the world suffering from heart failure might be cured. Not only did Anversa publish a slew of supportive papers in highly prestigious scientific journals to challenge the dogma of the quiescent heart, he also happened to publish them at a unique time in history which maximized their impact.

In the year 2001, there were few innovative treatments available to treat patients with heart failure. The standard approach was to use medications that would delay the progression of heart failure. But even the best medications could not prevent the gradual decline of heart function. Organ transplants were a cure, but transplantable hearts were rare and only a small fraction of heart failure patients would be fortunate enough to receive a new heart. Hopes for a definitive heart failure cure were buoyed when researchers isolated human embryonic stem cells in 1998. This discovery paved the way for using highly pliable embryonic stem cells to create new heart muscle cells, which might one day be used to restore the heart's pump function without  resorting to a heart transplant.

The dreams of using embryonic stem cells to regenerate human hearts were soon squashed when the Bush administration banned the generation of new human embryonic stem cells in 2001, citing ethical concerns. These federal regulations and the lobbying of religious and political groups against human embryonic stem cells were a major blow to research on cardiovascular regeneration. Amidst this looming hiatus in cardiovascular regeneration, Anversa's papers appeared and showed that one could steer clear of the ethical controversies surrounding embryonic stem cells by using an adult patient's own stem cells. The Anversa group re-energized the field of cardiovascular stem cell research and cleared the path for the first human stem cell treatments in heart disease.

Instead of having to wait for the US government to reverse its restrictive policy on human embryonic stem cells, one could now initiate clinical trials with adult stem cells, treating heart attack patients with their own cells and without having to worry about an ethical quagmire. Heart failure might soon become a disease of the past. The excitement at all major national and international cardiovascular conferences was palpable whenever the Anversa group, their collaborators or other scientists working on bone marrow and cardiac stem cells presented their dizzyingly successful results. Anversa received numerous accolades for his discoveries and research grants from the NIH (National Institutes of Health) to further develop his research program. He was so successful that some researchers believed Anversa might receive the Nobel Prize for his iconoclastic work which had redefined the regenerative potential of the heart. Many of the world's top universities were vying to recruit Anversa and his group, and he decided to relocate his research group to Harvard Medical School and Brigham and Women's Hospital 2008.

There were naysayers and skeptics who had resisted the adult stem cell euphoria. Some researchers had spent decades studying the heart and found little to no evidence for regeneration in the adult heart. They were having difficulties reconciling their own results with those of the Anversa group. A number of practicing cardiologists who treated heart failure patients were also skeptical because they did not see the near-miraculous regenerative power of the heart in their patients. One Anversa paper went as far as suggesting that the whole heart would completely regenerate itself roughly every 8-9 years, a claim that was at odds with the clinical experience of practicing cardiologists.  Other researchers pointed out serious flaws in the Anversa papers. For example, the 2002 paper on stem cells in human heart transplant patients claimed that the hearts were coated with the recipient's regenerative cells, including cells which contained the stem cell marker Sca-1. Within days of the paper's publication, many researchers were puzzled by this finding because Sca-1 was a marker of mouse and rat cells – not human cells! If Anversa's group was finding rat or mouse proteins in human hearts, it was most likely due to an artifact. And if they had mistakenly found rodent cells in human hearts, so these critics surmised, perhaps other aspects of Anversa's research were similarly flawed or riddled with artifacts.

At national and international meetings, one could observe heated debates between members of the Anversa camp and their critics. The critics then decided to change their tactics. Instead of just debating Anversa and commenting about errors in the Anversa papers, they invested substantial funds and efforts to replicate Anversa's findings. One of the most important and rigorous attempts to assess the validity of the Orlic paper was published in 2004, by the research teams of Chuck Murry and Loren Field. Murry and Field found no evidence of bone marrow cells converting into heart muscle cells. This was a major scientific blow to the burgeoning adult stem cell movement, but even this paper could not deter the bone marrow cell champions.

