The Firsts: the Milky Way’s supermassive black hole

 

Let’s wish Happy Birthday to Sir Donald Lynden-Bell, who turns today 81. In 1969 he published a paper where he proposed that massive black holes exist at the center of the galaxies. For this, he was rewarded the Kavli Prize in Astrophysics in 2008.

Before him, in 1951, Piddington & Minnet discovered a radio signal (at 1210 MHz) coming from the nucleus of Milky Way, named Sagittarius A.

Lynden-Bell was proven right in 1974 by astronomers Bruce Balick and Robert Brown who found evidence of Milky Way’s own supermassive black hole. Brown named it Sagittarius A* in 1982 (Sagittarius A* is part of Sagittarius A; and you thought biology nomenclature is confusing…).

Astrophysics terminology aside, happy birthday, Sir Donald!

sag - Copy

References:

 1. Lynden-Bell, D (16 Aug 1969). Galactic Nuclei as Collapsed Old Quasars. Nature, 223: 690-694. doi: 10.1038/223690a0. Article  | FULLTEXT PDF

2. Brown, RL (1 Nov 1982). Processing Jets in Sagittarius A: Gas Dynamics in the Central Parsec of the Galaxy. The Astrophysical Journal, 262: 110-119. doi: 10.1086/160401. FULL TEXT

 By Neuronicus, 5 April 2016

 

The Firsts: Anandamide (1992)

seedling cannabis-1062908_1920
Cannabis, the plant whose psychoactive tetrahydrocannabinol (THC) binds to the same receptors in the brain as anandamide.

A rare tragedy took place in France a few days ago when a Phase I clinical trial for a new drug destined to improve mood and alleviate pain has resulted in one person dead and five other hospitalized. Phase I means that the drug successfully passed all animal tests and was being tried for the first time in humans to test its safety (efficacy and potency are tested in phase II and III, respectively).

The trial has been suspended and an investigation is on the way. So far, it appears that both the manufacturer (Bial) and the testing company (Biotrial) have followed all the guidelines and regulations. The running hypothesis is that the drug (BIA 10-2474) is acting on an unexpected target. What does that mean?

BIA 10-2474 is a FAAH inhibitor (fatty acid amide hydrolase). This enzyme breaks down anandamide, which is an endocannabinoid. In other words, is a neurotransmitter in the brain that binds to the same receptors as THC, the main active component of marijuana. So, if you give someone BIA 10-2474, the result would be an increase in the availability of anandamide, presumably with anxiolytic and analgesic effects (yes, similar to smoking weed).

There are other FAAH inhibitors out there that had been previously tried in humans and they were never marketed not because they were unsafe, but because they were ineffective in producing the desired results, i.e. less pain and/or anxiety.

So we don’t know yet why BIA 10-2474 killed people, but the bet is that in addition to FAAH, it also binds to some other protein. Why they didn’t discover this in animal trials, is a mystery; perhaps the unknown protein is unique to humans? By the looks of the drug’s structure, I think is computer generated, meaning is composed of a bunch of functional groups that someone put together in the hopes that it would fit neatly on the target binding site; but so many functional groups thrown in together might bind unexpectedly to other places than the intended. More on the story in Nature.

Anyway, that was the very long intro to today’s featured paper: the discovery of anandamide. Which happened very recently, in 1992, by the Mechoulam group at the Hebrew University of Jerusalem, Israel. Anandamide is the first endocannabinoid to be isolated. Mechoulam’s postodcs, William Devane and Lumir Hanus, used mass spectroscopy and NMR (nuclear magnetic resonance, MRI is an application of the same principles) to identify and isolate the molecule in a pig brain. And then they named it, fittingly, the “amide of bliss”…

Of note, members of the same Mechoulam group identified two more of the six known endocannabinoids. The three pages paper is highly technical, but I am assured (by a chemist) that is an easy-peasy read for any organic chemist.

Reference: Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, & Mechoulam R (18 Dec 1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258(5090):1946-9. PMID: 1470919, DOI: 10.1126/science.1470919.  Article | Research Gate Full Text

By Neuronicus, 18 January 2016

The FIRSTS: Betz pyramidal neurons (1874)

Plate86betz
Betz cell in the dog cortex. Copyright: RA Bergman, AK Afifi, PM Heidger, & MP D’Alessandro. Pic taken from here.

