Tag Archives: Parkinson’s Disease

Better neuroprostheses for brain diseases and mental illneses

I don’t often get news releases from Sweden but I do on occasion and, sometimes, they even come in their original Swedish versions. In this case, Lund University sent me an English language version about their latest work making brain implants (neural prostheses) safer and effective. From a Sept. 29, 2015 Lund University news release (also on EurekAlert),

Neurons thrive and grow in a new type of nanowire material developed by researchers in Nanophysics and Ophthalmology at Lund University in Sweden. In time, the results might improve both neural and retinal implants, and reduce the risk of them losing their effectiveness over time, which is currently a problem

By implanting electrodes in the brain tissue one can stimulate or capture signals from different areas of the brain. These types of brain implants, or neuro-prostheses as they are sometimes called, are used to treat Parkinson’s disease and other neurological diseases.

They are currently being tested in other areas, such as depression, severe cases of autism, obsessive-compulsive disorders and paralysis. Another research track is to determine whether retinal implants are able to replace light-sensitive cells that die in cases of Retinitis Pigmentosa and other eye diseases.

However, there are severe drawbacks associated with today’s implants. One problem is that the body interprets the implants as foreign objects, resulting in an encapsulation of the electrode, which in turn leads to loss of signal.

One of the researchers explains the approach adopted by the research team (from the news release),

“Our nanowire structure prevents the cells that usually encapsulate the electrodes – glial cells – from doing so”, says Christelle Prinz, researcher in Nanophysics at Lund University in Sweden, who developed this technique together with Maria Thereza Perez, a researcher in Ophthalmology.

“I was very pleasantly surprised by these results. In previous in-vitro experiments, the glial cells usually attach strongly to the electrodes”, she says.

To avoid this, the researchers have developed a small substrate where regions of super thin nanowires are combined with flat regions. While neurons grow and extend processes on the nanowires, the glial cells primarily occupy the flat regions in between.

“The different types of cells continue to interact. This is necessary for the neurons to survive because the glial cells provide them with important molecules.”

So far, tests have only been done with cultured cells (in vitro) but hopefully they will soon be able to continue with experiments in vivo.

The substrate is made from the semiconductor material gallium phosphide where each outgrowing nanowire has a diameter of only 80 nanometres (billionths of a metre).

Here’s a link to and a citation for the paper,

Support of Neuronal Growth Over Glial Growth and Guidance of Optic Nerve Axons by Vertical Nanowire Arrays by Gaëlle Piret, Maria-Thereza Perez, and Christelle N. Prinz. ACS Appl. Mater. Interfaces, 2015, 7 (34), pp 18944–18948 DOI: 10.1021/acsami.5b03798 Publication Date (Web): August 11, 2015

Copyright © 2015 American Chemical Society

This paper appears to be open access as I was able to link to the PDF version.

Inhale the drugs for Parkinson’s disease

The news out of Northeastern University’s Dr. Barbara Waszczak’s lab is exciting but it’s a single high point in a larger narrative.  First, here’s the high point described in the Apr. 24, 2013 news item on Azonano,

Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms. The novelty of the approach lies in the nasal route of administration and nanoparticles containing a gene capable of rescuing dying neurons in the brain.

The Apr. 21, 2013 news release on EurekAlert, which originated the news item, provides some information about Parkinson’s disease,

Parkinson’s is a devastating neurodegenerative disorder caused by the death of dopamine neurons in a key motor area of the brain, the substantia nigra (SN). Loss of these neurons leads to the characteristic tremor and slowed movements of PD, which get increasingly worse with time. Currently, more than 1% of the population over age 60 has PD and approximately 60,000 Americans are newly diagnosed every year. The available drugs on the market for PD mimic or replace the lost dopamine but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons.

Here’s how the disease got its name, from the Wikipedia essay: Parkinson’s disease (Note: Links have been removed),

The disease is named after the English doctor James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy in 1817. Several major organizations promote research and improvement of quality of life of those with the disease and their families. Public awareness campaigns include Parkinson’s disease day (on the birthday of James Parkinson, April 11) and the use of a red tulip as the symbol of the disease. People with parkinsonism who have increased the public’s awareness include Michael J. Fox and Muhammad Ali.

Now for some information about the background work leading up to this new, exciting, high point (from the news release on EurekAlert),

The focus of Dr. Barbara Waszczak’s lab at Northeastern University in Boston is to find a way to harvest the potential of glial cell line-derived neurotrophic factor (GDNF) as a treatment for PD. GDNF is a protein known to nourish dopamine neurons by activating survival and growth-promoting pathways inside the cells. Not surprisingly, GDNF is able to protect dopamine neurons from injury and restore the function of damaged and dying neurons in many animal models of PD. However, the action of GDNF is limited by its inability to cross the blood-brain barrier (BBB), thus requiring direct surgical injection into the brain. To circumvent this problem, Waszczak’s lab is investigating intranasal delivery as a way to bypass the BBB. Their previous work showed that intranasal delivery of GDNF protects dopamine neurons from damage by the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard rat model of PD.

