Creating a Google Earth of the Brain

A recent New York Times article describes a $50 million project by more than a dozen research centers aiming to create a sort of Google Earth of the brain. In a series of 11 papers, published in Science and related journals, a consortium of researchers has produced the most richly detailed model of the brain’s genetic landscape to date, one that incorporates not only genes but also gene regulators, cellular data and developmental information across the human life span.

The PsychENCODE Consortium, initiated in 2015 and financed by the National Institute of Mental Health, involves more than a dozen research centers and scores of specialists in cell biology, genetics and bioinformatics. It is an all-hands, brute-force effort, coordinating top brain banks and brain scientists at major research centers, led by Yale, Mount Sinai, UCLA, and UCSF.

Dr. Matthew State, chair of the department of psychiatry at the University of California, San Francisco, and a co-author on two of the papers, said: “Essentially what these papers do is lay out cellular and molecular landscape at a resolution that’s never existed before. I see it as foundational work, and an investment that will pay off in giving us a far richer context to develop new hypotheses and study these disorders.”

Best of March 2014: Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule

The next in our "Best of the Month" series is from March 21, 2014:

Researchers at the Karolinska Institute in Sweden have introduced what could possibly be a revolution in glioblasoma treatment. In a recent article in Cell, researchers found that molecules known as vacquinols "reliably and selectively compromised" neoplastic cell viability. Vacquinols stimulate cell death by membrane ruffling, vacuolization, and -- ultimately -- cytoplasmic membrane rupture. Although in vivo testing has been restricted to mice thus far, this paper may prove to be the beginning of a new avenue of research into the selective killing of glioblastoma cells in patients.

Best Post of February 2014: Seizing Control of Brain Seizures

The next in our Best of the Month series comes from February 27, 2014:

How can trauma lead to chronic seizures? Berkeley researcher Daniela Kaufer found that only when albumin in the blood breaches the blood-brain barrier does the likelihood of post-traumatic epilepsy go up. Accelerated signaling between neurons results from this exposure, leaduing to seizures. “We were surprised, even a little disappointed, that it was such a common component of the blood  – nothing exotic at all  – that led to epilepsy,” recalls Kaufer, associate professor of integrative biology. She and colleagues went on to

Daniela Kaufer in the lab

show that albumin interacts with a ubiquitous cell protein TGF-Beta receptor to cause the damage. In the healthy brain, TGF-Beta signaling affects activity of astrocytes, which normally limit neuron-to-neuron firing signals across the synapse. But when albumin stimulates TGF-Beta receptors, astrocytes lose some of their control. Neuron signaling then spike dangerously, and promote the development of epileptic seizures. As luck would have it, statin drugs block TGF-Beta signaling.  Kaufer is now carrying out research to confirm that blocking abnormal TGF-Beta activity can prevent epilepsy from a range of insults. “Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50 percent chance of developing epilepsy. But you don’t know which ones, nor do you have a way of preventing it. And epilepsy from brain injuries is the type most unresponsive to drugs." says Kaufer. “I’m very hopeful and that our research can spare these patients the added trauma of epilepsy.”

(Thanks to Dr. Doug "Scout" Shevlin for alerting me to this potentially groundbreaking research.)

Seizing Control of Brain Seizures

How can trauma lead to chronic seizures? Berkeley researcher Daniela Kaufer found that only when albumin in the blood breaches the blood-brain barrier does the likelihood of post-traumatic epilepsy go up. Accelerated signaling between neurons results from this exposure, leaduing to seizures. “We were surprised, even a little disappointed, that it was such a common component of the blood  – nothing exotic at all  – that led to epilepsy,” recalls Kaufer, associate professor of integrative biology. She and colleagues went on to

Daniela Kaufer in the lab

show that albumin interacts with a ubiquitous cell protein TGF-Beta receptor to cause the damage. In the healthy brain, TGF-Beta signaling affects activity of astrocytes, which normally limit neuron-to-neuron firing signals across the synapse. But when albumin stimulates TGF-Beta receptors, astrocytes lose some of their control. Neuron signaling then spike dangerously, and promote the development of epileptic seizures. As luck would have it, statin drugs block TGF-Beta signaling.  Kaufer is now carrying out research to confirm that blocking abnormal TGF-Beta activity can prevent epilepsy from a range of insults. “Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50 percent chance of developing epilepsy. But you don’t know which ones, nor do you have a way of preventing it. And epilepsy from brain injuries is the type most unresponsive to drugs." says Kaufer. “I’m very hopeful and that our research can spare these patients the added trauma of epilepsy.”

(Thanks to Dr. Doug "Scout" Shevlin for alerting me to this potentially groundbreaking research.)

Children's Oncology Group Seeking Applicants for Young Investigator Program

Dr. Chris Pierson

I heard today from Dr. Christopher Pierson, neuropathologist and vice-chair of Children's Oncology Group Young Investigators. He asked me to share the following announcement about a fantastic program:

The Children’s Oncology Group Young Investigator (COG YI) mentor/mentee program is currently soliciting applications for potential mentees. The purpose of this program is to provide an opportunity for a junior pathologist to work with a senior pathologist and possibly advance toward serving as part of central pathology review for COG protocols and/or serving on COG committees. The program pairs a young investigator with a senior member of the COG pathology discipline who provides mentorship to the young investigator while executing a research project based on a tumor type or topic of mutual interest. YI mentees are expected to present their progress at the yearly fall COG meeting. The program does not fund specific research projects, but can help direct individuals to other funding sources if needed. Limited funds may or may not be available from COG to defray the cost of travel for mentees to attend yearly COG meetings.

