Currently one of the most common disease-causing bacterium in the world, Acinetobacter baumannii, for sure, is a nasty bug — an emerging nosocomial (hospital-associated) pathogen, being increasingly observed in serious conditions requiring intensive care (including ventilator-associated pneumonia, sepsis, meningitis, wound infection and urinary tract infection). Unfortunately for patients, particularly immune-suppressed ones, this bug is now known to be extensively drug resistant (XDR; resistant to most antibiotics including carbapenems, with the exception of two drugs of last resort, colistin and tigecycline), with a smaller proportion resistant to even these two (known as pan-drug resistant, PDR, which are therefore virtually untreatable with the current crop of FDA-approved medications).
Having been born and growing up in India, the land of the sacred cow, I am no stranger to this domesticated, quadrupedal ungulate of the subfamily Bovinae, genus Bos. It’s difficult not to have respect for an animal whose scientific name already proclaims it to be the boss, and I am culturally well-conditioned (‘well-done’, one might say) to accord an immediate reverence to this multi-faceted (not to mention, delectable) animal. After all, Gau-mata, or Cow the Mother, is an enduring socio-religious meme in India, stemming from simpler, more agrarian times — possibly a testament to the species’ intimate association with human history ever since it was domesticated about 10,500 years ago (archaeological and genetic evidence suggests that cows in Southeast Asia, Bos indicus, a different lineage from cows in Europe, were domesticated about 7000 years ago in the Harappan civilization).
Many of you know that I have been extremely concerned about the continuing deleterious effect of the sequestration on Federally-funded Biomedical Research in the United States. I have tried to highlight how Science funding and the future prosperity of this nation have been put on the line via drastic spending cuts. A piece of heartening news came through last month in which a proposed Senate Bill sought to boost the NIH budget. I wrote at that time: “I hope the American political leadership wakes up soon to the loss of intellectual capital they are incurring due to the sequester.”
Fat chance of that, it seems, as time passes on. Today, in Huffington Post, noted political reporter Sam Stein wrote a long essay in which he exposed the ugly effects of the sequester already weighing heavy on scientific research in the US. He has interviewed real researchers in different universities whose invaluable research work is in clear and present danger of being shut down. As the essay goes on to say:
Over the past few months, The Huffington Post has set out to understand the breadth of these cuts. The roughly two dozen scientists and academic officials interviewed were naturally distraught over the impact sequestration is having on their own work and institutions. The nature of the business is to assume you’re on the cusp of a major breakthrough.
But beyond that, they shuddered at the damage being done to the field at large. Yes, they conceded, the NIH’s budget remains large at $29 billion. But without more investment, the nation’s role as an international leader in scientific research is at risk. Moreover, the money being cut now will have lasting damage, both economic and medical, as cures to diseases are left undiscovered and treatments left unearthed.
A lot of people were hoping for the benevolence of for-profit private parties to keep the research efforts afloat. But as Stein points out, it is not a viable proposition. The times have been so desperate that several scientists are actively considering the idea of setting up shop in other, more conducive countries where they can carry on their work unimpeded.
The saddest and most dire message that Stein has portrayed? This:
… (At the University of Virginia) Patrick Grant, an Associate Professor of Biochemistry and Molecular Genetics, said his lab was down to two researchers from a peak of a dozen. His federal funding ran out last year.
“I wouldn’t advise people to go into science,” he said. “I think it’s a tough career to follow. It’s not the career that I thought it was, or that it was for me a couple of years ago.”
Do go read the HuffPo piece. It is disheartening and reeks of despair, but it needs to be read and the message spread. They also have a project to record the experiences of real people affected by the sequester, and are asking for input from the reading public.
The clinical entity of Chronic Fatigue Syndrome1 (CFS) has so long eluded explanation. Patients of CFS complain of extreme and prolonged fatigue that is disproportionate to their physical and mental activity, and is not alleviated by any amount of rest. The condition may well last for more than 6 months at a time, and may be accompanied by a variety of other symptoms, such as pain in the muscles and/or joints without swelling, memory impairment, significant lapse of concentration, headaches, painful lymph nodes in the neck or armpit, and so forth. Physicians currently employ the 1994 case definition in which persistent (>6 months) fatigue is to be present along with at least 4 of 8 known associated symptoms, for the condition to qualify as CFS; if these criteria aren’t fully met, the condition is referred to as ‘idiopathic’ (without known cause) fatigue. Management of both conditions are practically identical.