Bigger that Purkinje cerebellar neurons, the Betz pyramidal neurons (aka the giant pyramidal neurons) can have up to 100 micrometers in diameter. They are located in the fifth layer of the grey matter in the primary motor cortex. And they were discovered by a Ukrainian who did not receive the just place he deserves in the history of neuroscience, as most books on the subject ignore him. So let’s give him some attention.

Vladimir Alekseyevich Betz (1834–1894) was a professor of anatomy and a histologist at the Kiev University. Just like with Pavlov, sometimes there is nothing spectacular or weird or bizarre in the life of a great thinker. Betz was a child of a relatively wealthy family, went to good schools, then to Medical School, where he showed interest in the anatomy department. He continued his postgraduate studies in the West (that is Germany and Austria) after which he returned home where he got a position as a professor at his Alma Mater where he stayed until he died of heart problems at the age of 60.

Vladimir_Betz
Vladimir Alekseyevich Betz (1834 – 1894), License: PD

During his PhD, which was on the blood flow in the liver, Betz discovered an interest in histology. He was unsatisfied with the quality of the existing staining methods, so he worked for years to improve the fixation and staining methods of the brain tissue. His new methods allowed the cutting and preserving very thin slices and then he described what he saw. But Betz’s genius was in linking his cortical cytoarchitechtonic findings with physiological function, dividing the cortex into the motor and sensory areas. He also made revolutionary observations of the anatomical organization and development and various pathologies.

Original reference (which I did not find): Betz W (1874). Anatomischer Nachweis zweier Gehirncentra. Centralblatt für die medizinischen Wissenschaften. 12:578-580, 595-599.

Reference: Kushchayev SV, Moskalenko VF, Wiener PC, Tsymbaliuk VI, Cherkasov VG, Dzyavulska IV, Kovalchuk OI, Sonntag VK, Spetzler RF, & Preul MC (Jan 2012, Epub 10 Nov 2011). The discovery of the pyramidal neurons: Vladimir Betz and a new era of neuroscience. Brain, 135(Pt 1):285-300. doi: 10.1093/brain/awr276.  ArticleFREE FULLTEXT PDF

By Neuronicus, 17 December 2015

The FIRSTS: the isolation of tryptophan (1901)

thanksgiving
The post-Thanksgiving dinner drowsiness is due to the very carbohydrates-rich meal and not to the amounts of tryptophan in the turkey meat, which are not higher that those in chicken.

There is a myth that says the post-Thanksgiving dinner drowsiness is due to high amounts of tryptophan found in the turkey meat. Nothing farther from the truth; in fact, it is due to the high amounts of carbohydrates in the Thanksgiving dinner which trigger massive insulin production. Anyway, the myth still goes on, despite evidence that the turkey has about the same amount of tryptophan as the chicken. That being said, what’s this tryptophan business?

Tryptophan is an amino acid necessary for many things in the body, including the production of serotonin, a brain neurotransmitter. You cannot live without it and your body cannot make it. Thus, you need to eat it. There are many sources of tryptophan, like eggs, soybeans, cheeses, various meats and so on.

Tryptophan was first isolated by Hopkins & Cole (1901) through hydrolysis of casein, a protein found in milk. And there were no two ways about it: “there is indeed not the smallest doubt that our substance is the much-sought tryptophane” (p. 427). No “we’re confident that…”, “we’re suggesting this…”, no maybe, possibly, probably, and most likely’s that one finds in an overwhelming abundance in the cautious tone adopted by today’s studies. Many more scientists today, fewer job openings, one has a career to think about…

Digression aside, Hopkins went on later to prove that tryptophan is an essential amino acid by feeding mice a tryptophan-free diet (and the mice died). By 1929 he was knighted and he got the Nobel prize for his contributions in the vitamin field. Also, a little known fact for you, butter lovers, Hopkins proved that margarine is worse that butter because it lacks certain vitamins and you have him to thank for the vitamin-enriched margarine that you find today.

