Aurora Nerves

A Brief History of Neuroscience

2011-12-15T02:49:00.000-08:00

Silver chromate salt staining by Camillo Golgi during the late 1890s is easily one of the most important early advancements in the modern field of neuroscience. Dr. Golgi was an Italian physician, pathologist, scientist, and Nobel laureate who originally discovered this nervous tissue staining technique initially named it the black reaction; later named Golgi’s method, it is one of the many things named after him in the field of biomedical research. Previous staining methods were of little use in neural tissue because of it’s densely packed nature and the extremely thin axons and dendrites of neurons. This made things a jumbled mess when visualized using light microscopy. The golgi method stains at random a select number of cells, of which the exact mechanism of action is still unknown. The method consists primarily of fixing tissue with potassium dichromate and silver nitrate. The stained cells are filled by microcrystallization of silver chromate. In 1898, Camillo Golgi reported tha the discovered a ribbon-like apparatus inside neurons of the cerebellum. This structure now bears his name as the Golgi apparatus.

Beginning in 1887 Santiago Ramón y Cajal (a Spanish pathologist, histologist, neuroscientist, and also Nobel laureate) began to develop his neural network theories using Golgi’s method at the University of Barcelona. As a child he was continuously expelled and enrolled in many schools because of his poor behavior and anti-authoritarian attitude. When Santiago was eleven years old he destroyed his neighbor’s gate with a homemade cannon and spent three days in jail. Later at the University of Barcelona, after graduating from medical school in 1873, he began using silver nitrate staining he discovered the axonal growth cone, which lead to his development of neuron theory. Neuron theory disproved previous ideas that neurons were continuous and replaced it with the current understanding that neurons are very closely adjacent to each other. Ironically, Golgi maintained to his death that neurons were continuous; although Ramón y Cajal had used Golgi’s method to provide evidence showing otherwise. Using Golgi’s silver nitrate preparation Ramón y Cajal was also able to provide detailed description of neural cell types with corresponding structures.

The French Pierre Paul Broca was a child prodigy, prosecutor, surgeon, anatomist, and anthropologist. He differed from his predecessor in that he concentrated on the brain itself (specifically lesions and their clinical implications) rather than the shape of the skull. Broca is more commonly credited as the founder of neuropsychology. After examing the postmortem brains of several of his patients he was able localize the lesions associated with the motor deficits of speech. This region of the posterior frontal lobe is now referred to as Broca’s area.

Carl Wernicke a physician, anatomist, psychiatrist, and neuropathologist began his research soon after reading Broca’s published work. At 26, Wernicke published his work regarding receptive aphasia after noticing that not all deficits of language were due to Broca’s area lesions. As opposed to Broca’s patients, with receptive aphasia, Wernicke’s patients could speak but were unable to understand language. Wernicke isolated the lesion to the left posterior, superior temporal gyrus. This area was later named after him. Wernicke was also notable for attempting to merge the localization of functionally specific areas, as proposed by Gall, with the aggregate field theory that was popular at the time. He suggested that simple processes (such as basic perceptual and motor functions) were localized while complex cognitive tasks used several various areas simultaneously. This concept later became known as distributed processing.

Sir Henry Hallet Dale was a British pharmacologist and physiologist. He shared the 1936 Nobel Prize in Physiology or Medicine with Otto Loewi for his study of acetylcholine as an agent in the chemical transmission of impulses now known as neurotransmission. While working at the University College London he met and became friends with Otto Loewi. Although Dale and his colleagues first identified acetylcholine in 1914 as a possible neurotransmitter, Loewi showed its importance in the nervous system.

Otto Loewi was a German born pharmacologist who is commonly referred to as the, “Father of Neuroscience.” Loewi investigated how vital organs respond to chemical and electrical stimulation. Before Loewi, it was uncertain if signaling across the synapse was bioelectrical or chemical in nature. Loewi claims that the answer to this came to him in his sleep, from which work was published in 1921. He created a very simple experiment where he dissected beating hearts from frogs. The vagus nerve of some hearts were stimulated showing corresponding decrease in beat rate, which was to be expected. However, the interesting point of the experiment came about when he took the Ringer’s solution from the baths of the vagus stimulated hearts and applied it to the non-stimulated hearts. The application of the Ringer’s solution caused the second heart to slow it’s rate, showing that there was a soluble chemical released by the vagus that slowed heart rate.