Despite the fact that the refutation of the Orlic paper was published in 2004, the Orlic paper continues to carry the dubious distinction of being one of the most cited papers in the history of stem cell research. At first, Anversa and his colleagues would shrug off their critics' findings or publish refutations of refutations – but over time, an increasing number of research groups all over the world began to realize that many of the central tenets of Anversa's work could not be replicated and the number of critics and skeptics increased. As the signs of irreplicability and other concerns about Anversa's work mounted, Harvard and Brigham and Women's Hospital were forced to initiate an internal investigation which resulted in the retraction of one Anversa paper and an expression of concern about another major paper. Finally, a research group published a paper in May 2014 using mice in which c-kit cells were genetically labeled so that one could track their fate and found that c-kit cells have a minimal – if any – contribution to the formation of new heart cells: a fraction of a percent!

The skeptics who had doubted Anversa's claims all along may now feel vindicated, but this is not the time to gloat. Instead, the discipline of cardiovascular stem cell biology is now undergoing a process of soul-searching. How was it possible that some of the most widely read and cited papers were based on heavily flawed observations and assumptions? Why did it take more than a decade since the first refutation was published in 2004 for scientists to finally accept that the near-magical regenerative power of the heart turned out to be a pipe dream.

One reason for this lag time is pretty straightforward: It takes a tremendous amount of time to refute papers. Funding to conduct the experiments is difficult to obtain because grant funding agencies are not easily convinced to invest in studies replicating existing research. For a refutation to be accepted by the scientific community, it has to be at least as rigorous as the original, but in practice, refutations are subject to even greater scrutiny. Scientists trying to disprove another group's claim may be asked to develop even better research tools and technologies so that their results can be seen as more definitive than those of the original group. Instead of relying on antibodies to identify c-kit cells, the 2014 refutation developed a transgenic mouse in which all c-kit cells could be genetically traced to yield more definitive results - but developing new models and tools can take years.

The scientific peer review process by external researchers is a central pillar of the quality control process in modern scientific research, but one has to be cognizant of its limitations. Peer review of a scientific manuscript is routinely performed by experts for all the major academic journals which publish original scientific results. However, peer review only involves a "review", i.e. a general evaluation of major strengths and flaws, and peer reviewers do not see the original raw data nor are they provided with the resources to replicate the studies and confirm the veracity of the submitted results. Peer reviewers rely on the honor system, assuming that the scientists are submitting accurate representations of their data and that the data has been thoroughly scrutinized and critiqued by all the involved researchers before it is even submitted to a journal for publication. If peer reviewers were asked to actually wade through all the original data generated by the scientists and even perform confirmatory studies, then the peer review of every single manuscript could take years and one would have to find the money to pay for the replication or confirmation experiments conducted by peer reviewers. Publication of experiments would come to a grinding halt because thousands of manuscripts would be stuck in the purgatory of peer review. Relying on the integrity of the scientists submitting the data and their internal review processes may seem naïve, but it has always been the bedrock of scientific peer review. And it is precisely the internal review process which may have gone awry in the Anversa group.

Pygmalion and Glatea by Louis Gauffier (via Wikimedia - Public Domain)

Just like Pygmalion fell in love with Galatea, researchers fall in love with the hypotheses and theories that they have constructed. To minimize the effects of these personal biases, scientists regularly present their results to colleagues within their own groups at internal lab meetings and seminars or at external institutions and conferences long before they submit their data to a peer-reviewed journal. The preliminary presentations are intended to spark discussions, inviting the audience to challenge the veracity of the hypotheses and the data while the work is still in progress. Sometimes fellow group members are truly skeptical of the results, at other times they take on the devil's advocate role to see if they can find holes in their group's own research. The larger a group, the greater the chance that one will find colleagues within a group with dissenting views. This type of feedback is a necessary internal review process which provides valuable insights that can steer the direction of the research.
Considering the size of the Anversa group – consisting of 20, 30 or even more PhD students, postdoctoral fellows and senior scientists – it is puzzling why the discussions among the group members did not already internally challenge their hypotheses and findings, especially in light of the fact that they knew extramural scientists were having difficulties replicating the work.
Retraction Watch is one of the most widely read scientific watchdogs which tracks scientific misconduct and retractions of published scientific papers. Recently, Retraction Watch published the account of an anonymous whistleblower who had worked as a research fellow in Anversa's group and provided some unprecedented insights into the inner workings of the group, which explain why the internal review process had failed:

