Superbugs, Bugging news and Buggers galore

Events in our life are indeed connected in weird ways.... as one leads to another.... it is almost like a chain reaction which extends far beyond the realm of one's imagination.

As a result of a discussion with a friend over a cup of coffee, i decided to write a blog about the "superbug" controversy sometime ago. Reading this blog, I was invited to extend the small blog into aan article for a students' magazine at IISc which is my home for now... And this collaboration resulted in the following article... written by A and me...

And thats how a lot of stories begin.... over a cup of coffee... :-)

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It all started with dramatic news flashes such as “Superbug from India?”, and “bacteria spreading from India to UK?” and by the next morning, the prominent newspapers had their theories up on the first page. Finally, it seemed that at least one piece of the daily quota of “breaking news” was indeed interesting (and alarming) and would get some rightly-deserved focus over the next week. However, it was only a matter of time that yet another “breaking news” came along and the primary issue was reduced to rubble and its true significance chucked off to the bin!!

For someone who has not been following the news regularly, the recent reports will only lead to complete and utter cluelessness due to the mind numbing rhetoric. It thus makes sense to first address the question of what the furore was all about. Briefly, the reputed journal LANCET had published a collaborative work, involving several groups from India, Pakistan the UK, which claimed that a bacterial gene that confers resistance to practically all the β-lactam antibiotics was widespread across the subcontinent. Furthermore, riding on carriers and patients, this “superbug” was traveling to other continents. Since most antibiotics, including the frontline carbapenems were ineffective against the bacteria that harbored this gene, it seemed to be an unstoppable medical crisis. This resistance conferring gene is mainly carried on plasmids (small, autonomous DNA molecules which can “jump” from one bacterial species to another) and was called the New Delhi β-lactamase (NDM-1).

While a fact based, dispassionate analysis of what ensued was necessary to gain some perspective on the matter, and it was exactly the component that was missing in the entire reportage! The media and the government were quick to denounce the findings of the report. It was labeled unscientific and unacceptable in addition to being the handiwork of a pharmaceutical lobby! The panel discussions on TV had doctors, bureaucrats and politicians, but rarely a microbiologist or an epidemiologis. The consensus seemed to be that the entire work smelt of a conspiracy. A treacherous plot by the west to destroy our burgeoning “medical tourism industry”! What is Medical Tourism? Well, a large numbers of Westerners come to India every year for various medical treatments ranging from cosmetic surgery to dental treatments as a cheaper alternative destination. This was also encouraged at the national level as an effective strategy to cut down on the expenses for the NHS (in UK) and other such health care providers in the west. Now, if these “tourists” could be dissuaded from travel by the fear of infection, then the medical tourism industry and consequently the influx of foreign exchange would be hit. This report was thus portrayed as an attempt by the Occident to paint a dirty and disease-spreading image of India, the rising economic power. Hence, it was implied, that it is the duty of every patriotic Indian to protest to this “national insult” towards restoring the “India shining” image.

Here, we try to present the issue as we see it with our limited perspectives, based on reading the LANCET paper and couple of other reviews and some of the more rational and balanced news reports. As researchers who have a clearer understanding of field, it is horrifying specter to see how the issue has been completely blown out of proportion and the crux of the research has been conveniently sidelined.

For the uninitiated, it must be stated that the development of antibiotic resistance in bacteria is not a new phenomenon. The development of resistance to conventional antibiotics in bacteria from clinical and non-clinical settings is not a new phenomenon and has been a potential problem for a long time. Since the bacterial life spans are short the development of resistance in bacteria was always well anticipated and this never ending arms race with the humans developing newer and more potent antibiotics and the bacteria developing newer means of resistance is the fundamental feature of biological evolution. It has been known for 50 years now, and academic and industrial research has always been on the lookout for newer antibiotics. A decade ago, there was a surge of concern about the Meticillin resistant S. aureus (MRSA), a gram-positive bacterium notorious for causing nosocomial/hospital acquired infections. Today, there is a lot of worry about how to tackle the several multi-drug-resistant gram-negative bacteria that pose the greatest threat to public health. Resistance genes spreading across different species either by piggybacking on plasmids (as in the case of NDM-1) or by horizontal gene transfer are increasingly considered dangerous as we run out of potent antibiotics. Human air travel and migration are at an all-time high and are naturally contributing to the spread of resistant bacteria.

With this background, it might make you wonder like we did about what the hue and cry in the media was all about?

Firstly, NDM-1 - a “bad” gene named after the nation’s capital is being considered a national insult! The media was whipping up a frenzy by capitalizing on this as an issue of national pride. But, naming a new organism or enzyme after its source, site-of-first-identification or discoverer is part of scientific convention, specifically, with regard to this particular group of enzymes! More than50 β-lactamases have been identified between 2000 and 2006 and thus it is not surprising, as one review says, that “β-lactamase nomenclature has been nothing if not creative”. And, anyways, we have so many other examples all around. The banyan tree is named as Ficus benghalenesis. One of the most virulent of pathogens, the causative agent for TB, is called Mycobacterium tuberculosis Beijing. A new frog species found in Sahyadari (Western Ghats) has been named Nasikabatrachus sahyadrensis. In 1961, a dinosaur was named as Barapasaurus tagorei as its discovery coincided with the birth centenary of Tagore. There are other bacterial pathogens christened as Clostridium botulinum strain Alaska and Anaplasma centrale strain Israel. Further, the restriction enzymes such as EcoRI and BamHI, which are the scissors of molecular biology, have long been named after their source organism. Does anyone recall any protest from Beijing when the TB causing pathogenic train was named after it? Did we shout when we had a cute little frog and the majestic tree named after our lands? No, we probably clung to that reflected glory just as we did when Prof. Venki Ramakrishnan got the Nobel (and as a token of gratitude, jammed his e-mail inbox!). Resistant bacteria arise all over the world, and no matter how much we consider ourselves to be superior to the rest of the world, we cannot deny the fact that India is still on planet Earth. So, why is there a problem in accepting that an enzyme has been named after it was first identified in a Swedish patient who had been treated at a hospital in New Delhi, and probably acquired the infection there?

