Adios ‘2018

Few more days to go before 2019 walks in and it’s goodbye 2018. It has become customary to think of what has gone by and what better way to live the new year. The past year has been an absolute roller coaster. As far as memory goes, no other year has shaken me up with joys as well as absolute disasters like 2018. Peaks and valleys in both personal and professional fronts rocked our daily lives—sometimes the same day. I can go on and on and on…..

Despite all the drama, I managed to reach my reading challenge of a meagre 25 books through the whole year. And it so happens that one of the last books I read was “Sikkim: requiem for a Himalayan kingdom”. This was triggered by a recent trip to Sikkim and surprising revelations about the state.

On our first day in Sikkim, as we drove through the mountain roads, our driver guide casually said, “Please ask me whatever you want about Sikkim, including its history.” I thought for a while and wondered every Indian state has a similar history for the last two centuries since the British took over every nook and corner of the country. So what’s so different about Sikkim. May be he sensed my ignorance and summarised the history in one line. “We became the 22nd state of India in 1975. Until then we were a separate Buddhist kingdom.” My jaws dropped. How did I not know such an important part of our country’s history.

This is why the book by Andrew Duff ended up in my reading list. It took me a whole month to read through the book but at the end, I realised the Chogyal of Sikkim went through highs and lows throughout his life for his dream of an independent Sikkim which in any case came crashing down before he died. People came and went in his life—some in support and some against. Yet all along he stood to defend his unwavering love for his kingdom and to safeguard their interests. He might have been stubborn to an irrational degree but lived his life for his passion, dreams and belief. And taught an extremely important lesson to everybody—no amount of time spent chasing your dreams is enough and there is no guarantee of dreams coming true. But that’s the only way I would like to live my life.

Cape of storms

“Please stand in the queue here for your turn to take a picture with the CAPE OF GOOD HOPE board”, said Marcon. I was thrilled to know that we have reached the southernmost point of the African continent… Until our turn came and the board came into view.

Most southwestern point??? There has to be a mistake. Isn’t this supposed to be the southern most point? I gave a confused look to Marcon and before I could ask, he smiled and said the southernmost point of the dark continent is about three hours drive from here. And where would that be? Cape L’Agulhas! Where on earth is this? Why did I not know this earlier?

Marcon clarified later most people have this assumption that Cape of Good Hope is the southern most point but it’s just a popular place because it lies within Cape Town limits. Tourists flock this town and Cape Point is a half day tour. This Cape was first named as Cape of storms because ships sailing all across the world were never able to dock due to severe damages suffered in storms. But because it opened up the pathway from the Western Hemisphere to the eastern world for trade, it was renamed the Cape of Good Hope.

At this point I had decided we have to go to this ‘Cape whatever’ that marks the tip of the continent. So couple of days later when we head out towards Mossel Bay on the Garden Route we took the 80 kms diversion to go see this place. Overlooked by a typical lighthouse, this unassuming place was very significant in terms of geography of the continent.

The Indian ocean and the Atlantic ocean meet here. The warm Agulhas current for the Indian Ocean clashes with the cold current from the west resulting in strong winds and storms. Historically known as the Cape of Needles, it has been known to have sunk big ships in the early days due to the weather conditions and the rocky outcrops.

With only a bunch of tourists, and may be a few locals idling around on rocks, there was no queue here for a photograph with the plaque. One would probably see more sea gulls than people along the coastline of the town. A quaint little town, L’Agulhas, serving as it’s approach, the cape continues to maintain its importance in a quiet and a sombre way.

A great earthquake overdue in the central Himalaya

February 12, 2015

A team of scientists have been digging deeper into the central Himalayas, only to discover a previous pulse of great earthquakes followed by a long quiet period since the last great earthquake under the huge layers of rock and soil within those mountains.

The earth’s crust is broken into distinct regions, called “tectonic plates”. It is well known that Himalayas are the result of converging continental tectonic plates. There is an ongoing northward movement of the Indian plate towards Tibet at the rate of 20±3 mm/year and the southern part of Tibet that interfaces with India is absorbing about 80% of this convergence. This means that these regions are accumulating a large amount of strain, which they release in the form of great earthquakes (greater than magnitude 8).

