Bug Therapy to treat Diabetes and obesity in future?

The long held notion of ‘junk DNA’ has been found to be incorrect (ENCODE project), similarly, characterizing the gut microbiota as bystanders in the intestinal tract is now being widely challenged (Osborn O, Olefsky JM (2012), Nature Med 18(3):363-374).

A recent paper in Proceedings of National Academy of Sciences (PNAS) adds muscle to the fact that a single species of bacteria (Akkermansia muciniphila) can modulate diet induced obesity in mice. A. muciniphila is a Gram-negative bacteria that constitutes 3–5% of the gut microbial community. The paper also highlights the various mechanisms by which this bacterium might exert its effect (Everard A et al. (2013), PNAS)

The study shows dramatic decrease in gut A.muciniphila in diet induced obese mice. On restoring the abundance of this strain in obese and diabetic mice it was found that viable A. muciniphila controls gut barrier function, fat mass storage, and glucose homeostasis via several mechanisms. This study identified an association of obesity with a decrease in mucus thickness that is characteristic of obesity and associated disorders. Interestingly, the authors found that A. muciniphila restored this mucus layer. Strikingly, viable A. muciniphila induces these effects, whereas heat-killed A. muciniphila did not protect the mice from diet-induced obesity and associated disorders. One of the other key findings was that treatment with this bacteria led to increase in acylglycerol levels more specifically 2-OG and 2-AG. Incidentally, 2-OG is known to stimulate intestinal L cells which lead to secretion of GLP-1 (Hansen KB, et al. (2011), J Clin Endocrinol Metab 96(9):E1409–E1417). GLP-1 is known to increase insulin secretion. Also, A. muciniphila treatment completely reversed diet-induced fasting hyperglycemia via a mechanism that was associated with a 40% reduction in hepatic glucose-6-phosphatase expression thereby suggesting a reduction in gluconeogenesis. Hence this association might point to how A. muciniphila exerts its effects on glucose homeostasis. 

Many bacteria (Lactobacilus spp, Bifidobacterium spp etc.) have been shown to have effect on fat mass development during diet induced obesity (Fåk F, Bäckhed F (2012), PLoS ONE 7(10):e46837). However, in this study the emphasis was to study the bacterial strain that is affected during obesity and type 2 diabetes in humans and rodents. It would be interesting to see how this development would enthuse the world of gut microbiome research and interest the pharmaceutical/biotech companies to invest in this field which would then pave the way for not only treatment but prevention of inflammatory, lifestyle and even mental diseases in the near future.

India’s Supreme court ruling on Novartis’s Gleevec – A Perspective

Recently, the Apex court of India rejected the patent application of Novartis’s anti-cancer drug Gleevec (http://www.thehindu.com/news/national/landmark-verdict-gives-big-boost-to-cancer-patients/article4569056.ece?homepage=true)

As per Indian law "ever-greening" of the drugs is not encouraged whereas the big pharma companies keep on doing minor modifications to gain longer patent life in the US and other Western countries. This judgment therefore is in the right direction as it clearly defines what "innovation" is in the Indian drug market context and will give hope to millions of poor patients not only in India but across the world. 

But, I also have a point against the Indian pharma industry which is mostly focused on 'generics'. Indian pharma industry is not too keen on developing new drugs (NCEs) and is looking for major profits once the old drugs come off patent. This is not a healthy trend. Also, the amount being charged by these companies on these drugs can be slashed even more as they have not spent even a penny for the development of these drugs and so there is no point in even charging what they are right now for these drugs!!!

Of course, the above point holds true for NCEs but may not hold true for Biologics!. Biosimilars are a different ball game all together and it would be interesting to see what the future holds for the Indian pharma industry which is betting heavily on generics and biosimilars!

Finally, this verdict is definitely good for the patients and may be also good for the Indian pharma industry in the short run but I feel Indian pharma and Biotech industry need to innovate more and come out of the “profit making with minimal investment mindset"!

The next step in Life science/medicine!

Biology, like any other stream of modern science has seen great discoveries leading to mind-blowing inventions and a better understanding of disease, disease progression and ‘life’ in general. Great discoveries starting from the discovery of penicillin (in 1928 but actual use started in the 1940s) to advances in stem cells research led to a renaissance in the field of medicine. However, the current technologies and the drug discovery paradigm still leave a lot to be desired in terms of understanding the biology of the healthy and the diseased! So what is missing?

The basic understanding of the life processes has improved and different approaches both “top-down” and “Bottoms-up” viewpoints are being looked into. We have moved ahead with great advances in the hardware side wherein we can now observe single cell in action; we can sequence the whole genome/transcriptome of humans, yet I believe that we are not there where we should have been. What is missing is a holistic approach to understanding the healthy and the diseased. A collaborative effort looking at the broader picture is the need of the hour. Authors like Dr Amit Goswami (Book- The Quantum Doctor) has argued in the favour of an approach that takes into consideration not only the different branches of biology but also includes various aspects of quantum physics and alternate medicine to better understand and deal with disease. This is not a farfetched idea and is doable. Various well reputed thinkers/writers like Dr Roger Penrose, Dr Deepak Chopra have opined that the current thought process of considering the human body and the cellular processes therein as mechanistic sans consciousness is fraught with naivety and therefore a paradigm shift is probably needed!

So what is going to be the next “Eureka” moment in the field of Life sciences? Probably, a holistic approach to understanding life and disease!

Gut Microbiome – Type 2 diabetes association; outcome and possibilities

The phrase ‘my gut feeling’ has got another scientific validation with some new metagenomics studies published recently. After all, it seems that the gut can dictate the potential well being of an individual. A case in point is the latest paper in Nature journal in which the researchers conducted a gut metagenomic study on Chinese patients suffering from type 2 diabetes (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11450.html). Gut microbiome has been in the forefront of research especially after the advent of the Next Generation Sequencing technology. Today, the advancement in the field of development of sequencers and sequencing technology is even challenging the Moore’s law.

Gut microbiome also being called as the “other genome” or human’s “second genome” is implicated in many of the chronic diseases/disorders like obesity, inflammatory bowel disease and even depression so it is natural that with the latest technology in hand the scientists would focus on this in a much more refined manner. The present study finds some interesting facts about the commensals in the gut of Chinese patients suffering from type 2 diabetes. Functional characterization showed that there was a decrease in the level of bacterial chemotaxis, flagellar assembly, butyrate biosynthesis and metabolism of cofactors and vitamins in the gut bacteria of these patients. The researchers also found markers that indicated that the gut environment of a T2Dpatient is one that stimulates bacterial defence mechanisms against oxidative stress. This might be interesting as previous studies have implicated high oxidative stress levels to pre-disposition to type 2 diabetes. Strikingly, the researchers found orthologue markers that suggest that these diabetic patients might have a hostile gut environment. The researchers also found that there is moderate gut bacteria dysbiosis and an increase in several opportunistic pathogens.

The above mentioned salient outcomes of the study raise many exciting questions and possibilities. Does the change in gut microbiome composition a cause or an effect of the disease? Scientists would be addressing this part next with some studies in animals. Can in the future the gut microbiome sequencing be used as a predictive tool? Can modulating the gut microbiome cure such diseases? Can effective research in pro-biotics now fill in the space and fulfill what modern medicines could not achieve so far?

This is a perfect example of how a 21^st century technology has ignited a fresh look at the association of the microbiome with the human health