Frankly, the hyper-emotive response shows how pathetic we are with respect to “science as a way of life”. Also, it is possible that by projecting it as an “identity crisis” it becomes a case of “India versus non-Indians” and then the main issue can be deliberately and conveniently sidelined. In fact, it is not too difficult to counter-postulate that, those who are “protesting” have vested interests in the medical tourism business. The recent “paid news” scandals have only further exposed such forms of corruption.

The important thing however which deserves all the attention is the prevalence of such deadly antibiotic resistant strains in our hospitals and that issue has been completely sidelined. This study shows that such NDM-1 harboring bacteria are present in patients in all parts of the country, not only Haryana and Chennai and also in Pakistan (most likely, they’ll spread after the recent floods, and cross the LoC undetected). Additionally, this is not the first or only study of NDM-1 in the country. In March 2010, another paper showed that 22 cases of NDM-1 positive patients were identified in 3 months in a single Mumbai hospital. The LANCET article, however, has provided the spotlight to the subject. It also says that most of the patients have “community acquired urinary tract infections, pneumonia and blood stream infections”. Is India that spotlessly clean and hygienic? Are our sanitation and waste disposal systems the most efficient? A lack of statistical analysis is a drawback of this paper. But, if indeed 17 out of 37 NDM-1 positive UK patients (46%) had been recently admitted to hospitals in India, isn’t it possible that these could be nosocomial/hospital-acquired infections? With this of course, one can just pause and wonder that if the hi-fi hospitals catering to foreign patients are a source of these infections, then how bad is it in the real India of the aam admi? Don’t we have high incidences of so many infections – TB, HIV, diarrhea, malaria, and dengue? We all know that our health system is appalling. And while bacteria don’t give a damn to caste and class, many pathogens certainly thrive in unhealthy conditions and pass on their plasmids and resistant genes such as NDM-1.

Questions have been raised about the role of funding agencies. The paper categorically states, as we all do when we write our own, that the funders had no role in study design, etc etc. Is there any strong data to doubt this? Then, we have to doubt the ways we ourselves write our manuscripts. And in the “conflicts of interest”, the authors are honest about their travel grants and their interaction with the industry. All over the world, including in India, academics are increasingly becoming part of the industries. Wouldn’t denouncing the LANCET authors result in slandering almost the entire scientific community? And misreporting can go to such ridiculous levels That the National newspapers consistently referred to the “Welcome trust” as a pharmaceutical giant till the trust finally came out with a clarification. The fact of the matter is that the media is trying to blow up a story without an accurate understanding and this is only diverting the public focus from the more important issue of the development of resistance in microbes to the other peripheral issues of private funding, national pride etc etc.

Despite the baseless furore surrounding this whole episode, it is important that this issue is not relegated to the back burners in a week. The situation is critical especially in India since resistance to extended-spectrum beta-lactamases (ESBL) drugs like the third-generation Cephalosporins is between 60 to 70% on average, compared to the less than 15% seen in the developed countries. Thus, a more common way of treating the severe form of ESBL infections in India is through the use of Carbepenem - which becomes the drug of choice as it has (or rather had!) the lowest resistance and the broadest action against gram negative infections. The emergence of resistance against Carbepenem is bad news undoubtedly but for the patients and physicians in India who now have to look for new antibiotics but this is a self created nuisance too. The spread of resistance is not surprising keeping in view the fact that very potent drugs like Carbepenem are overused by the physicians. The easy over-the counter availability of these drugs also makes the problem more acute as patients end up self medicating in sub-lethal doses (For the bacteria of course), thus, leading to the acquisition of resistance. These are problems which have been known to the medical community for a very long time but have not been addressed by the government, the media or the Public. It is easy for us to blame the whole world for our woes. And it is also easy to malign the lead author, a Ph.D student at the University of Madras as a “traitor”. We can also conveniently ignore these scientific data till it is too late to do anything. For our mind however, if the work is a true whistle-blower, then as the national emblem says, “truth alone triumphs” and it shall in this case too. Ignoring this problem only takes us closer to the inconvenient truth of the origin antibiotic resistant, untreated diseases and a resultant death for millions of Indians. Let us hope that the people, the media, the politicians and the health professions wake up and seriously address this not-so-distant crisis.

Publish or perish - a lurking peril !!!

I am a graduate student who has just submitted by doctoral thesis in Molecular Oncology. As someone who has spent 5 years in science, I have come to understand that just like in any other field, in academics too, politics has a big role to play. This is a fact that I have come to accept with great disappointment because one of the primary reasons for my wanting to come to academia was the absence of socio-political machinations where attitude seemed to influence more than aptitude. Research always seemed to be the field where aptitude and merit would solely determine one's success or failure. Now, that was inexperience talking! Today after 5 years in a premier research institute in India, I realize that life in academics too, is plagued with problems and is a place where social skills and contacts can make or break you!

Research in science has come to a stage where "Publish or Perish" seems to be mantra as people are now willing to resort to any means to publish their work. The quality of science has been overtaken by the desire for quantity.