The central Himalaya is considered to be historically a “seismic gap”..In the past centuries, only two earthquakes have occurred in this region whose magnitudes weren’t enough to release the strain that is building within the plates. So, are we missing some great earthquakes that occurred sometime in the past?

The excavation sites near Ramnagar in Central Himalaya suggested that there have been successive occurrences of two great earthquakes in the region in 13th and 14th centuries AD but none since then. It means that the strain is accumulating and the region is currently locked, only to get released anytime in a great earthquake. Longer the relapse time since the last earthquake, larger will the expected dimensions of the potential future slip and greater would be its damage potential.

A great earthquake in the central Himalaya will be most devastating and damaging for a wide swath of Gangetic plains of north India and the Himalayan hills. Mitigation of damage from future earthquakes is based on hazard scenarios developed from earthquake history; geological evidence from past earthquakes is an essential component in probabilistic seismic hazard assessment models. This study helps to fill that important gap in data for the earthquake history of the central Himalaya, a region, which several previous studies have postulated to be ready for a great earthquake.

Further work in the area is required to refine the results and tectonic models to understand the rupture segmentations along the arc. Dr. Rajendran said, “All the major cities in the region need to get ready for this major hazard, which is going to be economically and otherwise most devastating, as the risk has increased multifold over the centuries due to population increase and expansion of built environment. From the Government level serious thinking should go into evolving effective methods to meet such eventualities. Effective hazard reduction models may be available from the western United States and Japan. Urgent action plan should be put in place for public awareness and enforcement of building codes and related environmental laws – important hazard reduction steps in the current context of expanding urban centres with high-rise buildings. Heritage structures and monuments and the critical facilities in the region require reinforcement and retrofitting to withstand severe ground shaking”.

– See more at: http://iisc.researchmedia.center/article/great-earthquake-overdue-central-himalaya#sthash.mHd86Pyy.dpuf

Next Generation Sequencing Meets Traditional medicine

June 4th, 2015

Traditional knowledge in combination with modern scientific techniques could help unravel deep hidden mysteries. Scientists from NCBS, Bangalore, have revisited the age old knowledge of “Tulsi and its medicinal effects” in their labs, only to be overwhelmed by their scientific findings. Ocimum tenuiflorum or commonly known as Tulsi has been mentioned in ancient Indian scriptures and has found wide usage in the Indian traditional system of medicine, Ayurveda. Known for producing many aromatic compounds, Tulsi gained an informal name as the “Queen of Herbs”. It is considered sacred in Hindu households and mostly used for spiritual and religious purposes in India.

Tulsi grows extensively in tropical climate, hence found in most parts of Asia, Africa, Central and South America. It consists of a wide range of bioactive compounds which are known for their anti-bacterial, anti-fungal, anti-pyretic and anti-cancer properties. These compounds or plant metabolites are very poorly understood because of absolute lack of genomic information. Prof. Ramanathan Sowdhamini and team have produced the first draft genome of O. tenuiflorum Krishna subtype which is a huge leap in understanding and identifying the genes responsible for production of metabolites with medicinal properties. Focussing on the important metabolite genes, the team used five different types of Tulsi, (Ocimum tenuflorium subtype Rama, O. tenuflorium subtype Krishna, O. gratissimum, O. saccharicum and O. kilmund) to collect the genomic data and compare it with the nearest genetically related species. “The genome sequencing projects involved generation of huge quantity of data. The genes were identified from this enormous amount of data using complex prediction models and then they were numbered for easy identification. This assembled genome and the set of genes served as a start point for all downstream analysis”, said Adwait Joshi, one of the team members.

Like every other plant, Tulsi also produces specialized metabolites as a part of its defence mechanism. Linalool, Linalyl, Geraniol, Camphor, Thymol, Safrol, Apigenin, Citral, Eugenol, Taxol and Urosolic acid are few examples among the important secondary metabolites of Ocimum species. “Apigenin, Taxol and Urosolic acid are implicated in anti-cancer properties of the plant, Citral for its anti-septic nature and Eugenol for its anti-infective properties and so on”, says Prof. Sowdhamini. Few metabolites have been used in the perfume and cosmetic industries. While others have been exploited in curing human ailments like malaria, bronchitis, diarrhea and dysentery, etc. The metabolic pathway concerning the synthesis of Ursolic acid was investigated as a case study. Studying mature roots, leaves, flowers, seeds and other parts of the plant, the team found that the precursors of these metabolites are synthesized in young tissues and retain their specific medicinal properties in their mature counterparts.

