Bionical Creativity Engineering

When you’re blind, being able to see even the basics of light, movement and shape can make a big difference. Both the Argus II Retinal Prosthesis, currently in U S Food and Drug Administration trials, and a system being developed by Harvard Research Fellow Dr. John Pezaris record basic visual information via camera, process it into electronic signals and send it wirelessly to implanted electrodes. The Argus II uses electrodes implanted in the eye, which could help people who’ve lost some of their retinal function. Dr. Pezaris’ system, still in the early stages of research, would bypass the eyes entirely, sending visual data straight to the brain. Both systems will work best with people who could once see because their brains will already know how to process the information. The visual brain depends on visual experience to develop normally.

Since the 1960s, researchers have known about proteins that can prompt bone tissue to grow its own patches for missing or damaged parts. Unfortunately, that technology never worked perfectly, often growing the wrong type of tissue or growing bone where bone shouldn’t be. In 2005, researchers at University of California, Los Angeles solved the problem, using a specially designed protein capable only of triggering growth in specific types of cells. Called UCB-1, the protein is now used to grow new bone that can fuse and immobilize sections of vertebrae, relieving severe back pain in some patients.

An artificial pancreas, capable of monitoring a person’s blood sugar and adjusting the level of insulin to meet their body’s needs, will likely be on the market within a few short years, said Aaron Kowalski, director of strategic research projects at the Juvenile Diabetes Research Foundation. The device initially will be a combination of two existing technologies: an insulin pump and continuous glucose monitor. The contraption could help insulin-dependent diabetics lead more normal lives and make it easier for them to avoid the disfiguring and life-threatening side effects of having too little or too much blood sugar.

The tongue can be a powerful tool, but also a highly subjective one, said Dean Neikirk, professor of computer and electrical engineering at the University of Texas at Austin. When food companies want to create the same flavor every time, they turn to the electronic tongue, a device developed by Neikirk and his team to analyze liquids and pick out their exact chemical make-up. Neikirk’s tongue uses microspheres, tiny sensors that change color when exposed to a specific target, such as certain kinds of sugars. The result is a system that can’t replace the person who says, “This tastes good!” but can make sure the chemistry of good taste is reliably replicated.

Amputees can now use a prosthetic arm the same way they’d use a real one. By the power of thought developed by Dr. Todd Kuiken of the Rehabilitation Institute of Chicago, the “bionic arm” is connected to the brain by healthy motor nerves that used to run into the patient’s missing limb. These nerves are re-routed to another area of the body, such as the chest, where the nerve impulses they carry can be picked up by electrodes in the bionic arm. When the patient decides to move her hand, the nerves that would have sent the signal to real hand send it to the prosthetic one instead. Dr. Kuiken’s team is working on improving the arm, using surviving sensory nerves to communicate the feeling of temperature, vibration and pressure from the bionic arm to the patient’s brain.

The knee isn’t a part of the body you’d expect to think for itself, but the RHEO, a prosthetic knee developed by Massachusetts Institute of Technology artificial intelligence researchers Hugh Herr and Ari Wilkenfeld, really does have a mind of its own. Earlier electronic knee systems usually had to be programmed by a technician when the patient first put them on. The RHEO knee, on the other hand, creates realistic, comfortable motion on its own, by learning the way the user walks and by using sensors to figure out what kind of terrain they’re walking on. The system makes walking with a prosthetic leg easier and less exhausting.

For people with failing kidneys, basic necessities of life like removing toxins from the blood and keeping fluid levels balanced requires hours hooked up to a dialysis machine the size of a clothes dryer. But a new, portable artificial kidney, small and light enough to fit on a belt system, could change that. Notwithstanding, small size, the automated wearable artificial kidney (AWAK), designed by Martin Roberts and David B.N. Lee of University of California, Los Angeles, can actually work better than traditional dialysis because it can be used 24 hours a day, seven days a week, just like a real kidney.

Sometimes, when you need to deliver drugs to just the right spot in the body, a pill or an injection won’t cut the mustard. Daniel Hammer, professor of bioengineering at the University of Pennsylvania, has a better method. Artificial cells, made from polymers, which can mimic the ease with which white blood cells travel through the body. Called c, these fake cells could deliver drugs directly where they’re needed, making it easier and safer to fight off certain diseases, including cancer.