Ever so often these days, one comes across leading scientists from some of the best institutions in the world resorting to fraud, deception, mis-conduct, cover ups and cook ups in their attempt to publish!!! The latest in the league of scientific fraud is of course the Harvard Professor - Mark Hauser, a well known psychologist, scientist and the author of the book "Moral minds" (the irony is inescapable eh ?). After a thorough review of his work by an internal review board at Harvard, Hauser was "found solely responsible... for eight instances of scientific misconduct." He is taking a year's "leave", and his future is uncertain. The current understanding of the nature of the misconduct is also alarming by its sheer magnitude and scale. Unfortunately, there was no official news on what exactly the misconduct was, and how much of Hauser's work is suspect. According to Harvard, only three publications were affected: a 2002 paper in Cognition, which has been retracted; a 2007 paper which has been "corrected" and another 2007 Science paper, which is still under discussion. Cognition editor Gerry Altmann with access to some of the Harvard internal investigation, concludes that Hauser simply invented some of the crucial data in the retracted 2002 paper. Basically, some monkeys were supposed to have been tested on two conditions, X and Y, and their responses were videotaped. The difference in the monkey's behavior between the two conditions was the scientifically interesting outcome. The videos of the experiment however showed them being tested only on condition X. There was no video evidence that condition Y was even tested. The "data" from condition Y, and by extension the differences, were, apparently, simply made up. If this is true, it is, in Altmann's words, "the worst form of academic misconduct." So it seems that either Hauser never tested the monkeys on condition B at all, and just made up the data, or he did test them, saw that they weren't behaving the "right" way, deleted the videos... and just made up the data. Either way it amounts to scientific fraud!!!

Now this is not an isolated incident. Every couple of years there are such major instances of grave scientific misconduct which are caught in action but there are probably also many more which are never discovered. All this is of course happening in the developed countries where scientific expenditure and the quality of infrastructure are several fold higher than in the developing countries like India.... If researchers in the world's top academic establishment like Harvard are culpable to such fraud and misconduct, it really makes me wonder if the entire academic system is rotting from inside ?

The problems plaguing science in developing countries like India are many and of a very different nature. A large body of the scientific work here is peripheral in nature aiming to address some of the more mundane problems in science. The fundamentals are still largely being ignored. The focus in these countries is on the most efficient utilization of the public money towards research. But what determines the most efficient utilization? Publications in peer-reviewed journals? With this aim, government agencies and the authorities use "publications" as "the" criteria to dispense funds. Thus, a scientist who intends to be financially competent for carrying out experiments is under immense pressure to maximize his publications. While quality of the publication (as is roughly inferred from the impact factor of the journal) is a criteria, the number of publications does seem to carry more weight with the funding agencies. What is happening thus is a great urgency to publish whatever results that can be put together in a reasonable period of time. The problems addressed are also extensions of previous work and not really fundamental in nature because the risk incurred by the investigators in these fields in much less. The chances of failure are much higher in a more fundamental, untouched problem than in the the usual run-off-the-mill stuff... To compound matters further, the government is increasingly focusing on applied science because that gives them the best excuse for spending the hard earned public money!! And so the researchers are increasingly under pressure to find new and fancy applications for their work. No matter how distant they may be from actual application, scientists are expected to provide possible utilities of their research !! And so basic research in the more fundamental problems takes a back seat as scientists strive for funds to compete internationally. Another question that comes up is about the scientific priorities of countries like India. Should they only focus on problems with an immediate application ? Is fundamental research a drain on the tax payers' money ? I was shocked to realize that a lot of people in the academic community also shared this view that we as a country should focus on application / goal driven research. I would beg to differ. As someone once rightly said, research is only of two types - applied and not yet applied. We as researchers must not work with blinders on and ignore the immense potential of tackling fundamental queries. If India aims to emerge as a superpower, it needs to develop as a knowledge producing economy, not just a services driven economy. We must encourage basic research and then try and look for applications for them in due course. As for the drain on the tax payers money, we all know that as a country plagued with bureaucracy, corruption and inefficiency, there are plenty of other sources for wastage and fundamental research is the last of these. Thus, in developing countries like India, under such competitive environments, quality is likely to be compromised. At the thresholds of being a part of the same establishment and the social structure, I wonder how to combat these problems.

The easiest alternative is of course to give more freedom to researchers and to not judge their contributions to the field in terms of their publications. Publications are after all only "an index" (and not "the index") of the work carried out and there are often long dry periods when one is addressing the more fundamental problems in science. But then giving a free reign to researchers is also not the way forward because taking off all pressure could also inspire lethargy and inefficiency.... Thus, what is seemingly required is periodic monitoring of the scientific progress by a board of competent researchers who are familiar with the nitty-gritties of academic research and are capable to evaluating the scientific work done in an unbiased and effective way.... Now, this sounds good on paper but this is exactly what could lead to the structuring of science and research into a social network.... people would then end up relying on building contacts and inter-personal contacts to navigate through these boards and commissions instead of tackling scientific problems. "You scratch my back and I scratch yours" becomes an unsaid rule!!

So what is the solution ?

Well, I, for now, am clueless !!!

The entire situation for now seems to me like a vicious cycle. Scientists need finances and infrastructure to work. Science is a field where an inspired and active mind is more productive than than an active body. And thus, the scientists need to be given a certain degree of freedom to pursue their work. At the same time, funding either comes from the government or from private companies. While private companies can give one freedom of approach and plenty of money, the stakes are high because the companies expect rapid returns from the research, thus prompting more applied and run-off-the-mill research. The government sponsored research though a tad more restrictive can also be more liberating because immediate applications are not the goal. However, the government is also under immense pressure to justify the ever increasing expenditure of the tax payers money with no clear benefits in sight !!!

At this time I can't but think of a time, not oo long ago, when researchers used to share the credit for any discovery with an open heart and where publication was a means to increase the accessibility of a finding in order to remove redundancy in research. After all every new discovery is made standing on the shoulder of giants and access to all the research happening in a field is vital for future developments. I was amazed when I read of a time in quantum physics when scientists like Carl Anderson were tempted to withdraw their article from Science (detailing the discovery of positrons) because in his mind he didn't have sufficient documentation to claim for the discovery of positrons !!

