NEUROTICS-DE-KASHIF

Vaccine Hunts Brain Cancer Stem Cells like a Bloodhound

2012-01-16T12:25:00.002-05:00

New vaccine targeting the glioma stem cells antigens will be tested at Wake Forest Baptist in a Phase II clinical trial. Professor Glenn Lesser who is leading this trial thinks this vaccine is unique since it targets the handful of cells that keeps the tumor alive and dividing. Other cells are likely not driving the tumor.

The brain cancer stem cells (CSCs) which were discovered by Dr. Peter Dirks team remain at the heart of this aggressive and fatal disease. Any breakthrough that will come in this regard will likely involve these brain CSCs.

So far vaccines remain as adjuvant therapies because in the battle against cancer immune system ultimately succumbs to the suicide inducing (apoptosis) effects of cancer cells if few of the the immune cells manage to get near those cancer cells. Additionally cancers in general and brain tumors in particular not only create a local immune suppressive milieu but also cause a systemic immunosuppression.

These are some of the hurdles that lie across immunotherapy of brain tumors. The efforts to develop other modes of therapy that target novel pathways implicated in brain tumorigenesis must continue to supplement the already existing, though scarce, therapies.

When mentoring goes bad

2011-08-03T23:02:00.000-04:00

Last year Wall Street Journal publish an impressive article entitled "when mentoring goes bad". It is something that every mentor and mentee should read before venturing on a mutual partnership professionally.

Glioma Cells of Origin

2011-07-20T00:50:00.000-04:00

A collaboration between Oregon Health Science Center and Standford University has resulted in the identification of cells of origin for brain tumors to be Oligodendrocyte Precursor Cells (OPCs), that seems to put an end to a long-standing controversy of whether or not brain tumors are of progenitor cell origin. The publication appears in the July Issue of highly prestigious journal, Cell.

Cellular Origin of Deadly Brain Cancer Identified

Mosaic Analysis with Double Markers Reveals Tumor Cell of Origin in Glioma

Money Can't Buy Happiness But Choices Can

2011-07-08T00:07:00.010-04:00

"My taya jee (uncle) didn't have any formal education but everyday he stepped out of the house praying, may I meet a generous person today (khuda kisay sakhi da mun dikhaye)." Perhaps growing up he had learnt that human beings could be so stingy at times...

For long, people have wondered what is the meaning of this life? The questions that have eluded the philosophers and thinkers for centuries are more recently being explored under the neuroscience arena. What can make ones mundane life more worthwhile? Is it the wealth? Would you be happier if you wake up one day only to find million dollars in your account? Can it be the beautiful mansion that you live in? Did staying in a $3000 a night hotel room make Mr. Dominique Strauss-Kahn more content? Can it be a dream vacation to one of the most surrealistic islands in the world? Would it be the company of the most beautiful woman? Or dining the most expensive meal or driving the most expensive car etc?

People have long wondered on the answers to these obvious questions, in the hope to ascribe some higher meaning to this apparently banal existence. The debate of religion and ethics, perhaps, ties in here. The concept of divinity and struggle to achieve a higher moral ground is woven in. Some reside on the top of mountains to remain in a life long practice of self-restraint and patience, while others try to achieve nirvana through various spiritual practices etc. Religious personnel turn to their holy places for guidance, having already ascribed a higher meaning to their lives, to eternally prostrate to the one who is the creator of these heavens and earths. Some delve into the mysteries of this universe. The physicists and biologists etc find solace in their inquisitive natures to answer, though on a minuscule scale compared to this expansive universe around, some fundamental questions about how life came to be and how it functions. Those higher meaning questions remain elusive even to the most acute. Some, not finding a plausible answer, give up their quest saying with the end of this life ends everything. The concept of heaven and hell vanishes in thin air.

As Richard Dawkins writes in his book, The Selfish Gene and many scientists also corroborate to those assertions is that even the most selfless acts of kindness that a member of specie shows towards another carries a hidden meaning to it i.e. to promote ones own survival. That survival, now it appears, doesn't have to be a physical one. This world has a tendency to remember either the kind or the cruel. The rest more modest ones are, in physical terms, just a recycling of energy that can neither be created nor destroyed; it only changes form. Even those whom you consider the most obtuse know this fact. A commander would have given a heart throbbing speech to his platoon at the gates of Normandy emphasizing, "make your country proud". When someone is not fighting with the enemy, a sports coach, for example, might say, make your team, state and/or country proud. In the face of high achievements in academics, teachers are often heard saying, you make your teachers and parents proud. In all these examples, no one is talking about physically living forever but only in the metaphysical terms; they want their names to survive from the banality and crowd of this world.

Perhaps given this preface, the study by Dr. Ronald Fischer, doesn't come as a surprise that people feel happier and much content when they have the option to express their unique self. That self-expression comes from having choices in life and the freedom to choose which one finds best. If ones basal monetary needs are met, people find it more satisfying to do what they would be best at. This number isn't surprising; having interviewed some 420,599 participants in some 63 countries, the team has finally concluded the most evident truth that "money doesn't buy happiness or well-being but it is the choices and autonomy that pleases one the most.

"Autonomy provides you with the option to pursue meaning in your life, to find activities that stimulate and excite you and keep you active", so admits doctor Fischer! For employers he says, people may not need the highest paying job but something that would give them greater happiness and satisfaction in life".