According to the Michael J. Fox Foundation, this research work dates from 2007 (at least), from the Intranasal Delivery of GDNF for Parkinson’s Disease: Next Steps grant page,

FINAL OUTCOME

The results of this Drug Delivery 2008 project confirm and extend the conclusions reached under a previous 2007 Rapid Response Innovation Award. The research team has demonstrated that intranasal administration of GDNF has neuroprotective efficacy in a preclinical model of Parkinson’s disease, that the protein gets into the brain and reaches target structures (the striatum and substantia nigra) within an hour of nasal administration, and that the nasal route causes no apparent toxicity in the nose. Longer term efficacy and toxicology studies will be necessary in other relevant preclinical models before testing can be initiated in humans.

The results of this work strongly supports pursuit of intranasal administration as a promising approach for harvesting the therapeutic potential of GDNF. Such an approach could ultimately provide an effective, non-invasive means of delivering GDNF to the brain for the treatment of Parkinson’s disease.

Here’s the 2013 innovation on intranasal delivery of GDNF therapy (from the news release on EurekAlert),

Taking this work a step further, Brendan Harmon, working in Waszczak’s lab, has adapted the intranasal approach so that cells in the brain can continuously produce GDNF. His work utilized nanoparticles, developed by Copernicus Therapeutics, Inc., which are able to transfect brain cells with an expression plasmid carrying the gene for GDNF (pGDNF). When given intranasally to rats, these pGDNF nanoparticles increase GDNF production throughout the brain for long periods, avoiding the need for frequent re-dosing. Now, in new research presented on April 20 at 12:30 pm during Experimental Biology 2013 in Boston, MA, Harmon reports that intranasal administration of Copernicus’ pGDNF nanoparticles results in GDNF expression sufficient to protect SN dopamine neurons in the 6-OHDA model of PD.

Waszczak and Harmon believe that intranasal delivery of Copernicus’ nanoparticles may provide an effective and non-invasive means of GDNF gene therapy for PD, and an avenue for transporting other gene therapy vectors to the brain. This work, which was funded in part by the Michael J. Fox Foundation for Parkinson’s Research and Northeastern University, has the potential to greatly expand treatment options for PD and many other central nervous system disorders.

For the curious, there’s more about Copernicus Therapeutics at the company website.

Congratulations to Harmon and Waszczak! I imagine the next step will be human clinical trials.

Self-assembling protein inspires University of Montreal’s researchers to smaller efforts

Protein folding doesn’t seem all that exciting to me and the notion that it might lead to self-assembled, living machines isn’t all that new (see my May 31, 2012 posting about a Living Foundries project). So the June 10, 2012 news item on Nanowerk left me with a flat feeling, initially,

Enabling bioengineers to design new molecular machines for nanotechnology applications is one of the possible outcomes of a study by University of Montreal researchers that was published in Nature Structural and Molecular Biology today (“Visualizing transient protein folding intermediates by tryptophan scanning mutagenesis” [behind a paywall]). The scientists have developed a new approach to visualize how proteins assemble, which may also significantly aid our understanding of diseases such as Alzheimer’s and Parkinson’s, which are caused by errors in assembly.

“In order to survive, all creatures, from bacteria to humans, monitor and transform their environments using small protein nanomachines made of thousands of atoms,” explained the senior author of the study, Prof. Stephen Michnick of the university’s department of biochemistry. “For example, in our sinuses, there are complex receptor proteins that are activated in the presence of different odor molecules. Some of those scents warn us of danger; others tell us that food is nearby.” Proteins are made of long linear chains of amino acids, which have evolved over millions of years to self-assemble extremely rapidly – often within thousandths of a split second – into a working nanomachine.

My ears pricked up when the talk turned to capturing images of action, which occurs in a “fleetingly short time,”

“To understand how a protein goes from a linear chain to a unique assembled structure, we need to capture snapshots of its shape at each stage of assembly said Dr. Alexis Vallée-Bélisle, first author of the study. “The problem is that each step exists for a fleetingly short time and no available technique enables us to obtain precise structural information on these states within such a small time frame. We developed a strategy to monitor protein assembly by integrating fluorescent probes throughout the linear protein chain so that we could detect the structure of each stage of protein assembly, step by step to its final structure.” The protein assembly process is not the end of its journey, as a protein can change, through chemical modifications or with age, to take on different forms and functions. “Understanding how a protein goes from being one thing to becoming another is the first step towards understanding and designing protein nanomachines for biotechnologies such as medical and environmental diagnostic sensors, drug synthesis or delivery,” Vallée-Bélisle said.