And a few decades down the line, today we are faced with a situation where top scientists are submitting cooked up results to premier journals in a desperate attempt to get published!!! The problem becomes more severe when additional theories and experiments are based on these fraudulent reports and then when young researchers start to question the veracity of every published result !!! That is indeed a sorry state of affairs in one of the fields where integrity was exemplary and the aptitude of a person was solely determinant of future success than his/her social skills.

I don't know where life takes me and I don't know what the future holds for the field of research which has charmed me since childhood, but, I do hope that these cases are only a few rotten apples who have been removed before greater damage has been inflicted. I hope that science, academics and research remain for a very long time untouched by the vile market forces that push researchers towards committing scientific fraud and misconduct. I hope that students today stop viewing science and research as just another career option but enter the field with a sense of passion and purpose. Because, for as long as I can see, science is driven forward by ingenuity and passion than by diplomacy and sycophancy.

For now, I seem to agree with Piet Hein when he talked of The Paradox of Life:

A bit beyond perception's reach
I sometimes believe I see
that Life is two locked boxes, each
containing the other's key.

Piet Hein, Danish mathematician, physicist, philosopher, writer and creator of puzzles and games.

Seeing the future in the light of the past...

I have always been fascinated by history. Somehow, viewing the present and the future in the light of the past always makes more sense and it makes one appreciate things a lot more.

Long ago I had come across this fascinating story of Coley's toxin and the development of his work into a burgeoning field of scientific study. A brief discussion with an acquaintance who is planning a presentation on immunotherapy and the recent interest in the use of bacterial DNA for cancer immunotherapy, made me revisit the article where I had first read about Coley's work. And I must say, the article by Frances Balkwill in Nature Reviews Cancer, tiled as "Tumor necrosis factor and cancer" manages to do a wonderful job at tracing the history of TNF (which is a ubiquitous factor in immunology jargon these days) and our present understanding of the same. It is a fascinating story that makes one really appreciate the hidden lessons in history and the sheer brilliance of scientific methodology. This story is also a great example for how serendipity knocks on our doors ever so often and then it is completely in our hands to make something out of the opportunity. William Coley did that and his life’s work is remembered long after he is gone as a landmark phenomenon we are still trying to understand. Such is the wonder of science and history plays a vital role in our understanding of science.

William Coley, a New York surgeon in the late 1800's was an expert surgeon and a very observant man. His fascinating work in 1890, at the start of his career laid the foundations of cancer immunotherapy and the role of bacterial toxins in the same. History says that in 1890, Coley was called in to treat a 17 year old woman who had a nagging pain in her right hand. However, in spite of Coley's expert surgical intervention, Elizabeth Dashiell died a few months later of an aggressive round cell sarcoma that disseminated at an alarming speed through out her body.

As an interesting footnote, Elizabeth Dashiell was a close friend of J D Rockefeller Jr and her death was an inspiration for the philanthropic work of his family which continues to this day in the form of the Rockefeller institute for medical research or the now Rockefeller University. It is amazing how much influence one person's death can sometimes indirectly have on history. Other than the extremely moving effects of Elizabeth's death on Rockefeller, its effect on Coley was also remarkable and this death heralded the beginning of our story. Dashiell's death had a profound effect on Coley as he immersed himself in pouring through hospital records to learn more about this rare but devastating malignancy.In his studies of the sarcoma induced deaths, Coley found an intriguing anecdote: the case of a German immigrant who 6 years previously had been dying of a large facial tumour. Fred Stein’s fate seemed to be sealed when a post-operative bacterial infection took hold but, as the fever subsided, the sarcoma has regressed. With dogged determination at this point, Coley searched the lower east side tenements for a man with a scar, and he found Stein alive and well 6 years after the surgery. Coley did not give up now. He began a line of enquiry which he pursued for is entire lifetime. Going by the case history of that one man, Coley first infected cancer patients with bacterial isolates, and then he made “Coley’s mixed toxins”, slightly less dangerous filtrates from cultures if Streptococcus pyogenes (the bacteria that causes Erysipelas) and Gram-negative endotoxin-producing Serratia marcasens. The work was controversial (not unexpected!) and few were able to reproduce the beneficial effects that Coley obtained but, if the published case histories are to be believed, Coley was able to obtain a rapid and sustained response in patients who would present a major challenge to the medical oncologists’ in the 21^st Century.

With the developments in radiotherapy and chemotherapy, the interest in Coley’s toxins waned over time but some scientists were still attempting to reproduce his results in animal models of cancer and under the principle underneath. One of the earliest studies was in 1931, when Gratia and Linz showed that bacterial extracts caused tumour necrosis in guinea pig model of Sarcoma. In 1944, another report by Shear et al, isolated lipopolysaccharides from bacterial extracts and showed them to be responsible for the tumour regression seen in a mouse model of cancer. Work by O’Malley showed that the serum from endotoxin-treated animals was also capable of causing tumour necrosis, thus leading to the conclusion that it contained a “tumour necrotizing factor”. The entire field made a leap in understanding when in 1975 Carswell et al, reported that it was a factor made by host cells in response to endotoxin and not the bacterial endotoxin itself that destroyed the tumours. Thus, the term “tumor necrosis factor” was coined to describe this activity, reportedly produced by macrophages, which led to the necrosis of both mouse and human tumours.

