I have spent a significant part of my doctoral work on the role and effects of a protein on the development and progression of a form of brain cancer called as "Gliomas". All this work of course was carried out in a premier research institute in India. Now, the work, since it involves a human disease, requires the involvement of patient samples, patient follow ups, tissue material, surgical intervention and a standardized treatment protocol. Unlike the west where medical research is carried out as part of a hospital and MD/PhDs constitute a large chunk of the researchers; In India the situation is quite different. Research in India is carried out with a complete disconnect from the medical community. Researchers and doctors have completely different training profiles and work platforms and there is minimal interaction between the two.
In this blog, I am trying to give a broad overview of this field and the work involved in it from the perspectives of all concerned. The intention of course is to highlight the fact that there is huge disconnect between the three groups of people involved in finding the cure to any disease - the researchers, the patients and the clinicians (I haven't yet involved the industry and the drug developers but they are a vital component of an translational research that needs to be taken from the bench to the bedside (as it is popularly stated!).
Now gliomas, as the name suggests are tumors of glial origin. The human brain is made up of billions and billions of neurons but these neurons cannot function and exist on their own. So the head on top that we all should be using (but are not always) is actually made up of billions of and billions of neurons and of many of these supporting cells called as astrocytes and glial cells. Now, as with any tumor, gliomas are named so because of their cells of origin - which are the glial cells. They arise because, somewhere deep in your brain, one cell is rebelling against the normal structure and has decided to be selfish and proliferate.
This errant cell, if left unchecked, will soon grow into a huge mass of cells all behaving the same way. A normal cell in the body becomes errant because it has accumulated some mutations - mutations which make some normal cellular proteins to lose their normal function or to alter their roles in the cell. A single cell usually requires multiple mutations before it gains the ability to proliferate uncontrollably - or as the scientists say to become transformed. This errant cells will now begin an epic journey as it divides and divides, ignorant of all other restrictive signals and indications. During these multiple rounds of divisions, more mutations are acquired all through the darwinian principle of evolution. Thus, a cancer cell, which acquires mutations favoring its growth and survival will multiply and give rise to more similar daughter cells. Like the parent cell, these progeny would also acquire the ability to migrate and move in search of better nesting grounds. But, we must not forget that this errant glial cell is actually in the brain and therefore cannot move out (for the novices, the brain, in view of its vitality has a impervious blood brain barrier which prevents the free exchange of materials from the rest of the body to the brain - this is one reason why not all chemicals and drugs will enter the brain). So what does it do ? It spreads its family through the existing brain and we will soon find that a widely infiltrating tumor will spread its way through the normal brain cortex. Soon however this massive proliferation will affect the normal brain and its functions.
The increasing intra-cranial pressure and destruction of the normal cortex ultimately result in multiple symptoms. Patients begin with symptoms like headache, nausea, weakness in extremities, dizziness, seizures, vomiting etc etc. Now we can all understand that all these symptoms can only arise pretty late into disease progression. By this time the brain is actually riddled with bad tissue arising from these errant clones. Patients also tend to ignore these symptoms till they are actually unbearable and things are not easy for a clinician too (I mean how many people immediately go for a doctor and an MRI when they have a headache - they suspect eye trouble, migrane, fatigue, stress etc etc till it becomes unbearable.
A clinician also has a number of possible neurological disorders to rule out before he can actually diagnose a tumor. An MRI needs to be done to detect and confirm the presence of a tumor and we all know that it is not an inexpensive proposition that will be one's first line of inquiry. Thus, by the time a glioma is diagnosed it is fairly advanced. Now once diagnosed, the first step is to remove the tumor mass but by this time large numbers of tumor cells would have actually infiltrated into the normal brain matrix thus making the excision very difficult.
Also making matters more difficult, the brain unlike the other organs of the body is a vital organ where complex functions are performed over very small regions. And we don't know with great clarity what all the functions are and where all they are localized? This is quite unlike other organs like the liver, the colon, the breast or the prostate. where we have more information and functions are redundant. So, now a surgeon is faced with the challenge of causing minimal invasion and removing the maximum tumor tissue possible. However, with great skill and with the aid of modern technology (like MRIs) a surgeon manages to pull out the tumor region from the brain to achieve what is called as a maximal safe resection.