Reference: Hopkins FG & Cole SW (Dec 1901). A contribution to the chemistry of proteids: Part I. A preliminary study of a hitherto undescribed product of tryptic digestion. The Journal of Physiology, 27 (4-5): 418–28. doi:10.1113/jphysiol.1901.sp000880. PMC 1540554. PMID 16992614. Article | FREE FULLTEXT PDF

By Neuronicus, 27 November 2015

The FIRSTS: the pons (1572)

The pons varolii, as described in plate 677 of Henry Gray's Anatomy of the Human Body (1918). License: PD.
The pons varolii, as described in plate 677 of Henry Gray’s Anatomy of the Human Body (1918). License: PD.

The name of the pons, that part of the brainstem that is so important for survival functions (like breathing) and holds the nuclei of several cranial nerves, is actually pons varolii. I was wondering why is that? When I learned neuroanatomy I was extremely lucky, because my knowledge of Latin, such as it is, contributed immensely to the memorization of brain structures; so the name of pons means “bridge” in Latin, which makes sense because it looks like one (see picture). But I was at a loss with varolii. Was it some sort of a joke that I missed? Was it the “rude bridge” or, more colloquially, the “a**hole bridge”?! Varo (or the closest thing) in Latin means rude or uncivilized.

Title page of Varolio's published letter in 1573.
Title page of Varolio’s published letter in 1573.

Well, turns out that the guy who described the pons for the first time is Costanzo Varolio (1543–1575) and the structure is named after him. Duh! As if it’s uncommon to name things after their discoverer… Anyway, I didn’t read the original account, which is free in its digitized-by-Google form of dubious quality (you can see the actual thumb of the dude who scanned it on the last page and many pages are illegible due to poor scanning technique). I got the information about the pons from the Pioneers in Neurology section in the Journal of Neurology. Varolio wrote a huge letter (seventy-some pages worth!) on 1 April 1572 to another physician describing the optical nerves and the pons. The letter has been published a year later in Padua, Italy. The pons may have been described and/or named earlier, but, alas, the works were not published or published much later. Goes to show that publication is more important that discovery…

Original reference: Varolio, C. (1573). De Nervis Opticis nonnullisque aliis praeter communem opinionem in Humano capite observatis (On the optic nerves observed in the human brain and a few other particulars adverse to the common opinion). Padua. Google ebook

Reference: Zago S & Meraviglia MV (July 2009, Epub 6 June 2009). Costanzo Varolio (1543–1575). Journal of Neurology, 256(7):1195-6. doi: 10.1007/s00415-009-5192-5. Article | FREE FULLTEXT PDF

By Neuronicus, 10 November 2015

The FIRSTS: discovery of the polymerase (1956)

Arthur Kornberg. License: PD, courtesy of the National Library of Medicine
Arthur Kornberg. License: PD, courtesy of the National Library of Medicine

Polymerases are enzymes that synthesize nucleic acids. The main types of polymerases are DNA polymerases and RNA polymerases. Everything alive has them. Saying that you cannot have cellular life on Earth without them is like saying you cannot have a skeleton without bones.

The first polymerase was discovered by Arthur Kornberg in 1956. Of note, his (and his two postdocs and lab technician) discovery was rejected for publication by The Journal of Biological Chemistry basically on the grounds that they don’t know what they’re talking about or they’re not qualified to talk about it. It took a new Editor-in-Chief to push the publication which finally appeared in the July 1958 issue. Talk about politicking in academia…

Diagram of DNA polymerase extending a DNA strand and proof-reading. License: PD. Credit: Madeleine Price Ball
Diagram of DNA polymerase extending a DNA strand and proof-reading. License: PD. Credit: Madeleine Price Ball

Anyway, less than a year since publication, in 1959, Kornberg (but not his co-authors) received the Nobel Prize for the discovery of the polymerase. Which he isolated from a bug called E. Coli, the same bacterium that can be found in your intestines and poop or can give you food poisoning (same species, but not necessarily the same strain).

