The brain is the last and grandest biological frontier, the most complex thing we have yet discovered in our universe. It contains hundreds of billions of cells interlinked through trillions of connections. The brain boggles the mind.
Dr. James D. Watson, Biophysicist, Nobel-prize winner, Co-discoverer of DNA
Like high-speed trains on overdrive barreling through the French countryside, recent discoveries in brain research have been opening new vistas of brain therapies and dramatically changing the outlook for millions with brain disease. Projects like the government-backed “Brain Research Advancing Initiative” (BRAIN) are speeding up the mapping of the human brain’s one hundred billion neurons – each with some ten thousand connections that come and go as we learn, remember, and forget. The incredible anatomical complexity of the human brain is surpassed only by the staggering amount of information that it processes each millisecond. Is the human brain capable of understanding the many trillions of interactions that enable it to approach the task? And then, designing therapies that heal its malfunctions? Medical science will soon have many of the answers.
Partially unraveling the enormous potentiality of the brain and its maladies, recent discoveries have unleashed an exponential surge of understanding which is being used to close the gaps between neuroscience theory and medical practice. We now know that just one microscopic patch of neurons, 1/100,000 the size of a grain of salt, contains about a thousand axons continuously carrying impulses away from the nerve cell center, with about 80 dendrites bringing in information from 600 or so other connections with other neurons. Each infinitesimally small plot of brain matter harnesses a hotbed of electrical, biochemical, and genetic activity – where exciting new therapies can affect cures.
Meanwhile, five million Americans are suffering from Alzheimer’s disease; one million from Parkinson’s; 400,000 from Multiple Sclerosis (MS); 30,000 from Amylotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s disease), 30,000 from Huntington’s disease, and 30,000 from Atypical Parkinson´s disease. In 2014, 23,400 new cases of malignant brain cancers were reported. In addition, many more millions suffer brain maladies of seizures, strokes, traumas, viral infections, prion infections, tumors, cancers, all kinds of vascular diseases and genetic conditions.
With the percentage of Americans over age 65 climbing from 12% to 21% over the next 30 years, and neuro-degenerative brain diseases “coming out of the closet” later in life, more than 12 million Americans will soon be suffering progressively debilitating brain disease, many without available treatments. Neuro-degenerative brain diseases often begin decades before first symptoms, such as“mild cognitive impairment” (MCI), appear. In all too many cases MCI progresses steadily toward dementia. In addition, the effects of undetected “silent strokes” can be cumulative, producing a similar progressive decline in function. Malignant brain cancers often prove fatal within a year, with 33.4% surviving five years. Developing treatments and cures for brain disease has become a goal of national urgency.
A “Turning Point”
Until recently, treatment and therapy options have been limited to surgery and pharmaceuticals, each with their own subset of serious side effects and complications. But within the last ten years exciting new discoveries in the treatment of brain disease have worked wonders for many patients. Medical science has learned to use several types of stem cells, the body´s own immune system, new classes of drugs, neuro-vaccines, how to switch the patient’s own genes on and off, and even how to suffuse brain tumors with new immune cells with new genes designed to kill specific cancer cells.
Treatments that were once theoretical gleams in a neuroscientist’s eyes have worked their way into clinical application with increasing success. Neuroscientists, like Professor Roger Morris, are extremely excited at what they see as a ”turning point,” in the search for treatments and therapies for brain disease. Dr. James Pickett of the Alzheimer´s Society remains more cautious saying, “We´ve seen a lot of breakthroughs.”
The Problem of “Delivery” Solved by a Multidisciplinary Approach
The brain performs a myriad of multidimensional functions well, so well in fact that when things run smoothly we generally don´t notice. When the brain fails to perform even one of its functions, however, a wide range of symptoms can appear – and we do notice. Weighing in at only 2% body weight, the brain requires a constant 20% of the body´s blood supply. If it receives much less of that blood supply because of a vascular, brain, heart, or lung ”disorder,” “condition,” “syndrome,” or “disease” neurons begin dying within 3 to 5 minutes. Without blood, the brain becomes clinically “dead” after 9 minutes.