When someone says that he or she is interested in something, e.g. science, arts, literature, perhaps, it is not the money that he or she is after, it is actually the science, arts or literature, in an instinctual way to carry on ones evanescent rubric so that it survives this ephemeral world. Eat and sleep, we all do but we should also open doors for those who are genuinely interested in something. Interest engenders unique perspectives; Santiago Remon y Cajal, ever since his medical schooling, was interested and preoccupied with histology. He had seen, perhaps, every organ under the microscope. He is considered the father of neuroscience as he discovered the cellular nature of the nervous system. We have to realize that this world is dying at a faster pace than we may have estimated; the threat of global warming and with that the energy and food crisis are very real. We could use the next big idea. Lets not crush the next Nicola Tesla who would lighten our gloomy existence. Let your name survive not as the antithesis of good but as pure good.

Are you that generous hearted person?

The Limits of Intelligence

2011-06-21T00:59:00.003-04:00

The article by Douglas Fox in the July, 2011 issue of Scientific American tries to address the most fundamental question that must have crossed our minds at some point in our lives; can we humans, as a specie, evolve to become even more intelligent? He argues in, "The Limits of Intelligence" borrowing strong evidence from the current neuroscience that the laws of physics prevent us from becoming an even smarter specie. By summarizing his conclusion in a flow diagram whereby he begins with a current brain size, and evaluates various ways by which it could be done to improve our brain functionality:

Tweak 1: Larger Brain; by adding more brain cells can increase the processing capacity of our brains.
Trade-offs: Neurons burn a lot of fuel, and with increasing brain size, longer axons are needed that increase resistance making the processing slow.

Tweak 2: Increase synapses. By increasing connectivity of existing neurons, processing can be made efficient.
Trade-offs: The added wiring consumes major chunks of energy.

Tweak 3: Increase signaling speed by making axons thicker.
Trade-offs: Thicker axons have higher energy demand.

Tweak 4: Pack more neurons into the existing space by shrinking neurons or axons or both.
Trade-offs: Thinner axons offer increased resistance to electrical signaling. Signaling gets too noisy as they tend to fire randomly.

Based upon these assumptions he concludes that the very laws of physics that made us smarter once, in the evolutionary ladder, are limiting our intelligence to increase further.

To read the article please visit Scientific American however a subscription might be needed to access the full-text of the article online or alternatively visit your nearest library.

History of Neuroscience

2011-06-15T02:23:00.000-04:00

"The year is 161. The gladiatorial games have just been closed. Galen heads to the Rome of Marcus Aurelius. At that time, in Rome, the relationships between the ruling politicians and aristocrats, and the intelligentsia, particularly philosophers and Sophists that also include physicians and scientists are pretty close. This period known as the "Second Sophist" the Empress Julia hosts a salon of philosophers and writers; Greek intellectuals marry Roman aristocrats; and the rulers of the empire sponsor and attend scientific demonstrations and lectures", an excerpt from the Charles Gross's "A Hole in the Head".

It seems that the elite of the past greatly valued scientific discourse and honored those who excelled in that arena; indeed, that was a time of great intellectual freedom. Many ground breaking insights emerged if one compares the prevalent humor concepts. The approach of those scientists and philosophers were very methodical. Perhaps, only through the eyes of history can we truly appreciate the remarkable progress the humankind has made, in such a short period of time, given the evolutionary age of this planet.

The Creating Brain: The Neuroscience of Genius

2011-05-13T18:35:00.012-04:00

Of the few neuroscience books that I have read, this is by far the best one that I have come across although in my readings there are few written by Nobel Laureates. Please allow me to highlight some unique points of this book.

Everytime, one sees a title of M.D., Ph.D., one quickly assumes that the doctorate must have been in one of the life sciences disciplines. Dr. Nancy C. Andersen is the first author that I know of, a prodigy in her own regard, who has done it differently. Having first acquired a doctorate in English literature from Oxford that she taught for several years, she then embarked upon a medical career. It was during her medical school years that she used to put baffling questions to then a neuroanatomy faculty. Unable to find a satisfactory answer, she herself decided to study the brain. Therefore, she is rightly placed to write this treatise that is terse yet presents a comprehensive but different perspective on brain than a neuroscientist would who has obtain a doctorate just in biological sciences.

The word economy is one of the most essential traits to emerge as an impressive writer. Being a professor of literature, Dr. Andersen could succinctly summarize the topic of creativity and genius that literally lies on the precipice of neuroscience, the last frontier of science. She managed to do it in mere hundred and some eighty pages that others might do in double of that.

Most importantly by citing the personal accounts of some of the most creative people in the history like Wolfgang Amadeus Mozart, Samuel Taylor Coleridge, Neil Simon, Peter Ilych Tachaikovsky etc, since such accounts of how creative geniuses come to be in sciences are rather scant, she lays the foundation for a more empirical analysis of the subject in the days to come.

A unified theme that emerges from the book, discussed in the the classical studies that saw little distinction between genius and creativity, and is corroborated by those personal accounts is that one need not be a genius, defined still by the high IQ scores, in order to be creative. An above average IQ with a zeal for something is impetus enough to create marvelous pieces, be it of literature, art or science, as cited by the many examples including those of Leonardo DaVinci, Michelangelo etc etc.

Additionally, genetics though confers an advantage by giving the opportunity to be born and bred amongst geniuses, isn't an incumbent condition to creativity. The backgrounds of the most famous creative geniuses were indeed quite modest. Michelangelo and DaVinci, none of them had a formal education, their parents were peasants and moms, simple housewives; none with any prior creativity streak in the family. Francis Galton who wrote Hereditary Genius never had proper schooling yet he was able to converse in French and Latin when he was little, he could solve geometry and algebraic problem when he was quite young and he managed to learn medical literature on his own. To sum up whereas genetic may provide one with the right genes, it is the environment that shapes up how those neurons connect with each other to give us unique insights into the biological and general life phenomenon. Van Gogh wouldn't have seen the world differently had his neurons not acquired distinct synaptic connctions, so would have shakespear not composed the Hamlet or the Road to Xanadu wouldn't have been written in a dream like state so admits Samuel Taylor Coleridge.