For patients of CFS, the bouts can be debilitating, perhaps made worse by the fact that scientific research has not yet identified the root cause of the condition, and can, therefore, offer no solution beyond symptomatic relief.
Many theories as to the cause of CFS abound, such as:
- Direct effect of viral infections;
- Specific induction of host immunity as a result of invasion by some pathogenic microbe, et cetera.
- Non-specific activation of the patients’ immune systems, a subset of which may be expressed as allergies;
- Direct involvement of the central nervous system, resulting in abnormal, neurally-mediated lowering of blood pressure, which may cause light-headedness and compensatory tachycardia (i.e. increase in heart rate);
- Indirect action of the brain, via the HPA (‘Hypothalamic-Pituitary-Adrenal’) axis, which may disturb the release of various stress-associated hormones.
In addition, symptoms in CFS may resemble those seen in many physiological, neurological, as well as psychological illnesses.
This, understandably, poses a diagnostic challenge; the problem is that all these phenomena in the human body are processed through physiological pathways that are highly inter-related, a fact which underscores the difficulty in arriving at a single factor responsible for CFS. Current thinking is, therefore, that CFS may be multi-factorial, i.e. triggered by a combination of an unknown number of factors.
In part, this is also the reason why there is no diagnostic test or ‘biomarker’ (an observable phenomenon that can be specifically attributed to the condition) for CFS, and why the diagnosis must be exclusionary, via a process of elimination of other possible conditions that may explain the symptoms. What makes diagnosis even more difficult – not to mention, controversial – is that the number, types and even severity of these symptoms are highly variable amongst patients, and the condition periodically goes into remission and relapses.
When symptoms arise, management – in absence of a cure – focuses on treating primarily those symptoms that disrupt life and activities most, such as pain, lack of sleep, memory problems, depression, anxiety, et cetera. Long term care involves specially-developed activity programs, behavioral therapy and other interventions that aim to mitigate the physiological and psychological effects of this chronic illness.
Given that many CFS symptoms mimic those of certain immune dysfunctions involving unregulated inflammation, a lot of research has focused on understanding the inflammatory pathophysiology of CFS patients. One recent study from the Stanford University medical school, published in the Journal of Translational Medicine2, investigated the role of cytokines in this condition. Cytokines are a group of small protein molecules produced and released by various types of cells in the body, including cells which comprise the immune system. Cytokines take part in cell-to-cell signaling; released by one type of cells, cytokines affect other cells, either in their immediate environment or elsewhere in the body, by binding to receptor molecules present on the surface of these cells. These receptors recognize specific cytokines, and the binding at the cell surface initiates cascades of sub-cellular (inside the cell) biochemical reactions which lead to a specific effect. For example, some cytokines are active in regulation of developmental processes3 during the implantation of the embryo and maintenance of pregnancy. Again, ‘pro-inflammatory’ cytokines, released by certain leukocytes of the innate immune system, can recruit other leukocytes and bring them to the site of infection or injury, in order to mediate various effects4.
The Stanford group, led by Elizabeth Stringer, hypothesized that the daily variability of the levels of various cytokines in the serum may correlate with the observed variations in the severity of CFS symptoms. In a pilot study they had monitored the daily levels of 51 different cytokines in 3 women with fibromyalgia (another chronic painful condition) and CFS, and discovered that one adipokine (cytokine released by fat cells, ‘adipocytes’), called Leptin, stood out. Leptin, which regulates appetite, metabolism and behavior5, and has profound inflammatory effects, as well as a protective role in mucosal immunity6, was found to correlate significantly with the self-reported fatigue severity.