The death of large numbers of neurons within any one vicinity of the brain causes a stroke or transient ischemic attack (TIA), or a silent cerebral infarct (when no symptoms appear). Breakage of a blood vessel or vessels is called an aneurysm, and can produce a potentially fatal brain hemorrhage if the bleeding does not stop.
Until only recently, giving brain problems a name and giving them a cure have been oceans apart. This gap is closing fast, however, with many new cures on the horizon. Molecular biology, neurophysiology, neuroscience, bio tech engineers, and physicians have teamed up to create exciting new treatment options for brain diseases that impact millions of lives.
Much of what has been done in the past has been limited by the problem of “delivery,” of getting large molecules past the very “tight junctions” of the cells that fuse tightly together to protect the brain. In general, only small molecules like Ibuprofen or opioids get past this cellular barricade, called the “blood-brain-barrier,” that defends the brain against chemicals, parasites, bacteria, and viruses. The problem of effectively delivering large therapeutic molecules to the brain has, in some cases, been solved by a multidisciplinary approach involving neurologists, molecular biologists, neurosurgeons, biochemists, pharmacologists, and epidemiologists.
Ablative Brain Surgery, or “Lesioning”
“I’ve got the brain of a four year old. I’ll bet he was glad to be rid of it.” — Groucho Marx
One of the most basic treatments, one that avoids the molecular dynamics of the blood-brain-barrieraltogether is ablative brain surgery, targeting deep brain tissue for destruction, or “lesioning.” More than a thousand years ago, Peruvians performed also various ablative surgical procedures on the brain… and with a 85% recovery rate! Today, fifty years after frontal lobotomies ablated frontal cortexes to treat psychological problems, ablative surgery of the brain has grown far more precise and selective. Techniques have become less and less invasive, while destroying malfunctioning, sometimes cancerous brain tissue with more and more precision. Three of the latest ablative surgery techniques are:
Focused Ultrasound has been used to treat Parkinsonian tremor and Parkinsonian dyskinesia as well as psychiatric disorders such as schizophrenia.
Radio-frequency Ablation uses stereotaxic heating to do destroy small cancers and tumors.
Lazer Ablation Surgery has been used to treat epilepsy and tumors.
One way or another, ablative brain surgery involves the irreversible destruction of brain tissue. Partly because brain function is dynamic and ever-changing and partly because of unforeseen conditions all ablations have the potential for serious side effects and complications. These surgeries are generally performed in extreme cases and as a last-resort.
“Deep Brain Stimulation”
Stimulating rather than destroying brain cells, “Deep Brain Stimulation” (DBS) is somewhat the opposite of ablation. Like ablative surgery DBS is a surgically invasive therapy, but with reversible, possibly adjusted, effects. “DBS” is currently used to treat only extreme cases of Parkinson´s disease, chronic pain, Obsessive-Compulsive Disorder (OCD), narcolepsy, and major depression, yet its mode of action remains unclear. At this time, DBS is also used to treat extreme cases of Tourette´s Syndromeand Schizophrenia, but this application remains highly experimental.
In DBS, an electrode is surgically implanted in a deep brain area where function has been well-mapped, and where increased electrical activity and/or neurotransmitter output would potentially correct a behavioral or physiological deficiency. Mico-wires connect the implanted electrode in the brain to a pacemaker and battery surgically placed beneath the skin in the neck. The pacemaker provides steady impulses to the delinquent area, reducing symptoms. DBS is not a cure, however, and psychiatric side effects and personality changes are not uncommon. According to a leading behavioral neurosurgeon at the Cleveland Clinic, Dr. Donald A. Malone, “Only patients with severe, debilitating, and treatment-refractory illness should be considered; while those with severe personality disorders and substance abuse problems should be excluded.”
Common Threads become “Neurofibrillary Tangles”
“One of the most significant things we have learned is just how much more complicated Alzheimer’s is than people imagined.” – Dr. Simon Ridley, Alzheimer’s Research, King’s College, UK
As neuro-degenerative diseases progress into their latter stages, the brain accumulates increasingly obvious deposits of proteins that gradually destroy function. Several brain diseases show abnormally shaped proteins that progressively begin to stick, or clump together.
- In Alzheimer´s disease, Tau proteins develop into the “neurofibrillary tangles” characteristic of the disease.