The common phenomenon that has been highlighted in this book is that creativity is not a conscious process; that someone can force you to sit down and compose a classic prose or come up with the idea of the century, isn't conceivable. Brain has a mind of it own; whereas it is in the context of memory but It seems plausible to assume that it is not we who have the brain but it is the brain that has us. Take the case of Schizophrenia; our realities change when brain's interpretation of the external world changes; those afflicted with this disease are mostly paralyzed by the symptoms but there are other like John Nash who go on to win the Nobel for their remarkable discoveries. A quote by John Irving from Gary Marcus's Kluge, in the chapter on memory, should further elucidate this point:

"Your memory is a monster; you forget - it doesn't. It simply files things away. It keeps things for you, or hides things from you - and summons them to your recall with a will of its own. You think you have a memory; but it has you!"

That creativity is a subconscious process, as it becomes apparent from these case studies, I cite only the introspective accounts of Wolfgang Amadeus Mozart:

"When I am, as it were, completely in myself, entirely alone, and of good cheer....it is on such occasions that my ideas flow best and most abundantly. Whence and how they come, I know not; nor can I force them."

"All this fires my soul, and provided, I am not disturbed, my subject enlarges itself, becomes methodized and defined, and in the whole, though it be long, stands almost complete and finished in my mind so that I could survey it, like a fine picture or a beautiful statue, at a glance....What a delight this is I cannot tell! All this inventing, this producing takes place in a pleasing lively dream...What has thus been produced I donot easily forget and this perhaps the best gift I have my Divine Maker to thank for...

Whereas the detailed such accounts of other creative geniuses can be read in Dr. Andersen's book, the science and the questions that are highlighted here are so myriad and so many that one needs a lifetime to pursue this elusive discipline.

April Readings

2011-04-12T15:37:00.008-04:00

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2011-03-14T23:32:00.000-04:00

The great perk of being a biologist is, perhaps, to decipher the inner workings of cellular systems, something that can be rewarding at many levels. In contrast, If you dare to figure out how the life system operates, you'll most likely experience hostility, derision and sometimes outright punishment.

Scraping off the rust with the Science that I like!

2011-02-01T11:37:00.004-05:00

1) The Accidental Mind - David J. Linden

It is a simplified account of the science of neuroscience that shares classical experiments and targets general audience alike. The "Split Brain Experiments' and how they have related those to the concept of God are quite intriguing.

2) Tall Tales about the Mind & Brain- Sergio Della Sala

This is a more scientific account of Mind and Brain and what we have come to learn about it over the years. Whereas the book serves to corroborate some of the established norms about the brain, it also presents scientific evidence and logical inferences to bust some of the myths that surround this elusive gelatin.

3) An Alchemy of Mind- Diane Ackerman
I must say despite being a little older book, this was a thoroughly impressive read. Diane Ackerman has a gift to write. She does an amazing job summarizing the current understanding of the subject then, by linking it to historical accounts and of to the prevailing general knowledge. If you are a book lover, it is a must read.

4) Still Alice - Lisa Genova
Lisa Genova tells the fictional tale of a psychology professor at Harvard whose life changes with an early onset Alzheimer's. This books provides insight into the lives of those who are afflicted with this chronic yet debilitating disease. She quite aptly conveys the messages that the very self that we rely on is itself slave to the 2.5lb gelatinous mass that we call brain. Should it loose its proper functioning, devastating changes take place that can rob us of our own uniqueness and cripple us to the point that we can't even function without assistance.

5)Never Change - Elizabeth Berg

Elizabeth Berg tells the story of a man afflicted with a highly malignant brain tumor and of a young nurse who had a longstanding crush on that guy. Their meeting at his terminal life stage and the days she takes care of him...Only recommended if you have interest in the subject of brain tumors. The books touches the concept of quality of life as the main character denies to accept chemo- and radio-therapy. There are so many questions that surround the science of brain tumors; longevity is just not one; quality of life matters equally and perhaps that is what has been discussed in this book though in a subtle way, apart from the importance of company in those last days....

Targetting Brain Tumor Stem Cell Niches Confers Survival Benefit

2010-08-22T13:19:00.003-04:00

In December 2008 a study published by Quintana et. al. brought into question the very existence of putative stem -like cells in various solid malignancies. With a slight modification of the already used assay, they were able to show that cancer stem cells (CSCs) which are considered a rare population, thus far, had significantly increased in proportion. The finding was shocking to the point that great many commentaries followed on the topic in many reputable journals. The Niche, a Nature blog that is now closed, followed up a historical account of the topic, beginning with John Dick's seminal discovery of cancer stem cells in leukemia and ending with the identification of these cells in solid tumors like breast, colon and brain etc. The article included opinions from world renowned stem cell biologists about the implications of this study on various malignancies. Although there was a consensus that there is a greater need to understand these cells further, the claims differed among the proponents and the opponents of cancer stem cell hypothesis. Whereas stem cell biologist argued in favor of their existence, the authors themselves hold the opinion that CSCs hypothesis may only be true for some solid malignancies whereas it may not apply to others. From a clinical perspective, it was proposed that what are the characteristics of resistant population of cells in cancer, therefore hinting that this debate is a moot point unless it has some translational significance. Although this debate remains an unsettling one even today, evidence continue to accumulate that favors CSC hypothesis.