Now this surgery is verified by an MRI (not the cheapest of techniques and noes not have a very good spatial resolution as well) and the solitary wandering cells will escape detection by this technique till they grow back as more vigorous tumors.... The next step after surgical intervention is radiotherapy. In this the patient is subjected to high doses of radiation to eradicate any errant tumor cells left behind. The last possible intervention in treating a glioma involves chemotherapy. This too is a tricky problem because the brain (being the special organ it is) is not freely accessible to all drugs and chemicals. Only a select family of drugs can actually access the brain through the blood-brain barrier - again limiting the treatment options. The current standard of care involves the use of Temozolomide, an alkylating agent (which adds alkyl groups to the DNA thereby damaging the DNA and the cell) as the single most commonly used chemotherapeutic agent for treatment of gliomas.
Now like all the other cancers, this toxic chemical will also cause multiple side effects as it will also affect normal brain tissue and other organs in the body. This is the extension of the agony for the patient and his family. Now depending on the severity of the disease, the time of diagnosis, the extent of infiltration, the effectiveness of the surgery, etc etc the tumor could respond differently to the different treatments in different patients. At this time now a pathologist needs to get a sample of the tumor to grade it such that the patient, his/her family can be informed of a predicted course of the disease to some accuracy. Every tumor is graded into different stages depending on how much the tumor has advanced. In an early tumor, the tumor cells would not have invaded deep into the normal brain and would be easy to resect. Also there will be lesser diversity in the types of tumor cells as they will be closer to the progenitor errant cell. These factors along with others make the low grade tumors easy to treat unlike the higher grade ones.
In gliomas, the tumors have been divided into 4 types according to the severity and the progression of the disease. Grade I and II tumors are the easiest to resect because they are still in the form of a compact mass. The cells in these tumors have still not started spreading and expanding their reach in the brain. Once resected mild chemo/radiotherapy can prevent the tumor from recurrance and patients are known to live for a very long time (atleast 10 years : While in absolute this is not a long time, considering the prognosis of a more malignant glioma this is actually really good). The grade III gliomas are more advanced and they show infiltration into the normal brain cortex which can be seen in an MRI as well. While surgery helps, further radio and chemotherapy only manage to provide a 2-3 year extension to the patient. The grade IV gliomas, on the other hand are the most malignant forms of this cancer. They show massive infiltration into the normal brain, extensive vascularization, nuclear atypia etc etc. Despite the extensive research happening in this field, the present day treatment only provides a median survival of a year to the patients and there are hardly any cases of complete remission. Even for the grade I and II tumors, the patients usually develop grade III or grade IV tumors within the next 5-10 years and succumb to the same fate. The disease thus only has a fatal prognosis and the only difference possible lies in the extent of fatality.
Imagine from the prospect of a family and an individual the kind of uncertainity and trauma that such a diagnosis can unfold. Imagine being told that you need to have a surgery the consequences of which can never be completely ascertained. And after the surgery, your system will be bombarded with toxic chemicals which will have side effects and all this will extend your life by a couple of years at max. The expense incurred is another aspect which takes the therapy beyond the reach of many in our country. To worsen the situation, its your brain which is targeted to all this trauma. The organ which defines you and your existence. Such massive invasion of the privacy of the brain only leaves behind side effects on the mind.... I am writing all this not to discourage people from undergoing a treatment because they should and at least it prolongs their life by a year to a decade. That can be valuable to any individual to organize their life and facilitate their family's existence.
