by Lone Frank
In his classic account, The Double Helix, Watson describes how he hit on the structure one day when he was sitting in the lab playing around with cardboard models of the four bases that serve as the genome’s universal building blocks: Adenine, Guanine, Cytosine, and Thymine. At once, the young but intensely ambitious researcher realized how these bases must fit together in fixed pairs: that A and T combine with two weak hydrogen bonds, while G and C bond with three. It also became obvious how the bases had to face each other and, thus, hold the molecule’s backbone – the two long phosphate strands – in a three-dimensional double helix. A beautiful, biological, winding staircase.
Until that moment, Watson and Crick had been engaged in a long and merciless race. On their perch at the University of Cambridge’s Cavendish Laboratory, they had been out in front, but the legendary Nobel Prize winner Linus Pauling, of the California Institute of Technology, had nearly caught up. It was difficult for most observers to believe that Pauling would not win the contest, but the old giant became mired in some blind alleys involving his work with proteins. That allowed Watson and Crick to cofound the genetic revolution.
To have hit upon the double helix structure was equivalent to breaking through a wall – a thick, reinforced concrete wall. Now they had discovered not only that the previously mysterious DNA was the bearer of an organism’s genetic heritage, but also how the whole thing was screwed together chemically. The molecule’s structure was crucial. Only once it was revealed did scientists finally have a key for unlocking the genetic mechanism’s operation at the most basic level: the manner in which characteristics that develop over the lifetime of an individual can be physically passed on from generation to generation, nicely packed into an egg and a sperm.
On the surface, that process almost seems like magic, like pure mysticism. In the nucleus of all cells are some genes – heritable units, so to speak – that are themselves unchanging and static but which nevertheless provide the source for the eternal change and dynamism that characterizes every living organism. A human being’s genome – his or her total hereditary material – consists of forty-six different chromosomes, each of which is one long DNA molecule. These comprise the two sex chromosomes, X and Y, and twenty-two ordinary, housekeeping chromosomes that are each supplied in two different copies – one from each of our parents. In a way, the genome behaves like a queen ant. She remains passive, hidden, and protected deep in the center of the colony, where she is serviced by diligent worker ants and from which, via her production of different types of offspring, she controls the life of the entire ant society. Correspondingly, the genome is found in the cell nucleus, from where its information is read and transmitted to the rest of the cell, and to the organism, through a series of molecular middlemen.
The miracle is that along the way an elegant and gradual transformation from a digital code to an analog reality takes place. Genes do not do anything; they just are. But the information they contain – the genes’ essence, as it were – is converted into the stuff that realizes biological ideas – namely, proteins. Proteins are the workhorses of the organism. These large, clumpy molecules with their moveable parts and biochemical capacities can carry out all the tasks life requires.
We are not only largely built of protein, which is found in every cell and organ structure, we also function via proteins. Enzymes are a specialized class of proteins that take care of our biochemistry, and another class of specialists are the receptors – proteins that are responsible for all sorts of internal communication, through conveying chemical signals within cells and between cells and organs. In short, there are proteins in everything, and every single one of them is built on the basis of information in a corresponding gene.
The process of changing from gene to protein is a precisely choreographed dance. Each of our forty-six chromosomes is a long, unbroken DNA molecule. Imagine a long spiral, like a zipper, the teeth of which on each side are the simple bases A, G, C, and T. When a protein is produced, the zipper is opened in the place at which the gene is found, and special enzymes start transcribing a copy of the information. The copy is produced in RNA, which is a structural cousin of DNA with slightly different chemical components.
The small molecular transcript from a gene is called a messenger RNA (mRNA), and it is just that – a messenger. It is dispatched from the compact nucleus out into the cell, where it offers itself for translation. The translation occurs in large protein factories, which are themselves built from a series of proteins and which read messenger RNA molecules as recipes.
The recipe for a protein is itself in the genetic code. A given sequence, that is, a sequence of bases in the RNA molecule, specifies one and only one corresponding sequence of amino acids which, when they are linked together, constitute a protein. A genetic sequence of three bases – a codon – specifies one and only one amino acid out of the twenty that organisms make use of. If you have a genetic sequence CCC followed by AGC and then ACA, it means that the amino acid proline is to be hooked up with serine, which in turn is to be connected to threonine.
