Skip to content

On the heels of reading Creativity Inc, penned by Ed Catmull, I wondered if scientists are really creative. Researchers are trained observers that ascribe to the scientific method, gather data, and analyze their data using statistics.  Statistics is an imagination snuffer.

Great discoveries sprang from scientists that showed imagination and out-of-the-box thinking.   Are the greatest scientists artists, as suggested by Albert Einstein? Can you teach creativity?  The book suggests an environment that fosters creativity is possible, but can that be done in the laboratory? Add a few cats to lounge around?

The four stages of creativity are preparation, incubation, illumination, and verification.  Where does creativity live?  It is said the step between incubation and illumination is where the mind-magic happens. Mind-magic is an internal process, perhaps day dreaming. The verification is the analytical process and is a different neural circuit. When one is taught by rote, and SOP’s, creativity declines. There is a place for repetition, and that’s churning out data.  The creativity we are discussing here is a leap of faith to grasp a paradigm-shifting novel concept.

Each persons creativity is honed by tools they stumble upon for themselves.  It may be mediation, exercise, whatever tool will turn down the noise of the conscious mind to let ideas flow. Scientific creativity is a process. A path to finding an answer. That is a linear and logical process. Built upon ideas that came before. We agree with Ed Catmull, that success in solving a big problem doesn’t come from a brilliant idea, it comes from a great team. Part of the team is the past, researchers that paved the way using technology to leap into the future.

We have undertaken the problem of identifying and treating ALS by forming a team.

Our team is a group of nineteen scientists and reaches from British Columbia across the US and on to Brazil.  Our topics are secretome, the elixir of stem cells that may normalize a corrupted system.  We look at nucleic acids (DNA, RNA, miRNA), antibodies and peptides. Some team members harnessed fat mesenchymal cells to assay for toxic properties and seek chemicals to reverse the damage. We are borrowing ideas from our EPM and PNE work, from pathology to curative molecules.

What we’ve discovered is that removing information silos and blurring the lines between disciplines is fostering progress.  We anticipate sharing our discoveries with a platform available to all.  Keep listening, I’ll let you know when we launch!

As Buzz Lightyear said: "To infinity and beyond!"

When chemists envision novel products, they undoubtedly have a target in mind. A vast knowledge of chemistry allow them to examine the binding sites on the  intended target molecule.  Back at the bench, they combines basic ingredients, and by trial and error, a novel drug is created.  Of course, the careful chemist has an end game and that is a testing system for the new compound.

The new drug has to be relatively non-toxic at an effective dose. Organic synthesis can take years of work with many dead ends.  High throughput computer systems may reduce the discovery tasks and even identify potential compounds and targets. Bioreactors are used in the laboratory to grow organisms that produce a desired product. Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms.

Sixty five years ago an inventive group of Belgium scientists fed a newly made drug to chickens and found it active against ascarids. The drug was also active against sheep ascarids, but it was inactive in the species infecting rats or mice.  They collected the chicken feces and separated out the drug metabolites that were passed in the manure.  Amazingly, the manure contained a new molecule active against another chicken parasite as well as parasites found in sheep.  This new molecule was active against those ascaris species infecting in rats and mice!  Further testing revealed activity against gastrointestinal and lung parasites found in cattle, pigs, horses, pigeons, pheasants, ducks, cats, tiers, monkeys and man! This experiment was great for discovery but is significant food for thought.

It is worth considering that the drugs that are given to horses can build up in pastures and water.  Many drugs are eliminated through the feces. Unintended contamination of the environment is a serious concern and one important reason not to chronically treat animals with unnecessary medications.  Not only are you medicating pasture mates at ineffective low doses or new compounds, you are treating the wildlife. Soil organisms, insects, small mammals, and pasture mates are all exposed. What effect do these metabolized drugs have on the environment? You can check the Freedom of Information Summary for the levels of compounds that are excreted and the types of laboratory experiments that were conducted to determine environmental safety.  However, if several animals are treated over long periods of time the unintended consequences can be significant.

Google is helping us with our work on equine protozoal myeloencephalitis (EPM) and polyneuritis equi (PNE), two important neurodegenerative diseases that affect horses. The Google questionnaire will help you, and us, with our ongoing work in this important field.

Does your horse have a neurodegenerative disease? These two forms are useful to tell us what is going on with the horse.

The  “Neurology Case Analysis for the Horse Owner” https://forms.gle/66qMFW8d2bCvxprq6 and “Neurology Case Analysis for the Veterinarian” https://forms.gle/LiVQR6zydeRTkVELA

If you have tested a horse by sending us a sample, we would like you to update our records.  To update the file please use this link to the form: https://forms.gle/HVzzLbezHDtjU1N18 Our records go back to 2001!  Your experiences are important to us, by updating our records you help us direct our attention to new research possibilities. Good communication led us to new diagnostics and novel treatment of PNE!