Here’s an image of protein self-assembly from the University of Montreal (Université de Montréal) website (Montréal, Québec, Canada),

Vallée-Bélisle and Michnick have developed a new approach to visualize how proteins assemble, which may also significantly aid our understanding of diseases such as Alzheimer's and Parkinson's, which are caused by errors in assembly. Here shown are two different assembly stages (purple and red) of the protein ubiquitin and the fluorescent probe used to visualize these stage (tryptophan: see yellow). Credit: Peter Allen

I would have liked a little more detail (e.g. how little time is there to capture the images?) but there isn’t always time either for the people who write these news releases or for me to follow up with questions. Given the huge political unrest amongst students over the proposed tuition fees and the Québec government’s attempts (sometimes described as draconian) to impose order, I’m impressed this news release was pulled together.

Overpromising and underdelivering: genome, stem cells, gene therapy and nano food

When people talk about overpromising (aka hype/hyperbole) and science, they’re usually referring to overexcited marketing collateral and/or a public relations initiative and/or news media coverage.  Scientists themselves don’t tend to be identified as one of the sources for hype even when that’s clearly the case. That’s right, scientists are people too and sometimes they get carried away by their enthusiasms as Emily Yoffe notes in her excellent Slate essay, The Medical Revolution; Where are the cures promised by stem cells, gene therapy, and the human genome? From Yoffe’s essay,

Dr. J. William Langston has been researching Parkinson’s disease for 25 years. At one time, it seemed likely he’d have to find another disease to study, because a cure for Parkinson’s looked imminent. In the late 1980s, the field of regenerative medicine seemed poised to make it possible for doctors to put healthy tissue in a damaged brain, reversing the destruction caused by the disease.

Langston was one of many optimists. In 1999, the then-head of the National Institute of Neurological Disorders and Stroke, Dr. Gerald Fischbach, testified before the Senate that with “skill and luck,” Parkinson’s could be cured in five to 10 years. Now Langston, who is 67, doesn’t think he’ll see a Parkinson’s cure in his professional lifetime. He no longer uses “the C word” and acknowledges he and others were naive. [emphasis mine] He understands the anger of patients who, he says, “are getting quite bitter” that they remain ill, long past the time when they thought they would have been restored to health.

The disappointments are so acute in part because the promises have been so big. Over the past two decades, we’ve been told that a new age of molecular medicine—using gene therapy, stem cells, and the knowledge gleaned from unlocking the human genome—would bring us medical miracles. [emphasis mine] Just as antibiotics conquered infectious diseases and vaccines eliminated the scourges of polio and smallpox, the ability to manipulate our cells and genes is supposed to vanquish everything from terrible inherited disorders, such as Huntington’s and cystic fibrosis, to widespread conditions like cancer, diabetes, and heart disease.

Yoffe goes on to outline the problems that researchers encounter when trying to ‘fix’ what’s gone wrong.

Parkinson’s disease was long held out as the model for new knowledge and technologies eradicating illnesses. Instead, it has become the model for its unforeseen consequences. [emphasis mine]

Langston, head of the Parkinson’s Institute and Clinical Center, explains that scientists believed the damage to patients took place in a discrete part of the brain, the substantia nigra. “It was a small target. All we’d have to do was replace the missing cells, do it once, and that would cure the disease,” Langston says. “We were wrong about that. This disease hits many other areas of the brain. You can’t just put transplants here and there. The brain is not a pincushion.”

Disease of all kinds have proven to be infinitely more complex than first realized. Disease is not ’cause and effect’ driven so much as it is a process with an infinite number of potential inputs and any number of potential outcomes. Take for example gene therapy (Note: the human genome project was supposed to yield gene therapies),

In some ways, gene therapy for boys with a deadly immune disorder, X-linked severe combined immune deficiency, also known as “bubble boy” disease, is the miracle made manifest. Inserting good genes into these children has allowed some to live normal lives. Unfortunately, within a few years of treatment, a significant minority have developed leukemia. The gene therapy, it turns out, activated existing cancer-causing genes in these children. This results in what the co-discoverer of the structure of DNA, James Watson, calls “the depressing calculus” of curing an invariably fatal disease—and hoping it doesn’t cause a sometimes-fatal one.

For me, it seems that that the human genome project was akin to taking a clock apart. Looking at the constituent parts and replacing broken ones does not guarantee that you will be able assemble a more efficient working version unless you know how the clock worked in the first place. We still don’t understand the basic parts, the genes,  interact with each other, within their environment, or with external inputs.