- In Lewy-Body Dementia, one protein normally associated with nerve synapses, Alpha-synuclein, forms aggregates found in Lewy-Bodies.
- In Huntington´s disease a form of the Huntingtin mutant protein (mHtt) causes neuronal inclusions that lead to decay of brain function.
- In Lou Gehrig´s disease, or Amyotrophic Lateral Sclerosis (ALS), motor neurons show an increasingly large percentage of protein inclusions specific to the progression of that disease.
- Still another neuro-degenerative disease, Frontotemporal Dementia, or Pick´s disease can be diagnosed by its Pick bodies of protein that we now know to be mutated forms of tau proteins. Tau proteins are involved in maintaining the structural support elements of axons, called microtubules. Excess tau proteins produce swelling in frontal and temporal neurons, release of glutamate, causing neurons to die, and fronto-temporal lobes to atrophy.
The common thread in neuro-degenerative diseases – the steady increase of protein aggregates, inclusions, or neurofibrillary tangles in the brain that correlates with progression of disease symptoms that often includes bewildering changes in behavior. Each neuro-degenerative disease seems to have its own variation of pathological proteins that destroy ever-increasing numbers of neurons and produce a steady decline in cerebral function. Each disease progresses steadily toward some variation of dementia.
As yet, there are no definitive “cures” for neuro-degenerative diseases. Typical treatment involves reducing risk factors such as smoking, drinking, and high cholesterol – while increasing exercise, circulation, and mental activities. In the last ten years, however, new therapies and treatments in brain disease have halted and even reversed the silent progression of several neuro-degenerative diseases. Lately, treatments have been successful in targeting the disease process that creates misfolded proteins.
“We were extremely excited when we saw the treatment stop the disease in its tracks.”
– Alzheimer’s researcher Professor Giovanna Mallucci, University of Leicester, UK
Until about 2004 the prospects for gene therapy as a treatment for brain disease looked grim. Several pharmaceutical companies, including Novartis and Chiron, had closed shop on their gene therapy research divisions. Too costly and without much promise was the prognosis. In the last ten years, however, a series of stunning breakthroughs have been reported. Gene therapy has been used with success in the treatment of Huntington´s disease, Adrenoleukodystrophy (ALD), Canavan´s disease, Tay-Sachs disease, Parkinson´s disease, and the rare Sanfilippo syndrome.
One area of gene therapy treatment, called “gene silencing,” involves identifying the disease-causing genes, then finding the incredibly specific RNA or DNA that will “turn off” or “silence” those genes, and then implanting those RNAs or DNAs in the brain in sufficient numbers to effectively “silence” the diseased genes.
The most successful type of gene therapy delivers desired genes into a diseased area of the brain by tightly packing huge molecules of genetic material into the emptied shells of lentiviruses, which are retroviruses like the AIDS virus. Like the AIDS virus, lentiviruses are proficient self-replicators while also integrating their genes into the host cell’s DNA. In gene therapy, huge numbers of genetically engineered lentiviruses are injected into the brain. These lentiviruses vectors then insert therapeutically engineered gene packages into the genome’s of diseased neurons. As the newly inserted genetic material activates production of its particular protein product that had been lacking, symptoms of the disease begin to disappear. As more and more viruses replicate and infect other neurons with the engineered gene, more and more neurons produce more and more of the needed product.
Gene therapy based on lentiviruses are unique in that they integrate their engineered genes into target neurons even if the cell is not dividing. Unlike other viruses, lentivirus used as vectors do not cause leukemia and other cancers. In lentivirus gene therapy, whole areas of the brain that were no longer making the neurotransmitter dopamine and causing Parkinson’s disease are transformed into making dopamine. Activated dopamine production quiets the tremors of Parkinson’s. Several other applications of this technique are in development.
Recently, novel therapeutic approaches for common brain disorders have been developed using various types of cells and tissues to replace deficient or malfunctioning brain cells. These “cell-based therapies” can be roughly divided into five categories:
Grafted Tissues: The idea of grafting healthy brain tissue goes back to Mary Shelly’s Frankenstein, but actual practice began in 1890. Recently, new techniques have refined the procedure considerably, however, allowing healthy brain tissues to be “grafted” or “transplanted” in place and to relieve brain disease symptoms. Research in the grafting of brain tissue to treat Alzheimer’s and other neuro-degenerative diseases is beginning to show real progress.
