This essay was written by James Briscoe and was first published in the 2008 Mill Hill Essays. An updated version was published in the Mill Hill Essays anthology.
It was my first time visiting Los Angeles. I was standing, staring in amazement not believing what I was seeing. Ostensibly I’d come to LA for work, at least that’s what I’d told the director of my own institute. I was staying with a colleague, a Professor at one of LA’s universities and I had lectured to her students and fellow researchers. I’d also talked about some results from my recent research and I’d listened to their thoughts and ideas about the work. But my secret real motive for being here was to see LA. I’d always wanted to experience the surf at Venice beach, see where the Hollywood stars lived and visit the shops on Rodeo Drive. I’d done all that and more. I’d laughed at the sun-burnt Elvis outside Grauman’s Chinese theatre, chortled at the vulgar mini-mansions in Beverley Hills and been frustrated by gridlock on the freeways. But this was the first time since arriving in the city that I had been drop-jawed astonished. And even more surprisingly I was in a library.
It was a small private library. As an academic, I always feel strangely attracted to specialist research libraries like this one. Perhaps its something about the hushed echoey atmosphere, the smell of books unopened for many years and the thought that libraries contain the collected knowledge of the centuries of human civilization. Or possibly it’s because I first met my girlfriend in a university library many years previously. The library I was visiting in LA contained a collection of some rare, important early printed documents and books. A long dead American industrialist, after making a mint from building railroads, put much of his money and passion into the collection. It contained some exceptional and famous items, the best of which were on display in glass cases: a Gutenberg bible printed on vellum, a manuscript of Chaucer’s “The Canterbury Tales” dating from the early 1400s, a First Folio of Shakespeare’s “Comedies, Histories & Tragedies”. What caught my attention, however, was off to the side of the main collection. All the same, it was sufficiently rare and significant to be in a glass case of its own. It was a copy of the first ever edition of the first ever scientific journal, Philosophical Transactions of The Royal Society. Printed in 1665 by the Royal Society in London, this document was the progenitor of all modern day science journals.
Journals are a central feature of scientists’ work and daily lives. We spend a lot of time either writing papers for journals or reading articles published by other researchers. So it wasn’t surprising that I was particularly interested in looking at a copy of the very first scientific journal. I knew a little of the history of Philosophical Transactions of The Royal Society. In it are published some of the most significant research findings of the last 500 years, from a description in 1672 of a reflecting telescope by Isaac Newton to papers from the 1970s and 1980s by Stephen Hawking. The journal is still going and is still published monthly. Although I had read papers in recent editions of the journal and even published some of my own articles in it, I had never looked at the first edition. And what I saw in the 450 year old journal stunned and excited me. The volume was open to the third article, which was entitled “Observables on a monstrous head” by a Mr Boyle. In it was a brief description of a physically deformed foal that had been born on a farm and shown to Mr Boyle soon after birth. On the page facing this article was a drawing of the head of the unfortunate animal. The foal had a single eye in the middle of its face, lacked any sign of a nose and had a strange protrusion emerging from the centre of its forehead. Mr Boyle wrote,
… the two eyes were united into one double eye, which was placed just in the middle of the brow, the nose being wanting, which should have separated them, whereby the two eye holes in the skull were united into one very large round hole… Just above the eyes, as it were in the midst of the forehead, was a very deep depression, and out of the midst of that grew a kind of double purse or bag…
What surprised me was not the archaic language or the exquisite detail of the drawing, or even the grotesqueness of the cyclopic head, but the fact that it related to my own research.
I’ve been studying neurobiology for most of my scientific career. I’m especially interested in trying to understand how the nerve cells that form our nervous system are produced. Our brains contain a great diversity of different types of nerves each with its own particular function. Some nerve cells connect to muscles to control their movement, others relay sensory information, like touch, heat and pain to our brains, while still others are involved, in ways we are yet to understand, in allowing us to think. These different types of nerve cells must be arranged in specific and complex patterns in the brain in order to connect together and function properly – just as the components on an electrical circuit board have to be in the right positions and wired together in the correct way to work. The arrangement of the nerves in our brains is set before we are born. In fact as soon as an embryo begins to develop from the ball of cells produced after fertilization, nerve cells are made and acquire their unique identity and location. These then begin to connect together to form the brain. Initially cells in the brain can form any nerve type, but in response to biochemical signals they are guided to become a specific type. I’d been studying one of these signals, made by a gene called Shh. Cells respond to different amounts of Shh by committing to become a particular type of nerve cell. For the last few years I’d been trying to find out how Shh did this. I’d identified several other genes, in addition to Shh, that were involved and in fact, this was the work I’d come to LA to talk about.