"I think that most scientists, perhaps with the exception of the most lucky or most dishonest, have personal experience with failure in science—experiments that are unreproducible, hypotheses that are fundamentally incorrect. Generally, we sigh, we alter hypotheses, we develop new methods, we move on. It is the data that should guide the science.
 In the Anversa group, a model with much less intellectual flexibility was applied. The "Hypothesis" was that c-kit (cd117) positive cells in the heart (or bone marrow if you read their earlier studies) were cardiac progenitors that could: 1) repair a scarred heart post-myocardial infarction, and: 2) supply the cells necessary for cardiomyocyte turnover in the normal heart.
 This central theme was that which supplied the lab with upwards of $50 million worth of public funding over a decade, a number which would be much higher if one considers collaborating labs that worked on related subjects.
 In theory, this hypothesis would be elegant in its simplicity and amenable to testing in current model systems. In practice, all data that did not point to the "truth" of the hypothesis were considered wrong, and experiments which would definitively show if this hypothesis was incorrect were never performed (lineage tracing e.g.)."

Discarding data that might have challenged the central hypothesis appears to have been a central principle.


According to the whistleblower, Anversa's group did not just discard undesirable data, they actually punished group members who would question the group's hypotheses:

"In essence, to Dr. Anversa all investigators who questioned the hypothesis were "morons," a word he used frequently at lab meetings. For one within the group to dare question the central hypothesis, or the methods used to support it, was a quick ticket to dismissal from your position."

The group also created an environment of strict information hierarchy and secrecy which is antithetical to the spirit of science:

"The day to day operation of the lab was conducted under a severe information embargo. The lab had Piero Anversa at the head with group leaders Annarosa Leri, Jan Kajstura and Marcello Rota immediately supervising experimentation. Below that was a group of around 25 instructors, research fellows, graduate students and technicians. Information flowed one way, which was up, and conversation between working groups was generally discouraged and often forbidden.
 Raw data left one's hands, went to the immediate superior (one of the three named above) and the next time it was seen would be in a manuscript or grant. What happened to that data in the intervening period is unclear.
 A side effect of this information embargo was the limitation of the average worker to determine what was really going on in a research project. It would also effectively limit the ability of an average worker to make allegations regarding specific data/experiments, a requirement for a formal investigation."

This segregation of information is a powerful method to maintain an authoritarian rule and is more typical for terrorist cells or intelligence agencies than for a scientific lab, but it would definitely explain how the Anversa group was able to mass produce numerous irreproducible papers without any major dissent from within the group.
In addition to the secrecy and segregation of information, the group also created an atmosphere of fear to ensure obedience:

"Although individually-tailored stated and unstated threats were present for lab members, the plight of many of us who were international fellows was especially harrowing. Many were technically and educationally underqualified compared to what might be considered average research fellows in the United States. Many also originated in Italy where Dr. Anversa continues to wield considerable influence over biomedical research.
 This combination of being undesirable to many other labs should they leave their position due to lack of experience/training, dependent upon employment for U.S. visa status, and under constant threat of career suicide in your home country should you leave, was enough to make many people play along.
 Even so, I witnessed several people question the findings during their time in the lab. These people and working groups were subsequently fired or resigned. I would like to note that this lab is not unique in this type of exploitative practice, but that does not make it ethically sound and certainly does not create an environment for creative, collaborative, or honest science."