Correspondingly, there are start and stop codes. A messenger RNA is translated into protein by the code being continuously read and translated into a growing chain of amino acids. When a stop code appears, the process completes, whereupon the finished protein is spit out into the larger, complicated cellular machinery with specialized compartments where further modifications and renovations are made.
Nearly every one of an organism’s cells contains basically the same information hidden in the genome. They each have their own special identity, due to the fact that the information inside is treated differently. Only those genes that are suited to the individual cell’s tasks are read, translated, and allowed to produce protein. A liver cell forms protein from a certain array of genes, while a brain cell uses a completely different array.
In the midst of all this reading and translating, genetic mutations occasionally occur. Mutation means change, and genetic mutations assume many forms. There are point mutations in which one base is changed into another base, and there are larger changes that either remove a number of bases (deletion) or add new ones (expansion). Finally, pieces of the DNA of chromosomes can be rotated so its base sequence is inverted.
Genetic mutations can change an organism’s proteins in several ways. A single point mutation can replace an amino acid in a protein, thereby making the protein fold in a new way and, perhaps, making it more or less effective for the tasks it performs. Larger mutations can likewise change the function or completely inactivate the protein. Finally, mutations in DNA regions that do not themselves produce protein but, on the contrary, regulate production, can give rise to the formation of more or less protein.
These changes can trigger physiological effects, some of which are beneficial and some of which are harmful. Mutations arise all the time because of damage to the genome or mistakes in DNA copying, and these mutations, which are passed on to the next generation, may over time be dispersed in the broader population or disappear again. They are, so to speak, the fuel of evolution.
We all have the same genes, each in two copies, one from each parent (apart from the single genes of the sex chromosomes). However, because of the mutations that have occurred over the course of evolution, millions of which have survived and spread throughout the species, most genes exist in different variants. The astronomical number of possible combinations of these variants means every one of us is physically and physiologically different. Even identical twins. Although the twins’ original genome sequences are identical, mutations, and especially individual epigenetic modifications, accumulate throughout life, differentiating their genomes. Each of us carries a unique, beautiful genome.
NOT UNTIL 1963, ten years after the DNA structure was served up by Watson and Crick, was the genetic code – the language of genes – finally cracked. And with very few exceptions, that language is universal across Earth-bound life. Whether you are a flu virus, a slime mold, a manatee, or a manager, your genetic code
contains the same components. From this scientists derived another piece of knowledge:
Life is not based on chemical substances or molecules but on information, pure and simple.
Well, “duh,” we say today with a shrug. And without raising an eyebrow, we can recite the statistics that human beings share ninety-eight percent of their genome with a screeching chimpanzee, sixty percent with a skittering mouse, and even twenty percent with a lowly roundworm a millimeter long. But take a moment to think about this, slowly and carefully. This insight goes deep, and touches on something central, something almost psychologically jarring.
For one thing, it testifies to a common and global biological heritage that is not superficial, but reaches into the very core of all living creatures.
For another, it forces us to think about life in a new way. The phenomenon of life should not be viewed as a number of fixed, defined forms – slime mold, manatees, managers. Rather, it is a continuous stream of information. The myriad specific life forms are just temporary vessels holding the genetic information before it is transmitted on and on through time in novel combinations.
It also allows us to consider biology in terms of the digital world. Genetic information is like software programs and data that are expressed in binary code and can be read in the same way by different computers, whether a monstrosity of a stationary IBM, a sleek little Mac or, for that matter, a mobile phone. The genetic code’s message is the same. In a corresponding way, a brain cell in a human being reads and translates “gene language” in the same way as a yeast cell.
The significance of this realization stretches far beyond the psychological. Biology’s fundamentally digital nature has a dramatic consequence: genetic information does not belong to a particular place but can be freely transplanted between very different organisms. There is nothing particularly “rose-like” about a gene found in a rose; the same gene can just as easily produce its protein in any other living organism.