Most of our current understanding of ion channels in neuronal cell membranes comes from the use of voltage clamp experimentation. The voltage clamp concept and technique was developed by Kenneth Cole and George Marmount in the 1940s. However, it wasn’t until 1952 that Alan Hodgkin and Andrew Huxley used the voltage clamp technique to outline the ion flux involved in an action potential. Hodgkin & Huxley shared the 1963 Nobel Prize in Physiology or Medicine for their discoveries. Before this, Julius Bernstein’s, “membrane hypothesis,” was the prevailing theory at the time. Although he correctly hypothesized that excitable cells were permeable K+ ions at rest and that during excitation the membrane would be permeable to other ions; he incorrectly suggested that there was a membrane breakdown during excitation.

The voltage clamp is a two electrode system with one electrode relative to ground, while the other electrode passes current into the cell. The system uses a negative feedback system to maintain the cell at a command potential/holding voltage. The voltage clamp allows an experimenter to maintain a membrane potential at a certain predetermined voltage. The ion channels of the neuronal membrane will continue to respond to changes in current, but the voltage clamp prevents the change of membrane potential. Thus the potential change of membrane voltage can be studied during either excitation or inhibition.

The patch clamp technique is basically the same as the voltage clamp method, however it allows the study of current flow through a single ion channel or a spatially localized group of multiple ion channels as opposed to the entire cell. This provided distinct proof of ion channel involvement during the process of action potentials. Not only is this useful for neurons, but it can be applied to a host of excitable cells such as cardiomyocytes, muscle fibers, pancreatic beta cells, and bacterial ion channels in giant spheroplasts. The patch clamp was refined from the voltage clamp by Erwin Neher and Bert Sakmann during the late 1970s – early 1980s. Neher & Sakman also, like their counterparts Hodgkin & Huxley, received a Nobel Prize in Physiology or Medicine (1991).

It has been known since the 1890s that blood flow and blood oxygenation is correlated with brain activity. However, up until the early 1990s most imaging of brain activity was done via radiolabeled glucose. This was invasive, had high levels of radiation exposure, and was limited to mostly large academic medical institutions. Imaging from fMRI has high resolution in the range of 1mm-3mm, can record signals from deep structures of the brain, and is widely available.

The concept behind the MRI was first engineered in the early 1930s by Isidor Isaac Rabi, a Columbia University physicist, for which he was given a Nobel Prize in physics in 1944. He detailed the properties of magnetic resonance, while observing the change in the nuclei of atoms when exposed to a magnetic field and radio waves combined. Physicist Seiji Ogawa at AT&T Bell Labs first discovered the MRI contrast of blood deoxyhemoglobin, more commonly known as blood oxygen level dependence (BOLD) in 1990. The first fMRI study was published by John Belliveau in 1991 using gadolinium. Since neurons have such a high metabolic consumption there is little room to maintain reserves. Thus high neural activity requires that glucose and oxygen be delivered continuously through the blood to adapt to demand. Blood releases glucose to active neurons more rapidly. Because of this oxyhemoglobin begins to build up veins thus changing the oxyhemoglobin : deoxyhemoglobin ratio, which is the BOLD measurement for MRI. Oxyhemoglobin is diamagnetic while deoxyhemoglobin is paramagnetic; thus the magnetic resonance is dependent on oxygenation levels. If an MRI scanner is programmed within these parameters, BOLD parameters can be assessed according to either positive or negative changes depending on both cerebral blood flow and oxygen consumption.

fMRI has high spatial resolution but low temporal resolution, in contrast to EEGs which have high temporal resolution but low spatial resolution. The two techniques complement each other and are commonly used side by side in studies. Before fMRI, functional imaging of the brain was commonly done with PET scanners or rarely with SPECT scanners. Some of the earliest attempts at functional neuroimaging were done by Niels A. Lassen using radioactive gases. Currently fMRI have shown to very usefull in neurosurgical planning, diagnosis in pain management, studies in the physiological basis of neurological disorders, and in experiments revolving around the physiological basis for cognitive and perceptual events.