Owing to the 3000 years of cultivation of Krishna Tulsi and extensive descriptions in the Vedas and Puranas, it is assumed to be of Indian origin. The findings of the experiments at CCAMP, NCBS, reinstate the household knowledge passed on by grandma, even when prodded by the modern scientific techniques. Prof. Sowdhamini said, “This is the first report of draft genome sequencing of a plant species from NCBS and we hope to do more”. Convinced of the huge array of genes and their respective downstream compounds yet to be unraveled in further research, the team looks forward to working in collaboration with an independent parallel initiative by CAMP, Lucknow, to provide the next version of the draft of Tulsi genome.

Conference report

INTERNATIONAL CONFERENCE ON BRAIN DISORDERS  & TREATMENTS

16-18 November 2015

Faculty Hall, Indian Institute of Science Bangalore

What is dementia and how is it caused?

The underlying genetic bases of Alzheimer’s disease

Can we prevent the onset of dementia in Alzheimer’s disease?

These are some of the key areas that will come under the lens at the international conference: “Neurodegenerative Diseases: Pathogenesis to Therapy” conference, which will be held between 16-18 November 2015 at the Faculty Hall, Indian Institute of Science, Bangalore. The conference is being organised by the Centre for Brain Research, an autonomous centre at the IISc. Scientists from various national and international research institutes and Universities will present their studies and findings during these three days and explore novel therapies. The main focus will be on neurological disorders related to age: their causes, mitigation and possible treatments.

Dementia refers to a range of symptoms that includes the loss of memory and decline in mental abilities like thinking, problem solving and language, caused due to brain degeneration. It is a common symptom of Alzheimer’s disease (AD) and has been noted in people in their mid-60s. Research suggests the onset of dementia could be delayed, and that there are treatments for the symptoms of the disease which can slow down the progression of dementia.

The degeneration of the brain as we age is primarily a medical problem. But, with the increasing ageing population across the world, it has now become an economic issue also. “Age related neurological  disorders have been a cause for public health concern in developed countries. In the near future, India and China will see the largest increase in new cases of dementia. So, there is growing global concern about ageing disorders, in general and dementia, in particular”, said Professor Vijayalakshmi Ravindranath, chairman, Centre for Neuroscience, IISc, Bangalore.

The first day of the conference will focus on Alzheimer disease- its causes, symptoms and possible therapy of its primary symptom – dementia. The day’s talks include

  • John C. Morris, a lifetime achievement award winner from the Alzheimer’s Association for his contributions to this field, currently at the Washington University School of Medicine will speak about delaying the onset of dementia in AD and the ongoing trials.
  • Yves Joanette, University of Montreal, Canada, will talk about the challenge that dementia poses and the collaborative efforts at a global level to understand the origins of the diseases causing dementia.
  • Arthur Toga, founder of the Laboratory of NeuroImaging, University of California, Los Angeles, describing his work on making data from various laboratories accessible, and using a wide range of instruments and different protocols, to discover meaningful patterns.
  • Sudha Seshadri from Boston University School of Medicine, will present the genetic aspect of Alzheimer disease research.
  • The possible links between Dementia and type 2 diabetes will be discussed by Prof. Velandai Srikanth, a geriatrician at the Monash medical centre, Monash University, Melbourne.
  • Suvarna Alladi, Nizam Institute of medical Sciences, Hyderabad, will address the possible role of multilingualism in the delay of onset of dementia.
  • Mary Ganguli, University of Pittsburgh will speak about the relationship of brain’s function and dysfunction to the overall population as opposed to an individual.
  • Murali Krishna will present his research from populations of Mysore and how nutrition and growth in early life and socio-economic adversities affect cognition in individuals.

The second day will be a range of topics on factors and mitigation of neurodegeneration due to age, how lifestyle factors and other diseases can influence brain damage owing to AD, Parkinson, Lafora disease or Amylotrophic Lateral Sclerosis. Dr. Ana Ines Ansaldo from University of Montreal, Canada, will talk about mitigation of neurodegenerative symptoms. Dr. Rosalyn Moran from Virginia Tech Carilion Research Institute, will present a mathematical predictive model to examine the impact of life experiences in aging neurobiology. Dr. Stanley Fahn, Columbia University Medical centre, followed by Dr. Uday Muthane’s, (Parkinson aging and research foundation, Bangalore) talk on Parkinson’s disease and mitigation probabilities.

