In IIT Kanpur,one of the oldest IITs in the country,a relatively young department is bustling with exciting ideascancer reversal,an artificial liver,answers to osteoporosis and osteoarthritis and many more.
V. SHOBA visits IIT Kanpurs Department of Biological Sciences and Bioengineering.
The lab smells like browning bananas. Its a mixture of powdered maize,sugar and yeast,with propionic acid added as a preservative, says Aarti Mishra. The porridge,as the geneticist and research scientist at IIT Kanpurs Department of Biological Sciences and Bioengineering calls it,is thickened in a large stainless steel vat,the kind used in five-star kitchens to boil soup. After all,it is the favoured delicacy of the thousands of resident fruit flies that live and breed in translucent plastic bottles,with a generous layer of the food at the bottom. Its an ideal fruit fly world,where the temperature is always 18 degrees Celsius. It doesnt last forever though. Once the flies are out of their bottles,they become Drosophila melanogaster,laboratory organisms that are regularly interfered with,their genes tame and amenable to the harshest,and most crucial,biological experiments. Such as having tumours grown in them,so we can hope to learn more about cancer.
Cancer modelling has been one of the research staples at the Department since its inception about a decade ago. In the eco-friendly buildingcool air is sucked up from a pit outside and circulated through the foyerwith 16 labs on three floors,Head of the Department,Professor Pradip Sinha,dressed in a golf shirt,jeans and trainers,remembers how it all began. The department was conceived,in principle,in 1999,when we got generous MPLADS funding from Rajya Sabha MP Mr Arun Shourie. I came here in 2001,and the others joined,and we got started. In the last eight-nine years,one of the common threads of research has been human diseaseunderstanding,modelling,diagnosis and therapy. So if someone is unravelling the fundamental mechanics of cancer,others are working on neural degeneration,epilepsy,nanomaterials for drug delivery,tissue engineering and such areas, he says. We are knocking on the doors of translational medicine.
One visit to the department is all it takes to see its more than a knock.
In Mishras lab,when tumours were induced in fruit flies by manipulating genes known to be responsible for organ growth,size and cell proliferation,the carcinogenesis threw up remarkable results. Were upset, Mishra says,half joking. Its too big a result and we want to corroborate it for the nth time before we say anything for certain, she says. The result goes like this: when a gene,known as wingless and responsible for cellular division and adhesion,was introduced in excess in fruit flies,they developed tumours,andthis is the surprising partwhen the gene was controlled,the cancer progression was reversed and the flies,miraculously,were normal again. What this means is that even after a cancerous lesion,cells could be rescued from carcinogenesis, says Mishra,who hopes to publish the results,so far tested only in fruit flies,soon. While the findings offer fundamental insights into cancer mechanisms and may help develop drugs that can reverse cancer,Mishra and Sinha,who is also involved in the cancer modelling exercise,hasten to add that they are still at a very early phase of the research. As of now,the only widely-known way of overcoming the disease has been to physically kill the cancerous cells.
The wingless gene is part of what is called the Wnt signalling pathwaya series of cascading signals that tell the cells what to do,and thereby control cell morphology,division and growth. When Wnt signalling is in excess,the adherence between cells starts to weaken and they are able to divide more and move physically from one part of the body to anothera process known as metastasis. The gene,which is responsible for forming wings in fruit flies,is cancerous in humans too when mutated. In fact,it has been found to be in excess in cases of colon cancer. In the flies,when there is too much of it,the sack of cells that differentiates into the eyes,the head and the antennae receives faulty signals,so that the eye cells are lost and multiple antennae are formed instead, Mishra explains. However,when another gene,which binds to Wnt,was introduced,it stopped the cancerous gene from entering the cells and interrupted the faulty signalling,thereby reversing the carcinogenesisthe dream of every cancer researcher.
Artificial liver,lab-grown cartilage
If Mishra is trying to curtail excessive division of cells,Ashok Kumar,department researcher and associate professor of bioengineering,is growing them. Kumar has grown,for the first time in a laboratory,articular cartilagethe tissue that covers joints,enabling the movement of bone against bonethat he hopes will help osteoarthritis patients repair their joints instead of taking recourse to painful joint replacement surgery.
His lab has churned out a fleet of achievements: an artificial liver that can support a patients damaged liver from outside the body; a self-degrading biomaterial scaffold to help in wound healing,blood adsorption and skin tissue formation; filters for removing leukocytes from blood for effective transfusion; nanoparticles for targeted drug delivery; and stem cell separation.
At the heart of all this high science is a deceptively simple ideaa porous polymer,which Kumar calls a cryogel,synthesised in a cold bath at -12 to -20 degrees Celsius. When polymer solution is frozen,the water forms interlinked crystals,which upon thawing leave behind a gel with 200-micron-sized pores. Since a cell is at best 10 microns,the polymer matrix provides a suitable microenvironment for cells to grow and develop tissue. It also makes an excellent filter,which can be characterised as per medical requirements, says Kumar. When articular cartilage cells were allowed to grow on a cryogel scaffold,a neocartilage with the properties of natural cartilage was formed in six to eight weeks in laboratory conditions,and the polymer degraded simultaneously. The laboratory-made cartilage was seen to integrate well in pre-clinical trials on animals.
