Thursday, August 27, 2009
Wednesday, August 05, 2009
Itasca & Cajal
So, I am at this beautiful place learning and doing the science which I like the most, of course. "We walk on the shoulder of giants" is such a true satement as on our very first day, there was mention of Dr. Santiago Ramon Y Cajal, whose work we continue to appreciate since he was awarded Nobel Prize in 1906. Dr. Lorene Lanier while referencing to his work compiled in a two volume book that contains the origional drawings of Dr. Cajal of the central nervous system histology which stands as accurate a depiction today, even with technological and scientific advancements, as it was over a century ago. Soon after the lecture was over, I couldn't help but flip through the initial pages of the book and I found this statement by Dr. Cajal himself really moving."I finally chose the cautious path of histology, the way of the tranquil enjoyments. I knew well that I should never be able to drive through such a narrow path in a luxurious carriage; but I should feel myself happy in contemplating that captivating spectacle of minute life in my forgotten corner and listening, entranced, from the ocular of the microscope, to the hum of the restless behive which we all have within us." The irony of this humble choice did not escape Cajal's attention on winning the Nobel Prize little more than 20 years later.
This is the science at its best, nothing more captivating than the science itself.
This is the science at its best, nothing more captivating than the science itself.
Monday, June 08, 2009
The Maze of Brain Tumors
In this long hiatus from writing some interesting findings in the science of brain tumors have surfaced. But it demands some background information first. A year into 21st century i.e. 2001, we were introduced to a book entitled "Brain tumor Immunotherapy" written by Linda M. Liau, M.D.,PhD., a faculty at UCLA. The idea indeed is novel, and may potentially lead to a break through in finding a cure for this ravaging disease. Whereas many of the Phase II and Phase III clinical trials on brain tumor immunotherapy are underway, we have still a long way to go, says John S. Kuo,M.D.,PhD. of University of Wisconsin in, "Tumour vaccine approaches for CNS malignancies: progress to date", published in Drugs 2009;69(3):241-9
It was in 2004 that Sheila K. Singh M.D.,PhD., now a faculty at McMaster University, discovered a population of cells within primary brain tumors that mimicked stem cell-like characteristics. She was under training at Hospital for Sick Children at University of Toronto then, under the supervision of Dr. Peter B. Dirks, M.D., PhD. The publication made it to Nature, and thus began the era of brain tumor stem cells. A year before that, in 2003, Dr. Harley L. Kornblums lab had already identified brain tumor stem cells from pediatric brain tumors. The publication appeared in PNAS. The number of publications that have followed, in just five years, are enormous. It can be judged from the fact that a simple keyword search for "brain tumor stem cells" through pubmed yields more than 2191 articles, published to date.
The modern practice of neurosurgery didn't begin until 1879 when the first meningioma was surgically excised by Dr. William Macewen of Glasgow. More than one and a quarter of a century in, with all the technological and scientific advancements, the outcome for patients with brain tumors hasn't still changed much. There have, of course, been cases where, with the help of immunotherapy, a longevity of, maximum, 36 months have been achieved (Please refer to Dr. Linda M. Lau's presentation on google). However, such cases remain few in number. For the majority, however, outcome remains dismal, with the average progression free survival of 9-12 months post surgery. I must emphasize here that this statement might seem overly simplified, the actual outcomes might vary with respect to centers at which patient is being treated and with regards to the treatment regimen being practiced by the neurosurgeon. However the typical route taken by a neurosurgeon, at any center today is to excise as much of the tumor as possible, give radiotherapy and chemotherapy, and then administer immunotherapy. For the most part these therapies are "adjunct", and none of them is effective, singly.
Given the excess of information that is available on brain tumor stem cells, however, alternative hypothesis are also actively and rigorously being explored. Charles S. Cobbs M.D., a neurosurgeon at California Pacific Medical Center firmly believes that during developmental years our brains get infected with CMV. A sequence homologous to CMV genome have been found in the genome of brain tumor cells which has convinced Dr. Cobbs to pursue this path of investigation. By exploring into immunotherapy options, in collaboration with brilliant Dr. Linda M. Lau, Dr. Cobbs has witnessed that in one patient immune response against CMV antigen was extremely strong such that that patient remains disease free, so far. But, how such an immune response gets mounted isn't known entirely, yet. Further research is being carried out, to extend the therapy to other patients.
