If it has an effect, there is a reason
I qualify myself as a “molecular embryologist” and vote to invest heavily in the newly-coined field of “molecular teratogenics”. We know a bit about why neural tube closure defects, eye malformations and other effects happen in the presence of maternal exposure to various chemicals and drugs (teratogens). I’d love to know more (eg. you may have come across an earlier post of mine on holoprosencephaly).
From a press release and with my touch-ups for the details, which I find interesting:
Molecules naturally produced by our brains and functionally similar to THC from cannabis, play unexpectedly significant roles in establishing how certain nerve cells connect to each other.
Endogenous cannabinoids use the same mechanism as THC, engaging the CB1 cannabinoid receptor, to exert their effects on nerve cells (neurons). Therefore, the recent finding that cannabinoids normally control the establishment of connections amongst certain neurons convinces the authors of the study that they have defined a key mechanism through which maternal cannabis use might impair fetal brain development and impose life-long cognitive, social, and motor deficits in affected offspring.
A synthetic cannabinoid was used to stimulate the CB1 receptor in cultured rat brain neurons that usually mediate inhibition of noise and signal spread in the brain upon neural stimulation. This treatment induced collapse of the exploratory cell projections that are responsible for setting up the network of physical contacts between this cell type and the target neurons on which they exert their effects.
The collapse was confirmed to take place after a localized contraction of the actin-based cytoskeletal network that underlies the cell membrane, leading to directional turning of the neural projection away from the source of the cannabinoid. When the scientists in the study applied a chemical that blocks the contraction, the repulsion was converted into attraction. This seems to suggest that engagement of the CB1 cannabinoid receptor by endogenous cannabinoids conditions such neuronal projections to be receptive to either kind of directional signals in the developing microenvironment in which they navigate.
“Besides identifying a fundamental mechanism in brain development, our findings may provide new perspectives to identifying the molecular changes in the brains of individuals prenatally affected by maternal cannabis abuse”, says Dr. Tibor Harkany who has led the studies. “This is of social impact given the continuous growing use of marijuana, the most common illicit drug, in our society.’’
Earlier studies have already found that children of marijuana-smoking mothers more frequently suffer from permanent cognitive deficits, concentration disorders, hyperactivity, and impaired social interactions than non-exposed children of the same age and social background.
Publication:
“Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity” by Paul Berghius, Ann M Rajnicek, Yury M Morozov, Ruth A Ross, Jan Mulder, Gabriella M Urbán, Krisztina Monory, Giovanni Marsicano, Michela Matteoli, Alison Canty, Andrew J Irving, István Katona, Yuchio Yanagawa, Pasko Rakic, Beat Lutz, Ken Mackie and Tibor Harkany in Science, 25 May 2007
Holoprosencephaly and cyclopia – the real story that won’t make it onto AP
Here’s another example of how scientists sometimes have a hard time communicating with the public.
There was an Associated Press story recently about a woman whose cat gave birth last December 28th to a cyclopic kitten. Discussion about the veracity of the photo overtook the wonder at its condition. Those who initially broadcast the news mid-January were mocked as being naive, to the extent that
Associated Press regional photo editor Tom Stathis says he took “extensive steps” to authenticate it, including examining the memory card of the digital camera with which it was taken. He concluded it would have been “virtually impossible” to fabricate.
But there were/are still skeptics. To resume the reactions:
- The kitten’s eye is too enormous.
- It’s open, when kittens are usually born with their eyes closed.
- My kid has holoprosencephaly and looks nothing like that.
- What a great opportunity to talk about disfiguring congenital conditions in “a dignified manner. (The term “sonic hedgehog gene” notwithstanding….) “
- “Whatever you do, don’t do a Google images search for cyclopia.” (I’d second that for the squeamish).
I know this is “old news” by way of the Internet. I’m put out, though, that although the consensus based on parental testimony that the picture is not a hoax, the easily available links I consulted had no doctors or scientists to refute the skeptics.
If you’re curious, here is why I think that the photos are likely to be perfectly authentic and that it is not necessary for Traci Allen to keep the kitten any longer in her freezer.
Holoprosencephaly describes what happens when the left and right hemispheres of the forebrain are not sufficiently lateralized – they are fused into one median hemisphere. This can happen in any vertebrate (only vertebrates have a bilateral forebrain). There is a very in-depth discussion of this at the Developmental Biology textbook website at this link.
The area of the tubiform brain that is going to pouch out on each side of the head and become the eyeballs (in humans they swing around front secondarily) is adjacent to and just behind the areas devoted to the right and left hemispheres. So, when the forebrain is fused very severely along the midline, the space can be reduced between the eyes (hypotelorism), the eyeballs can touch (synophthalmia), or they can be downright married to each other (cyclopia). All the intervening structures are correspondingly missing according to degree – the nasal bones, the midline teeth of the upper jaw, the philtrum, the optic nerve chiasma and sometimes even the pituitary gland behind.
In the severest forms of cyclopia, where nothing subsists between the eye territories, the skin that was programmed to form nostrils and cover the nose and middle upper lip stays stuck up *above* the eye. It looks very much like a flaccid penis but is known as a proboscis. If you want to see an example – but it’s shocking unless you’re a fetopathologist – you can see a 35-week human cyclopic fetus here.
I’ve been interested in this malformation for years because it affects many tissues derived from my favorite embryonic cell type, the neural crest. Holoprosencephaly can be caused by lots and lots of things:
Mutations in a gene coding for a signaling protein called Sonic hedgehog or any of its effectors. The mutant fruitfly in which the gene was first identified has prickly bristles at the larval stage and looks like a hedgehog. Nintendo was popular in that lab.
Teratogens that affect the Sonic hedgehog signaling pathway, such as cyclopamine that occurs naturally in a plant, Veratrum californicum (hey, I just found out that it is skunk cabbage! ah, but that’s to the West of the Rockies. To the east, the plant is unrelated). Animals that nibble the plant while pregant may have cyclopic offspring.
Experimental ablation of neural crest cells that normally give rise to those facial structures. When we saw that, we were surprised because there was an effect on the brain – which is not the face! but clearly, the Sonic hedgehog pathway both requires their presence and is vital for their survival. Ethanol inhibits their growth, leading to fetal alcohol syndrome (mild end of the holoprosencephalic spectrum).
I’m trying to find the photo from the era of my thesis where I showed the spectrum of facial anomalies induced by surgical removal of neural crest cells in chick embryos. Ok, I found it. The embryo on the left is normal for its age. The one on the right was actually also strictly synophthalmic; it had two retinae but one lens.