Optogenetics

2011-12-13T16:03:00.000-08:00

Optogenetics, over the past six years, has quickly become one of the fastest growing fields in Neuroscience. It consists of the precise control of neural pathways with light through the use of genetically modified neurons. Neural stimulation is not a new idea, however. It has been commonly practiced in vivo through the use of electroconvulsive shock therapy in those with refractory schizophrenia and refractory depression. Electroconvulsive therapy lacks specificity, and cannot be used to target particular neural networks of interest. Intracranial electrical stimulation has been used in treatment for tinnitus, depression and insomnia. It also lacks specificity, due to passive dissipation of electric charges to neighboring neurons.

Opsins are light sensitive ion pumps with seven helical transmembrane proteins. They have been studied since the early 1970s in Halobacterium Salinarum which produces bacteriorhodopsin and halorhodopsin. Bacteriorhodopsin pumps protons out of cells when exposed to green light, while halorhodopsin pumps chloride into a cell when exposed to orange light. In 2004 an opsin (channelrhodopsin-2) was discovered in a green alga (Chlamydomonas reinhardtii) that allows free flow of positively charged ions into a cell when exposed to blue light. In 2005 channelrhodopsin-2 (ChR2) was cloned into a lentiviral vector, which produced a lentivirus that was able to create ChR2 expression in neurons. Although vector uptake by a particular group of neurons is less of an issue in vitro, in vivo specificity has been more of a challenge. A popular technique at the moment is the use of transgenic mice who express opsin on specific neuron types.

The use of optogenetics to switch on or off in vitro is groundbreaking, however it is in vivo stimulation through the use intracranial optic fibers that shows greatest potential for future research. Animals implanted with transcortical optic fibers to the dopaminergic areas of the brain have been trained using only light as a reward. Behavioral studies using the stimulation or silencing of particular neurons have now been conducted in C. elegans, Drosphila, zebrafish, mouse, rat, and nonhuman primate. Because of low cost lasers and optic fibers, entrance into this field of research has been booming. Past studies have examined behavioral functions such as learning, wakening, somatosensation, vision, breathing, and movement.

The potential for therapeutic uses in neurological and psychiatric disorders is great. Pharmacological antiepileptic therapies are difficult to dose correctly, have long term adverse effects, and are not always effective. Optogenetic therapy would be of great benefit to those suffering from chronic seizures or status epilepticus. If dopaminergic centers are hit relatively easily in animals, then the same could be done in humans. Stimulation or inhibition of those areas in humans may help those with Parkinson’s or addiction, respectively. If a postprocessing device could be installed to correct aberrant pathways as they fire, it may help those with severe learning disabilities. Interesting work has also recently been done in knockout mice that have been created to replicate neurogenic blindness. When opsins are attached to retinal bipolar cell layer, which normally do not contain photosensitive elements, these mice are able to function as well as mice with normal vision on maze trials.

Consent & Coercion in Clinical Practice and Biomedical Research

2011-12-12T04:34:00.000-08:00

Informed consent is given based upon a clear appraisal and comprehension of the data, implications, and future consequences of any action. That action may refer to repair work for you vehicle, a product purchase, or any numerous possibilities where an individual asks something from another. Informed consent in the specific case of, “The Immortal Life of Henrietta Lacks,” by Rebecca Skloot is in reference to procedures conducted by physicians and researchers at Johns Hopkins. It has been suggested that Henrietta Lacks, or her husband David Lacks, may have been coerced into providing consent at one or more points during her treatment. I maintain that informed consent was provided as far as legally needed during the early 1950s and that there were no means of coercion used.

The American Medical Association policy on informed consent is as follows, “The patient’s right of self-decision can be effectively exercised only if the patient possesses enough information to enable an informed choice. The patient should make his or her own determination about treatment. The physician’s obligation is to present the medical facts accurately to the patient’s care and to make recommendations for management in accordance with good medical practice. The physician has an ethical obligation to help the patient make choices from among the therapeutic alternatives consistent with good medical practice.”¹ I believe that this was followed to the best ability possible by the physicians at Johns Hopkins during early 1951 in the care of Henrietta Lacks. Although it is now commonly accepted that Henrietta was most likely misdiagnosed as having epidermoid carcinoma, as opposed to adenocarcinoma (which explains the rapid prolific dissemination in her case), it still would not have changed her treatment at the time. Henrietta, in good judgment, deferred the terms of her treatment to her doctors.