Animal models that have long been used to study different diseases have been promising in areas for brain tumor immunotherapy, nanoparticles based chemotherapy, or chemotherapeutic agents alone etc. but most success have come through in canine models; Dr. John Ohlfest PhD., of University of Minnesota have been very active in developing immune therapies for canine brain tumors, and he believes one day it would lead to a break through in treating human disease. Batman, the dog, which received this therapy remains disease free and active, to date. There are clinical trials going on that combine the science of stem cells with brain tumor immunotherapy. Dr. Mitchell's group, from Duke University, who is actively exploring such therapies, is just one such example, out of the many. However, the story isn't as simple, again, as it might have seemed. When Shinya Yamanaka M.D.,PhD., published his induced pluripotent stem cells paper, he also wrote a commentary on using immunotherapy against epitopes of brain tumors. Peter Dirks M.D.,PhD., also concurred on the idea by writing a similar paper although his main area of focus remains brain tumor stem cells. Technically speaking, these hypotheses are sound but somehow the findings from animal models have failed to translate onto human subjects, says John S. Kuo, M.D.,PhD., of University of Wisconsin in his publications, " Tumour vaccine approaches for CNS malignancies: progress to date", and there is still a long way to go.
This brings me to the point that I had mentioned to my mentor few months back that we need to actively explore into this area by using real human tissues from the operating room. It is not surprising that Dr. Alfredo Quinone Hinojosa M.D., a neurosurgeon at Johns Hopkins University who also runs a Brain Tumor Stem cell Laboratory has presented this perspective in his latest article entitled, " Intra-operatively obtained human tissue: protocols and techniques for the study of neural stem cells", published in J Neuroscience Methods 2009 May 30;180(1):116-25. Aside from making the point that one has to move quickly in science this article genuinely underpins to the fact that if a real progress has to be made in brain tumor field, we need to study the normal and abnormal tissue of the patient rather than rely heavily on animal models which no doubt are important in increasing our understanding but that is the tissue we are devising therapies against, after all, hence that should be the focus of our attention.
But what I find even more interesting is the fact that even the most celebrated ones are coming back to the basics. Dr. Linda M. Liau who has been a great proponent of Immunotherapy for brain tumors has finally succumbed to the seductions of brain tumor stem cells as manifested by her latest publication in J Neurooncol. 2009 May 26, entitled, " Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors". The point that this article makes is that if we identify the intrinsic and extrinsic cues that regulate these CD133+ brain tumor stem cells, we might be better equipped in devising strategies to curb the recurrence of these highly malignant tumors. Dr. Peter Dirks, on the other hand, is focussing on establishing the hierarchy of brain tumor stem cells to neural stem cells. But these latest advancement in science are hardly surprising, infact these were the most logical ones to begin with. After surgery, when exposed to radiotherapy and chemotherapy, CD133+ positive cells are the ones that get most resistant to both these adjuvant therapies. It is because of these cells that the cancer recurs. If we have to check that growth, we have to strike that Achille's tendon. Our arrow could be a vector, an immune cell or some miracle drug but a thorough understanding, as highlights Dr. Lau's paper, of the regulatory mechanisms of BTSCs must come first.
Not to complicate this any further, Dr. Austin Smith PhD., of Cambridge University, has picked up the most obvious point whether CD133+ cells are the only progenitor cells in developing brain. Not so surprisingly, a population of CD133- cells with a different set of progenitor markers was identified by his team that also shows stem cell characteristics. But the simple point that emerges from this discussion is that CD133+ cells closely correlate with disease severity, recurrence, early progression to advanced disease that is responsible for high mortality in brain tumors.
It was in 2004 that Sheila K. Singh M.D.,PhD., now a faculty at McMaster University, discovered a population of cells within primary brain tumors that mimicked stem cell-like characteristics. She was under training at Hospital for Sick Children at University of Toronto then, under the supervision of Dr. Peter B. Dirks, M.D., PhD. The publication made it to Nature, and thus began the era of brain tumor stem cells. A year before that, in 2003, Dr. Harley L. Kornblums lab had already identified brain tumor stem cells from pediatric brain tumors. The publication appeared in PNAS. The number of publications that have followed, in just five years, are enormous. It can be judged from the fact that a simple keyword search for "brain tumor stem cells" through pubmed yields more than 2191 articles, published to date.
The modern practice of neurosurgery didn't begin until 1879 when the first meningioma was surgically excised by Dr. William Macewen of Glasgow. More than one and a quarter of a century in, with all the technological and scientific advancements, the outcome for patients with brain tumors hasn't still changed much. There have, of course, been cases where, with the help of immunotherapy, a longevity of, maximum, 36 months have been achieved (Please refer to Dr. Linda M. Lau's presentation on google). However, such cases remain few in number. For the majority, however, outcome remains dismal, with the average progression free survival of 9-12 months post surgery. I must emphasize here that this statement might seem overly simplified, the actual outcomes might vary with respect to centers at which patient is being treated and with regards to the treatment regimen being practiced by the neurosurgeon. However the typical route taken by a neurosurgeon, at any center today is to excise as much of the tumor as possible, give radiotherapy and chemotherapy, and then administer immunotherapy. For the most part these therapies are "adjunct", and none of them is effective, singly.