 

The last day will be a presentation by Dr. Sangram Sisodia from University of Chicago, on genetic mutations causing Alzheimer followed by Dr. M. M. Panicker’s (NCBS, Bangalore) research on stem cell modelling on late onset of the disease. Prof. Colin Masters, University of Melbourne, will speak on possible gene therapy in Alzheimers before the concluding session of the conference – a panel discussion on dementia.

 

 

Day 1

16-18 November 2015

Faculty Hall, Indian Institute of Science Bangalore

“By 2050, more than 50% of the ageing population will be in South East Asia”, said Prof Yves Joanette, during the first session of the International Conference ‘Neurodegenerative Diseases: Pathogenesis to Therapy’ at the IISc today. “Globally, about 30% of the population would be 60+ very soon”, she added.

This immediately implies an increase in incidence of dementia. With an increasing aged population, dementia is becoming more of an economic problem, rather than a medical problem.

“India will contribute to dementia research both within the country and globally”, said Joanette, pointing out to the Rs 225 crore grant provided by Kris Gopalakrishnan to IISc. During his speech at the inauguration, Gopalakrishnan said “Understanding the human brain would help us improve the condition of people whose lives are affected by these diseases. There is a huge avenue for computational research, where India can really provide inputs”.

Dementia refers to a range of symptoms that includes the loss of memory and decline in mental abilities like thinking, problem solving and language, caused due to brain degeneration. It is a common symptom of Alzheimer’s disease (AD) and has been noted in people in their mid-60s. Dementia is also caused by other factors, said Joanette. “We need to examine the cascade of events that end up in dementia”, she said.

“We also need to find ways to deal with dementia-affected population – their quality of life and strengthening services for caregivers and families”, she added.

AD, first diagnosed in 1906, is a disease where neurons in the brain die and the brain wastes away as a result. Dr John Morris from the Washington University in St Louis called it a ‘global epidemic’. “The first stage of the disease is generally silent, and cannot be detected by current diagnosis methods”, he said. “The second phase is characterised by dementia and cognitive impairment. We currently have no therapy for the underlying cause of AD – the neuronal degeneration”, he added.

“We need population level studies to complement clinical ones”, said Dr Mary Ganguli from the University of Pittsburgh. Human beings are hetergenous subjects, not uniform like lab rats, she said. “It is crucial to examine the external factors from the population around a patient. Such data is lacking from countries like India”.

Ganguli has developed an India-specific questionnaire which can be used for population level dementia surveys. Neuro-physiological tests, the usual norm for diagnosis, were not feasible with illiterate people. She found an incidence of 1.17% in a population in Haryana, as opposed to 8% at a locality in the US. “The study needs to be expanded to other socio-economic classes, and across the country”, she said.

Dr Sudha Seshadri, an alumnus of CMC Vellore who is now at Boston University, has been “looking at new genes or new targets for understanding the biology of AD, which would help discover new drugs and therapeutic approaches”. She suggested genome-wide surveys to look at possible targets for gene therapy.

Murali Krishna, an Early Career Wellcome Trust-DBT fellow from Mysore, examined the hypothesis that a smaller birth weight, because of a smaller head, increases chances of dementia when the person ages. Examining more than 1000 people born in a particular hospital in Mysore, he was able to establish that low birth weight, combined with low socio-economic status, increased the prevalence of dementia and cardiometabolic disorders.

Suvarna Alladi of Nizam’s Institute of Medical Sciences, Hyderabad, said that India was ideal to test the hypothesis of whether speaking more than one language maintains cognitive functions better. “Switching between languages maintains higher cognitive functioning”, she said. “Irrespective of literacy, being multi-lingual helps to delay dementia. Illiterate but skilled workers like artisans, potters and weavers had heightened cognitive abilities and hence late onset of dementia”, she added.