But what does this have to do with one-eyed animals? It turns out that genes are great multi-taskers, often doing different things at different times and places. Shh is no exception. When the brain is initially formed in a developing embryo it resembles a cylindrical tube. Only later does it split down the middle to form what we know as the left and right hemispheres. This division is important not only for brain formation but also for constructing the two sides of the face. If the split doesn’t happen then the face produces a single central eye, like the Cyclops monster, and some or all of the features found in the centre of the face, such as nostrils and incisors, can be partially or completely absent. In addition to making different types of nerve cells, Shh is required for this splitting of the brain down the middle. This “morphogenic” function of Shh became apparent several years ago when a team of scientists made mice embryos that completely lacked the Shh gene. These mice failed to make some types of nerve cells, as predicted by the involvement of Shh in producing the usual diversity of nerves. Surprisingly, however, the mutant mice also developed with defects much like those described in Mr Boyle’s foal back in 1665. The mice lacking Shh had a single cyclopic central eye. Moreover, they didn’t have separate left and right brain hemispheres. Instead the brain retained the simple cylindrical appearance that you find in very young embryos. This tube of brain tissue protruded from the middle of what should have been the forehead of the mouse. When Mr Boyle described, in his article, the “double bag or purse” protruding from the foal’s forehead above the cyclopic eye it must have been the abnormal brain tissue that resulted from the brain failing to split into left and right hemispheres.
The significance of the discovery that Shh is involved in shaping the bilateral structure of the brain and face goes well beyond the purely academic. In the 1950s there was a spate of sheep born with cyclopia on farms in Idaho in the USA. This prompted an investigation by the US Department of Agriculture, lasting eleven years, which traced the cause to a species of corn lily, Veratrum californicum, abundant in the pasture on which the sheep grazed. Analysis of the lilies revealed that they contained an unusually high concentration of a particular chemical, later named cyclopamine. This chemical was demonstrated to be responsible for the deformities in the lambs born to sheep grazing on the corn lily. More recently cyclopamine was found to block the action of Shh in embryos. This explains why eating lilies containing cyclopamine has the same consequences as blocking the Shh gene.
The finding that a lack of Shh can cause abnormalities in the face and brain structure also sparked much medical interest. It is estimated that up to 1 in 200 conceptions have defects in bilateral splitting of the forming brain similar to those seen in the mice lacking Shh. Many of these pregnancies are miscarried at very early stages so the number of babies born with cyclopia is low. Nevertheless, when such a birth occurs it can be devastating. Mutations in the Shh gene or other genes that carry out Shh action have been found to be the cause in some cases. Consequently, developing ways in which the incidence of the syndrome could be reduced or the defect corrected would be enormously beneficial. A better understanding of how Shh works is a necessary first step towards this.
But the medical interest doesn’t end with a relatively rare birth defect. Over the past few years it has become apparent that Shh is also involved in the incidence and progression of cancer. In fact, Shh has been implicated in the growth of several different types of malignant tumour. Of particular importance are two types of cancer: basal cell carcinoma, a kind of skin cancer frequently found in older people which is the most common cancer in Western countries, and medulloblastoma, a childhood brain cancer. Medulloblastoma is an unusually aggressive tumour that has an almost invariably poor prognosis and causes the death of thousands of children every year. Consequently there is a need for drugs that could treat medulloblastoma. Moreover, even though a basal cell carcinoma can often be eradicated with an operation, this is not always the case, and the surgery can result in severe scarring. So developing drugs for these conditions could alleviate the suffering of significant numbers of people. The discovery that Shh is involved in these types of tumours has raised the hope that it may be possible to develop specific drugs to cure these conditions. In contrast to the birth defects caused by Shh in which a block in the gene function results in disease, in the case of cancer, overactivity of Shh is responsible. Thus a drug that reduces or blocks Shh activity could be used to treat cancers such as basal cell carcinoma and medulloblastoma. In point of fact, just such a drug may already exist – cyclopamine. The knowledge that cyclopamine blocks the action of Shh in embryos suggests that it might be an effective treatment for tumours with over active Shh. Drug trials to test this possibility have been initiated. The results from the first animal tests look encouraging but more work will be needed before it is known whether cyclopamine is safe and effective for treating people. Indeed cyclopamine may not be an ideal drug for these diseases, not least because enormous numbers of corn lilies would be required to purify significant quantities. For this reason, inspired by cyclopamine, several pharmaceutical companies have started to develop drugs with similar activity to cyclopamine but with properties that would make them better medicines. The first results from these efforts also show promise, whether the promise is fully realized remains to be seen. Trials are continuing, including some early stage tests in people, so the next few years will be an exciting time for the scientists and doctors working on these problems.
As I was contemplating these many different avenues of research, I was roused from my thoughts by another visitor to the library wanting to look at the same display case. As I took a final look at the 1665 article in the ageing journal, I deliberated whether the deformed foal in the picture had a mutation in the Shh gene or whether its mother had eaten something containing cyclopamine during pregnancy. We’ll never know. I marveled at how much we now understand that could have helped Mr Boyle explain his unexpected animal. I also wondered if Mr Boyle or the other authors of articles in this first edition of the journal could have anticipated where their observations and ideas would lead. Much of this knowledge is collected and passed onto today’s scientists in journals like Philosophical Transactions of the Royal Society. But despite the advances we’ve made, our knowledge is far from complete. What other genes are involved and how do they work to produce the right structure of the face and brain? Could we identify and correct problems in embryos to ensure that fetuses are not miscarried and babies are not born with severe handicaps? Can we use this knowledge to develop effective treatments for diseases as devastating as medulloblastoma? As I stood in the library, I also wondered whether 500 years from now anyone would look at one of my scientific articles and be equally surprised by something familiar from so long ago. I doubt it very much. But, then again, I was off to take a tour of a Hollywood studio in the afternoon and if you are not allowed to imagine impossible things in Hollywood, where can you?