Over years skeptics of stem cell hypothesis have raised many questions. Whereas markers of leukemia stem cells were clear, the lack of a reliable surface marker for some solid malignancies has strengthened their resolve that perhaps cancer stem cells are a myth in those solid tumors. It only seems logical to assume that there could exist cells in an organ that carry greater potential of malignant transformation. Once hit by irreparable mutations, these cells could give rise to tumors. Take the case of brain tumors for example. Whereas the world community rejoiced over the discovery of stem-like cells in gliomas, that CD-133 hasn't turned out to be a uniform marker has raised many concerns among cancer biologists and surgeons alike who deal with these tumors. However if CD-133 is supplemented with bunch of other markers for neural stem cells lineage, for example, the sensitivity of assay goes up and these putative cells can be identified with reasonable certainty. Admitting that the discovery of stem-like cells within brain tumors was a notable finding, Dr. Peter Dirks was awarded Farber award last year at Society for Neuro-Oncology meeting where I, fortunately, had the pleasure to meet with him in person as well. Of note is also the fact that the stochastic model of tumorigenesis has also been inconclusive one about the origin of any malignancy as various scientists have tried to induce mutations in differentiated cells yet those experiments have produced too few malignancies thus lending further evidence, though unwittingly, to the CSC hypothesis.

Another point that needs to be noted is the unavailability of a reliable assay, in some solid tumors, that captures the microenvironment of the tumor in-vivo and faithfully replicates it in vitro. Take again the case of brain tumors; here the microenvironment is such that these CSCs reside within two distinct niches; one around the blood vessels (perivascular niche) and others in more remote hypoxic regions. These are the areas where highest proportions of CSCs resides. The tumor cells present in rest of the brain regions show a spectrum of gene expression and differentiated states that are in between these extreme, highly undifferentiated stem-cell like condition. Most assays use a serum free, growth factor supplemented media to culture these cells in vitro. A tumor heterogeneity that exists within brain is therefore lost here as this technique tends to enrich CSCs whereas other more differentiated clones just die out. The end result being that most of our analysis based upon these cell culture studies are biased towards a CSC concept. However, large scale array based studies have shown that despite a lack of faithful recapitulation of the tumor microenvironment in vitro, this technique tends to retain a genetic signature of that is reminiscent of the original brain tumor in vivo.

However, this scheme of organization isn’t as simple as it appears. In his latest commentary, Cancer stem cell, invitations to a second round, Dr. Peter Dirks argues that while interpreting the results of many studies concerning CSCs, the findings must be interpreted cautiously. Attention must be paid to the experimental conditions and to the sensitivity of the assay used in the detection of these cells. Secondly, CSC are not a static population rather a dynamic one. Just one property of cancer, a lack of differentiation, could render various clones of cells to behave like stem-cell like in a cancer whereas other cells under different microenvironmental factors could exhibit traits that are more reminiscent of a differentiated state. However, at any point in time there exist at least two different type of populations in a cancer; one population that is primitive and less differentiated and the other that is more differentiated. There also exist a spectrum of cells within each tumors that show differenatiation states in between these two. Therefore, entire tumor mass isn't a dichotomy of cells but there exist many grey zones. Additionally, under different treatments for example, cells undergo evolution due to different selection pressures of the drug thus producing less differentiated clones that have gotten resistance to the drug at the same time exhibiting characteristics of cells that resemble stem cells. Therefore the same cell which now behaves like a stem cell might not have origin from another stem cells but of a less differentiated clone that under a certain mutation now reverted back to a more primitive genetic signature. One marker could therefore temporarily appear or disappear under these circumstances, thus making cancer a more devious disease than already assumed under CSC hypothesis.

So having identified as stem cells being a moving target, it seems even more complicated to target a specific population with a single agent. The cancer as it appears has a mind of its own that works by adopting to itsenvironment. Whatever the underlying mechanisms may be, it goes without doubt that even though dynamic a population, the CSCs lies at the heart of any malignancy, making it worse and ultimately claiming the life of the individual. It also follows logically from this discussion that question of the origin of cancer becomes even more vital, thus great effort must be invested in understanding the cells that could acquire the first hit to give rise to a particular solid malignancy i.e. the tumor intiating cells (TICs)

For decades scientists have argued in favor of the CSC hypothesis e.g. of brain tumor origin (BTIC). That neural stem cells reside in particular niches is a known fact. They have argued that only cells present within these niches could be the sources of a particular malignancy and in case of brain tumors subventricular zone has been identified as an area of great interest. Building upon this premise a team of scientists at UCLA did a retrospective analysis on 55 adult patients with WHO grade III and grade IV tumors. Those patients who had received greater radiotherapy doses in regions of subventricular zone and in subgranular layer had longer progression free survival (15 months) as compared to those who received lower doses in these regions (7.2 months).

Despite its several limitations as it being a retrospective analysis, this is the first human study of its kind that lends credence to the CSC hypothesis of brain tumors origin. In case of leukemias, the logical reasoning has lead to developing stem cell transplantation protocols; that sieving through all the putative CSCs via bone marrow ablation and transplanting with non malignant hematopoeitic stem cells had improved progression free survival and overall survival in these patient. Similarly, we foresee a time when it would become a norm to target the very niches of CSCs or more specifically the CSCs themselves through selective approaches that will also improve the survival patterns of brain tumor patients.