Foreign researchers are particularly dependent on their employment to maintain their visa status and the prospect of being fired from one's job can be terrifying for anyone.
This is an anonymous account of a whistleblower and as such, it is problematic. The use of anonymous sources in science journalism could open the doors for all sorts of unfounded and malicious accusations, which is why the ethics of using anonymous sources was heavily debated at the recent ScienceOnline conference. But the claims of the whistleblower are not made in a vacuum – they have to be evaluated in the context of known facts. The whistleblower's claim that the Anversa group and their collaborators received more than $50 million to study bone marrow cell and c-kit cell regeneration of the heart can be easily verified at the public NIH grant funding RePORTer website. The whistleblower's claim that many of the Anversa group's findings could not be replicated is also a verifiable fact. It may seem unfair to condemn Anversa and his group for creating an atmosphere of secrecy and obedience which undermined the scientific enterprise, caused torment among trainees and wasted millions of dollars of tax payer money simply based on one whistleblower's account. However, if one looks at the entire picture of the amazing rise and decline of the Anversa group's foray into cardiac regeneration, then the whistleblower's description of the atmosphere of secrecy and hierarchy seems very plausible.

The investigation of Harvard into the Anversa group is not open to the public and therefore it is difficult to know whether the university is primarily investigating scientific errors or whether it is also looking into such claims of egregious scientific misconduct and abuse of scientific trainees. It is unlikely that Anversa's group is the only group that might have engaged in such forms of misconduct. Threatening dissenting junior researchers with a loss of employment or visa status may be far more common than we think. The gravity of the problem requires that the NIH – the major funding agency for biomedical research in the US – should look into the prevalence of such practices in research labs and develop safeguards to prevent the abuse of science and scientists.

Scientism Reloaded

The "Reclaim Scientism" movement is gaining momentum. In his recent book "The Atheist's Guide to Reality: Enjoying Life without Illusions", the American philosopher Alexander Rosenberg suggests that instead of viewing the word "scientism" as an epithet, atheists should expropriate it and use it as a positive term which describes their worldview. Rosenberg also provides a descriptive explanation of how the term "scientism" is currently used:

Scientism — noun; scientistic — adjective.
Scientism has two related meanings, both of them pejorative. According to one of these meanings, scientism names the improper or mistaken application of scientific methods or findings outside their appropriate domain, especially to questions treated by the humanities. The second meaning is more common: Scientism is the exaggerated confidence in the methods of science as the most (or the only) reliable tools of inquiry, and an equally unfounded belief that at least the most well established of its findings are the only objective truths there are.

Rosenberg's explanation of "scientism" is helpful because it highlights the difference between science and scientism. Science refers to applying scientific methods as tools of inquiry to collect and interpret data, whereas "scientism" refers to cultural and ideological views promoting the primacy or superiority of scientific methods over all other tools of inquiry.  Some scientists embrace scientistic views, in part because scientism provides a much-needed counterbalance to aggressive anti-science attitudes that are prevalent on both ends of the political spectrum and among some religious institutions. However, other scientists are concerned about propping up scientism as a bulwark against ideological science-bashing because it smacks of throwing out the baby with the bathwater. Science is characterized by healthy skepticism, the dismantling of dogmatic views and a continuous process of introspection and self-criticism. Infusing science with ideological stances concerning the primacy of the scientific method could undermine the power of science which is rooted in its willingness to oppose ideological posturing.

As a scientist who investigates signaling mechanisms and the metabolic activity of stem cells, I am concerned about the rise of some movements that fall under the "scientism" umbrella, because they have the possibility to impede scientific discovery. Scientific progress relies on recognizing the limitations and flaws in existing scientific concepts and refuting scientific views that cannot be adequately explained by newer scientific observations. An exaggerated confidence in the validity of scientific findings could stifle such refutations. For example, some of the most widely cited scientific papers in the field of stem cell biology cannot be replicated, but they have had an enormous detrimental impact on the science and medicine, in part because of an exaggerated faith in the validity of some initial experiments.