Any horse that was treated for EPM can give us valuable information.  If a sample was submitted to us and the horse was treated, please use this form to update us:https://forms.gle/CQcFqYsRjZbB8y196.  Remember, to have a horse in our records we must have a consult request from the veterinarian. The consult request was by the veterinarian.

Another form that is useful evaluates horses with a history of extended use of drugs.  This can be an important part of field safety evaluations.  To update us, please use this link: https://forms.gle/9dPR2nU5uoE7591i7

We have several ongoing studies that are useful for evaluating and licensing new therapies for horses.  To look at the inclusion criteria for a horse these links will take you to the proper form: If you treated with any product for EPM and the horse didn’t resolve the signs or has relapsed, use this link: https://forms.gle/rwUo6Tyfc7N9omTS6 and if your veterinarian suspects polyneuritis equi, use this study link https://forms.gle/fwDTrUfj25SK1aLe7

We hope you find these forms useful.

Often neurologic diseases look alike.  For instance, two diseases that look like EPM to the untrained eye. The difference between equine motor neuron disease (EMD) and equine degenerative myeloencephalopathy (EDM) can be subtle even to the expert.  The onset of age should be considered, EMD is often diagnosed in older animals while EDM is present in younger animals, although signs of EDM may not be present until the horse is 5-10 years old.  Signs are weakness and muscle loss. EMD horses show weight loss and sweating, EDM horses have a classical presentation of symmetrical ataxia.  Both diseases resemble wobbler syndrome, EPM or EHV-1 infections.  The diseases are distinguished because EMD is a neuropathy of lower motor neurons (LMN) while EDM involves upper motor neurons (UMN), it affects the brain stem and spinal cord.  A veterinarian can determine if a disease involves the LMN’s or UMN’s and this distinction weighs heavily in the potential diagnosis and treatment plan.

EMD accounts for 23% of neurological diagnosis in horses seen at major universities and has been likened to amyotrophic lateral sclerosis (ALS) in people.  A treatment for EMD is vitamin E supplementation in horses that have a deficiency.  Deficient vitamin E levels are determined by analysis of plasma levels. Forty percent of EMD horses may improve, forty percent are expected to show no improvement, and twenty percent will decline.

EDM can sometimes respond to vitamin E treatment.  It is suspected that there is a genetic cause of disease that has an environmental trigger.  The treatment may stabilize the neuropathy, but the animals don’t improve. Once diagnosed these horses should not be ridden. They are retired and can often end up in rescue facilities.

It is interesting that these diseased horses have a pigment retinopathy. The retina has a high rate of oxidative metabolism and high lipid peroxidation in the outer photoreceptors.  Oxidative stress in tissues causes damage. Horses are animals with a tapetum and the pigment deposits left  by oxidative damage are observed in the retina during an eye examination.  Recently, the etiology of a unique retinal pathology was described in a former high incidence foci of Western Pacific ALS and Parkinson dementia complex, ALS/PDC, in Guam (USA) and the Kii peninsula of Honshu Island (Japan).  It was suggested that the ALS/PDC-associated retinopathy could be due to in utero exposure of a genotoxic metabolite. It is interesting that mice with a genetically induced form of ALS (SOD 1) show retinal ganglion cell loss and microglial activation. The microglia are mediators of inflammation the central nervous system. The mouse model indicates the nervous system pathology may be a result of oxidative stress. What is an interesting finding is that some inflammatory markers can be measured in the mouse using special histopathology stains. If the mice were treated effectively for disease-associated oxidative stress it would evident on histopath.

We are continuing to developing new treatments for neurodegenerative diseases in people and horses.  One encouraging new therapy targets issues found in lower motor neuron axons and another targets multiple pathways, including neuroinflammation.  We are using the ALS mouse models initially, and thenf10-09-9781437708462.tif we will look for the disease in equine patients. We continue to build our database for potential patients, if you have a horse with EDM or EMD, or have donated a horse to a rescue diagnosed with these diseases, please let us know.

This is a picture of the normal equine eye showing the optic nerve and tapetum.

Nothing illustrates that change is the essence of life quite like the butterfly.  How does this cloudless sulphur caterpillar, eating the toxic blooms of a cassia bush, become a butterfly? How did it know the cassia toxin would protect it from predators ensuring a next generation? How did it select the bright colors that warn birds that it has a toxin and they should stay away? And how does it transform into the butterfly for the next phase of its life?

All information for life is carried in genes encoded by DNA. The DNA is a hard code passed from generation to generation from parents to their offspring. If you look closely at two caterpillars you may note differences in size or color.  These differences are phenotypic expressions of genes.  Phenotype is controlled by modifying molecules that are applied to DNA and can be changed by diet and environment.  Amazingly, DNA modifiers can be inherited from prior generations.  A well-studied transgenerational DNA modifier is the effect of starvation on the genome.  Epigenetics is the field of science discovering and understanding DNA modifications and an important branch of this science is an ability to treat disease.