In the present model, once diagnosed by a pathologist, the patient begins a standardized therapeutic regimen under the guidance of a qualified oncologist. His treatment is followed through a routine MRI imaging and the treatment is modulated accordingly. We as researchers access the tissue through the surgeons as part of single consortium. The tissue from the tumor is bisected into two halves and snap frozen. One half is used for the isolation of RNA, protein, DNA etc which enable us as researchers in molecular biology to study the disease. The other half is provided to the pathologist where the tissue is fixed and processed to develop tumor sections which can be used to grade the tumor and study the expression and localization of select proteins. The study begins with large scale profiling of RNA, DNA, proteins and microRNAs whose expression is compared across normal brain samples and the different grades of gliomas. The candidate genes are then studied in cell culture models to identify their functions in tumor development. The study is further extended to animal models of the disease where the role of the gene in the disease is studied and validated. The ultimate aim of us researchers is to try and identify novel methods of diagnosis and prognosis to predict the course of the disease and to identify novel molecular targets for therapy. The development of novel drugs based on these studies would be the ultimate and ideal culmination of an entire such study.
However as researchers, we need to be aware of this personal apsect of every disease all through our studies. For doctors, each individual should be a human being and not a mere case to follow a standardized treatment protocol. His needs, his comfort, his discomfort, his financial situation, family - all these aspects need to be considered as part of the treatment protocol. For researchers such as me, the disease, the patient and the prognosis should mean more than numbers, statistics, jargon and a degree at the end. The need of the hour is to develop treatment protocols and that cannot happen by pure research in a laboratory. What is needed is an inclusive interaction between the patients, the doctors and the research community.
I stress on the inclusion of the researchers because being one myself, I see that we are living a complete disconnect with the patients. For us the patients are cases who have died and whose tissue is what we need to work with. It is a sad spectre but it is true because unless an until there is an emotional connect, we tend to lose perspective in our mad rush for the end. A researcher aims for results, publications, patents, grants and degrees. He is untouched by the miseries that haunt the hospital corridors, the traumas that people have to face. True to human nature, we stay in a state of complete disconnect until forced to face reality by a personal experience.
Such a model also breeds differences between the clinicians and the researchers because both are unaware of each other's skills and both end up presuming their indispensability and supremacy to the task on hand. What is needed is a model like in the United states where research is carried out within or in close connect with the premises of a hospital. This will not only ensure a first hand understanding of the disease and its symptoms to the researchers but it will also ensure a real understanding of the problems plaguing the clinicians. It will also allow easy access to the patient resources to the researchers in addition to providing clinicians with greater access to the developments in the laboratory.
In this blog, I am trying to give a broad overview of this field and the work involved in it from the perspectives of all concerned. The intention of course is to highlight the fact that there is huge disconnect between the three groups of people involved in finding the cure to any disease - the researchers, the patients and the clinicians (I haven't yet involved the industry and the drug developers but they are a vital component of an translational research that needs to be taken from the bench to the bedside (as it is popularly stated!).
Now gliomas, as the name suggests are tumors of glial origin. The human brain is made up of billions and billions of neurons but these neurons cannot function and exist on their own. So the head on top that we all should be using (but are not always) is actually made up of billions of and billions of neurons and of many of these supporting cells called as astrocytes and glial cells. Now, as with any tumor, gliomas are named so because of their cells of origin - which are the glial cells. They arise because, somewhere deep in your brain, one cell is rebelling against the normal structure and has decided to be selfish and proliferate.
This errant cell, if left unchecked, will soon grow into a huge mass of cells all behaving the same way. A normal cell in the body becomes errant because it has accumulated some mutations - mutations which make some normal cellular proteins to lose their normal function or to alter their roles in the cell. A single cell usually requires multiple mutations before it gains the ability to proliferate uncontrollably - or as the scientists say to become transformed. This errant cells will now begin an epic journey as it divides and divides, ignorant of all other restrictive signals and indications. During these multiple rounds of divisions, more mutations are acquired all through the darwinian principle of evolution. Thus, a cancer cell, which acquires mutations favoring its growth and survival will multiply and give rise to more similar daughter cells. Like the parent cell, these progeny would also acquire the ability to migrate and move in search of better nesting grounds. But, we must not forget that this errant glial cell is actually in the brain and therefore cannot move out (for the novices, the brain, in view of its vitality has a impervious blood brain barrier which prevents the free exchange of materials from the rest of the body to the brain - this is one reason why not all chemicals and drugs will enter the brain). So what does it do ? It spreads its family through the existing brain and we will soon find that a widely infiltrating tumor will spread its way through the normal brain cortex. Soon however this massive proliferation will affect the normal brain and its functions.