Erectile dysfunction can take the fun out of a man’s life, but Anthony Atala and his team at Wake Forest University have come up with a method that could put the spring back in many guys. In 2006, Atala succeeded in growing new corpora cavernosa, the spongy tissue that fills with blood during an erection, for male rabbits that’d had theirs removed. The new tissue was grown from the rabbits’ own cells and, after a month, the bunnies were back to doing what they do best.

Replacing a part of your brain isn’t as simple as replacing a limb, but in the future it could be. Theodore Berger, a professor at the University of Southern California, created a computer chip that could take the place of the hippocampus, a part of the brain which controls short-term memory and spatial understanding. Frequently damaged by things like Alzheimer’s and strokes, a hippocampus implant could help maintain normal function in people who’d otherwise be severely disabled. Berger is still testing this implant.

Future Medicine in light of Systems Biology

Current views of human disease are based on simple correlation between clinical syndromes and pathological analysis dating from the late 19th century. Although, this approach to disease diagnosis, prognosis, and treatment has served the medical establishment and society well for many years, it has serious shortcomings for the modern era of the genomic medicine that stem from its reliance on reductionist principles of experimentation and analysis. Quantitative, holistic systems biology applied to human disease offers a unique approach for diagnosing established disease, defining disease predilection, and developing personalized treatment strategies that can take full advantage of modern molecular pathobiology and the comprehensive data sets that are rapidly becoming available for populations and individuals. In this way, systems pathobiology offers the promise of redefining our approach to disease and the field of medicine.

The translation of new knowledge about mechanisms that govern human pathobiology into effective preventive, diagnostic, and therapeutic strategies is a slow and cumbersome process. A major contributor to this translational delay is the use of the traditional characterization and definition of human disease, which dates to the 19th century and is largely based on Oslerian clinicopathological correlation. The Oslerian formalism for human disease links clinical presentation with pathological findings. As a result, disease is defined on the basis of the principal organ system in which symptoms and signs are manifest, and in which gross anatomic pathology and histopathology are correlated. This approach has held sway for over a century, and although there has been continual refinement of the pathological markers used for correlation, for example, biochemical measurements, immunohistochemistry, flow cytometry, and, more recently, molecular pathological analyses of expressed genes, the general principles remain the same as when the approach was first proposed. Current classification of disease pathophenotype is, then, the result of inductive generalization from clinicopathological evidence predicated on the law of reductive parsimony. This paradigm has been helpful to clinicians as it establishes syndromic patterns that limit the number of potential pathophenotypes they may need to consider. Although quite useful in an earlier era, classifying disease in this way vastly over generalizes pathophenotypes, does not usually take into consideration susceptibility states or preclinical disease manifestations, and cannot be used to individualize disease diagnosis or therapy.

Based on this history, it is hardly surprising that these conventional pathophenotypes are far too limited to be useful in the postgenomic era. A simple example illustrates this shortcoming. The classic Mendelian disorder, sickle cell disease, is caused by a single point mutation at position 6 of the β-chain of hemoglobin, which changes hemoglobin’s oxygen affinity and promotes polymerization under hypoxic conditions. Notwithstanding Mendelian predictions to the contrary, this simple biochemical phenotype and its corresponding monogenotype do not yield a single pathophenotype. Individuals with sickle cell disease can present with painful crisis, osteonecrosis, acute chest syndrome, stroke, profound anemia, or mild anemia. There are many reasons for these different clinical pathophenotypes, ranging from the presence of disease modifying genes, for example, hemoglobin F to environmental influences; for example, hypoxia. Clearly, even the simplest genetically determined disease is manifestly complex in its expression, a fundamental observation that emphasizes the importance of the genomic and environmental contexts within which disease evolves.

Although conventional reductionist pathophenotyping has guided steady progress in diagnostics and therapeutics for many years, it is fraught with shortcomings, some of which are highlighted by this example, that are particularly problematic for contemporary molecular and genomic analyses. Put another way, in using this sorely outdated approach to defining human disease, one can construct nosological silos that focus exclusively on end-stage pathological processes in a single organ largely driven by late-appearing, generic end-stage mechanisms rather than true disease-specific susceptibility determinants viewed in their holistic, systems-based complexity.