UCSF Brain Tumor Stem Cell Grant

2009-12-12T15:35:00.002-05:00

UCSF Brain Tumor Stem Cell Grant to Drive Development of Novel Therapy

A team of scientists representing 5 California-based institutions have received a grant from the California Institute for Regenerative Medicine (CIRM) to advance stem cell based strategies for treating brain tumors. The objective of the grant is to file a new drug application with the U.S. Food and Drug Administration within four years, driving a stem cell-associated therapy towards clinical trial.

The brain tumor team is led by Mitchel Berger, MD, chair of the UCSF Department of Neurosurgery, and includes collaborators at the Ludwig Institute for Cancer Research at UCSD (Webster Cavenee, PhD and Co-PI, and Frank Furnari, PhD), UCLA (Paul Mischel, MD, PhD, Tim Cloughesy, MD, and Linda Liau, MD, PhD), the Burnham Institute for Medical Research (Evan Snyder, MD, PhD and Co-PI), and the Salk Institute (Inder Verma, PhD). Other key investigators for the UCSF group include C. David James, PhD, Tomoko Ozawa, MD, PhD, Russell Pieper, PhD, Mei-Yin Polley, PhD, Michael Prados, MD, and Elizabeth Read, MD.

The brain tumor team will receive $19,162,435 to genetically engineer stem cells that home to and deliver products resulting in cell death specific to glioblastoma multiforme (GBM). The concept is based on the team's discovery that neural stem cells naturally seek out brain tumor cells. If the product of this research is approved by the FDA, it would be tested first in patients with recurrent GBM.

* Currently 5/5

Genomics Research Lends Support to Brain Tumor Stem Cells

2009-11-13T22:21:00.000-05:00

Voltaire had once said, “doctors give drugs of which they know little, into bodies, of which they know less, for diseases of which they know nothing at all".

Not as radically, however, this likely is the case for brain tumors.

If you repeat something so many times, the expression becomes trite. However to say that brain tumors such as glioblastomas are an extremely fatal disease, every times raises a red flag sign. Every paper begins with, despite advances in adjuvant therapies the population overall survival remains less than a year. I don't think statements like, the current regimen of care involves resection of as much of the tumor as possible followed by chemotherapy and radiotherapy, will ever be cliched because they deal with patient's lives. To add further, at majority of the centers, now, immunotherapy is also being increasingly offered as an adjuvant.

Modern genetics tools like microarrays and comparative genomic hybridization have given us insights into the biology of brain tumors that we weren’t familiar with before. Patterns have emerged with regards to brain tumor treatment across all adjuvant therapies, that brain tumor is a heterogeneous disease. With the help of these tools, scientists have identified subset of patients, harboring tumors of the same grade (WHO type IV; glioblastomas), that respond differentially to therapies, including immunotherapy; some respond while others do not. In “escapers” there occurs progression of disease, the timing of which is variable and the tumor claims the life of the patient, ultimately. These techniques have revolutionized the field of genetics including cancer genomics to the extent that some of the established lines of research in brain tumor field seem otiose. A recent study by Radlwimmer et al. published in Clinical Cancer Research [15 November 1, 2009] overhauls some of the established cell lines which even today are being used as models for studying brain tumors, in vitro. This and many other similar studies set the stage that these advanced genomic tools would become the standard of investigation from now onwards.

Jadus et. al. [Clin Cancer Res 2007;13(2) January 15, 2007] have reported that there exist around 27 tumor associated antigens that could potentially be used for devising immunotherapy against tumors. However, this study is limited by the fact that many of these antigens were from cell lines which were grown in serum which is known to destabilize the genetic signatures of the tumors thus producing variants not reminiscent of the original tumor. Secondly, many of the reported antigens are also expressed on normal brain tissue and they are not specific for brain tumors. However, there have emerged some interesting associations as well; IL-13Rα2 is a tumor associated antigen that is uniformly expressed in 100% of the original tumor samples. Among other antigens that are also highly expressed are survivin, hTert, Mage-1, Gage-1, Sart-1, and Aim-2. Except IL13Rα2, little is known about others in this list whether they are present on normal brain tissue or not. On the other hand antigens which have been in clinial trials for immunotherapy against brain tumors include, EGFRVIII, CMV, and some of the ones from the previously mentioned list.

In the light of recent evidence, the above study needs to be repeated, and high throughput genomic analysis of original tumor grown in serum free medium must be carried out, and it must include normal brain tissue as controls to see which are the antigens unique to the tumor. Additonally, a new set of cell lines need to be developed or better yet spontaneously brain tumor models that are available, at present, need to be utilized and improved further to study the disease in laboratory.

The study by Radlwimmer and colleagues [Clinical Cancer Research ( 2009; 15 November 1, 2009] which professes that tumors grown under serum free stem-like spheroids conditions tend to preserve genetic signature of the original tumor is a land mark one. It not only proves the existence of stem like cells in brain tumors, it also point towards the cells that feed the brain tumor in toto. Scientist like Peter Dirk, Angelo Vescovi, Eric Holland, Alvarez Buyella, Robert Weinberg, Luis Prada, just to quote a few of the many, have been asserting for years about the existence of tumor initiating, radio- and chemo- resistant stem-like cells [Holland et. al. Expert Reviews Neurotherapeutics, 9 (10) 1447 – 1449 (2009)] that get enriched following treatment. Keeping in touch with surgeons is the best way to re-evaluate the ongoing research because ultimately the goal is to heal the patients whichever way possible.

Glioblastoma Claims Senator's Life

2009-08-27T20:28:00.004-04:00

The death of senator Kennedy, who was treated for GBM at Duke fifteen months back, raises further concerns on progress against brain tumors.

Itasca & Cajal

2009-08-05T13:52:00.003-04:00

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.