I can attest to patients deferring decisions of treatment to their doctors after rotating through hospitals in lower socio-economic areas of New York City, Chicago, and Atlanta. Patient education is of primary interest to a doctor. Not only does it promote the best preventative measures for illness (which is good for the patient), but it also promotes patient autonomy in their care. In a roundabout manner it also removes some measure of liability from the doctor if things go awkwardly and places the patient in a Catch-22. Even if something might go wrong during treatment, the patient cannot blame the care giver of negligence because the patient was fully aware of any potential negative consequence before requesting the health related services in question.

This all goes out the window when the patient is of adequate aptitude yet lower educational status. A common situation is refusal of care against recommended medical advice. Such a position is fully within the rights of a patient; it could be because of personal, religious, ethical or any number of beliefs. It was not very long ago when people were admitting their spouse or children into horrid psychiatric institutions against their will under a false diagnosis and forced into unnecessary treatment. Situations with the right to die may also arise. Patients may forgo treatment to speed the end of a terminal illness. However, this was not the case with Henrietta Lacks. Henrietta espoused all treatment decisions to her doctors.

When a patient gives full leeway to their doctors is when things become especially tricky. Patients may empower their physicians in such a manner for many reasons. Some, because of a lower educational background, may be intimidated by the type and amount of information provided. This can be intimately seen in the case of Deborah Lacks and her search for more information of her mother, Henrietta. Although Deborah spends endless hours and sleepless nights pouring over medical textbooks and online resources, her lack of understanding of the basics of science leads to widely fantastic ideations of the implications of her mother’s cells, HeLa. In her specific case, Deborah may have been handicapped by more than deprived education. She shows indications of underlying persistent lifelong psychiatric disorder(s). Toward the end of her life she also demonstrated behavioral changes consistent with microvascular emboli, commonly referred to as mini-strokes.

Deborah Lacks may have had only a slight understanding of the biomedical sciences involved in the development of the HeLa cell line, but her mother’s understanding of her illness pales in comparison. It is for such a reason that Henrietta would have agreed to anything proposed to her by her doctors. Although cell culture of biopsies is commonly done in the modern era for diagnostic and prognostic purposes, during the early 1950s it was quite rare. Although Henrietta’s biopsy was done for neither diagnosis nor prognosis, it can still be classified under accordance of, “good medical practice,” because it in order to further medical knowledge. In so doing good medical practice can be used as an umbrella term to benefit man collectively, while no direct harm was inflicted upon the individual unlike the Tuskegee syphilis experiments.

Later, in policy E-8.08 Informed Consent of the American Medical Association, it is further elaborated by stating that, “Physicians should sensitively and respectfully disclose all relevant medical information to patients. The quantity and specificity of this information should be tailored to meet the preferences and needs of individual patients. Physicians need not communicate all information at one time, but should assess the amount of information that patients are capable of receiving at a given time and present the remainder when appropriate.”¹ Respectful disclosure was used appropriately by the physicians and researchers at Johns Hopkins throughout Henrietta Lack’s treatment. It seems implicit in Rebecca Skloot’s telling of the story that Henrietta may have not been so forthcoming toward her own kin. Although much of the information of what was said behind closed doors during her visits to the Johns Hopkins Hospital is lost to history, it is clear that she did not wish to worry her friends and family. On many occasions Rebecca Skloot retells how generous and kind Henrietta was in every respect. I believe if she knew how invaluable that particular biopsy would be to the future of biomedical research, she would have happily have given it.

Some may argue that Henrietta may have been coerced into submitting to the will of those presiding over her at Johns Hopkins. If she had not allowed the doctors to do as they wished, would she have been denied treatment? This is highly unlikely. Although Jim Crow laws and racism was rampant even in zones where we would normally consider neutral, such as hospitals, Johns Hopkins did their best to go against the grain. While many other hospitals would refuse care and allow a black patient to die in the parking lot, Johns Hopkins, a world renowned health care facility and research center even at that time, treated black patients for free. Even when Henrietta’s illness was approaching end stage she was still provided with analgesics and allowed to stay in the comfort of the hospital ward. In this era of health insurance reform policies, I am unsure if the same would be done in most modern hospitals regardless of the patient’s skin tone.