In the current study, participants (CFS patients and healthy controls, all female) were chosen carefully to account for or exclude other existing conditions that may confound (i.e. not allow proper interpretation of) the observations. Twice a day, 20 participants answered questions about the severity of fatigue, muscle/joint pain and sleep quality that they experienced during the study period, which included blood draws for 25 consecutive days. In the CFS patients, serum Leptin levels correlated strongly with daily levels of fatigue; although Leptin levels were associated with a plethora of pro-inflammatory cytokines, no other direct correlation was found, indicating that Leptin may be the central player in the CFS-associated inflammatory process mediated by a network of cytokines. None of these associations were observed in healthy controls. Leptin levels were predictive of daily fatigue levels in women with CFS, and using cytokine predictors, the authors were able to distinguish between high fatigue and low fatigue days with 78% accuracy.
Illustrative image composite made from parts of Fig. 2 & 3 of Stringer et al. (Ref. 2)
Interestingly, absolute Leptin levels, as well as the range of daily fluctuations, were not abnormal in CFS patients, which suggests that Leptin alone may not be responsible for causing the inflammation in CFS. As the authors indicate, larger and more detailed studies are necessary to explore a causal role of Leptin and/or its cytokine network in driving CFS severity, and uncover hitherto elusive diagnostic biomarker(s) and therapeutic targets.
- CDC information website on Chronic Fatigue Syndrome.
- Stringer, EA, et al. Journal of Translational Medicine 2013, 11:93; doi:10.1186/1479-5876-11-93.
- Saito, S. Journal of Reproductive Immunology 2001, 52:15-33; PMID: 11600175
- Whitney, NP, et al. Journal of Neurochemistry 2009, 108:1343-59; PMCID: 2707502.
- Gautron L, Elmquist JK. Journal of Clinical Investigation 2011, 121:2087-93; PMCID: 3104762.
- Mackey-Lawrence NM, Petri WA Jr. Mucosal Immunology 2012, 5:472-9; PMCID: 3425733.
Another post after a brief hiatus because of work-related pressure. I’m sure nobody missed me, though. [Sniff!] Well, the pressure’s still on, but let’s say I was inspired to write this post by a chance occurrence, a question asked by a physician friend of mine. An accomplished and established surgeon in India, he is considering various possibilities and options, having recently learnt that his young son is desirous of coming to the US to pursue a career in biological research.
He asked me: how is life as a scientist in biological sciences or genetics etc? Very tough, boring life that leaves you no time? Or fulfilling and all that?
You could hear from a mile the sound of my mental machinery creaking and groaning and whirring. Naturally, I’d be delighted to welcome a budding scientist to the fold, but I also wanted to provide my friend with as true and complete a picture as I possibly could.
Shying away from the usual spiel on the quality of scientific research done at noted US universities and institutions of renown (my friend is aware of all that), I focused on the core of his question – the life as a scientist. What exactly is life as a scientist? Is it, like, life in all its glories as presented with a sonorous narration in a Discovery Channel documentary, or is it more of life, as in “Dude! Get a life!“? Does life of the latter kind come to the scientists in the manner of the proverbial Cheshire Cat of Alice in Wonderland, appearing suddenly with a mischievous grin and then vanishing slowly and unattainably until nothing but the grin is left, and then –Poof!– that is gone, too?
Pushing aside these philosophical (and ultimately useless) cogitations, I set to writing him a reply. Here’s a part of what I wrote:
There are several angles to this question, all of which – in the final synthesis – boil down to the matter of temperament.
First, as with every other profession, the rewards of a career in science are not consistent – and indeed, may even be considered insignificant under certain lights. There will be work-related irritation, frustration, aggravation and denial, some of which may even spill into one’s personal life if one cannot carefully separate the personal from the professional.
Secondly, even if one is passionate about the work to begin with, it would be difficult to sustain that same level of passion through the years. However, professional scientists can usually keep their interest aflame by diversifying into multiple research questions and/or refocusing their priorities.
Thirdly, life as a young researcher may be impecunious. One simply doesn’t become a scientist if one’s goal in life is to become a millionaire outright. I admit that in rare moments of self-doubt, I have thought about young adult basket-ball players and other athletes (especially the talented Jeremy Lin in recent times), who seem to command an exorbitant amount of money in exchange for their prowess and agility, whereas we, the science researchers in the same country, despite contributing day in and day out towards the betterment and progress of humanity, are doomed to live in relative penury.
To the discerning mind, however, the rewards are manifold, even though they may not readily translate to wads of greenbacks or pots of gold. Fulfillment is often a matter of perception, after all.