Reference: Lehman IR, Bessman MJ, Simms ES, & Kornberg A (July 1958). Enzymatic Synthesis of Deoxyribonucleic Acid. I. Preparation of Substrates and Partial Purification of an enzyme from Escherichia Coli. The Journal of Biological Chemistry, 233:163-170. FREE FULLTEXT PDF | 2005 JBC Centennial Cover

By Neuronicus, 7 November 2015

The FIRSTS: the discovery of the telomerase (1985)

WIKI-Working_principle_of_telomerase, licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.
Telomerase at work. Credit: Fatma Uzbas. License: CC BY-S.A. 3.0

A telomere is a genetic sequence (TTAGGG for vertebrates) that is repeated at the end of the chromosomes many thousands of times and serves as a protective cap that keep the chromosome stable and protected from degradation. Every time a cell divides, the telomere length shortens. This shortening had been linked to aging or, in other words, the shorter the telomere, the shorter the lifespan. But in some cells, like the germ cells, stem cells, or malignant cells, there is an enzyme that adds the telomere sequence back on the chromosome after the cell has divided.

The telomerase has been discovered in 1984 by Carol W. Greider and Elizabeth Blackburn in a protozoan (i.e. a unicellular eukaryotic organism) commonly found in puddles and ponds called Tetrahymena. I wanted to give a synopsis of their experiments, but who better to explain the work then the authors themselves? Here is a video of Dr. Blackburn herself explaining step by step in 20 minutes the rationale and the findings of the experiments for which she and Carol W. Greider received the Nobel Prize in Physiology or Medicine in 2009. If 20 minutes of genetics just whet your appetite, perhaps you will want to watch the extended 3 hours lecture (Part 1, Part 2, Part 3).

Reference: Greider, C.W. & Blackburn, E.H. (December 1985). Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. Vol. 43, Issue 2, Part 1, pg. 405-413. DOI: 10.1016/0092-8674(85)90170-9. Article | FREE FULLTEXT PDF

By Neuronicus, 25 October 2015

The FIRSTS: Axon description (1865)

Human medulla oblongata sectioned at the level of the olivary nuclei. Drawing by Deiters (1965). Original caption: Fig. 15. Durchschnitt der medulla oblongata des Menschen in der Höhe der Olive (OL). R.R Raphe, Hyi). Nervus hypoglossus. Vag. Nervus vagus, deren Kerne in V und H liegen, aber in der Zeichnung nicht feiner ausgeführt sind. Den Haupttlißil der Figur nimmt die Formatio reticularis ein mit ihren zerstreuten Ganglienzellen, und die Olive mit den zu ihr hinzutretenden Fasern des Stratum zonale; C.c crura cerebelli ad medullam oblongatam; P Pyramidenstrang.
Human medulla oblongata sectioned at the level of the olivary nuclei. Drawing by Deiters (1865). Original caption: “Fig. 15. Durchschnitt der medulla oblongata des Menschen in der Höhe der Olive (OL). R.R Raphe, Hyi). Nervus hypoglossus. Vag. Nervus vagus, deren Kerne in V und H liegen, aber in der Zeichnung nicht feiner ausgeführt sind. Den Haupttlißil der Figur nimmt die Formatio reticularis ein mit ihren zerstreuten Ganglienzellen, und die Olive mit den zu ihr hinzutretenden Fasern des Stratum zonale; C.c crura cerebelli ad medullam oblongatam; P Pyramidenstrang”.

In 1863, using the microscope, a german neuroanatomist from the University of Bonn by the name of Otto Friedrich Karl Deiters describes in exquisite detail the branch-like processes of the neuron (i. e. dendrites) and the long, single “axis cylinder” (i.e. axon). Deiters’ nucleus is named after him (the place where a good portion of the cranial nerve VIII ends).

The book with the findings is published in German, posthumously (in 1865), with preface and under the editorial guidance of Max Schultze, another famous German anatomist. I got the information from Debanne et al. (2011), which is nice review on axon physiology (my German is kindda rusty due to lack of use). But I got my hands on the original German book (see link below) and, like a kid that doesn’t know how to read yet, all I could do was marvel at the absolutely stunning drawings by OFK Deiters. Which are truly and unequivocally beautiful. See for yourself.

Neurons with axons and dendrites. Drawings buy Deiters (1865.)
Neurons with axons and dendrites. Drawings by Deiters (1865.)