 

http://cbr.iisc.ernet.in/conference.php

Prof. John C. Morris http://neuro.wustl.edu/aboutus/facultybiographies/morris

Mary Ganguli http://www.wpic.pitt.edu/research/dementia_epidemiology/

Murali Krishna http://wellcomedbt.org/fellowsprofile/dr-murali-krishna-125

 

 

Day 2

17 November 2015

Faculty Hall, Indian Institute of Science Bangalore

“Sitting is the new smoking. Eight hours of sitting does similar damage to what smoking does to you”, said Manjari Tripathi, a Professor of Neurology at the All India Institute of Medical Sciences, New Delhi. Life expectancy in India has shot up in the last 50 years, thanks to better medical facilities.

“Soon, India will have the third largest ageing population following the US and China”, she said. “One in six women beyond 55 are likely to develop dementia. However, the factors leading to dementia are still an enigma”. Tripathi has initiated a study that will monitor the health of a rural and an urban group, over the next couple of decades.

Dementia refers to a range of symptoms that includes the loss of memory and decline in mental abilities like thinking, problem solving and language, caused due to brain degeneration. It is a common symptom of Alzheimer’s disease (AD) and has been noted in people in their mid-60s.

Can we remodel the brain after it has aged? At a very interesting talk during the second day of the International Conference ‘Neurodegenerative Diseases: Pathogenesis to Therapy’ at the IISc today, Ana Ines Ansaldo from the University of Montreal discussed brain remodelling as a therapy for Alzheimer’s Disease.

The brain is capable of some degree of plasticity, or remodelling. With age, this ability typically decreases. Ansaldo has found that engaging the brain in novel, complex tasks provides it with an ‘enriched environment’ that delays onset of brain degeneration. Therapy induced plasticity can potentially prove beneficial for Alzheimer’s patients, her research has shown.

Stanley Fahn from Columbia University spoke on the symptoms and pathogenesis of Parkinson’s Disease. The disease is caused due to degeneration of neurons, and it progresses slowly in most people; the person’s brain slowly stops producing dopamine, a neurotransmitter – a chemical used to communicate between neurons. Hirsch Etienne from the Brain and spine institute, Paris, spoke on the unmet therapeutic needs in Parkinson’s disease. K P Mohan Kumar spoke on the specific protein Prohibitin and its relation with Parkinson’s.

Jean-Pierre Julien from Laval university, Canada, spoke on possible therapies for the disease Amylotrophic Lateral Sclerosis (ALS). The disease affects motor neurons, the brain and spinal cord, causing muscle weakness and paralysis.

Rosalyn Moran from Virginia Tech spoke about her research on the mathematical modelling of the brain, which can help predict long term ageing patterns and propensity for disease.

LINKS

http://cbr.iisc.ernet.in/conference.php

Ana Ines Ansaldo: http://www.laboansaldo.com/ana_ines_e.html

Manjari Tripathi: http://www.aiims.edu/aiims/departments/spcenter/nsc/neurology/manjari-t.htm

K P Mohan Kumar: http://iicb.res.in/divisionwiselistofscientists/cbp/kpmohankumar.html

 

 

Day 3

18 November 2015

Faculty Hall, Indian Institute of Science Bangalore

The last day of the International Conference ‘Neurodegenerative Diseases: Pathogenesis to Therapy’ was packed with discussions regarding the latest research about Alzheimer’s and dementia, especially detection and therapy.

A panel discussion in the afternoon discussed the Dementia Network – designed to improve the system of care for individuals with Alzheimer’s Disease and dementia. Stanley Fahn from Columbia University stressed the need for collaboration among institutes, and among different streams – doctors, nurses, academicians, caregivers and families of affected people. Such a network can be used to establish common protocols and assessments for diagnosis, treatment and data collection.

Sangram Sisodia from the University of Chicago stressed the need for scientists to network together and use technology to the best possible extent. Yves Joanette from the University of Montreal stressed on the need for Big Data; and the need for large international collaborations to generate Big Data. Narahari from IISc stressed further on the need for complex algorithms that can handle the kind of data needed to understand neurological diseases. He spoke of the need to complement crowdsourced data with expert data, to get a good picture.

Upinder Bhalla from the National Centre for Biological Sciences said that the Centre for Brain Research established at IISc was an excellent starting point to setup the Dementia Network in India. Mathew Varghese from NIMHANS also stressed the same – when setting up the network was discussed 6 years ago, he said “research into Alzheimer’s Disease was in its infancy”.