The increasing intra-cranial pressure and destruction of the normal cortex ultimately result in multiple symptoms. Patients begin with symptoms like headache, nausea, weakness in extremities, dizziness, seizures, vomiting etc etc. Now we can all understand that all these symptoms can only arise pretty late into disease progression. By this time the brain is actually riddled with bad tissue arising from these errant clones. Patients also tend to ignore these symptoms till they are actually unbearable and things are not easy for a clinician too (I mean how many people immediately go for a doctor and an MRI when they have a headache - they suspect eye trouble, migrane, fatigue, stress etc etc till it becomes unbearable.
A clinician also has a number of possible neurological disorders to rule out before he can actually diagnose a tumor. An MRI needs to be done to detect and confirm the presence of a tumor and we all know that it is not an inexpensive proposition that will be one's first line of inquiry. Thus, by the time a glioma is diagnosed it is fairly advanced. Now once diagnosed, the first step is to remove the tumor mass but by this time large numbers of tumor cells would have actually infiltrated into the normal brain matrix thus making the excision very difficult.
Also making matters more difficult, the brain unlike the other organs of the body is a vital organ where complex functions are performed over very small regions. And we don't know with great clarity what all the functions are and where all they are localized? This is quite unlike other organs like the liver, the colon, the breast or the prostate. where we have more information and functions are redundant. So, now a surgeon is faced with the challenge of causing minimal invasion and removing the maximum tumor tissue possible. However, with great skill and with the aid of modern technology (like MRIs) a surgeon manages to pull out the tumor region from the brain to achieve what is called as a maximal safe resection.
Now this surgery is verified by an MRI (not the cheapest of techniques and noes not have a very good spatial resolution as well) and the solitary wandering cells will escape detection by this technique till they grow back as more vigorous tumors.... The next step after surgical intervention is radiotherapy. In this the patient is subjected to high doses of radiation to eradicate any errant tumor cells left behind. The last possible intervention in treating a glioma involves chemotherapy. This too is a tricky problem because the brain (being the special organ it is) is not freely accessible to all drugs and chemicals. Only a select family of drugs can actually access the brain through the blood-brain barrier - again limiting the treatment options. The current standard of care involves the use of Temozolomide, an alkylating agent (which adds alkyl groups to the DNA thereby damaging the DNA and the cell) as the single most commonly used chemotherapeutic agent for treatment of gliomas.
Now like all the other cancers, this toxic chemical will also cause multiple side effects as it will also affect normal brain tissue and other organs in the body. This is the extension of the agony for the patient and his family. Now depending on the severity of the disease, the time of diagnosis, the extent of infiltration, the effectiveness of the surgery, etc etc the tumor could respond differently to the different treatments in different patients. At this time now a pathologist needs to get a sample of the tumor to grade it such that the patient, his/her family can be informed of a predicted course of the disease to some accuracy. Every tumor is graded into different stages depending on how much the tumor has advanced. In an early tumor, the tumor cells would not have invaded deep into the normal brain and would be easy to resect. Also there will be lesser diversity in the types of tumor cells as they will be closer to the progenitor errant cell. These factors along with others make the low grade tumors easy to treat unlike the higher grade ones.
