Legend has it that, on the morning of 28 February 1953, James Watson and Francis Crick blew into the Eagle pub in Cambridge proclaiming to the regulars and the world, “We have discovered the Secret of Life.” They weren’t crazy – the molecular biologists had discovered the structure of DNA, which instantly suggested, as their paper in the journal Nature would put it a few months later, “a possible copying mechanism for the genetic material”.
The DNA molecule, they proposed, was a very long double helix: two strands intertwined like a twisted ladder, with the bases linking up as the rungs holding the strands together. This molecule could reproduce itself by unzipping the two strands and adding the complementary bases to make two new double helixes identical to the original. They had discovered, in outline, how living things manage to reproduce themselves so faithfully.
In the 1960s, there was further revelation: we discovered that the bases also constituted another code. This provided the blueprint for the production of the very many proteins that do all the major work in our living cells. Today, every one of the 3 billion bases in human DNA has been fully sequenced. But that doesn’t mean we’ve cracked the Secret of Life. Understanding that it is DNA that transmits the hereditary information and makes proteins was a great breakthrough. But a puzzle remained: for all the insight we have gained into the reproduction of genetic material, it still didn’t answer a fundamental question, one that has dogged scientists for centuries: how is an animal built? In other words, once the design is in place, how does the construction happen?
We might think of a symphony, where the DNA constitutes the score. The symphony of life – “endless forms most beautiful” in Darwin’s words – is created from this DNA code or sequence, this “score”. You can reproduce a Beethoven symphony by photocopying the score, but that doesn’t tell you how musical instruments and human hands and brains work to turn the notes into living music. What instructs a human, for example, to grow its arms and legs and fingers and toes – all derived originally from a single cell?
This extract from the 2005 poem “The Spirit Is Too Blunt an Instrument” by Anne Stevenson tells us how it’s not done:
The spirit is too blunt an instrument
to have made this baby.
Nothing so unskilful as human passions
could have managed the intricate
exacting particulars …
But some great principle of biological engineering does create “intricate exacting particulars”. Clearly, it’s not achieved by the human spirit, God or abracadabra. Rather, as we’ll see, it is governed by particular protein products of the DNA: a class of chemical agent known as a morphogen, a generator of form.
The fundamental “bricks” of life
To understand how morphogens work we need to start with the fundamental “bricks” of life: the cells. Living things can only develop by means of cells dividing into two and then two again, and so forth. To learn how to build an animal, we therefore need to investigate the properties of these “bricks”. Biochemically and physiologically, there are many different kinds of cell, but they all look more or less the same. The biochemist Nick Lane puts it like this: “I challenge you to look at one of your own cells down a microscope and distinguish it from the cells of a mushroom. They are practically identical.”
Given that we always start from a single living cell, let’s pose what seems a manageable question: how do animals acquire four limbs and their attached appendages? We have already shown how DNA can be imagined as a score, a blueprint or a building plan. Without such a plan, dividing cells would simply produce a constantly expanding ball. Of course, that’s not what happens. Cells divide more in one direction than another, breaking the symmetry of what would otherwise be a sphere, and creating the shape of the animal.
The most basic plan for an animal is a trunk with four limbs. All living things have to eat, and, unlike some primitive bacteria that can live off mere raw chemicals, animals have to eat other preformed creatures. Some tiny creatures are just a sausage-tube with a front and back: the front is the end that ingests the food; the end is where waste is expelled. But bigger animals need appendages, which eventually appeared in evolution as fins, arms, legs and wings.
So, the next schematic stage for our animal is for limbs to grow off that trunk. All the higher animals – such as amphibians, reptiles, birds, marsupials and mammals – have four limbs. Why is that so? Because they evolved from fish, which have just two front and two hind-fins. In birds and bats, two of these limbs became wings. In most of the rest, the four limbs all effectively function as legs. In humans, two of them became arms.