The manipulation of gene expression and silencing can be purposeful and directed. A particularly useful analogy is that DNA is the organisms operating system, OS, while epigenetics refers to apps that can be applied to the OS.  The apps give profound plasticity to increasing or decreasing expression of genes. Manipulating gene expression is a natural phenomenon and could be exploited as a step to personized medicine.

An organism’s genotype confers the code for everything required to survive. At conception, the stem cell has unlimited potential, the cell receives signals from its local environment and begins a one-way path to its destiny. DNA modifications are tags that are added onto the DNA by the surroundings that up or down regulate, or even silence, genes.  Daughter cells from the differentiated cells inherit the DNA modifications.  The collective modifications are the resulting phenotype of the organism. Epigenetics is about gene expression or gene silencing, understanding the apps. There are two periods of resetting DNA, at conception, when epigenic tags from the parent are erased and at six to eight weeks of gestation (in humans) when tags are again reset.

The epigenetic clock is a term to describe when on or off signals are expressed. Epigeneticists also realized there is epigenetic memory passed from the mother to the offspring because some tags are not erased. How is the DNA controlled by an epigenetic tag? DNA is packaged in the cell by wrapping around proteins called histones.  Mechanisms of histone control are acetylation and methylation.  Acetylation is the modification that relaxes DNA histone binding by an enzyme, histone acetylase.  Relaxing the binding of a section of DNA makes the gene available for reading and therefore expressed.

This image shows the DNA helix (orange tube) physically packaged in the cell, wrapped around histone proteins (green balls).  The position of acetylation of histone lysine residues by histone acetylase (HAT) are illustrated by the gray strings. You can click this image to read the discussion in Nature and the source of the image.  When a gene is expressed, a section of the DNA is unwrapped from its histone, read by enzymes that write/edit/erase the RNA that will code for protein synthesis.  The tightness of DNA wrapping on a histone is determined by modifications on the DNA.  A histone deacetylase (HDAC) will prevent unwrapping and inhibit gene expression because it will remove the acetyl group from histones lysine residues.  An enzyme that inhibits histone deacetylase results in gene expression, this is a technique that is being employed to create drugs to treat Alzheimer’s disease. You can imagine how this system can regulate the amount of a protein that is produced.

Methylation is a modification that make genes inactive. Methylation is inherited to daughter cells.  That means gene silencing can be inherited from cell to cell. An adaptation of genes to overcome silencing is a change in location in a chromosome. Methyl donor compounds, and those found in the diet, are also treatment opportunities to overcome disease by silencing genes because increasing DNA methylation is a mechanism that inactivates genes. The drug budesonide, which is DNA methyltransferase activator, results in increased methylation of DNA and ultimately decrease in the size of some tumors that are under the control of tumor suppressor genes. The research suggests that modification of DNA methylation either by hypo- or hypermethylation is effective in different types of tumors.

Genes can gain/lose function.  If a gene is moved to a different location in the chromosome or there is a mutation in the genetic code function can change.  Some bits of DNA are known to be particularly sensitive to moving location and some areas of DNA code are hyperexcitable and can be particularly prone to mutation. In disease, a tumor suppressor gene can be turned off and result in cancer. It would be possible to impact epigenetic tags to increase the expression of a tumor suppressor gene and stop the tumors growth.

In addition to acetylation and methylation, some RNA molecules are regulatory.  Regulatory RNA’s can neutralize genes or block messenger RNA. This process isn’t all or nothing and gives fine tuning to gene expression.

Transgenerational epigenetic inheritance is recognized and is the transmission of epigenome or epigenetic markers from one generation to the next. This adaptation doesn’t affect the structure of DNA but provides a unique survival mechanism allowing organisms to adapt to changing conditions. The effect of starvation has been studied,  decreased nutrition was shown to affect subsequent generations through modifications that are inherited from the mother.

The cloudless sulphur larvae becomes a butterfly because the epigenetic tags on the DNA are uniquely choreographed. The larval genes are silenced after sufficient food intake and the next stage genes are turned on, giving wings for flight.

There are many interesting ideas that come to mind, one is the unmet need for biomarkers and treating metabolic diseases.

Disease pathologies arise from dysregulation of the immune system, oxidative stress, abnormal axonal transport, and other metabolic malfunctions. Discovering epigenetic controls of the pathologies in metabolic dysregulation may lead to targeted treatments and hope for patients.

Right click on this link to open an active PDF in a new window.  Click on the pictures in the PDF and you will see more epigenetics information, including exciting You Tube Ted talks.