With this background, one can rationally catalog the limitations of traditional disease definition as disease is typically defined by late-appearing manifestations in a dysfunctional organ system, without regard for or knowledge of preclinical pathophenotype or susceptibility factors that precede overt abnormalities. Thus, the focus is not on the specific genetic or environmental susceptibility determinants of the disease phenotype, but, rather, on the late-appearing, intermediate pathophenotypes like generic endopathophenotypes, including inflammation, immunity, fibrosis, thrombosis, hemorrhage, cell proliferation, apoptosis, and necrosis within a given organ system. As a result, typical therapeutic strategies do not focus on truly unique, targeted disease determinants, but on these same intermediate pathophenotypes, for example, anti-inflammatory or antithrombotic therapies for acute myocardial infarction.

Conventional disease paradigms generally neglect underlying pathobiological mechanisms that may extend beyond the disease-defining organ system, and do not typically consider the molecular (deterministic) and environmental (stochastic) factors that govern disease evolution from susceptibility state to preclinical pathophenotype to overt pathophenotype.

Conventional definitions of disease are excessively inclusive of the range of pathophenotypes and are based on the pathophysiological characterizations largely of the premolecular era. These inclusive definitions of disease not only obscure subtle, but potentially important, differences among individuals with common clinical presentations, but also neglect underlying disease mechanisms that cross organ systems and may yield more appropriate and specific therapeutic targets.

Yet another dimension to this problem stems from the reductionist approach we use to identify disease mechanisms or therapeutic targets. Disease is rarely, if ever, a simple consequence of

an abnormality in a single effector gene product, but, rather, is a reflection of pathobiological processes (deterministic and stochastic) that interact in a complex network to yield pathophenotype, which may be viewed as an emergent property, that is to say, discernible only by appreciating the behavior of the network as a whole rather than of its component parts in reductionist isolation of a pathobiological system.

These shortcomings of conventional disease definition account for many limitations of major recent genomebased efforts to define disease determinants, for example, the weak effect size of linked alleles observed in genomewide association studies of complex disease and to design rational therapies, for example, the failure of >90% of drug candidates. Thus, solving this problem is not simply an exercise in nosology, but is essential for moving the entire health care enterprise forward to reduce the burden of human disease and suffering.

This highlights the clear need to reconsider and redefine the determinants of human disease. All disease is complex, even simple Mendelian disorders. Pathophenotype reflects the action of a deterministic, defective molecular network within a stochastic environmental context that modulates network function. Defined in this way, disease is the result of the output of a complex modular network of –omic and environmental nodes linked mechanistically to yield pathophenotype. With this background and rationale, we can redefine all human disease using a combination of approaches to identify systems-based pathobiological mechanisms that render one susceptible to preclinical and overt pathophenotypes. This approach challenges the existing disease paradigm directly, and is justifiable owing to the largely heuristic strategies that have been used to identify disease mechanisms and treatments to date.

The Deleterious Effects of Huntington’s Gene


Biological engineers at Massachusetts Institute of Technology in the US have discovered that the gene that causes Huntington’s disease, a fatal neurodegenerative disorder, damages brain cell function by upsetting the on-off switching patterns of other genes. This detection will lead to ways of reinstating normal gene expression that can be used in treatments to slow or stop the evolution of the disease in early stages. The earliest phases of Huntington’s is most interesting, because that’s when there is large anticipation that one could either slow down or stop progression of the disease, and allow people to live healthy lives much longer. By the time there is much more severe neurodegeneration, it’s improbable that one would be able to turn round the damage.

Huntington’s disease is a deadly neurodegenerative disorder. It is a genetic disease that characteristically hits in midlife and causes progressive death of specific areas of the brain. Most of the injury is to the basal ganglia, a part of the brain that is responsible for many functions, including intentional control of muscles and habit configuration. The gene for Huntington’s disease, which was discovered about 20 years ago, codes for a mutant protein called “huntingtin” that collects in cells. The mutant gene contains many extra repeats of DNA sequences, but until this study, how such extra length produces the symptoms of Huntington’s was a complete mystery.