The bio-artificial liver device,which has a cryogel filter,has been tested offline in the lab on plasma from patients suffering from acute liver failureIIT Kanpur has tied up with G.B. Pant Hospital and the Institute of Liver and Biliary Sciences,both based in New Delhi,for pre-clinical testing. A bi-layered cryogel bandage is also undergoing pre-clinical trials and an absorbent towel capable of instantly clotting a large quantity of blood is being developed.
Tanushree Vishnoi,one of the young research scholars at the tissue engineering lab,is working on an electro-conductive cryogel,made of a polymer that can conduct electric signals,which,she says,can help stimulate the growth of cardiac and neural cells. Neural cells are not regenerative by nature. But they are excitable cellsthey proliferate when electrically stimulated. So the idea is to create a conducting polymer medium,through which electric signal can be passed,for them to grow in, she says.
Genetic answers to osteoporosis
On the other side of the clinical research on osteoarthritis is Amitabha Bandopadhyay,a developmental biologisthe left Harvard Medical School for IIT Kanpur in 2006who is probing the genes critical for bone formation,the absence of which results in osteoporosis. All bones were once cartilagethough quite different from the articular cartilage that supports adult joints, he says. So what is it that forms bones? Half a century ago,a gene capable of initiating a reparative response in bones was found to reside within bone itself,and the term bone morphogenetic protein (BMP) was coined to describe the molecules responsible for it. In a 2006 issue of the journal Nature Genetics,Bandopadhyay and fellow-researchers published results from experiments on adult transgenicgenetically modifiedmice that lacked a component called BMP2. The mice were found to suffer spontaneous fractures that did not heal with time. In bones lacking BMP2,the researchers concluded,the earliest steps of fracture healing seem to be blocked.
BMP is manufactured as an FDA-approved implant for fracture healing in the US,but it costs $25,000 per implant. IIT Kanpur has a collaboration with the University of Nottingham,UK,under which we are testing drugs that behave like BMP, Bandopadhyay says. As of today,there is no known chemical analog for BMP.
Jamuna Subramaniam is addressing a fundamental question: how to live longer. In a 2008 report in Biogerontology,Subramaniam and fellow-researchers made a case for reserpineknown as an antipsychotic,FDA- approved antihypertensive drug that was frowned upon after a high dose resulted in schizophrenia in the 1950sbased on their finding that chronic reserpine treatment from embryo stage or young adults extends the lifespan of Caenorhabditis elegans robustly by modulating the neural system. The report also said that the reserpine-treated worms were active for a longer time. Interestingly,reserpine is a plant alkaloid purified from the roots of the plant Rauwolfia serpentine,traditionally used for hypertension and as an antipsychotic remedy in India. Its commonly known as snakeroot, she says.
Another neural researcher,S. Ganesh,who moved to IIT Kanpur in 2002 after a stint at the RIKEN Brain Sciences Institute,Tokyo,to focus on finding the genes that affect brain function,identifying population-specific diseases and observing the cell-level mechanism behind neural diseases,has made notable progress in the fieldhe discovered the role of two antagonistic protein variants coded by one gene that result in Lafora disease,a rare and fatal neurodegenerative disorder. Ganesh got the Elsevier Young Scientist Award in 2006 and the Birla Science Prize for Biology in 2008 for his work.
The ultimate objective for neuroscientists,says Jonaki Sen,who is studying the wiringspecific connections made by neurons with one anotherof the brain,is to coax damaged neurons to grow new processes,which will then rewire themselves accurately.
Even as Jamuna Subramaniam helps C. elegans,a worm that belongs to the nematode family,live a longer,more active life,her husband,K. Subramaniam,associate professor at the department,focuses on how these tiny organisms make their reproductive cells,or germcells. After modelling the laboratory organisms,he has genetically engineered plants to resist parasitic nematodes as part of a project funded by the World Banks National Agricultural Innovation Project. With RNA-mediated interference in the worm,the germcell development of the nematode can be halted and proliferation controlled, he says.
Points of convergence
Dhirendra Katti is a biomaterials researcher whose areas of interest overlap with those of fellow-faculty,be it with Kumar and Bandopadhyay on the idea of an artificial matrix that can provide a near-native environment for cartilage cells to grow,or with the cancer modelling lab by way of his research in nanoparticles as drug carriers that can recognise cell types of interest. Anupam Pal,the departments only mechanical engineer,is engaged in probing the mechanical forces at work in articular cartilage.
Then there is R. Sankararamakrishnan,whose bioinformatics lab models protein structures using computational biology. Ganesh looks at molecules that cause neurodegenerative disorderswe look at proteins,those involved in cell survival and cell death,and model them, he says. Balaji Prakash,who studies proteins,too,says they are smart nanomachines that can break strong bonds,a process that would otherwise require very high energy,in a very short time. With X-ray crystallography,we try to understand how these moleculesproteinscome about, says Prakash,who worked at the Max Planck Institute,Germany,before he joined IIT Kanpur in 2003. Take,for example,the protein that makes the thick cell wall of the mycobacterium in case of TBhow does it work? says Prakash,who got the Wellcome Trust Fellowship in 2004 for his work. K. Subramaniam got the Wellcome fellowship in 2003. For a new department,getting two fellowships in such a short period of time is nice, he says.
Professor Govind Dhande,Director,IIT Kanpur,says they have stayed true to the word excellence,a point underscored by Mr Shourie while pledging the MPLADS funds for the Department. Sinha says the Department,with its able faculty and 70-80 Ph D students,has grown a lot. Climbing the double-helix staircase that winds up the facade of the Department building after meeting the group of unassuming scientists,one understands just how much.