Reference: Debanne D, Campanac E, Bialowas A, Carlier E, & Alcaraz G (April 2011). Axon physiology. Physiological Reviews, 91(2):555-602. doi: 10.1152/physrev.00048.2009. Article | FREE FULLTEXT PDF

Original citation: Deiters OFK (1865). Untersuchungen über Gehirn und Rückenmark des Menschen und der Säugethiere. Ed. Max Schultze, Braunschweig: Vieweg, 1865. doi: 10.5962/bhl.title.15270. Book | PDF

By Neuronicus, 24 October 2015

The FIRSTS: Dopamine is a neurotransmitter (1957)

Swedish pharmacologist and Nobel laureate Arvid Carlsson giving a lecture at the 2011 Göteborg Science Festival. By Vogler, released under CC BY-SA 3.0
Swedish pharmacologist and Nobel laureate Arvid Carlsson giving a lecture at the 2011 Göteborg Science Festival. By Vogler, released under CC BY-SA 3.0 on Wikipedia.

Dopamine is probably the most investigated brain substance. Tens of thousands of researchers are owing their career to this small molecule. And quite a few non-scientists, too. The chemical rose to partial notoriety after several studies linked it to the Parkinson’s disease in the 60’s and but its true fame came a decade later when dopamine’s role in pleasure and addiction became apparent.

And yet not so many years before that, not only nobody thought of dopamine as a central player in the neuronal chemical waltz, but even after it was shown that it is a neurotransmitter, few believed it and the authors of those studies were a mark for ridicule. The main author, Arvid Carlsson, was finally vindicated 50 years later when he was awarded the Nobel Prize in Medicine (2000) for showing that dopamine is not a just a precursor of adrenaline and noradrenaline, but also a neurotransmitter in its own right. The work barely covered more than a column in Nature, in 1957. Basically, he and colleagues did a series of pharmacological experiments where they injected rabbits or mice with known antipsychotics and antidepressants and various monoamine precursors. And then observed the critters’ behavior.

Dopamine
Dopamine

The crux of the rationale was (still is in the pharmacological experiments): if drug X modifies behavior and this modification is reversed by drug Y, then drug X and Y interact somehow either directly or have a common target. If not, then they don’t and some other substance, let’s call it Z, is responsible for the behavior. If you go and read the actual paper, for the modern neuroscientist that has been uprooted from his/her chemistry classes, remember that 3-hydroxytyramine is dopamine,  3,4-dihydroxyphenylalanine is L-DOPA, and y’all professionals should know serotonin is 5-hydroxytryptamine with its precursor 5-hydroxytryptophan.

Reference: Carlsson, A., Lindquist, M., & Magnusson, T. (November 1957). 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature, 180(4596): 1200. doi:10.1038/1801200a0. Article | FULLTEXT PDF | Nature cover

By Neuronicus, 19 October 2015

The FIRSTS: brain active before conscious intent (1983)

Actor Jim Carry pretending to be attacked by its own hand in the movie Liar Liar. Dir. Tom Shadyac. Universal Pictures, 1997.
Actor Jim Carrey pretending to be attacked by its own hand in the movie Liar Liar. Dir. Tom Shadyac. Universal Pictures, 1997.

Free will. And with these two words I just opened a can of worms, didn’t I? Modern neuroscience poked its fingers at the eternal problem of whether humans have free will or not, usually with the help of the fMRI, and, more recently trying (and succeeding) to manipulate it with rTMS. But before these fancy techniques, there was the old-fashioned EEG.

In 1983, Libet et al. had 5 subjects sitting comfortably in a chair and watching a clock. Subjects were instructed to make a move of their right hand whenever they want AND to remember the position of the clock hand when they felt the urge to move. During the experiments, the subjects had electrodes on the scalp that measured their cortical activity and electrodes on their hand that measured muscle activity.

The brain activity began at least 1 second before the hand movement and Libet et al. called this activity the “readiness potential”. The muscle activity began 200 miliseconds before the person reported that s/he wanted to move their hand. In other words, brain tells the hand to move and very shortly after you are aware of the want to move your hand. “Brain activity therefore causes conscious intention rather than the other way around: there is no ‘ghost in the machine’.” (Haggard, 2008).