DNA carries directions for making proteins that do the work of creating and controlling cells. A process called transcription uses a special group of proteins to “read” the directives in the DNA. But a transcription protein can’t read a DNA instruction if the matching section of DNA is blocked. This is how genes can be “switched on and off,” forming complex pattern of gene expression that makes certain the correct instruction is transcribed at the right time for a healthy organism to grow and live. One way of blocking access to genes is to attach methyl groups to the related sections of DNA. There are genes that do this as a method to control when other genes are switched on and off.

Recently scientists comprehended that DNA methylation patterns aren’t fixed during embryonic development, but can change during an adult’s lifetime. In fact, it is an active process involved in a wide range of normal cell behavior.

Fraenkel and colleagues measured changes in DNA methylation patterns in cells from the brains of mouse embryos with early stage Huntington’s disease. The cells were from the striatum, which is the largest part of the basal ganglia. The striatum is the center for planning of movement and is severely affected by Huntington’s disease. The researchers found cells with normal forms of huntingtin protein had a different methylation pattern to cells with mutant forms. Some extended part of DNA had lost methylation, while others had gained it. They noted that most of the sites involved were in regions of the genome that control the switching on and off of neighbouring genes responsible for the growth and survival of brain cells. It seems like the mutant form of huntingtin exclusively targets genes involved in brain function disruption in those genes that explain the brain-wasting symptoms characteristic of Huntington’s disease, including early changes in cognition.

Noticing the differences in methylation patterns, the team identified many of the proteins that would bind to the sites involved, including Sox2, and other genes known to control genes involved in brain cell growth and behavior. The question is how the changes to methylation actually produce the disease symptoms. These findings points to new treatment targets. One could imagine that if one can figure out, in mechanistic detail, what is causing these changes in methylation, one might be able to block this process and restore normal levels of transcription early on in the patients. Team is also finding out whether patterns of methylation change as the disease progresses.

In November 2012, researchers at the University of Montreal identified and “switched off” a chemical chain that caused neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis and dementia.

Persistent Intractable Hiccups

If you have got persistent and intractable hiccups I would like share the latest pharmacological approach with you! The power of a teaspoon of dry sugar to stop hiccups in their tracks has been documented by the New England Journal of Medicine. So take your medicine!

Hiccups are a reflex, a nerve twitch that cycle through your body when something has irritated your diaphragm or one of the vagus nerves that run from the brain to the abdomen. Incidental fun fact; the vagus nerve is what makes us pass out when we have violent stomach illnesses. To cure the hicks, distract yourself with any number of techniques that you’ve probably heard before like get someone to scare you, drink a glass of water from the far side of the glass, hold your breath and count backwards from 100, etc.

Magnesium is a natural muscle relaxer. Hiccups are little more than muscle spasms. Chew on an antacid tablet or two; many of them contain magnesium, and that will break off the jerk cycle and deport the hicks. This one isn’t so helpful if you’re already hiccupping away your afternoon, but being over-full, eating spicy foods, and eating or drinking quickly are roots of hiccups. So please don’t do that!

Take a deep breath and exhale forcefully, visualizing your lungs getting small and tight, and your diaphragm sink all the way down in your abdomen. Visualize the hiccups as a bubble that your diaphragm is trying to pop; like we used to sit on balloons when we were kids. Then inhale and exhale really tiny breaths, not letting up on the abdomen-clenching, bubble-bursting pressure.

Persistent and intractable hiccups are a rather rare, but distressing gastrointestinal symptom found in palliative care patients. Although several recommendations for treatment are given, hiccups often persist. I describe a new pharmacological approach for successfully treating hiccups in four cancer patients. In the first patient, chronic and intractable hiccups lasted for more than 18 months, but left straight away after ingesting a viscous 2 % lidocaine solution for treatment of mucositis. Based on this experience, we successfully treated three further patients suffering from singultus using a lidocaine-containing gel. To the best of my knowledge, this is the first report about managing hiccups by oral application of a lidocaine solution.

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