To many scientists, there is an element of thrill-seeking in what they do. Understanding a problem, analyzing it, putting forth a rational hypothesis and then performing rigorous experiments to test its validity, anticipation of the results, the joy that one feels when the observed data vindicate one’s hypothesis or the sobering effect when they don’t and push the scientist back to the drawing board – there is a lot of drama, excitement, emotional upheavals therein that can be quite enjoyable overall.
There are many scientists who find the challenge of an intractable problem very attractive and engrossing. To them, the systematic attempts at puzzle-solving, especially if the problem happens to be multi-layered, are themselves fulfilling; if they do manage to unravel the mystery, it can be very rewarding, sometimes even lucrative.
Many scientists, especially those working upon problems of immediate consequences to, say, the health and well-being of living beings, including their fellow humans, are often fortunate enough to observe the benefits of their work in relatively real-time. It can be incredibly fulfilling as well as humbling. On the other hand, even those scientists, whose professional endeavors are distally related to health, and more proximally, to basic and/or applied problems in biology, have the satisfaction of knowing that their work connects them to a larger continuum, because modern living organisms, having evolved from same or similar ancestors at different levels, often share a surprising degree of relatedness.
In addition, the sharing and communication of one’s research outcomes within the scientific community and without is no less gratifying. Having one’s work accepted for publication in a scientific journal of repute can be quite life-affirming. Recognition and renown for one’s work, when they eventually arrive, ain’t too shabby either. Accomplished scientists often wish to spread or share their experience and life’s journey, thereby hoping to influence younger minds and instilling the spirit of enquiry.
Many of these intellectual rewards or fulfillment that I mentioned above may initially seem too esoteric and far-fetched, but they exist – they require a fair bit of hard work, but they are not unattainable goals. This is important to understand, especially for a new graduate student.
The entire period of graduate studies (leading to a PhD degree) is – as I see it – essentially a period of training. One learns not only technical skills of various sorts, one also learns how to integrate one’s knowledge in one’s work. One grasps the value of perspectives – how to view one’s own work in the context of a larger picture. One picks up valuable people skills, skills of interaction, communication, presentation and the art of networking, as well as how to work cohesively in a group setting and independently at the same time. One assimilates the ways and means of effective time management, and the benefits thereof. Most importantly, under competent mentorship, one gets a thorough grounding in the scientific method.
To me, this is the most crucial aspect of training as, and being, a scientist. A scientist is much more than what one does; it refers to what one is. It is possible to integrate in one’s life, or one’s attitude towards life, the basic tenets of the scientific method, objectivity, reliance on empirical evidence, a rational and skeptical outlook, and an ability to question, observe and analyze, to varying degrees. People who successfully do that are also able to effortlessly transition from their workbench to life outside and back.
As far as having ‘time’ to do other things is concerned, I have found that it largely depends on the individual. It is indeed possible to manage one’s time effectively, so as to be able to pursue other interests. Examples abound. Just to randomly name a few instances, Paul Z Myers is an accomplished and popular biology professor, with a tremendously celebrated blog. Stephen Curry is a noted structural biologist who still finds time to blog and write for the Guardian. Russian composer Alexander Borodin was a life-long and distinguished researcher in organic chemistry. Jennifer Rohn is a working cell biologist who is a champion for the genre of “Lab-Lit”, is an author, as well as finds time for political advocacy for science funding in the UK. Canadian physicist Diane Nalini de Kerckhove combines a career as a successful scientist with her job as a professional jazz singer. As I said right at the beginning, it is a matter of temperament. If one loves what one does, one does it well – no matter what – and garners fulfillment from it.
What do you think, gentle readers? Please throw in your comments, suggestions, bouquets and brickbats in the comment section.
This, most certainly, is not the forum where I want to discuss politics. Yet, inevitably, politics spilleth over into the sphere of science and scientific research in the US. Last night, the Republicans gained control of the House of Representatives, and increased their numbers in the Senate. Ever since Barack Obama became the President of the US eighteen months back, the only agendum of the extremely partisan Congressional Republicans has been to block every move that he and his office have made. Today, an alarming report in the New York Times states that money for scientific research may be scarce with a Republican-led House.