I first began studying the use of stem and progenitor cells to enhance cardiovascular repair and regeneration over a decade ago. At that time, many of my colleagues and I were excited about a recent paper published by a group of scientists based at New York Medical College in the high-profile scientific journal Nature in 2001. The paper suggested that injected adult bone marrow stem cells could be successfully converted into functional heart cells and recover heart function after a heart attack by generating new heart tissue. The usage of adult regenerative cells was a very attractive option because it would allow patients to be treated with their own cells and could circumvent the ethical and political controversies associated with embryonic stem cells. This animal study gained even more traction when supportive experimental and human studies were published by other scientists. Then a German research group under the direction of the cardiologist Bodo Strauer published a paper in 2002 which showed that not only could adult human bone marrow cells be safely injected into heart attack patients but that these adult cells  even appeared to improve  heart function.

The stir caused by these discoveries was not just confined to scientists. The findings were widely reported in the media and I recall numerous discussions with physicians who claimed that cardiovascular disease would soon be a problem of the past, because patients would receive routine bone marrow injections after heart attacks. One colleague even advised me to reconsider my career choices since the usage of bone marrow cells could address most if not all issues in cardiovascular regeneration.

This excitement was somewhat dampened when a refutation of the 2001 Nature paper was published in 2004, also in the journal Nature. A collaborative effort of two US-based stem cell research groups was not able to replicate the findings of the 2001 paper. The scientists were unable to find any significant conversion of adult bone marrow cells into functional heart cells. However, many physicians, scientists and patients had already adopted an unshakable belief in the validity of the bone marrow cell treatments after heart attacks. Hundreds of heart attack patients were being enrolled in clinical trials involving the injection of bone marrow cells. Clinics in Thailand or Mexico began offering bone marrow injections to heart patients from all around the world– for a hefty price, both in terms of monetary payments and in terms of safety because they exposed patients to the risks of invasive injections of bone marrow cells into their hearts.

Despite the fact that the initial clinical studies with small numbers of enrolled patients had shown a beneficial effect of bone marrow cell injections, subsequent trials could not confirm these early successes. It became apparent that even if bone marrow cell injections did exert a therapeutic benefit in heart attack patients, these benefits were rather modest. Scientists increasingly realized that the observed benefits may have been causally unrelated to the small fraction of stem cells contained within the bone marrow. Instead of bone marrow stem cells becoming functional heart cells, some bone marrow cells may have merely released protective proteins which could explain the slight improvement in heart function, without necessarily generating new heart tissue. One of the largest bone marrow cell treatment trials for heart attack patients to date was just recently published in 2013 and showed no evidence of improved heart function following the cell injections.  

In hindsight, many of us have wondered why we were not more skeptical of the initial findings. When compared to embryonic stem cells, adult bone marrow stem cells have a very limited ability to differentiate into cell types other than those typically found in the bone marrow. Furthermore, the clinical studies which reported successful treatment of heart attack patients used unpurified bone marrow cells from the patients. The stem cell content of such unpurified preparations is roughly 1% or less, which means that 99% of the injected bone marrow cells were NOT stem cells. For the tiny fraction of bona fide stem cells in the bone marrow to convert into sufficient numbers of beating heart cells and even create new functional heart tissue would have been akin to a miracle.

Critical thinking and healthy skepticism, the scientific peer review processor and even common sense should have alerted us to the problems associated with these claims, but they all failed. Perhaps scientists, physicians and patients were so excited by the prospect of creating new heart tissue that they suspended much-needed skepticism. Exaggerated confidence in the validity of the scientific data published in highly regarded scientific journals may have played an important role. Unintentional cognitive biases of scientists who conducted the experiments and a disregard for alternative explanations could have also contributed to the propagation of ideas that would withstand subsequent testing. Scientific misconduct may also play a role. For example, the cardiologist who conducted the first clinical studies with bone marrow cell infusions in heart attack patients was investigated by his university for scientific misconduct because a review of his work had identified massive errors.