How does this building process work? A few months before Watson and Crick burst into the Eagle, another great thinker made a discovery that would give us our first clue. Alan Turing – mathematician, Enigma code-breaker and inventor of the concept of the digital computer – made a contribution to the Secret of Life that is only now receiving its due recognition. Turing showed theoretically how spreading zones of migrating chemicals could create coloured patterns on the coats of animals, whether they be spots or stripes. They had shape-generating properties, and he called them “morphogens”. Eat your heart out, Kipling and his Just So story “How the Leopard Got His Spots”.
But the scope of morphogens has expanded dramatically since Turing’s pioneering work. They are now understood to help create not only two-dimensional patterns but also three-dimensional forms, such as arms and legs and their terminal digits. They do this by diffusing through developing cells, instructing them to change their character as they go, gradually building the appropriate kinds of cells for each part of the body.
Making our heads, arms and legs
In the late 1960s, a related idea was taken up by the inspirational embryologist Lewis Wolpert, who died in January 2021 aged 91. Wolpert was an imaginative thinker, a great team leader and a vigorous populariser of science in books like The Unnatural Nature of Science (2000). Wolpert suggested the theory that morphogens, as they made their way from their source, diffusing through a growing mass of cells, caused different effects as they travelled further away and their concentration weakened. Near to the source they have one effect; further away a different one. Wolpert called this the “French Flag model”: one could imagine a “French Flag” animal that was red at one end, white in the middle and blue at the other end, all produced by the same morphogen.
In the 1980s, genes with a related pattern-forming purpose, the hox genes, came into detailed focus, thanks to advances in gene sequencing and manipulation. The protein products of hox genes are “super morphogens”, specifying the overall body plans of all animals, most significantly the head and the trunk. These super morphogens specify the room plan of the house, if you like, while the morphogens go to work in choosing the kind of cooker, fridge and sink, and decide where they should go in the kitchen.
In the early 20th century, we had our first inkling of what happens when a super morphogen goes wrong: fruit flies were found with organs growing on the wrong part of the body – a leg where an antenna should be, or vice versa. Something that told a leg or antenna where to form was malfunctioning. Now we know that something is a hox gene.
So the super morphogen hox genes specify where the shoulder and pelvic girdle start and then another morphogen comes into play. In 1993, the whimsically named morphogen “sonic hedgehog” (named on account of its relation to the so-called “hedgehog genes” that produce bristles on flies) was discovered to control the structure-forming gradients in many parts of the body: how wide apart our eyes are, for example; how the limbs develop from those buds off the main trunk, and how many fingers and toes we have. The latter, for example, shows the French Flag model in action, creating a gradient from thumb (“blue”), through middle fingers (“white”) to pinkie (“red”).
The function of sonic hedgehog can be seen most clearly in cases where it has been disabled. This happened in Utah in 1957, when sheep were born with a Cyclopean single eye and other deformities. The culprit, identified 10 years later, was a chemical called cyclopamine, found in the plant Veratrum californicum, which the sheep were eating. Drought had driven them to higher pastures where the plant was growing. In the 1980s, cyclopamine was shown to block sonic hedgehog.
We saw an equivalent case in humans with the drug thalidomide. Widely prescribed to pregnant women in Europe between 1957 and 1961 as a treatment for nausea, the drug interfered with the working of sonic hedgehog. Before thalidomide was withdrawn, it caused all manner of birth defects, including hands that grew from the shoulders. But even in normal development, sonic hedgehog sometimes gets it wrong: people with six or seven digits occur in one out of 700-1000 live births.
"Just a very large clitoris"
If morphogens and hox genes can seem a bit abstract, the way that nature sculpts an animal comes vividly into focus when we get to the business end: the genitals. “La différence” maybe, but in developmental terms the male and female genitals are really all of a piece, woven from the same tissue. Only very small changes at the molecular level distinguish the male testosterone from the female oestrogen. It’s quite hard to spot the difference unless you’re a chemist.