Others may suggest that the threat of kidnapping, extortion, force, or violence may have influenced Henrietta’s decisions throughout her final care. “Since at least the 1800s, black oral history has been filled with tales of ‘night doctors’ who kidnapped black people for research… To discourage slaves from meeting or escaping, slave owners told tales of gruesome research done on black bodies then covered themselves in white sheets and crept around at night, posing as spirits coming to infect black people with disease or steal them for research.”² There is the possibility that Henrietta may have thought that if she did not agree to the research that was undertaken with her tissue that it may have been forcibly taken and her killed to cover up any evidence of wrong doing. I doubt that coercion was involved here simply because I doubt she knew that her cells would be experimented on; I also doubt that Dr. George Gey thought anything would come of these cells, as all of his previous experiments in culturing tissue had failed miserably.

Coercion cannot be dismissed so easily though. It was a very important aspect of medical research of the day, and in some respects still is. There still exists a great gap between the quality of health services from trusted health providers toward marginalized populations. This has gone so far as maintaining the fear held by such old myths such as the, “Night Doctors.” This may date from long ago when wealthy urbanites would receive medical treatment at home. If they did not recover, they would die at home and be buried at the family estate. The poor, who would not recover from home remedies, would be taken for free medical care at the city hospital or teaching hospital where they would most likely die due to iatrogenic infections. If they died and no one claimed the corpse then they would be used for study, experiments, autopsy, and dissection. Although such practices are no longer commonly done in the United States, I can state from hearsay as a doctor having studied abroad that such practices are still common in Eastern European and Asian medical schools. The common understanding between student and professor is that if no questions are asked then no lies need be said.

All in all, through the reading of, “The Immortal Life of Henrietta Lacks,” I believe that Henrietta was given the best treatment possible for the time. She was given a fair shake by Johns Hopkins, even if many other situations in her life were not so equally kind. Mob mentality can extend to corporate ethics. Employees will model themselves after their managers, while all strive to emulate those in the upper echelon of the institution. This can be seen in Johns Hopkins, who was born on a prosperous tobacco plantation where his father freed his slaves almost sixty years before the Emancipation. After making millions as a banker and grocer he donated it after his death to start a medical school and charity hospital. In a letter to his board of trustees he outlined his wishes and purpose of Hopkins Hospital. “The indigent sick of this city and its environs, without regard to sex, age, or color, who require surgical or medical treatment, and who can be received into the hospital without peril to other inmates, and the poor of the city and State, of all races, who are stricken down by any casualty, shall be received into the hospital without charge.”³ I hope my resounding support of their previous actions doesn’t come across as a yes man, a person on their team, or as if I am applying for a job at Hopkins. However, being a scientist and a physician is not an easy job ethically. Difficult decisions are posed continuously while trying to do the greater good. It is truly a never ending struggle with new complications every day. I myself, as a doctor, scientist, and racial minority would be happy to work at an institution grounded in such moral principles.

Citations

1. “E-8.08 Informed Consent.” ama-assn.org. Web. June 2006.

2. Skloot, Rebecca. The Immortal Life of Henrietta Lacks. New York: Random House. 2010. 165-166.

3. Skloot, Rebecca. The Immortal Life of Henrietta Lacks. New York: Random House. 2010. 166-167.

Optimal Integration of Sensory Evidence: A Bayesian Journey Through Our Sixth Sense

2011-12-08T03:12:00.001-08:00

The vestibular system runs into two main computational dilemmas. The first is from the sensory vagueness that arises from the otolith organs, which are equally sensitive to head tilt relative to gravity and to linear acceleration. Due to the natural laws of physics this can be extremely problematic, especially if you are flying a jet airplane. The second challenge is derived from the integration from various other senses to form a unified perception. Optimal integration models predict that the relative reliability of multisensory integration depends on the reliability of those cues.