The Maze of Brain Tumors

2009-06-08T14:12:00.006-04:00

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.

On Doing Science - Advice from the Expert!

2009-04-08T23:48:00.004-04:00

You should be doing experiments because you want the answer. You shouldn't be doing it looking over your shoulder that someone might beat you to the answer, says John Dick, the scientist who first identified cancer stem cells from AML.

Questioning Sociability in Science?

2009-04-07T01:28:00.002-04:00

Dr. Sosumu Tonegawa October 13, 1987.

The science that inspires!

2009-03-28T01:45:00.003-04:00

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.

Massry Prize-2008

2009-01-25T16:14:00.006-05:00

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.

Cancer Stem Cells

2009-01-03T18:01:00.011-05:00

The much talked about paper by Quintana et al (Nature 2008(Dec 4); 456(7222): 593-8.) brings into question the rarity of existence of cancer stem cells and a detailed analysis of this publication has been made on various sites, including the Nature Publishing Group's blog, "The Niche". Jim Till, who is a member of the Board of Directors of the Cancer Stem Cell Consortium (CSCC), based in Ottawa, Canada, does a comprehensive review of literature on the topic and the implication of this particular study. Another comprehensive blog run by Alexey Bersenev of Children's Hospital of Philadephia summarizes the findings on the topic with a stem cells perspective in hematological malignancies.

There are few points that emerge from these discussions:

Cancer stem cells don't necessarily have to be rare.

The results of this particular study can not be generalized to all malignancies.

The most important point that emerges from these exhaustive discourses of the subject is that there is a need to identify and understand that population of cells which is resistant to therapy. This unequivocally points towards cells which we now label as cancer stem cells, be it the hematological malignancies or of solid tumors like breast or brain tumors.

This particular study doesn't imply in any way to reject the well established stem cell hypothesis, for example, in the case of brain tumors. It would not have any implications what so ever, admits Dr. Peter Dirks whose team first identified brain tumor stem cells. He professes that the results in the case of brain malignancies would not change much as immune responses are already crippled in brain milieu against tumors. Further readings about lowered immune reactivity against malignant cells, from an earlier, though unethical, study are available here.

In case of brain tumors, the question is not whether CD-133 is a marker for brain tumor stem cells but it is more of this marker being necessary and sufficient. There is little doubt about it being sufficient as xenografting of cells expressing CD-133 were able to recapitulate tumor characteristics at numbers as low as 100 whereas even 100,000 of CD133 negative cells were not able to initiate tumors. It is not by chance that the same cells expressing this marker happen to be resistant to chemotherapy and radiotherapy. It is also not serendipitous for these cells to be present at lower proportions in low grade gliomas and at higher numbers in high grade tumors like glioblastomas. So from a purely translational-research perspective, and borrowing from Jim Till's argument and from Jenny Chang's argument that in the clinical setting, the only importance is ‘what are the characteristics of the resistant population that appear to be able to make new cancers, we can conclude that this should be our main point of focus.

All these observations point towards, though an obvious, fact that cancers comprise of very heterogeneous population of cells. A recent BMC article by Zhang et al (J Exp Clin Cancer Res. 2008 Dec 24;27(1):85.) addresses their significance by using a combination makers such as Nestin and CD-133 by employing immunohistochemistry to positively identify brain tumor stem cells. The use of more than one marker should suffice in addressing the controversy surrounding any single marker, and there should be an active search for newer more specific markers.

Finally, coming to the debate of "cells of origin" and CSCs, many points have been made in both of these blogs about not confusing the two, though indirectly hardly any ambiguity remains as to what would the cells of origin for tumors and of stem cells present in these tumors be. Much indirect evidence comes from studies in mouse models and Dr. Alvarez-Buylla and Dr. Luis F. Parada just published their finding in Cancer Cell. 2009 Jan 6;15(1):45-56, lending further support to the already accumulating evidence that tries to answer the cells of origin question, at least in part for brain tumors. Here is what John Dick, who identified for the first time human CSCs from leukemic patients, says about the "cells of origin" dilemma that should clarify some of the ambiguity:

"As a final point, we would like to re-iterate the distinction between the concepts of CSCs (cells within a tumor that possess stem-like properties) and “cell of origin” (the normal cell type in which the tumorigenic process is initiated, whether a stem cell or progenitor). The CSC model does not make any assumptions regarding the origins of CSCs – indeed, there is now abundant evidence that CSCs in mice may arise from either normal stem or progenitor cells depending on the specific transforming events, although evidence in human cancers is still lacking."

Transcriptomic, proteomic, bioinformatics, nanotechnology or systems biology etc, whatever the means may be, a better understaning of the resistant population of cells is necessary if only we are to eradicate brain tumors. Equally important is the understanding of approaches, for example immunological, pharmacological, osmotic, oncolytic viruses, gene therapy, microRNA or nanotechnology based approaches that employ various combinations of available technique, in order to get rid of brain tumors, after all responses tend to stall after some time following exposure to these therapeutic strategies. The goal is to ameliorate human suffering, decrease morbidity and mortality, improve quality of life, and increase longevity with the ultimate aim to cure the disease. What, therefore, matters is the end, not the means to an end but equally important are the resources that remain limited, thus dictating us further in allocating them wisely.

Peter Doherty

2008-12-21T01:59:00.005-05:00

I usually don't skim books. It spoils the ending but that generalization is hardly applicable to genres other than fiction or plays, may be. Autobiographies are exceptions, in particular. But the reason why I skipped pages of this book was the dictatorial nature of the title which obviously stirred some expectations.