Stem Cell Therapies: Perhaps the most promising area of research and therapy involves the site-specific grafting of stem cells after harvesting them from the patient’s own brain, bone marrow, or especially from the patient’s own umbilical cord.
Brain Stem Cells: Immature stem cells produced in the dendate gyrus of the hippocampus through the process of neurogenesis have been shown to migrate naturally to areas in the brain where they are most needed, regions where effort is most applied. These immature brain stem cells then integrate themselves in form and function, mature in place, and fill in the functional gaps left by dying neurons. By harvesting these “pluripotent” brain stem cells from the hippocampus and concentrating them in places where they are most needed, doctors have helped the brain to heal itself.
Adult Stem Cells: In practice, adult stem cells are derived from bone marrow, taken from leg bones, concentrated in the lab, and injected into damaged areas. These mesenchymal stem cells are designated as “multipotent,”” meaning that their potential to differentiate into has already been partially defined, and designated to replacing various types of blood cells. Their potential to replace “non-blood” cell types – brain cells for example – is limited.
Embryonic Stem Cells: At the other end of the spectrum, stem cells derived from the blastocyte, the fertilized egg that has divided into 50 to 100 cells before it implants into the uterine wall, are calledembryonic stem cells. These earliest of all body cells have the greatest potential to differentiate into all types of body tissues.
Embryonic stem cells are most versatile, dividing as needed and then differentiating into whatever specialized tissues are most deficient. They hold great promise in the treatment of brain disease and many other conditions, too. Yet, because embryonic stem cells are obtained from human fetuses, federal funding for research and their use in medical procedures has been restricted in the US. As a way around this problem, researchers at Wake Forest University report,
“Stem cells drawn from amniotic fluid donated by pregnant women hold much of the same promise as embryonic stem cells.”
“The best way to predict the future is to create it.” – Kaye Beach, science writer
By teaching the body’s own immune system to neutralize abnormal proteins before they proliferate, neuro-vaccines could soon provide immunization against many neuro-degenerative diseases. In theory, a neuro-vaccine for Alzheimer’s could stimulate the production of antibodies that identify and attack diseased neurons, eliminating the disease before it begins. In practice, though, the immune system is complex and reactions to a neuro-vaccine that attacks brain cells could cause far more serious and immediate neurological conditions.
Another avenue of protection could be a vaccine that prevents damage from strokes, damage caused by the excess of glutamate that accumulates in damaged areas afterward. Such a vaccine could“switch on” existing genes that prevent further damage after strokes, damage caused by the over-accumulation of of the neurotransmitter glutamate. Such damage from glutamate is also associated with several neuro-degenerative disease.
Antibiotics, too, could act as “neuro-vaccines.” Research by Dr. Jefferey Rothstein and colleagues demonstrates that various antibiotics can protect against the excess of glutamate found in amyotrophic lateral sclerosis (ALS), dementia, stroke and epilepsy.
Prion Disease, Transmissible Spongiform Encephalopathies (TSEs), and Kuru kuru
In the early 1950s medical researchers discovered a strange neural disease that afflicted the Forepeople of highland Papau New Guinea. Victims suffered a slow onset of increasingly dramatic seizures, what was then described as “the shaking death” called Kuru kuru. The disease was traced back to a funeral ritual particular to the Fore people – funeral feasting on the brain of deceased loved ones so that the power of their spirits could live on. Investigation revealed that, not only did their spirits live on but something both non-bacterial, non-viral and non-parasitic lived on as well. The disease called kuru kuru was caused by the practice of “endocannabalism.”
We now know that the Fore people were feasting on one of many different prions, the incredibly small, non-living protein molecules that caused their fatal brain diseases over various periods of time. Prion disease incubation periods can be decades or weeks. At least eight, and perhaps even hundreds of variations of small proteins self-replicate and cause prion diseases, or transmissible spongiform encephalopathies (TSEs). Outside the brain, natural antibodies protect the body from prion infections. But natural antibodies are much too large to pass through the blood-brain-barrier (BBB) where they would protect the brain from prion infection. If prions are ingested in sufficient quantities to overwhelm peripheral antibody defenses, they pass easily through the BBB into the brain.