Even creatures with relatively simple nervous systems (e.g. jellyfish, crustaceans) have basic graviceptors that provide information about orientation with respect to gravity. The vestibular system plays a vital role in contributing to gaze stabilization, balance and postural control, spatial navigation, spatial perception and memory, voluntary movement planning, and autonomic function. With other sensory modalities we are usually very aware of their input; with the vestibular system it is not brought to the forefront of our consciousness until uncertainty gives rise to illusions or motion sickness. This is felt most acutely during vestibular disorders such as vestibular hair cell loss, vestibular neuritis, central and peripheral lesion. The results of such vestibular deficits will result in disorientation, loss of balance, postural control, loss of visual acuity, and perceptual distortions. Since the vestibular system is quite phylogenetically old, it can provide great insight into the computational strategies used by the brain.

Most recent work using computation modeling in the vestibular system has focused on four main research questions. The sensorimotor transformations for reflex generation has been the main question recently. The next involves the neural computations for inertial motion estimation. Another is the computations used to distinguish active from passive movements. Lastly, the integration of vestibular and proprioceptive signals for body motion estimation.

Estimation of one’s direction of movement relies heavily on multisensory integration. It is because of this that the visual and vestibular signals converge frequently in the nervous system. Through this convergence these signals interact in many ways to produce behavior and perception. This convergence is consistent with what is known as optimal integration theory. This cue integration relies on that fact that all sensory information hold a certain degree of uncertainty. This limits perceptual performance. When multiple independent sources of information (sensory cues) are received, combining them reduces uncertainty and improves performance. This principle has been used in many varying psychophysical studies based around cue integration. Assessment of this data uses mathematical principles (much of which is quite beyond me) borrowed from ideal observer analysis, signal detection theory and statistical (Bayesian) decision theory. Bayesian decision theory relies on weighted cues which are proportional to each cue’s reliability.

Improving Academic Research

2011-12-07T17:47:00.001-08:00

Truth be told, I believe there is very little we can do to improve the inadequacies of academic research mentioned in, “The Truth Wears Off,” by Jonah Leherer. There are to many ways for a researcher to unconsciously slant their findings through either recording or analysis of data. The only possible solution I could think to resolve this would be to take the researcher out of the lab. If the entire process could be mechanized from start to finish, perhaps we could state more conclusively that the results were truly empiric. However, in the end this would most likely collect very little useful data. There is something special to the art of work in a lab, that cannot be fully replicated by a robot. Although they are good at some tasks, they are still far from a fully capable lab tech.

Because my personal interests slant toward technology, my other suggestions also follow in similar theme. All journals should have an area of their website dedicated to peer reviewed articles they have received but would not normally be published in print because of low impact, such as projects with negative data. This straight to DVD version of publishing would at least put that information out there. Even if no one cares at the time of release, it has been publicly recorded and can be used for future reference. This would greatly reduce the number of redundant experiments done. Publishing in web journal version might not be as prestigious, but would give a more democratic voice to the scientific community.

My last suggestion coincides with Jonathan Schooler’s concept for an open source database. Although his idea for researchers to outline planned investigations is ridiculous, since no one would go for this. With the looming fear of being scooped, who would be interested in posting their ideas for future projects online? However, a unified open source database for every researcher in the world to upload all their documented results would be brilliant! Being able to instantly access every data point for a any released paper could really change the game. Not only would this allow peers to check analysis, but it would facilitate the development of alternative conclusions to the same results.

Dr. Incredible & Mr. Fantastic

2011-12-07T17:45:00.001-08:00

Dr. Incredible, an older tenured professor at MIT who is bordering on retirement, has recently been working with a quite extraordinary PhD student, Mr. Fantastic on brain/computer interfaces. Mr. Fantastic’s masters thesis has already produced a primary authored paper in Science and a well funded grant from the NSF. Dr. Incredible believes that if Mr. Fantastic continues at this pace then his PhD dissertation will surely make him a shoe in for a Nobel Prize. Both the chairs of the Computer Science department and the Neuroscience department have expressed growing interest to Dr. Incredible about Mr. Fantastic’s research. Dr. Incredible is sure that MIT will patent Mr. Fantastic’s work upon completion.

Yesterday, Mr. Fantastic received a phone call from President Shoot First of the United States of America. President First stated that Mr. Fantastic’s work was of utmost military importance and has the potential to save millions of lives. President First extended an invitation to visit to a top secret laboratory where he could continue his cutting edge work without any monetary restrictions. However, the President mentioned (almost as a side note) that any work done would be classified and could not be disclosed publicly for an undetermined number of years.