The next two decades marked the identification of this elusive tumour necrosis factor and it was soon realised that this protein belonged to a family of related cytotoxic proteins. By the 1990s, in addition to the TNF, the genes for the two receptors which bind to TNF were also cloned. By mid 1990s, it was becoming clear that neutralizing antibodies and soluble receptor fusion proteins targeting this cytokine TNF would be successful treatments for a range of human inflammatory diseases and the cytokine itself was under investigation as a cancer therapeutic. In good agreement with the research done for the previous 40 years, recombinant TNF induced necrosis of both syngeneic and xenografted tumours. TNF was injected locally and repeatedly and it managed to cause a regression except in the periphery where there was a risk of regrowth. The tumour necrosis caused by TNF was found to be haemorrhagic in nature with major destruction of the vascular bed which was believed to lead to increased tissue concentrations of the administered chemotherapy.

However, the course of scientific research never really runs smooth and by around 1987, intriguing reports started to emerge which demonstrated increased presence of TNF mRNA and protein in cancer biopsies and blood plasma of the patients. There were also these paradoxical observations that suggested that TNF might actually stimulate tumour growth. By the early 1990s however the entire TNF saga was one giant cauldron of confusion as reports found TNF to contribute to oncogene activation and DNA damage. Long term TNF treatment was found to result in transformation of immortalized cells. These studies thus raised the possibility that TNF might actually be a target instead of a treatment and that it might be beneficial to neutralize TNF activity in cancer patients. This was tried in Phase I and II clinical cancer trials with TNF antagonists as single agents, with some evidence of clinical activity. Even today the role of TNF antagonists in cancer prevention is not clear as some of the studies suggest a role for TNF in the promotion of early cancers, but then given our current understanding of the role of TNF in regulating innate immunity, the increased risk of infection precludes the wider use of the current TNF antagonists. However, TNF antagonists are being used for the treatment of chronic inflammatory diseases like rheumatoid arthritis and the incidence of cancer under these conditions is being monitored closely.

Our current understanding of TNF is quite a mixed bag and as the TNF timeline moves into the future a number if questions remain to be answered. How can we explain the apparent efficacy of Coley’s missed toxins and the long but anecdotal history of cancer regression associated with acute bacterial infection? Can the tumour necrosis ability of TNF be harnessed without promoting cancer or inducing a cytokine storm? Will TNF antagonists have a more important role in cancer therapy and if so then under what conditions must it be administered?

Our understanding of Coley’s work although still not completely clear has had some significant strides. We now realise that Coley’s mixed toxins must have been powerful stimulants of TLRs thereby inducing a range of inflammatory mediators, not just TNF. As a closest recent approximation to Coley’s work, bladder cancer was reportedly successfully treated with Bacillus-Calmette-Guerin. The current thinking is that probably both the BCG and the Coley’s toxins trigger an inflammatory response through the TLRs which not only stimulates macrophages to kill the tumour cells but also promotes the development of sustained and effective adaptive immunity to the tumour. This type of a response may also contribute to a more successful chemo or radiotherapy as dying tumour cells were able to cross-present the antigen to the dendritic cells in a TLR4 the efficacy of chemotherapy and radiotherapy was reduced.

Interestingly, in 1949, Coley’s daughter, Helen Colet-Nauts reviewed the case histories of the 484 patients who were treated with the toxin preparations an recorded that approximately 50% of his patients were alive 5 years after the treatment began. The toxins were given both locally and systemically for maximum effectiveness and the treatment was continued for long periods ranging from months to even years.

The history of TNF is interesting in many ways. It began with a serendipitous discovery and with the dogged determination of one man. TNF shows us how inflammation can have both positive and negative effects on cancer and how its effects will have to be controlled and manipulated to attain the desired effects (In an anthropomorphic explanation, TNF like us has a good and bad side and it depends on the situations and the context as to where which instinct dominates!). The kind of work done by Coley is certainly no longer possible in a world dictated by social rules and norms (as it is today) but despite all the legal and ethical obligations, one must remember the preliminary insight which was provided by Coley which has laid the foundations of an entire field of cancer immunotherapy. It was his preparedness to observe and analyze, his dogged determination and his ingenuity that has opened new vistas and no matter in what time scale we live, these are the qualities that propel science forward.

Its not all about the mean....

Biology as we understand today is a result of the study of averages. We attempt to study the life and fate of the individuals by studying the properties of the population. The assumption has always been that the properties of the mean is a good representation of the individual. The outliers were ignored as a minor population whose fate may not change things much. However, it is increasingly clear that the study of the outliers could largely determine more phenomena. For example, imagine treating a population of bacteria with a particular antibiotic... while most would succumb, it is the few outliers who are resistant to the drug who will determine the next outbreak. Imagine the case of chemotherapy... while resecting a tumor and chemotherapy will take care of the bulk of the tumor, the few resistant cells are sufficient to repopulate a tumor. This has increasingly shifted the focus towards measuring the properties of individual cells and not the mean or the median of the population. The conventional outlook was of course largely adopted due to technological limitations and not just as a matter of choice. The sensitivity of our imaging systems and the size of our cells make population measurements the only option left. Of late however, technology has evolved to permit the study of individual cells but the availability and the accessibility have been other limitations still preventing their widespread usage.

I have however remained a skeptic about these fancy single cell imaging systems till I came across a recent paper in the reputed journal "Cell" by Loewer et al, detailing the novel dynamics of an important tumor suppressor protein- p53, in individual cells. p53 is one of the most widely studied tumor suppressor (proteins which suppress tumor growth) which is lost in more than 50% of the cancers and is inactivated in most of the others. Since its discovery in 1979, p53 has emerged at the center stage of cancer biology as a possible therapeutic target whose restoration and reactivation in cancer cells could hold the key to successful therapy. Thus, a comprehensive understanding of this protein and its cellular functions is essential. What is presently understood is that the p53 protein, having a short half life, gets activated in cells upon conditions of cellular stress. Upon activation, p53 activates a set of downstream targets which subsequently determine cell fate. The activation of p53 was known to be mediated through post-translational modifications which alter its stability and activity.