In the developing foetus, it is the sex hormones, acting as morphogens, that build either the female or male genitalia from the same original tissues. In the early embryo, the primordial organs, so far undifferentiated, become male or female depending on the signal from one or other of the so-similar hormones. Once development has finished, switching hormones can accentuate or diminish secondary sexual characteristics but they cannot reverse the plumbing. That requires surgery. So it’s either labia or scrotum, clitoris or penis, ovaries or testes (which are formed in the male in the same place in the stomach as the ovaries but which then descend into the scrotal sac). The default is the female form.
Remember that animal forms can only be produced by cells dividing and moving in one direction rather than another. So the scrotal sac is just a large hollow version of the labia, with a sealed seam where the vagina would be. Indeed, the whole appendage of which males are so proud is just a very large clitoris with the urethra diverted down the middle, and a connection to the testes and the prostate gland.
The ingenious plasticity of most of these processes is highlighted by the bizarre case of the spotted hyena, which gives birth through the clitoris. How evolution succeeded with this apparently grotesquely malformed plumbing is a mystery. Birth this way is hard: 60 per cent of the firstborn hyenas and 9 per cent of their mothers die at birth. It sounds like a challenge to Darwin, but despite its extreme reproductive strategy, the spotted hyena is an abundant, successful species.
The growth of an animal is a cascade: once it gets going, it can’t stop. But it can go wrong. Timing and positioning are a large part of the developmental process. Because many processes can only be turned on at the correct time in development, a wrong turn early on cannot later be made good. The reason that thalidomide wreaked such deadly and lasting damage is that the sonic hedgehog morphogen is busy patterning the limbs during weeks five and six of gestation, when the pregnant mothers were taking the drug.
Just as there is no one Secret of Life, many processes are brought to bear to hone and fine-tune the actions of morphogens like sonic hedgehog. Building an animal is a concerted job between the genes, the protein-signalling morphogens, the different kinds of cells they produce and the messenger molecules on their surfaces. There is a powerful analogy with language here. The linguist Guy Deutscher, in The Unfolding of Language (2005), shows how language evolved its complexity by a process akin to biological evolution: “Languages have… developed a range of… techniques to help make the bricks stick, such as the use of various adhesives which facilitate the construction of much more complex edifices.”
From a single egg to the finished animal
Our knowledge of how to build an animal is still very broad-brush. Recent work, reported in Science magazine, sheds new light on the fine-tuning of the construction technique. Working with zebrafish, scientists have found that sonic hedgehog patterning is actually a bit sloppy, but that it interacts with and is fine-tuned by interactions with the proteins that stick cells together. These cell adhesion proteins also specify cell types and they make sure that the broad pattern laid down by sonic hedgehog, at least most of the time, produces the correct result. In the zebrafish experiment, they were found to produce the 13 pre-patterning “stripes” that parcel out the early spinal cord – not only in zebrafish, but in all vertebrates. In humans they also ensure, most of the time, that we have 20 tiny fingers and 20 tiny toes.
When the successful completion of the Human Genome Project, the international mission to map and understand our DNA, was announced at a White House press conference in 2000, President Clinton told the world that “Today we are learning the language in which God created life.” He said that the genome was the “book of life” which we could now decode – “the most wondrous map ever produced by humankind”. In fact, the genome was only 83 per cent complete at the time. But even if it had been fully complete, as it is now, Clinton would have been jumping the gun. DNA is only one piece of the puzzle.
The DNA sequence of any organism’s total complement of genes, the genome, is fundamental, but how it functions at different stages in the development – from a single egg to the finished animal – is intricately subtle. This article has covered a few prime examples of this. They were mostly surprises; many unknown unknowns still await us on this quest.
So where do we find the Secret of Life? It turns out that there isn’t one. In evolving life’s complexity over four billion years, many processes have been deployed. Let’s call them “secrets” then – although a growing number aren’t secrets any more.
This piece is from the New Humanist winter 2021 edition. Subscribe today.