Requirements for potential mentee:         

1.         Children’s Oncology Group (COG) Member

2.         Less than 5 years from completion of fellowship/residency 

3.         Precise area of interest within a specific pediatric tumor

4.         Completed application (see below)

An optimal mentee is an individual with a defined focus in a specific pediatric tumor. Mentees should submit a project proposal related to this area of interest that utilizes resources unique to the COG, such as H+E slides, paraffin sections, tissue microarrays, and in some cases frozen samples.  

This three-year program is aimed to provide guidance to COG young investigators who have matured in their career to a level of interest in one particular pediatric tumor.  Those who are still exploring or examining various subjects within pediatric tumors should not apply. Interested applicants must apply by September 30, 2013.

To apply for the COG YI pathology mentorship program, please prepare the following:

1.      Project proposal (1-2 pages with brief description of background, hypothesis, proposed methods, and brief references).

2.            Curriculum vitae

3.            Letter of support from Department Chair

4.            Documentation of COG membership (can be obtained at the COG website)

Completed applications should be sent to:

Chris Pierson, M.D., Ph.D

COG Pathology Discipline YI Liaison

Vice-Chair, COG YI Committee

Christopher.pierson@nationwidechildrens.org

Best Post of February 2012: Eberhart questions glial-to-endothelial transdifferentiation in real-world glioblastomas

The next in our "Best of the Month" series is from February 24, 2012. To read the comments engendered by Dr. Eberhart's question, go to the original post.

I'd like to share with you this email, which I received from the illustrious Dr. Charles Eberhart this morning:

Hi Brian,

I was curious what other neuropathologists thought about the issue of brain tumor cells transdifferentiating into endothelium and making up significant proportions of the growing vasculature. As you may know, last year two high profile papers stated that half or more of vascular endothelial cells in brain tumors derived from genetically altered neoplastic cells. This seemed inconsistent with our clinical experience, and four of us recently published a report expressing our views. I would be curious to know what other practicing surgical neuropathologists thought, and your blog might be one forum in which to have that conversation. This is one area where I believe that practicing pathologists have something to teach basic scientists.

Regards,

Charles Eberhart, MD PhD

Professor of Pathology, Ophthalmology and Oncology Director of Neuropathology Chief of Ophthalmic Pathology Johns Hopkins University School of Medicine

Please post your comments. If for some reason you are unable to access the article through the link provided above, here is the reference and abstract:

Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG. Neoplastic Cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106.

Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. Although rare CD34 positive neoplastic cells unassociated with vessels were identified (<1%), this analysis did not identify EGFR amplified cells within vascular linings, and further supports our observations that incorporation of glioblastoma cells into the tumor vessels is at best extremely rare, and therefore of questionable clinical or therapeutic significance.

Eberhart questions glial-to-endothelial transdifferentiation in real-world glioblastomas

I'd like to share with you this email, which I received from the illustrious Dr. Charles Eberhart this morning:
 

Hi Brian,

I was curious what other neuropathologists thought about the issue of brain tumor cells transdifferentiating into endothelium and making up significant proportions of the growing vasculature. As you may know, last year two high profile papers stated that half or more of vascular endothelial cells in brain tumors derived from genetically altered neoplastic cells. This seemed inconsistent with our clinical experience, and four of us recently published a report expressing our views. I would be curious to know what other practicing surgical neuropathologists thought, and your blog might be one forum in which to have that conversation. This is one area where I believe that practicing pathologists have something to teach basic scientists.

Regards,

Charles Eberhart, MD PhD

Professor of Pathology, Ophthalmology and Oncology Director of Neuropathology Chief of Ophthalmic Pathology Johns Hopkins University School of Medicine

Please post your comments. If for some reason you are unable to access the article through the link provided above, here is the reference and abstract:

Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG. Neoplastic Cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106.

Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. Although rare CD34 positive neoplastic cells unassociated with vessels were identified (<1%), this analysis did not identify EGFR amplified cells within vascular linings, and further supports our observations that incorporation of glioblastoma cells into the tumor vessels is at best extremely rare, and therefore of questionable clinical or therapeutic significance.

NIH Loan Repayment Program a godsend for young neuropathologists interested in research

Today I feature a guest post from the illustrious Dr. Mike Lawlor.

Hi Everyone,

I'd just like to tell everyone about a program that the NIH offers, which may be of great interest to Neuropathology Fellows, Research Fellows, and Junior Faculty.  It's called the NIH Loan Repayment Program (LRP), and it's designed to encourage people with an interest in research to remain in the academic research environment.  From what I've heard, the NIH created this program so that people with lots of student loans (mostly medical doctors) with an interest in research would not give up their research careers due to their loan debt.