Through imaging p53 dynamics in live cells, this paper shows that the p53 protein exhibits pulsatile dynamics in both stressed and unstressed cells spanning over a few hours. The difference under the two conditions only being in the synchorinicity and the frequency of the pulses. This however could not have been detected earlier since the occurrence of sporadic increases in the p53 protein would not have been detected by the earlier population averages.

In a very elegant way, this study causes a paradigm shift in our current understanding of p53 biology. They show that instead of being absent under stress-free conditions and active upon conditions of DNA damage, the p53 protein is actually pulsing in the cells showing a cyclical increase and decrease. The activation seen upon stress by conventional studies is only a result of the increased frequency and duration of these pulses arising out of post translational modifications of the p53 protein.


Thus, this paper by Galit Lahav from the Harvard Medical school, has managed to convince the skeptic in me that the mean, no matter how informative can still be misleading in biology. And it is thus wiser to focus on the single cell dynamics of the various proteins and signal transduction cascades towards garnering a more comprehensive understanding.

And if SJ Gould came to the conclusion that the "median isn't the message", it seems true that the mean too, is not always the message !!

Here's to a new wave in biology focusing on the individuals and not just the population...

Of bugs, superbugs and the buggers galore !!

The last week in the Indian media has been raging with reports about a new superbug, a new plasmid which confers resistance to all beta-lactam antibiotics which are of course our primary mode of treatment for gram negative bacterial infections. More than the concern for the antibiotic resistance, the media and the Indian politics is going gung-ho about the 'assumed' implications for medical tourism in India and the supposed attack on national pride!

It is appalling that the media is blowing an issue completely out of proportion without a clear understanding of the science behind it. There have been accusations to the tune of a conspiracy by the western powers to destroy the burgeoning medical tourism in India. The involvement of Wellcome trust and the Wyeth pharmaceuticals as funding sources for the study is also used as insinuations against the Western powers. The fact of the matter is that the media is trying to blow up a story without an accurate understanding and this is only diverting the public focus from the more important issue of the development of resistance in microbes to the other peripheral issues of private funding, national pride etc etc.

I am trying to present here the issue as i see it with my limited perspectives... based on a reading of the research paper and some of the more rational and balanced news reports...

Firstly, one must realize that bacteria from clinical and non-clinical settings are fast becoming resistant to conventional antibiotics. This is not a new phenomenon and has been a potential problem that was known for a long time. Since the bacterial life spans are short, the development of resistance in bacteria was always well anticipated and this has spurred the search for newer and newer antibiotics for a very long time. The possibility of horizontal gene transfer in bacteria only hastens the process of acquisition of resistance several fold and this has also been know for long!

Ten years ago, concern was focused on gram positive bacteria, particularly the meticillin-resistant Staphylococcus aureus (MRSA) and the Vancomycin-resistant Enterococcus spp. The current concern arises because clinical microbiologists are increasingly agreeing that multi-drug gram negative bacteria pose the greatest threat to public health particularly since there are fewer new and developmental antibiotics active against gram-negative bacteria. The increase in the resistance of Gram-negative bacteria is mainly due to mobile genes on plasmids that can readily spread through bacterial populations. Human air travel and migration, which are happening at unprecedented levels now, are also reasons for the spread of such resistance markers.

So what's the latest hue and cry all about ?

The latest in line of acquired resistance among bacteria is the new so-called super bug... This drug resistance bacterial gene, the so called super-bug was named as NDM-1 or New Delhi Metallo-beta-lactamase-1... Why NDM-1? Well, because, as is customary in the naming of a new pathogen or organism or species or chemical, NDM-1 was first identified in 2009 in a Swedish national who was admitted in New Delhi.

But for some reason this nomenclature for the plasmid is being perceived as a national insult especially in the way it is being projected in the media by the politicians... No one raised a question when Nasikabatrachus sahyadrensis, a new frog species found in Sahyadari was named so... There is even a Mycobacterium lineage named after Beijing... I don't remember Beijing raising a storm over that !! This is not a question of national pride... it is just a tradition of scientific nomenclature. How can we want to claim our name on anything complimentary (however distantly related it might be - from V Ramakrishnan's Nobel to the identification of N. sahyadrensis !!) and shun anything which might be remotely incriminating ? Why is the Indian media not putting forth the facts as they are and instead feeding the public frenzy ?

The entire controversy however began when Lancet Infectious Diseases published a study by Kumaraswamy et al in august 2010 ("Emergence of a new antibiotic resistant mechanism in India, Pakistan and the UK: a molecular, biological and epidemiological study"). The study reports the identification of gram negative enterobacteriaceae strains which are found to be resistant to Carbapenem, which is a powerful antibiotic and one of the last lines of treatment for infections caused by gram negative bacteria. The present report, has carried out a large scale sampling of enterobacteriaceae from different cities in India and the UK and has identified a good proportion of the bacteria to be resistant to Carbepenem. Interestingly, a previous study published by Journal of association of Physicians of India (JAPI) in March, around 22 cases of Carbapenem-resistant NDM-1 were collected within three months from a Mumbai hospital. Thus, the entire issue is not necessarily new although it has come to public light only relatively recently.

Magnitude of the problem ?

While i am saying that there is a needless media created hype surrounding the issue, the fact of the matter is that the issue is indeed important. The rise of resistance species is of critical importance and a recent editorial by Dr Ghafur highlights the major issues associated with this "super bug" in the Indian context in sharp, punishing tones !