The 1996 winner of Nobel Prize in Physiology or Medicine, a scientist of humble origins from Australia recounts his unlikely path to becoming a Nobel Laureate in his, much acclaimed and an instructive autobiography,"The Beginner's Guide to Winning the Nobel Prize, a Life in Science". The book is available at Columbia University Press. Fortunately, we happen to be at the Society for Neuroscience 2008 Conference in Washington DC where at the CUP stall, I picked two of these books, the other one being "In search of Memory, the Emergence of New Science of Mind" signed by Dr. Eric Kendal himself.

As I begin reading Dr. Doherty's autobiographical account, I instinctively find myself skipping to the pages where he advises novice minds the following lessons that he learned through his lifelong scientific pursuits:

1. Try to solve major problems and make really big discoveries
2. Be realistic and play to your strengths
3. Acquire the basic skills, and work with the right people
4. Work in an appropriate field
5. Find and cultivate your true passion
6. Focus and don't be a dilettante
7. Be selective about where you work
8. Value evidence and learn to see what's in front of your nose
9. Think outside the box
10. Talk about the problem
11. Tell the truth
12. Be generous and culturally aware
13. Be persistent and be tenacious, but be prepared to fail
14. Your time is precious
15. Avoid prestigious administrative roles
16. Take care of yourself, and live a long time
17. Have fun, behave like a winner

But these seventeen principles come with a disclaimer.

"So you want to win a Nobel prize, says Dr. Doherty; to become famous, powerful and maybe even very wealthy? If that's your ambition I can't help you. There is no instruction manual or course that can guide you to a Nobel Prize and, numerically speaking, most of us have more chance of winning an Olympic gold medal. There is also another difference; an Olympic medalist might go on to win a Nobel, but can you imagine Albert Einstein or Bertrand Russell competing in the decathlon? I was brutally reminded of this when I had to present a large cheque to Michael Chang for winning St. Jude Tennis Classic in Memphis. We were both winners in one sense or another but, though Michael might conceivably change his life at some stage to become a great scientist or writer, there is no way that I could ever beat an 85 year-old Chang or Sampras on the court".

Dr. Doherty along with Dr. Zinkernagel were awarded Nobel Prize for their discovery of how immune system works against virus infected cells.

Perfection in Imperfection

2008-09-18T18:31:00.004-04:00

Looking back now on the long path my life has followed, on the lives of my peers and colleagues, and on the briefer ones of the young recruits who have worked with us, I have become persuaded that, in scientific research, neither the degree of one's intelligence nor the ability to carry out one's tasks with thoroughness and precision are factors essential to personal success and fulfillment. More important for the attaining of both ends are total dedication and a tendency to underestimate difficulties, which cause one to tackle problems that other, more critical and acute persons instead opt to avoid.

An excerpt from "In Praise of Imperfection; My life and Work" by Rita Levi Montalcini, 1988.

Solution in Integration

2008-08-22T06:57:00.006-04:00

The TechTalk that got me thinking that in integration lie the solutions of many medical problems. Few precedents are cited below.

1. MIT radar technology fights breast cancer.
2. Preset patterns discovered in neuronal stem cells could complicate therapy.
3. Remote-control nanoparticles deliver drugs directly into tumors.
4. Interdisciplinary cancer study cited.
5. The David H. Koch Institute for Integrative Cancer Research to be launched in 2010 at MIT.

5. The last one, an institute, is infact a five prong strategy launched towards countering the most feared of all diseases, the cancers.

4. In the Interdisciplinary cancer study, scientists find that with the help of nanotechnology they can detect cancer from bodily fluids at early stages. The case studied is of liver cancer. The malignant cells are much loose compared to their normal counterparts and their dissociation begins much earlier in the disease. Nanoparticles have been designed to detect these malignant cells early.

3. Dr. Sangeeta Bhatia, another engineer and a professor at the Harvard-MIT research program, have developed nanoparticles that can safely home in and deliver drugs to the tumors. This is an ingenious work because the nanoparticles are attached to DNA probes; the length of the DNA probe determines the melting point of the particles, hence the delivery of the drug is controlled using electromagnetic waves, the trascripts to which these particles "talk back" amazingly.

1. Focussed microwave heat treatment along with cancer chemotherapy can shrunk as much as 50% of the breast tumors, a study cited in the November, 2007 issue of Cancer Therapy.

2. Carlos Lois, a neuroscientist at MIT is skeptical of using neural stem cell therapy for various CNS disorders, including storkes and neurodegenerative disorders. His findings render him so; he has discovered that each neural stem cell is preset to formulate only a specific set of neuronal connection, hence taking any of the adult neural stem cells, proliferating them in vitro and then transplanting them into any site of injury within CNS, he says, might not work. The scientist need to figure out how to manipulate these NSCs genetically to help figure out how to stop the preset differentiations of NSCs and then push them into formulation of cells of choice before using them for therapy.

Milestones in Developmental Neurobiology

2008-07-24T11:34:00.005-04:00

The field of Developmental Neurobiology, within the umbrella of Developmental Biology, has grown in parallel with the parent discipline. The following milestones have been sifted only to highlight the significant achievements in Developmental Neurobiology*.

1907. R. Harrison shows that axons grow out from neuronal cell bodies, founding the field of developmental neurobiology, and invents tissue culture in the course of these experiments.

1917. S. Detwiler studies the origin of the neural crest and the mechanisms of spinal nerve development.

1924. H. Spemann develops microsurgical techniques for embryos and with H. Mangold, discovers the organizer and the phenomenon of neural induction.

1933. C. H. Waddington discovers that Hensen's node is equivalent to Spemann's organizer, and shows that the role of the organizer in neural induction is conserved across species.