Given the excess of information that is available on brain tumor stem cells, however, alternative hypothesis are also actively and rigorously being explored. Charles S. Cobbs M.D., a neurosurgeon at California Pacific Medical Center firmly believes that during developmental years our brains get infected with CMV. A sequence homologous to CMV genome have been found in the genome of brain tumor cells which has convinced Dr. Cobbs to pursue this path of investigation. By exploring into immunotherapy options, in collaboration with brilliant Dr. Linda M. Lau, Dr. Cobbs has witnessed that in one patient immune response against CMV antigen was extremely strong such that that patient remains disease free, so far. But, how such an immune response gets mounted isn't known entirely, yet. Further research is being carried out, to extend the therapy to other patients.
Animal models that have long been used to study different diseases have been promising in areas for brain tumor immunotherapy, nanoparticles based chemotherapy, or chemotherapeutic agents alone etc. but most success have come through in canine models; Dr. John Ohlfest PhD., of University of Minnesota have been very active in developing immune therapies for canine brain tumors, and he believes one day it would lead to a break through in treating human disease. Batman, the dog, which received this therapy remains disease free and active, to date. There are clinical trials going on that combine the science of stem cells with brain tumor immunotherapy. Dr. Mitchell's group, from Duke University, who is actively exploring such therapies, is just one such example, out of the many. However, the story isn't as simple, again, as it might have seemed. When Shinya Yamanaka M.D.,PhD., published his induced pluripotent stem cells paper, he also wrote a commentary on using immunotherapy against epitopes of brain tumors. Peter Dirks M.D.,PhD., also concurred on the idea by writing a similar paper although his main area of focus remains brain tumor stem cells. Technically speaking, these hypotheses are sound but somehow the findings from animal models have failed to translate onto human subjects, says John S. Kuo, M.D.,PhD., of University of Wisconsin in his publications, " Tumour vaccine approaches for CNS malignancies: progress to date", and there is still a long way to go.
This brings me to the point that I had mentioned to my mentor few months back that we need to actively explore into this area by using real human tissues from the operating room. It is not surprising that Dr. Alfredo Quinone Hinojosa M.D., a neurosurgeon at Johns Hopkins University who also runs a Brain Tumor Stem cell Laboratory has presented this perspective in his latest article entitled, " Intra-operatively obtained human tissue: protocols and techniques for the study of neural stem cells", published in J Neuroscience Methods 2009 May 30;180(1):116-25. Aside from making the point that one has to move quickly in science this article genuinely underpins to the fact that if a real progress has to be made in brain tumor field, we need to study the normal and abnormal tissue of the patient rather than rely heavily on animal models which no doubt are important in increasing our understanding but that is the tissue we are devising therapies against, after all, hence that should be the focus of our attention.
But what I find even more interesting is the fact that even the most celebrated ones are coming back to the basics. Dr. Linda M. Liau who has been a great proponent of Immunotherapy for brain tumors has finally succumbed to the seductions of brain tumor stem cells as manifested by her latest publication in J Neurooncol. 2009 May 26, entitled, " Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors". The point that this article makes is that if we identify the intrinsic and extrinsic cues that regulate these CD133+ brain tumor stem cells, we might be better equipped in devising strategies to curb the recurrence of these highly malignant tumors. Dr. Peter Dirks, on the other hand, is focussing on establishing the hierarchy of brain tumor stem cells to neural stem cells. But these latest advancement in science are hardly surprising, infact these were the most logical ones to begin with. After surgery, when exposed to radiotherapy and chemotherapy, CD133+ positive cells are the ones that get most resistant to both these adjuvant therapies. It is because of these cells that the cancer recurs. If we have to check that growth, we have to strike that Achille's tendon. Our arrow could be a vector, an immune cell or some miracle drug but a thorough understanding, as highlights Dr. Lau's paper, of the regulatory mechanisms of BTSCs must come first.
Not to complicate this any further, Dr. Austin Smith PhD., of Cambridge University, has picked up the most obvious point whether CD133+ cells are the only progenitor cells in developing brain. Not so surprisingly, a population of CD133- cells with a different set of progenitor markers was identified by his team that also shows stem cell characteristics. But the simple point that emerges from this discussion is that CD133+ cells closely correlate with disease severity, recurrence, early progression to advanced disease that is responsible for high mortality in brain tumors.
Wednesday, April 08, 2009
On Doing Science - Advice from the Expert!
Tuesday, April 07, 2009
Saturday, March 28, 2009
The science that inspires!
The last page of the MIT TechTalk,-Volume 53, No. 17, March 4, 2009-displays the photograph of a smiling young man. The wall behind and the floor below him, are both chalked with seemingly esoteric inscriptions . This is Geoffrey von Maltzahn, the winner of this years Lemelson-MIT student Prize, an accolade that recognizes an outstanding inventor who proposes sustainable and innovative solutions to the worldly problems. "The $30,000 Lemelson-MIT Student Prize is awarded annually to an MIT senior or graduate student who has created or improved a product or process, applied a technology in a new way, redesigned a system, or demonstrated remarkable inventiveness in other ways. A distinguished panel of MIT alumni including scientists, technologists, engineers and entrepreneurs chooses the winner."