In gliomas, the tumors have been divided into 4 types according to the severity and the progression of the disease. Grade I and II tumors are the easiest to resect because they are still in the form of a compact mass. The cells in these tumors have still not started spreading and expanding their reach in the brain. Once resected mild chemo/radiotherapy can prevent the tumor from recurrance and patients are known to live for a very long time (atleast 10 years : While in absolute this is not a long time, considering the prognosis of a more malignant glioma this is actually really good). The grade III gliomas are more advanced and they show infiltration into the normal brain cortex which can be seen in an MRI as well. While surgery helps, further radio and chemotherapy only manage to provide a 2-3 year extension to the patient. The grade IV gliomas, on the other hand are the most malignant forms of this cancer. They show massive infiltration into the normal brain, extensive vascularization, nuclear atypia etc etc. Despite the extensive research happening in this field, the present day treatment only provides a median survival of a year to the patients and there are hardly any cases of complete remission. Even for the grade I and II tumors, the patients usually develop grade III or grade IV tumors within the next 5-10 years and succumb to the same fate. The disease thus only has a fatal prognosis and the only difference possible lies in the extent of fatality.
Imagine from the prospect of a family and an individual the kind of uncertainity and trauma that such a diagnosis can unfold. Imagine being told that you need to have a surgery the consequences of which can never be completely ascertained. And after the surgery, your system will be bombarded with toxic chemicals which will have side effects and all this will extend your life by a couple of years at max. The expense incurred is another aspect which takes the therapy beyond the reach of many in our country. To worsen the situation, its your brain which is targeted to all this trauma. The organ which defines you and your existence. Such massive invasion of the privacy of the brain only leaves behind side effects on the mind.... I am writing all this not to discourage people from undergoing a treatment because they should and at least it prolongs their life by a year to a decade. That can be valuable to any individual to organize their life and facilitate their family's existence.
In the present model, once diagnosed by a pathologist, the patient begins a standardized therapeutic regimen under the guidance of a qualified oncologist. His treatment is followed through a routine MRI imaging and the treatment is modulated accordingly. We as researchers access the tissue through the surgeons as part of single consortium. The tissue from the tumor is bisected into two halves and snap frozen. One half is used for the isolation of RNA, protein, DNA etc which enable us as researchers in molecular biology to study the disease. The other half is provided to the pathologist where the tissue is fixed and processed to develop tumor sections which can be used to grade the tumor and study the expression and localization of select proteins. The study begins with large scale profiling of RNA, DNA, proteins and microRNAs whose expression is compared across normal brain samples and the different grades of gliomas. The candidate genes are then studied in cell culture models to identify their functions in tumor development. The study is further extended to animal models of the disease where the role of the gene in the disease is studied and validated. The ultimate aim of us researchers is to try and identify novel methods of diagnosis and prognosis to predict the course of the disease and to identify novel molecular targets for therapy. The development of novel drugs based on these studies would be the ultimate and ideal culmination of an entire such study.
However as researchers, we need to be aware of this personal apsect of every disease all through our studies. For doctors, each individual should be a human being and not a mere case to follow a standardized treatment protocol. His needs, his comfort, his discomfort, his financial situation, family - all these aspects need to be considered as part of the treatment protocol. For researchers such as me, the disease, the patient and the prognosis should mean more than numbers, statistics, jargon and a degree at the end. The need of the hour is to develop treatment protocols and that cannot happen by pure research in a laboratory. What is needed is an inclusive interaction between the patients, the doctors and the research community.
I stress on the inclusion of the researchers because being one myself, I see that we are living a complete disconnect with the patients. For us the patients are cases who have died and whose tissue is what we need to work with. It is a sad spectre but it is true because unless an until there is an emotional connect, we tend to lose perspective in our mad rush for the end. A researcher aims for results, publications, patents, grants and degrees. He is untouched by the miseries that haunt the hospital corridors, the traumas that people have to face. True to human nature, we stay in a state of complete disconnect until forced to face reality by a personal experience.
Such a model also breeds differences between the clinicians and the researchers because both are unaware of each other's skills and both end up presuming their indispensability and supremacy to the task on hand. What is needed is a model like in the United states where research is carried out within or in close connect with the premises of a hospital. This will not only ensure a first hand understanding of the disease and its symptoms to the researchers but it will also ensure a real understanding of the problems plaguing the clinicians. It will also allow easy access to the patient resources to the researchers in addition to providing clinicians with greater access to the developments in the laboratory.
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