1934. Using limb bud ablations, V. Hamburger shows that survival of motor neurons within the spinal cord depends on interactions with the periphery. This insight leads to the discovery of NGF and to the 1986 Nobel Prize to S. Cohen and R. Levi-Montalcini.

1965. R. Watterson shows that cells undergo interkinetic nuclear migration within the wall of the neural tube. It was later shown that this phenomenon occurs throughout development as neurons and glia are born, and that cells migrate within the wall of the neural tube to occupy new locations (P. Rakic and co-workers).

1966. G. Rosenquist generate more accurate fate of blastula, gatrula and neurula by using triated labelled thymidine in unlabelled embryos. This technique was used by J. Weston and D. Noden to map the fate of neural crest cells.

1971. T. Schroeder proposes that neurulation involves the constriction of apical bands of microfilaments within the neural plate.

1976. A.G. Jacobson and R. Gordon show that shaping of the neural plate and closure of the neural groove require convergent extension movements.

1980. G. Schoenwolf and co-workers study the cellular basis of morphogenetic movements of neurulation, showing that bending of neural plate requires intrinsic and extrinsic forces.

1985. R. Keller and co-workers use the so-called "Keller sandwiches" to study the morphogenetic movements of gastrulation. T. Doniach, J. Gerhart and C. Phillips used the same model to study planar signalling during neural induction.

1989. T. Jessell and co-workers' cellular and molecular studies of dorsoventral patterning (especially of the spinal cord), show the importance of the notochord and floor plate in dorsoventral patterning, and the role of sonic hedgehog in floor plate and motor neuron induction.

1990. Knockout mice are used to study dorsoventral patterning of the neural tube by P. Beachy and co-workers; T. Jessell and co-workers; M. Tessier-lavigne and co-workers.

1990. Knockout mice are used to study rostrocaudal patterning in hindbrain by M. Capechhi and co-workers; D. Wilkinson and co-workers, in midbrain by A. Joyner and co-workers; A. McMahon and co-workers; G. Martin and co-workers, and in forebrain by J. Rubenstein and co-workers.

1990- 2001. G. Schoefnwolf and co-workers and C. Stern and co-workers determine cell-fate mapping using flourescent dye injections.

Early 1990-2001. Molecular markers are used to identify the subpopulations of cells, reducing reliance on morphology and increasing specificity and resolution of the experimental analysis. These markers are used simultaneously in chick, mouse and zebrafish embryos.

1990-2001. Rostrocaudal patterning is established using cellular and molecular studies; by R. Krumalauf and co-workers, and A. Lumsden and co-workers in hindbrain; by R. Alvarado-Mallart, L. Bally Cuif and M. Wassef; D. Darnell and G. Schoenwolf in midbrain, and by L. Puelles and J. Rubenstein in forebrain.

Late 1990s-2001. Mutant fish are used to study neural induction, rostrocaudal and dorsoventral patterning, and axonal guidance by W. Driever, J. Eisen, M. Halpern, P. Ingham, C. Kimmel, C. Nusslein-Volhard.

1992. J. Eisen, D. Raible, J. Weston and co-workers map neural crest migration through injection of the single cells and time lapse videomicroscopy, and subsequently in 1996 screen embryos for mutations that affect neural crest migration.

1993. R. Harland and co-workers identify noggin, the first candidate neural inducer, by taking advantage of animal cap assays.

1993. Dr. Turner and H. Weintraub show that basic Helix Loop Helix (bHLH) achaete scute-like gene (NeuroD) induce ectopic neurons when overexpressed, as they do in drosophila.

1994. A. Hemmati-Brivanlou and D. Melton identify follistatin, a candidate neural inducer known to inhibit activin. By inactivating TGF-β signalling, they further show that default state of the extoderm is neural, not epidermal as previously believed.

1994-1996. E. DE Robertis and Y. Sasai identify chordin, a candidate neural inducer that binds to BMPs to block their signalling.

1994. R. Beddington shows that the node induces a secondary body axis that lacks a head when transplanted to an ectopic site in the gastrula.

1995. Molecular and cellular organization of the organizer by G. Schoenwolf and co-workers and C. Stern and co-workers.

1995. A. Chitnis and co-workers show that lateral inhibition acts in the vertebrate neural plate through Notch-Delta signalling in a manner similar to that found in the invertebrate ventral nerve cord.

1998. R. Beddington, E. Robertson and their co-workers identify the anterior visceral endoderm as a signalling centre equivalent to the head organizer of amphibians.

1998. C. Nusslein-Volhard and co-workers use a large-scale mutagenesis screen to identify genes that have unique and essential functions during development.

A cursory look at these achievements tells us that earlier discoveries within developmental neuroscience were widely spaced. However, the decade of 1990-2001 saw many more of these discoveries. The discipline's progress paralleled with significant developments in technology. As the tools to study the developmental processes got sophisticated, we saw more and more new findings in almost every existing discipline of biology including developmental neuroscience. Dr. Fiona Watt, the current chairperson of International Society for Stem Cell Research asserts that we are sitting on an information gold mine. We need the tools to analyze that data in a comprehensive fashion. Systems Biology has already revolutionized many fields of biological research. The reductionist approach that has been our main tool to study biological phenomenon is being reinforced by this emerging science. I can foresee the day, that I think isn't far now, when we will have a complete picture of processes that once considered to be isolated which, infact, are very intricate, interwoven and interdependent.

* Nat. Rev. Neurosci. 2, 763-771 (2001).
* Nat. Rev. Neurosci. 5, S526-527 (2004).