The "Gold Star" as the article is titled reporting Geoff's contribution is actually a pithy expression of his innovative approach in fighting, the scourge of all diseases, cancer. What made him the most deserving candidate for the prize were his two remarkable achievements; the development of new class of cancer therapeutics and establishment of new paradigm to enhance drug delivery to tumors.
I had reported in one of my previous posts about Dr. Sangeeta Bhatia who had developed nanoparticles that could precisely home in on tumor cells and deliver drugs specifically while convecting heat to the malignant cells at the same time when being subjected to microwaves. Geoff had been working with Dr. Bhatia on these "nano antennas" as they are named that made from gold particles that when injected in blood localize to the cancerous tissue by passing through the leaky blood vessels in tumor niches. Once there, the antennas are heated by non-invasive near-infrared radiations. This approach kills 100% of tumors in mice, says Dr. Bhatia, in preclinical trials.
His second invention is the efficient drug delivery to tumors by first sending in the benign particles that "locate" the tumors. These navigator particles then send signals to what he calls "assassin" particles that then home in on the tumor and deliver the drug at concentrations that would otherwise be toxic to the normal tissues if administered systemically.
At age 28, Geoff, a Harvard-MIT Health Sciences and Technology graduate student, has 8 patent applications, 19 publications and two companies, Nanopartz Inc. (www.nanopartz.com) and Resonance Therapeutics, to his credit.
The "Gold Star" as the article is titled reporting Geoff's contribution is actually a pithy expression of his innovative approach in fighting, the scourge of all diseases, cancer. What made him the most deserving candidate for the prize were his two remarkable achievements; the development of new class of cancer therapeutics and establishment of new paradigm to enhance drug delivery to tumors.
I had reported in one of my previous posts about Dr. Sangeeta Bhatia who had developed nanoparticles that could precisely home in on tumor cells and deliver drugs specifically while convecting heat to the malignant cells at the same time when being subjected to microwaves. Geoff had been working with Dr. Bhatia on these "nano antennas" as they are named that made from gold particles that when injected in blood localize to the cancerous tissue by passing through the leaky blood vessels in tumor niches. Once there, the antennas are heated by non-invasive near-infrared radiations. This approach kills 100% of tumors in mice, says Dr. Bhatia, in preclinical trials.
His second invention is the efficient drug delivery to tumors by first sending in the benign particles that "locate" the tumors. These navigator particles then send signals to what he calls "assassin" particles that then home in on the tumor and deliver the drug at concentrations that would otherwise be toxic to the normal tissues if administered systemically.
At age 28, Geoff, a Harvard-MIT Health Sciences and Technology graduate student, has 8 patent applications, 19 publications and two companies, Nanopartz Inc. (www.nanopartz.com) and Resonance Therapeutics, to his credit.
Sunday, January 25, 2009
Massry Prize-2008
In words quite clear,"our thought is that we should recognize it before the Nobel Prize did" Dr. Shaul G. Massry, a professor emeritus of medicine at the University of Southern California has predicted the future Nobel Laureate trio of Dr. James A. Thomson, Dr. Shinya Yamanaka and Dr. Rudolf Jeanich who shared the Massry Prize for the year 2008.
Eight of its 21 recipients, since its establishment in 1996, have gone on to win the Nobel Prize. That highlights the significant contribution to science that this prize recognizes.
The three recipients reversed the differentiated skin cells to obtain iPS cells. Dr. Jeanich, however, has used these cells to successfully treat Parkinson's disease in mouse model.
The full story can be read here.
There is much hope in this science of transdifferentiation. A team of researchers from University of Bath, center for Regenerative Medicine that includes Dr. Jonathan Slack who is currently the head of the Stem cell Institute at University of Minnesota have already used the technique to transdifferentiate liver cells to pancreatic Beta-cells that carries the promise of helping diabetic patients.
Eight of its 21 recipients, since its establishment in 1996, have gone on to win the Nobel Prize. That highlights the significant contribution to science that this prize recognizes.
The three recipients reversed the differentiated skin cells to obtain iPS cells. Dr. Jeanich, however, has used these cells to successfully treat Parkinson's disease in mouse model.
The full story can be read here.
There is much hope in this science of transdifferentiation. A team of researchers from University of Bath, center for Regenerative Medicine that includes Dr. Jonathan Slack who is currently the head of the Stem cell Institute at University of Minnesota have already used the technique to transdifferentiate liver cells to pancreatic Beta-cells that carries the promise of helping diabetic patients.
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