The state of our ignorance is illustrated by the recent sequencing of the genome of Bishop Desmond Tutu and four Bushmen. Three of the Bushmen had a gene mutation associated with a liver disease that kills people while young. But the Bushmen are all over 80—which means either the variation doesn’t actually cause the disease, or there are other factors protecting the Bushmen.

As for the pressures acting on the scientists themselves,

There are forces, both external and internal, on scientists that almost require them to oversell. Without money, there’s no science. Researchers must constantly convince administrators who control tax dollars, investors, and individual donors that the work they are doing will make a difference. Nancy Wexler says that in order to get funding, “You have to promise cures, that you’ll meet certain milestones within a certain time frame.”

The infomercial-level hype for both gene therapy and stem cells is not just because scientists are trying to convince funders, but because they want to believe. [emphases mine]

Scientific advances as one of Yoffe’s interview subjects points out involve a process dogged with failure and setbacks requiring an attitude of humility laced with patience and practiced over decades before an ‘overnight success’ occurs, if it ever does.

I was reminded of Yoffe’s article after reading a nano food article recently written by Kate Kelland for Reuters,

In a taste of things to come, food scientists say they have cooked up a way of using nanotechnology to make low-fat or fat-free foods just as appetizing and satisfying as their full-fat fellows.

The implications could be significant in combating the spread of health problems such as obesity, diabetes and heart disease.

There are two promising areas of research. First, they are looking at ways to slow digestion,

One thing they might look into is work by scientists at Britain’s Institute of Food Research (IFR), who said last month they had found an unexpected synergy that helped break down fat and might lead to new ways of slowing digestion, and ultimately to creating foods that made consumers feel fuller.

“Much of the fat in processed foods is eaten in the form of emulsions such as soups, yoghurt, ice cream and mayonnaise,” said the IFR’s Peter Wilde. “We are unpicking the mechanisms of digestion used to break them down so we can design fats in a rational way that are digested more slowly.”

The idea is that if digestion is slower, the final section of the intestine called the ileum will be put on its “ileal brake,” sending a signal to the consumer that means they feel full even though they have eaten less fat

This sounds harmless and it’s even possible it’s a good idea but then replacing diseased tissue with healthy tissue, as they tried with Parkinson’s Disease gene therapies, seemed like a good idea too. Just how well is the digestive process understood?

As for the second promising area of research,

Experts see promise in another nano technique which involves encapsulating nutrients in bubble-like structures known as vesicles that can be engineered to break down and release their contents at specific stages in the digestive system.

According to Vic Morris, a nano expert at the IFR, this technique in a larger form, micro-encapsulation, was well established in the food industry. The major difference with nano-encapsulation was that the smaller size might be able to take nutrients further or deliver them to more appropriate places. [emphasis mine]

They’ve been talking about trying to encapsulate and target medicines to more appropriate places and, as far as I’m aware, to no avail. I sense a little overenthusiasm on the experts’ part. Kelland does try to counterbalance this by discussing other issues with nanofood such as secretiveness about the food companies’ research, experts’ concerns over nanoparticles, and public concerns over genetically modified food. Still the allure of ‘all you can eat with no consequences’ is likely to overshadow any journalist’s attempt at balanced reporting with resulting disappointment when somebody realizes it’s all much more complicated than we thought.

Dexter Johnson’s Sept. 22, 2010 posting ( Protein-based Nanotubes Pass Electrical Signals Between Cells) on his Nanoclast blog offers more proof that we still have a lot to learn about basic biological processes,

A few years back, scientists led by Hans-Hermann Gerdes at the University of Bergen noticed that there were nanoscale tubes connecting cells sometimes over significant distances. This discovery launched a field known somewhat by the term in the biological community as the “nanotube field.”

Microbiologists remained somewhat skeptical on what this phenomenon was and weren’t entirely pleased with some explanations offered because they seemed to fall outside “existing biological concepts.”

So let’s start summing up.  The team notices nanotubes that connect cells over distances which microbiologists have difficulty accepting as “they [seem] to fall outside existing biological concepts. [emphasis mine] Now the team has published a paper which suggests that electrical signals pass through the nanotubes and that a ‘gap junction’ enables transmission to nonadjacent cells.  (Dexter’s description provides  more technical detail in an accessible writing style.)

As Dexter notes,

Another key biological question it helps address–or complicate, as the case may be–is the complexity of the human brain. This research makes the brain drastically more complex than originally thought, according to Gerdes. [emphasis mine]

Getting back to where I started, scientists are people too. They have their enthusiasms as well as pressure to get grants and produce results for governments and other investors, not to mention their own egos.  And while I’ve focused on the biological and medical sciences in this article, I think that all the sciences yield more questions than answers and that everything is far more complicated and  interconnected than we have yet to realize.