This is just one example to illustrate problems associated with an exaggerated confidence in the validity of scientific findings, a kind of confidence which scientism engenders. Such examples are by no means restricted to stem cell biology. A recent analysis of scientific reproducibility in cancer research claimed that only 11% of published cancer biology papers could be independently validated, and other areas of scientific research may be similarly afflicted by the problem of irreproducibility of published, peer-reviewed scientific papers.
Increasing numbers of scientists are recognizing that current approaches to interpreting and publishing scientific data are severely flawed. Exaggerated confidence in the validity of scientific findings is frequently misplaced and claims that scientific results represent objective truths need to be re-evaluated particularly when a high percentage of experimental results cannot be replicated by fellow scientists. In this particular context, the views of scientists who are trying to learn lessons from the failures of the scientific peer review process are not so different from those of "scientism" critics. However, many scientists, myself included, remain reluctant to use the expression "scientism".  

Rosenberg illustrates the problems associated with the word "scientism". Since "scientism" is often used as an epithet, invoking "scientism" may impede constructive discussions about the appropriateness of applying scientific methods. While a question such as "Can issues of morality be answered by scientific experiments?" may be important, introducing the term "scientism" with all its baggage distracts from addressing the question in a rational manner.
The other major issue associated with the term "scientism" is its vagueness. It is difficult to discuss "scientism" if it encompasses a broad range of distinct concepts such as the notion that science has to remain within certain boundaries as well as a criticism of overweening confidence in the validity of scientific findings. I can easily identify with asking for a realistic reappraisal of whether or not scientific results obtained by one laboratory constitute an objective, scientific truth but I am opposed to creating boundary lines that forbid certain forms of scientific inquiry because it might infringe on the domains of the humanities. Instead of the diffuse expression "scientism", I prefer the term "science mystique" to criticize the exaggerated, near-mythical confidence in the infallibility of scientific results. 

Rosenberg's view that the expression "scientism" and also the culture of "scientism" should be embraced received a big boost when the scientist Steven Pinker published his polemic essay "Science Is Not Your Enemy: An impassioned plea to neglected novelists, embattled professors, and tenure-less historians". Like Rosenberg, Pinker wants to rehabilitate the expression "scientism" and use it to indicate a positive, science-affirming worldview. Unfortunately, instead of engaging in a constructive dialogue about the culture of "scientism", Pinker reveals his condescending attitude towards the humanities throughout the essay. His notion of respect for the humanities consists of pointing out how much better off classical philosophers might have been if they had been aware of modern neuroscience. 

But Pinker does not comment on the converse proposition: Would scientists be better off if they knew more about philosophy? Pinker goes on to portray scientists as dynamic forward thinkers, while humanities scholars are supposedly weighed down by their intellectual inertia:

"Several university presidents and provosts have lamented to me that when a scientist comes into their office, it's to announce some exciting new research opportunity and demand the resources to pursue it. When a humanities scholar drops by, it's to plead for respect for the way things have always been done."

Pinker glosses over the reproducibility issues in science and reaffirms his faith in the current system of scientific peer review without commenting on the limitations of scientific peer review:

"Scientism, in this good sense, is not the belief that members of the occupational guild called "science" are particularly wise or noble. On the contrary, the defining practices of science, including open debate, peer review, and double-blind methods, are explicitly designed to circumvent the errors and sins to which scientists, being human, are vulnerable."

The philosopher and scientist Massimo Pigliucci wrote an excellent response to Steven Pinker, discussing the flaws inherent in Pinker's polemic and explaining why promoting a culture of scientism or a "science mystique" is not in the interest of science. I also agree with the physicist Sean Carroll who reminds us that we should get rid of the term "scientism"; not because he wants to get rid of a critical evaluation of science, but because he thinks this poorly defined term is not very helpful.

Whether or not we use the word "scientism", it is apparent that the debates between the critics and defenders of the culture of "scientism" are here to stay. It is unlikely that rehabilitating the unhelpful word "scientism" or polemical stances towards the humanities will contribute to this debate in a meaningful manner. The challenge for scientists and non-scientists is to embrace and address the legitimate criticisms of science without promoting the agenda of irrational anti-science bashing. 



Note: An earlier version of this article was first published on the 3Quarksdaily blog