The situation is critical especially in India since resistance to extended-spectrum beta-lactamases (ESBL) drugs like the third-generation Cephalosporins is between 60 to 70% on average, compared to the less than 15% seen in the developed countries. Thus, a more common way of treating the severe form of ESBL infections is through the use of Carbepenem - which becomes the drug of choice as it has the lowest resistance and the broadest action against gram negative infections. The emergence of resistance against Carbepenem is bad news undoubtedly but for the patients and physicians in India who now have to look for new antibiotics but this is a self created nuisance too. The spread of resistance is not surprising keeping in view the fact that the drug is over used by the physicians. The easy over-the counter availability of these drugs also makes the problem more acute as patients end up self medicating in sub-lethal doses (For the bacteria of course), thus, leading to the acquisition of resistance. These are problems which have been known to the medical community for a very long time but have not been addressed by the government, the media or the Public...

It took a report such as this where the introduction of NDM-1 to the UK was attributed to the emergent practice of medical tourism (where a number of patients in UK were coming to India for medical treatment, esp for things like cosmetic surgery, dental treatment etc as a cost effective measure which could aid the NHS in saving money). The Indian politicians of course do not want to let go of this easy source of foreign exchange and are over zealously contradicting the problem. The fact of the matter is that medical tourism is only part of the reason for the spread of the disease. In fact, typing the plasmid did not even identify common strains of E. coli of K. pneumoniae between the indian subcontinent and the UK or between the north and south India, suggesting disparate origins. The Indian subcontinent has always been a rich source of many infectious diseases - HIV, TB, Enterobacterial infections, malaria, dengue etc etc. There never was a hue and cry about any of these diseases ever affecting medical tourism. The western countries are also battling with their share of health concerns - emergent resistant strains like MRSA, VRSA; increasing health care costs etc etc. No one is going to stop traveling there !! Also the spread of the NDM-1 plasmid can occur because of routine travel of people... and there is no way that travel across the world is going to come down because of this "superbug"!!

It is thus pragmatic that the Indian media focus on the more important issues such as educating people against self medication and the government focus on increasing its efforts towards R&D for newer more effective treatments and towards getting a more accurate picture of the actual spread of the superbug; instead of raising a hue and cry about something which is frivolous and a completely fruitless exercise !!

The Indian government, public, medical community and the media need to work in close synchrony to understand the real severity of the problem and to counter the same - if not for the foreign currency but for the future health of this country where epidemics spread faster than wild fire and where health is already a major challenge. Thus, instead of creating a storm in the tea cup, the Indian media, the public and the politicians should focus on the threatening storm on the horizon and be prepared for that !!!

Subjective objectivity.... and the pitfalls therein...

"Science is rooted in creative interpretation. Numbers suggest, constrain and refute; they do not, by themselves, specify the content of scientific theories. Theories are built upon the interpretation of numbers, and interpreters are often trapped by their own rhetoric. They believe in their own objectivity and, and fail to discern the prejudice that leads them to one interpretation among the many consistent with their numbers."

- SJ Gould

A wonderfully true statement which not many can appreciate !

The subjectivity involved in being objective... :-)

It is the true understanding of our inherent biases and conditioning that can make science truly objective. This is where lessons from history become invaluable in our understanding and appreciating the magnitude of bias that we introduce in science. Hindsight is often the best form of sight that can make things appear in new light !! :-)

The Panglossian Paradigm in evolution

"All this is a manifestation of the rightness of things, since if there is a volcano at Lisbon it could not be anywhere else. For it is impossible for things not to be where they are, because everything is for the best...."

Dr Pangloss in "Candide" on the great Lisbon earthquake of 1755 in which up to 50,000 people lost their lives.

Voltaire heaped ridicule on Dr Pangloss in "Candide":

"Things cannot be other than they are.... everything is made for the best purpose. Our noses were meant to carry spectacles, so we have spectacles. Legs were clearly intended for breeches, and we wear them."


Point being made :

Evolutionary biologists tend to focus exclusively on the immediate adaptation to local conditions, and tend to ignore architectural constraints and preform just such an inversion of explanation.

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Courtesy: The Spandrels of San Marco, An essay by SJ Gould.

Evolution and beyond ?

The following is the mail from a physicist expressing his concerns about the widespread acceptance of the evolutionary theory. I was asked by a friend to respond to the same and what followed was a letter attempting to address some of the issues raised here...

The following analogy from physics might help clarify what I am referring to. In the late 1600's when Newton discovered patterns in planetary motion and proposed his laws, everyone thought we had discovered how the universe functions. In fact by the mid 1800's, armed with many physicists had assumed we understood almost everything about the laws governing nature. But they were all shocked in the late 1800's and early 1900's that they had not appreciated a completely new approach to physics described by quantum mechanics where classical mechanics was merely an "effective" approach. Of course quantum effects are rather subtle and Newton's ideas are still valid almost in all daily experiences. So Newton certainly deserves a lot of credit.

In the same way, I feel the theory of evolution of Darwin, could be a very useful first step in our understanding of life. But there may be many surprises on the way! And as scientists we should be ready for it. In my opinion there are already many questions that evolutionary theorists should be asking. Hopefully, they are building more realistic models and testing the theory of evolution rigorously. Trying to poke holes into the theory. would be surprised if they are not!

For example, some of the subtler questions could be related to the quantum mechanical effects that govern the probabilities in the evolutionary mechanism. I have heard that the physics of protein folding is an open problem in biochemistry and I some people believe quantum mechanics is playing an important role there.

Finally, I am sure you will agree that human emotions and feelings are "observed facts". At some point of time we should address them. How do they arise? We cannot just say "these arise from "complex" connections in the human brain"! You can almost explain anything away through the use of word "complexity" these days and you are not allowed to ask any more questions! Why? "Because it is complex"! Sounds very much like religion to me!

Why did evolution create a human brain that is capable of "sacrifice" for the sake of others that by very nature goes against preserving the "gene"? Why did evolution create many human brains that thinks that "sacrifice" for others is an admirable trait in a human being and respect those people rather than "kill" them at first site! These are some questions I wonder about. I hope scientists just dont use "complexity" to explain away these observed facts and shut me up!