In other talks, Sisodia from the University of Chicago has been working on the function of presenilin, a protein that is involved in the generation of beta-amyloid, which accumulates to form the ‘amyloid plaques’ typical of Alzheimer’s Disease. Deepak Nair from the Centre for Neurosciences, IISc has been studying the Amyloid Precursor Protein, which generates the beta-amyloid that leads to plaques. Vijayalakshmi Ravindranath studies how the plaques accumulate.

Balaji Jayaprakash from the Centre for Neurosciences, IISc has been studying mice affected by Alzheimer’s Disease to test memory and how it disappears with time.

Using laboratory strains of patient cells, Mitradas Panicker from the National Centre for Biological Sciences has developed a ‘gene map’ of the neural cells, which can help in earmarking the genes responsible for Alzheimer’s Disease.

Interviews

Prof. John Morris is the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, Professor of Pathology and Immunology, Professor of Physical Therapy, and Professor of Occupational Therapy at Washington University. He also is the Director and Principal Investigator of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center. He studies various aspects of Alzheimer disease.

Based on your experience in dementia research in the western world, what would be you suggestions to Indian researchers or researchers focussing on dementia in India?

In the US, the only area where we have done really well in approaching the issue of dementing illness is a combination of clinical research in following patients and healthy control people to see how the disease progresses in them in conjunction with basic science. So the two work together and not separately. In IISc, there is tremendous basic research but no or very little clinical research. In the US, we have exclusive Alzheimer’s research centres that are funded by national institute of health which started in 1984 and since then they have brought clinical and basic science people together. It’s not a tradition in India but I would say that is the only way to advance research in dementia here.

Do you think that lifestyle changes in Indians could help curb the rising number of dementia affected people here?

No one knows the answer yet but it might be possible. That makes India a wonderful place for this kind of research because of the diverse populations, cultures and lifestyles – diet, aging, obesity etc. factors can be checked for their links to dementia. India makes for a perfect laboratory to check for these questions and examine them in clinical cohorts. There will be a lot of challenges to that. Also the population above 65 is much lower in India as opposed to the US or Japan but the existing number is huge and it is only going to get bigger. Hence there is an imperative to do this research.

Available drugs have failed to stop or delay dementia. The ongoing genetic research in that direction is also in its nascent stages. Is there any other alternative that can help deal with dementia in the present situation?

Two paths that we haven’t tried –

  1. Administering past failed drugs during the earlier course of the disease, right when the symptoms show up. The research has just begun in that aspect.
  2. Using combination of drugs- each drug attacking a different mechanism leading to dementia. This is yet to start.

 

 

Perfectionism on part of proteins in cargo delivery could save lives

August 2015

A minor fault in any member of the team of proteins carrying structural elements for melanin pigment maturation could deprive us of not just our colour, but could be fatal when combined with few other factors.

Trucks and lorries rule the world of cargo delivery. Any malfunction in them affects the timely delivery of the cargo at the destination and where and how they are used in the further processes. This chain of events is not very different at a cellular level. Our cells also have their own transport pathways responsible for the cargo delivery at the right destination at the right time. Any variations to that system shows up as symptoms to fatal diseases. Dr. Subba Rao and team from the Indian Institute of Science, Bangalore, unravel the nitty gritties of one such transport pathway in animal cells where failure to deliver the cargo, in this case melanin synthesizing enzymes, could result in fatalities.

Melanin pigments are responsible for the colour of our skin and also play an important role in protection against radiations and any other damage from light. Melanin pigment is produced in cellular organelles called melanosomes which need melanin synthesizing enzymes transported from other organelles. The enzymes transported into premature melanosomes facilitate the maturation into fully pigmented melanosomes. The transport pathway is completed with the help of four multi subunit protein complexes, BLOC 1, 2, 3 and Adaptor protein 3 complex.

BLOC 1 consists of 8 subunits, functioning in the upstream of the pathway while BLOC 2, a 3-subunit protein complex, functions towards the end of the pathway in directing the transfer of molecules towards maturing melanosomes for subsequent reactions. It does so by the specific method of “tethering” or by stabilizing the intermediate molecules that need to be transported.