Any treatment for prion disease requires greater understanding of the prion infection and remains a long way way off. Fortunately prion disease is rare.
“Hitting the Genetic Jackpot” – “Serial Killers” in the Brain – A Cure for Cancer?
Considered a “paradigm shift” in the treatment of cancer, and a “revolutionary” discovery in the treatment of brain disease,adoptive immunotherapy , from the lab of Dr. Carl June at the University of Pennsylvania, now stands center stage as treatment for glioblastoma multiforme, a particularly aggressive brain cancer. Accounting for half of all brain tumors,glioblastoma multiforme generally proves fatal within a year. This past year, however, Dr. June and his team have been able to eradicate signs of the disease altogether in an experimental group of patients. By injecting about 3 billion of disabled AIDS-like adenoviruses, equipped with engineered genes directly into the patient’s tumors Dr. June’s team was able to literally synthesize a full-scale immune response specific to this cancer. The adenovirus delta 24 was re-packaged with genes that produce T-cells specifically designed to destroy glioblastomal cells. The AIDS-like adenovirus self-replicates in the brain producing more and more T-cells that search and destroy cancer cells, acting like “serial killers,” according to Dr. June. Within months these T-cells had “cleaned house,” and achieved full remission in all patients.
This same type of treatment, using the AIDS-adenovirus, but programming cytotoxic T-cells to wipe out leukemic B-cells instead, produces the same success in patients with deadly acute lymphoblastic leukemia. Dr. June’s team is also working on a similar line of attack against deadly pancreatic cancers, targeting them for extermination by re-programmed T-cell genes injected, then inserted via AIDS adenoviruses. By using the combination of self-replicating adenoviruses and engineered genes that produce an immune response of “serial killer” T-cells, Dr. June’s team has “hit the genetic jackpot” in treating brain cancer.
Just as amazing, a team of researchers led by neurosurgeon Dr. Mattias Gromeier at Duke University have just treated five glioblastoma patients with injections of a modified polio virus and achieved similar remissions, and shrinkages of brain tumors. The polio viruses at Duke, like the adenoviruses at U. Penn, had been packed with genes that both produce “serial killer” T-cells and self-replicate in the brain. These once deadly viruses now produce more T-cells and less cancer.
Currently, FDA approval for this therapy is on “fast-track, ” so that T-cell Therapy could be approved, go to market, and be turning around more lives within two years. Dr. John Wagner at the University of Minnesota calls these clinical results“phenomenal,” adding that, “They’re what we’ve all been working and hoping for but not seeing to this extent.”
Collectively, these types of treatments are called “Adoptive Immunotherapy.” The patients own immune system “adopts” the engineered genes within virus vectors that are injected directly into tumors. Specific immune cells in the patient’s own body are genetically co-opted and re-trained. T-cells produced from virus-injected genes come equipped with an extensive capacity to self-replicate and turn into a progressively larger army of “serial killers,” as Dr. June describes them. Based on the “phenomenal”clinical success of Dr. Carl June’s (and Dr. Gromeier’s) team, the pharmaceutical Novartis has just committed $20 million to building a cancer research center at the University of Pennsylvania.
An Ounce of Prevention – A Mind/Body Continuum with Spirit
Even though treatments, therapies, even cures for brain disease are being developed and used successfully at an astounding rate, as with all afflictions, “an ounce of prevention is worth a pound of cure.” Anything that improves blood circulation to, within, and from the brain improves the health of individual neurons and provides the best preventative against brain disease. Regular exercise, a healthy diet, staying socially active, and regularly expending mental effort remain the mantras for brain health, and overall health, too. Brain exercise programs like “Lumosity “ cause anatomical improvements in the brain.
“The more you use your brain, the more brain you will have to use.””– George Dorsey
Maintaining a cheerful and positive spirit, a belief in one’s own power to continually expand, improve, and being of service have been shown to be essential also, especially later in life. After all, our mind and body form a continuum but our spirit embraces everything.