The bottom line is that some people become happy with an explanation about the observed phenomena. Others do not. People who accept an explanation easily are always happy. The question always is where do you draw the line? We scientists have developed some bit of arrogance as compared to non-scientists. We think we understand something better. That may be! Unfortunately, we too have to draw the line somewhere else and say, I am happy with the current explanation since I cannot go beyond this. It is too complex!

My response :

Well, I appreciate the sentiments behind the mail and the spirit behind the questions raised but as someone who has been in a closer association with the field, I do think that some of these thoughts are a result of lack of in-depth study of the field.

Let me clarify, while as scientists, it is right to be a little skeptical about any fact till it is completely proven, Darwin's evolutionary theory is pretty much at that stage in biology. However, the questions that you raised are valid and have been the subject of several studies. Our current understanding is progressing and has still not been able to refute the fundamental principles of evolution. However, yes, we still do not have explanations for all such conundrums in biology. The origin of altruism (sacrificing oneself for others) is one such problem, there are others such as the origin of handicap principle (the male peacock has huge tail feathers which completely incapacitate its flight movements - why it would evolve something like this is another problem which has puzzled evolutionary biologists for long), the evolution of consciousness, the evolution of our mental faculties, emotions etc, the origin of antlers in a stag etc etc… there are numerous such examples for which we do not have proper explanations but the hypotheses that are available are all based on the framework of evolution.

However, there is a caveat here. Evolution as is understood today is of a very different form from that which is commonly understood. In fact, a greater understanding of the subject can be obtained from Stephen J Gould's essays.

There are few things that we need to remember when looking at things from an evolutionary perspective -

1. What exists today is a result of a large number of random events operating at different levels (natural cataclysms to random mutations at the gene level)… but the outcome of these random events is shaped by the process of natural selection (as was proposed by Darwin).

2. Also, one must be careful when ascribing an evolutionarily selective benefit to every trait or character we see. Some of these characters may actually be a case of "spandrels" (as was written by SJ Gould in his essay on the Spandrels of San Marco) i.e. they may not have a selective advantage and may just be a by product of the constraints of life and evolution. Like the spandrels which just exist because of the nature of the construction of the building and not because of the purpose they serve, in this case too, a lot of features in biology are not advantageous all the time.

3. Also, some of the features we see in life today are actually natural consequences or by products of certain other constraints and may not in themselves be subject to the forces of natural selection.

4. Addressing some of your questions specifically,

• The origin of altruism has been a subject of scrutiny in several societies, not just the human. It is seen in other insect societies as well. The "kin selection theory" tries to explain this by speculating that sacrificing oneself still could be advantageous in an evolutionary perspective if one tries to save one's closest kins (because your genes still survive… ). In fact, the genetic relatedness between individuals has been seen as a measure of the tendency to give up one's life. Man, however, is the part of a more complex social structure where the social structure is based on cooperation and coexistence. (I speculate that humans lack the physical strength/skills necessary to subsist as solitary creatures and therefore had to resort a more social living where interdependencies are mandatory).

• In fact, the fields of evolutionary psychology and sociobiology have been attempting to address these and other such questions which are of relevance to explaining human social behavior and psychology in the light of evolution.

• The question of peacock feathers, antlers is another intriguing phenomenon - the handicap principle has come up with another hypotheses to explain the same. It is believed that the bearing of such handicaps could indeed be a symbol of greater ability as individuals (males) surviving despite such handicaps (very evidently responsible for the name of theory) are actually perceived as more attractive for their ability to survive despite such handicaps. There are other theories to explain the same and studies are attempting to prove one as against the other.

• The origin of human consciousness, mental faculties, emotions etc are also areas of intense investigation in evolutionary light. One other aspect which needs to be remembered is that, some traits and features are exaptations - i.e structures which arise for a certain purpose but then gradually evolve for a different purpose all together. That is some of these structures may actually be a consequence of some other evolutionary features. The evolution of human consciousness for example is something which is often explained as a natural end product of a highly developed brain with a very "complex" neural network underneath. A lot of our mental faculties also may not have a natural selective advantage - they may be a natural consequence of certain other features for eg, the evolutionary increase in brain size may have as a consequence developed our faculties for language, social structure, arts etc. These areas still remain in the arena of speculation and are branded as "complexities" not with the intention of evading the problem but because they are genuinely not understood. The human brain remains one of the biggest "black boxes" in life sciences and efforts are underway to try and understand the molecular processes underlying the complexities of memory, perception, thought etc etc.

Lastly, while biologists are working at trying to understand life and the underlying complexities, they are all only trying to do it in the light of evolution because honestly there has not been a better alternative for our understanding of the same. However, the definition of evolution has been expanding ever since the term was coined and newer perspectives are being added with each passing year.

I hope I have managed to shed at least some light on the questions that have been raised by you. I do not claim to be an expert but as an occupational hazard, if not anything else, I have been more acquainted with the evolutionary principles. And, as time goes by I only realize that there is a lot more I need to know. Some things make intuitive sense while some are more difficult to understand and appreciate. It only requires deeper study of the views and counter views to arrive at a clearer picture of the complexities of evolution.

I am sure you will find many more questions and answers to many of your already existing questions if you go through the existing literature in the field. References in case you are interested further -

The selfish gene

The essays of Stephen J Gould

The greatest show on earth

The blind watchmaker

The moral animal

Rise and fall of the third Chimpanzee

Finally, I would like to say that I do agree with you when you say that we should not be blind to other possibilities and as scientists be open and skeptical… but, it just necessitates a more open approach where evidence is interpreted unbiased by prejudices. And that holds true for every subject and field not just with evolution and biology.