Today Dr. Incredible scheduled time out of his incredibly busy schedule to discuss Mr. Fantastic’s fantastic future possibilities. During this meeting Dr. Incredible suggested that Mr. Fantastic drop out of the PhD program and create a startup company before MIT’s patent department had a strangle hold on the implementation of his unique techniques. Mr. Fantastic’s pupils immediately dilated into the shape of dollar signs.

Where should Mr. Fantastic continue his work?

Vipul Bhrigu

2011-12-07T17:43:00.001-08:00

I found the case of Vipul Bhrigu, PhD of University of Michigan Medical School (UMMS) to be the most interesting of the 2011 findings of research misconduct reported by the Office of Research Integrity, US Department of Health and Human Services. Dr. Bhrigu’s case was most unusual because unlike other situations that have come to light this year, he did not falsify or fabricate data, nor did he plagiarize information to help progress his career. He sabotaged a colleague’s work!

His nefarious behavior extended to tampering with materials related to five immunoprecipitation/western blot experiments, switching the labels on four cell culture dishes in similar experiments, and (my favorite on the grand scale of evil things one could do) he poured ethanol into his colleague’s cell culture media with intent to kill the cell line. He engaged in these actions for several months before being caught. He initially denied the allegations, but eventually admitted to his actions after the University of Michigan police informed him that he had been videotaped while in the act. After deliberation ORI proclaimed that, “these acts seriously deviated from those that are commonly accepted within the scientific community.” This is easily one of the greatest understatements that I have ever heard. I suppose you are right. If you’re going to do something crazy, you might as well go all out bonkers.

Dr. Bhrigu has been banned for three years from any contracting or subcontracting with any US Government agency. He has also been banned for three years from serving in any advisory capacity to the US Public Health Service. In my opinion, the penalty was quite insufficient. It is one thing to attempt to push one’s own career forward under duress; but it is quite another thing to directly interfere with the progress of another individual’s livelihood.

A Neanderthal Perspective on Human Origins

2011-12-07T17:11:00.001-08:00

Svante Pääbo is a Swedish biologist working in evolutionary genetics at the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig, Germany. His earlier work made a large impact with the discovery of FOXP2, commonly known as the language gene, which is mutated in certain language orientated neurological pathologies. He is known as one of the founders of paleogenetics, the study of early humans using a genetic toolbox. In 2007 he was named one of TIME Magazine’s 100 most influential people of the year.

Using a, “capture technique,” with two rounds of, “target enrichment,” DNA from Pleistocene fossils can be sequenced. Obtaining good samples of Neandertal genome sequences has been a problem previously because of DNA contamination with microbes over the years. Although the colonization of microbes are the worst offender when working with ancient sample derived DNA; there is also the aging process to consider. The DNA itself has severely degraded because of chemical aging, known as deamination. In a recent article (Burbano et al., 2010, Targeted Investigation of Neandertal Genome by Array-Based Sequence Capture, Science, v. 328, p. 723) with Pääbo as the senior investigator, it was shown that whole genome shotgun sequencing as well as capture of specific genomic regions for extinct organisms is possible. Using hybridization capture on microarrays they recovered more than a megabase of target regions from Neandertals in the presence of approximately 99.8% microbial DNA. When compared with 50 present day humans, they found about 14,000 protein coding positions which have changed and 88 amino acid substitutions that have become fixed since our divergence.

Svante Pääbo mentioned in his talk at the 2011 Society for Neuroscience, “There is a great interest in the relationship of Neandertals to people. Questions like, ‘Did our ancestors interbreed with Neandertals?’ are of interest, but also how our genome differs from that of Neandertals. Since Neandertals are our closest relatives, when we compare ourselves to them we can identify features in our genome that set us apart from other organisms on the planet.” After sequencing 1.3 fold genomic coverage of Neandertals, it is found that 2.5% of the genomes from people living outside of Africa are derived from Neandertals. This implies that after humans exited Africa there was interbreeding with Neandertals, before their extinction 30,000 years ago. When looking for subjects Pääbo mentioned that a couple of hundred men came forth, curious about whether they they had Neandertal origin. However, only about 20 women came forth wishing to participate in the study. He jokingly stated that when asked, over 50% of the women who were married believed that their husbands may have Neandertal origins while 0% of the married men thought that their wives had Neandertal origins.