Mutations in BLOC 1 or BLOC 2 proteins result in inefficient delivery of melanin synthesizing proteins to melanosomes and thus failure in full expression of the melanin pigment. This malfunction manifests in the form of albinism of skin, ear and eye, also referred to as oculocutaneous albinism. This is one of the primary symptoms in Hermansky-Pudlak Syndrome (HPS). The other symptoms are lung infections, which are mistaken as Tuberculosis in most cases in India. Both the lung pathology and albinism put together result in HPS but the confirmatory diagnosis is genetic sequencing of the patient and the parents. HPS generally shows up in children within the age group of 4-6. Out of the 16 possible genetic mutations that can result in HPS, only 9 are known so far. Three out of those nine subtypes are a result of mutations to the BLOC 2 protein.

Even though BLOC 1 and 2 play their respective roles in the overall transport pathway, their molecular functions are not yet clear. There are additional proteins that are responsible for membrane trafficking throughout the cell in most transport pathways. These proteins are called Soluble NSF (N-ethylmaleimide sensitive fusion proteins) Attachment Protein REceptor (SNARE). SNARE proteins, a family of about 60 proteins has been known for their role in membrane fusion during transfer of information. For the first time, the team from IISc has identified two members from the SNARE family that are involved in the transport pathway to melanosome. Immortal melanocyte cell lines from mice, both wild type and mutated, were used for the experiments. The expression of these cell lines were estimated by their absorbance at certain wavelengths and compared with levels of protein expressions found in healthy cells. The team concluded that not only do SNAREs play a vital role in the endosome and melanosome membrane trafficking but are also responsible for maintaining the melanosomal proteins in their stable states until delivered to the maturing melanosomes. Very strong interactions between the SNARE proteins and BLOC 1 has been reported in the initial steps of the transport pathway.

Dr. Subba Rao and team intends to further work on uncovering the details of the interactions between the SNAREs and BLOC 1 and 2 complexes. It is important to understand the specific roles that BLOC 2 plays in the cell and would help in filling the gaps in the transport pathway. How and what delivers the cargo at the destination is yet to be understood. Whether the membranes actually fuse for the transport of the proteins or only the proximity of molecules with the opposite membrane to the surface completes the transport? What are the guiding proteins? If the SNAREs go back to their respective states after the transfer is completed? These are few questions the team is looking forward to resolve in their future research.

 

Keeping DNA in good shape

December 1, 2014

A stitch in time saves nine, goes the old saying. And here a team of scientists at Indian Institute of Science study RAGs (recombination activating genes) to understand the stitching and unstitching of the DNA, which in certain ways leads to genomic instability and cancer.

The RAG complex consists of two genes, RAG1 and RAG2. These genes produce the RAG proteins – RAG1 and RAG2 — which are expressed in the B and T cells of our immune system. The B and T cells help in locating and dealing with foreign substances that enter our bodies like bacteria and other microbes. The cells can recognise foreign bodies using proteins on their surfaces. The RAG gene complex helps in the generation of these surface proteins.

The high number of surface proteins that need to be produced sometimes leads to genomic instability and “chromosomal translocations” – rearrangement of bits of the chromosome, which can lead to incorrect arrangement of genes. This can lead to diseases like lymphoma and leukemia.

In a previous study, Dr. Sathees C Raghavan and Rupa Kumari showed that RAG proteins cleave DNA when they spot a particular sequence of nucleotides. In this paper, they have focussed on studying the factors that can regulate DNA cleavage efficiency of the RAG proteins. This can improve our understanding of how the DNA cleaving activity of these genes is turned on and off.

They found that apart from the sequence of a particular DNA complex, the sequence of the regions surrounding it are important in determining where the RAG proteins bind and where they cleave. The presence of cytosine and thymine in a single stranded region of the DNA complex dictates the position of nicking. A minimum of two cytosines are required for the RAGs cleavage efficiency. The deletion of certain sequences could result in the loss of sequence specific nuclease activity of RAG but it retains its structure specific nuclease activity.

The further understanding of these factors which regulate the stability of the above mentioned DNA complex could help us decipher the mutations that act as the root causes leading to cancers like lymphoma and leukemia.

The paper has been published online on 14th November in The FEBS Journal. http://onlinelibrary.wiley.com/doi/10.1111/febs.13121/abstract

– See more at: http://iisc.researchmedia.center/article/keeping-dna-good-shape#sthash.XZ8Y4mUA.dpuf