Reference: Libet B, Gleason CA, Wright EW, Pearl DK. (September 1983). Time of conscious intention to act in relation to onset of cerebral activity (readiness-potential). The unconscious initiation of a freely voluntary act. Brain, 106 (Pt 3):623-42. DOI: dx.doi.org/10.1093/brain/106.3.623. Article

By Neuronicus, 10 October 2015

The FIRSTS: out-of-body experience induced by brain stimulation (1941)

Fgi.1. Penfield’s (light blue) and Blanke’s (red) stimulation sites for eliciting out-of body experiences. Adapted from Tong (2003).
Fig.1. Penfield’s (light blue) and Blanke’s (red) stimulation sites for eliciting out-of-body experiences. Adapted from Tong (2003).

Olaf Blanke is today’s famous neuroscientist for investigating bizarre body perceptions, like out-of-body experiences or the felt presence of a doppelganger. Without doubt, he deserves the fame for conducting the most comprehensive, rigorous, and methodical studies of the phenomena to date. But before him… there was Penfield.

Out-of-body experience.
Out-of-body experience.

Wilder Penfield’s patient G.A. had epilepsy, without hallucinations. Penfield was habitually inserting electrodes and stimulating his patients’ brains in order to find the epileptic focus and destroy it. The G.A. patient reported out-of-body experiences when stimulated in the posterior superior temporal gyrus in the temporal lobe, a region close enough to Blanke’s today stimulations experiments (although, to be fair, either Penfield was a little more posterior than he thought, into the angular gyrus of the temporo-parietal junction, or he did not report the auditory hallucinations that he must have obtained with the stimulation of the posterior superior temporal gyrus. One of these days I will feature a Blanke paper. Until then, see Fig. 1).

The report is in a book (Penfield, W. & Erickson, T.C. (1941). Epilepsy and Cerebral Localization, Oxford, England: Charles C. Thomas, 623 pp), which I don’t have. Instead, I got the information second hand, via:

Reference: Tong F (March 2003). Out-of-body experiences: from Penfield to present. TRENDS in Cognitive Sciences, 7(3): 104-106. Article | FULLTEXT PDF

By Neuronicus, 6 October 2015

The FIRSTS: Adult neurogenesis (1962)

New neurons in the granular layer of the hippocampus. Fig. 30 from Altman & Das (1965).
New neurons in the granular layer of the hippocampus. Fig. 30 from Altman & Das (1965).

I am starting a new category today: the Firsts. It will feature articles that showed something really interesting for the first time. Yes, all articles show something for the first time, that’s why they are published. But I have noticed either a lack of acknowledgment (“it is known that x”) or a disregard for the old papers (“doesn’t count if it’s before, say, 2001”), particularly among the new generation of scientists. So I will feature both the really big ones (e.g., first proof of adult neurogenesis) or the more obscure, but nonetheless, first in their field (e.g., first synthesis of morphine).

Today, first proof of adult neurogenesis. Altman (1962) wanted to see the kinetics of glial proliferation after brain injury. Glial cells are the other type of cells in the brain and they outnumber the neurons 10 to 1. Altman lesioned the rat lateral geniculate nucleus (a portion of the thalamus that deals primarily with vision) and then injected the rats with thymidine-H3, a dye that labels the newly formed cells. In addition to the expected glial proliferation, he also observed (by microscope and careful histology) that some neurons were also stained with the dye, which means that they were born after the injection. The new neurons were in many regions of the brain (so not only those associated with the lesioned area), including the cortical areas.

Altman followed up and three years later published the first comprehensive study of postnatal (not adult) neurogenesis in dendate gyrus of the hippocampus.

References:

  1. Altman, J. (30 March 1962). Are New Neurons Formed in the Brains of Adult Mammals?. Science, 135 (3509): 1127-1128. DOI: 10.1126/science.135.3509.1127. Article | PDF
  2. Altman, J, & Das, G. D. (June 1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. The Journal of Comparative Neurology, 124 (3): 319 –335. DOI: 10.1002/cne.901240303. Article | PDF

by Neuronicus, 30 September 2015