Also of interest during Pääbo’s presentation during the 2011 SfN conference was his sequencing (1.9 fold coverage) of a new hominin, the Denisovans, discovered in Denisova Cave in southern Siberia. The Denisovans share common genetic ancestry with both Neandertals and present humans from approximately 650,000 and 800,000 years ago, respectively. Approximately 4.8% of the genomes amongst people who now live in Papua New Guinea are derived from Denisovans; which suggests interbreeding between modern humans of eastern Asia and Denisovans. This is most interesting because until recently it was thought that our ancestors left Africa all at once from Africa about 100,000 years ago. But, this new genetic fossil findings suggest that our ancestors left Africa in several waves. Some exodus populations vanished while other survived, coexisted and intermingled with each other. It is still uncertain what evolutionary advantages may be held by the Denisovan genome; unlike the Neandertals genes, which may have had an improved immune system.

FOXP2 (Forkhead box protein P2) is a protein encoded by the FOXP2 gene on 7q31 at SPCH1 locus. Mutations of FOXP2 cause both speech and language disorders. FOXP2 also exists in other vertebrates and cause similar pathologies in mice, songbirds, fish, and reptiles such as alligators suggesting a similar neural circuit. However, contrary evidence has been shown in echolocating bats which show extremely diverse protein sequencing from FOXP2. Although FOXP2 is required for both brain and lung development, it is it’s expression in several regions (cortical plate, basal ganglia, thalamus, inferior olive, and cerebellum) of the developing brain. While knockout mice with no functional copies show reduced vocalizations as pups; physiological analysis shows functional neural control, vocal tract, and brainstem. Those with no FOXP2 are runted, show abnormalities in the Purkinje layer and subtle cerebellar abnormalities, and die at around 21 days due to lung malformation. Although there is increasing evidence that a susceptibility for autism is related to the FOXP2 locus, negative findings have also been found. Links to autism have produced further studies which have shown that FOXP2 mutation is not simply because of a deficit in motor control. There are impairments with comprehension of language, and imaging of affected show deficits in (as mentioned earlier) in language related cortical and basal/ganglia regions.

Human FOXP2 differs from chimp FOXP2 by two amino acids, mouse FOXP2 by 3 amino acids, and zebra finch by 7 amino acids. Svante Pääbo has also found that Neandertals and Denisovians share the same allele of FOXP2 as modern humans. Some have gone so far as to suggest that the two amino acid difference between chimps and humans may have led to the evolution of language in humans. Pääbo jokingly suggests that the best way to elucidate this distinction is to create a study with transgenic humans with chimp FOXP2 and transgenic chimp with human FOXP2. There may be a few ethical dilemmas posed with such a study.

My First Semester in the PhD Program

2011-12-07T17:04:00.001-08:00

I had quite a rough time initially. I had no hot water for the first week during my first semester in the graduate program . I had no internet for the first two weeks. The television didn’t arrive for a couple months till my wife and children moved. Classes seemed more like a slow paced elementary review rather than the cutting edge research I expected. I was intensely pleased to finally pursue my life’s ambition, but quite miserable at the same time.

I spent most of my time during the initial portion of the semester, because of less than challenging classes, watching TED lectures and doing follow up research via PubMed. I could not stop thinking about who I would choose to spend the next five years of my life with. What would/could/should we do? It was quite obvious that I was one of the belles of the ball with my academic background, personality, and maturity. This is both flattering and frightening. It is quite comforting to be a big fish in a small pond, but I worry about expectations. Perhaps all the cajolery in the lab search process has left me with slightly grandiose ideations of my own capabilities; in which case, my greatest chance of failure will be in regards to my own expectations and not that of others.

Although there are a few minor details which I might change about the program, all in all it is good. Being forced to take things slowly during the first semester, tamed me from chomping at the bit. . I feel much more secure with the future now that I have chosen an advisor. Wetting my toes first was exactly what I needed, even if I was eager to jump in head first. The class work load has gradually tapered upward, which is nice. However, I am looking forward to finishing classes so I can devote my time fully to research. That’s when the fun, and the start of my new career, really begins.