I just got an email from the LRP people, and they now have a webinar available to help people apply.  The link for the webinar is: http://bit.ly/nihlrptutorial 

Michael W. Lawlor, MD, PhD

The award offers up to $35,000 per year for up to two years, and you're able to apply for renewals whenever it runs out.  This counts as income, but the NIH also pays the federal income tax on this grant for you.  I ended up owing about $2000 in state tax every year for having the award, but that doesn't seem like much as you watch your student loans disappear.

Here's what you'll need:

1) The grant application, which can be found this site.  The forms aren't too labor-intensive, and you need to propose a 2-year research program and be able to guarantee a 50% effort commitment to the research.

2) A bunch of info on your student loans, most/all of which can be found on your monthly statements.  Your student loan burden needs to exceed a certain amount before you qualify, and the amount you need is dependent on your income.  Given the non-stellar income of most neuropath fellows and research fellows, it's actually pretty easy to qualify on financial grounds.  You may continue to apply for renewals as long as you continue to meet the eligibility requirements.

3) Someone to vouch for you.  Your research adviser will need to reply to an email that confirms that you are devoting 50% effort to your research every quarter.  After that confirmation is made, and you confirm that the prior payment made it to the right account, they apply a payment to your educational loans.

Anyway, I've been in this program for the past 2 years, had it renewed for another year, and am in the process of writing another renewal.  It really is a fantastic program with excellent support.  The next deadline is November 15th, so there's definitely time for you guys to put something together.  Once you submit the application, you'll hear nothing for about 6 months, and then they'll ask you for some updated student loan information if you've made it through their scientific review process.  The application cycle is once per year.

I hope that this helps some of you, and good luck!

Thanks for this helpful information, Mike!

Treatable Neurological Disorders Misdiagnosed as Creutzfeldt-Jakob Disease

A case of primary CNS angiitis thought to be sCJD

Dr. Mark Cohen and a team of workers at Case Medical Center in Cleveland, Ohio have published an important article in the Annals of Neurology entitled Treatable Neurological Disorders Misdiagnosed as Creutzfeldt-Jakob Disease (Ann Neurol 2011;70:437–444). Why is this article important? Well, because mistaking a survivable, treatable disorder for a fatal, non-treatable disorder is not optimal. Cohen's team reviewed the pathologic diagnoses of 1,106 patients who were referred for potential prion disease to the National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University from 2006 to 2009. About one-third of the cases did not have prion disease, with Alzheimer disease and vascular disease being the most common conditions accounting for dementia. Further, about one-quarter of the non-prion cases had treatable diseases, including immune-mediated disorders, neoplastic disorders such as lymphoma, as well as infectious and metabolic disorders. The immune-mediated disorders included primary angiitis of the CNS, acute disseminated encephalomyelitis, limbic encephalitis, neurosarcoidosis, paraneoplastic cerebellar degeneration, and one case of Wegener granulomatosis. Of note, more than half of patients with a treatable dementia had a positive CSF 14-3-3 protein test, highlighting the danger of relying too heavily on this test in making a diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). It turns out that the most specific test for distinguishing CJD from other diseases was magnetic resonance imaging. Drs. David Perry and Michael Geschwind, in a review of this study in the September 2011 issue of Nature Reviews Neurology, (Perry, D. C. & Geschwind, M. D. Nat. Rev. Neurol. 2011:7, 479–480) write: "The fact that many of the non-prion diagnoses in the present study were potentially treatable RPDs [rapidly progressive dementias] should prompt thorough diagnostic testing in patients who are suspected of having sCJD, in order to rule out mimics. The use of CSF testing, contrast-enhanced MRI, and autoimmune antibody screening is supported by this study."

Marathon brain cutting session at UCSD streamed live today

The Brain Observatory at the University of California San Diego is today beginning a 30-hour brain cutting session with a live online stream of the procedure wherein the brain of H.M., an amnestic patient, is being thinly sliced from front to back into whole-mount frozen histologic sections. Each brain slice will be approximately 70 microns thick, about the thickness of a human hair. An average-sized brain produces 2,600 to 3,000 such slices. The UCSD Brain Observatory, headed by Dr. Jacopo Annese, is dedicated to the study of the architecture of the human brain using multiple complementary imaging modalities, including autopsy. Thanks to Thomasina Bailey for alerting me to this extraordinary brain cutting event!

Research team succeeds in intranasal delivery of stem cells to brain

"[I]t is possible without surgery to deliver stem cells to the brain," says Dr. William H. Frey (pictured) of the University of Minnesota in the August 3rd issue of Neurology Today. According to the article, a team including Frey have shown that stem cells delivered intranasally in the rat can bypass the blood-brain barrier and make their way into the brain. This kind of delivery mechanism brings us one step closer to stem cell therapy for the central nervous system. The stem cells used in the study are of two types: bone marrow derived, and human glioma cells. Both types of stem cells were shown to reach the brain within an hour. "This could revolutionize regenerative medicine," said Frey. The original report appears in the European Journal of Cell Biology (Danielyan L, Shafer R, Frey WH, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol 2009;88(6)315-324. E-pub 2009 Mar 25).