This knowledge became tangible in 1973, when the molecular biologists Stanley Cohen, Herbert Boyer, and Paul Berg showed they could move information between organisms. By using naturally-occurring enzymes that clip and cut DNA, they showed that a gene cut from the skin cell of a frog could be transferred to a bacterial cell and that, undaunted, the bacterium proceeded to produce the protein specified in the frog gene. In other words: a gene is a gene is a gene.
Thus gene splicing, also known as gene technology, was born, and science kicked down the door to a new world, in which genetic information could be moved freely between individuals and even between species that could never have mixed their genes in nature. New forms of life were imagined, from plants with practical traits designed specifically for agriculture, to microbes engineered to produce medicinal proteins. Incredibly clever, all of it.
The scientific community’s high enthusiasm was matched by its high anxiety. What unimagined life form might pop up along the way? Could the manipulation of nature’s creations wind up disturbing or destroying the complicated ecological puzzle that billions of years of evolution had created, honed, and fine-tuned? Were we playing with Pandora’s box?
To tackle such questions, in 1975, the top researchers of the time gathered together in California, at the now-legendary Asilomar Conference on Recombinant DNA. They did not just want to discuss how gene technology could be pursued with the greatest possible safety; they also wanted to jumpstart a public debate on the subject. It was just after the Watergate scandal, and there was a general longing for transparency in societal institutions. Now it was science’s turn to come out of the closet. One faction believed that the only sensible approach was to impose, for a defined time, an immediate moratorium during which everyone desisted from gene technology experiments while they considered what the consequences might be. Another faction argued that guidelines should be immediately established, and experiments should be run within defensible safety margins.
The latter group won the day. And with their victory, molecular biology reshaped the entire field of biology. Within a couple of decades, work on gene technology dominated biological research. Today, there is not a single sub-discipline in biology that does not involve genetic knowledge or genetic data. Even a botanist must occasionally take off his rubber boots and log onto a database. Kinships between plants are no longer determined by fiddling with petals or reproductive organs but by comparing genetic sequences among species.
The list of organisms that have been subject to gene manipulation is long, almost boundless. Strawberries have been pumped full of antifreeze proteins, which they produce via a gene borrowed from a deep-sea fish. Genes that code for a spider’s silk proteins are placed in yeast cells, which then happily produce great quantities of fine spider silk that can be spun into super-strong, flexible materials. Christmas trees are made resistant to disease, and flowers are equipped with colors they would never have discovered themselves. Innocent aquarium fish have been given a gene from a jellyfish that makes their bodies glow fluorescent green. And pigs are given genes for human diseases, such as Alzheimer’s, so that they can serve as model organisms for research into a cure.
Manipulation is one broad lane in the gene research highway; mapping is the other. We are living our version of the Enlightenment’s obsession with taking a census of the planet’s manifold life forms, describing them, comparing them, and thus creating order in their mutual kinship. Now, genetics is the key to all order and understanding. One organism after another has had its genome sequenced from one end to the other, and the sequences have been entered onto massive databases.
It began with the smallest life forms, viruses, which are not actually alive, but rather “parasites” built exclusively of genetic material. Then came “real” organisms, from bacteria and molds to plants and animals – almost four thousand organisms, including Homo sapiens, from every step in the evolutionary ladder.
“The most wondrous map ever produced by humankind” is the map of the human genome. It began in the 1980s, as a crazy idea among the most far-sighted geneticists, who envisioned a tool that would unravel the inner workings of our biology and speed up disease research considerably. The project was monumental for the technology then available, and the Human Genome Project, an international consortium, was established to get it up and running. James Watson, by then no longer a lanky boy with big ears and sharp elbows, but a power to be reckoned with in the research world, was one of the driving forces. The consortium would piece together the entire human genome, a sort of encyclopedia of us. When the project was officially launched in 1990, it was expected to take fifteen years to compile this great reference work.
For years, mapping proceeded apace without much ado. Scientists at the Sanger Institute, near Cambridge, UK, and the National Institutes of Health near Washington, DC, among other laboratories, steadily worked away. Then, out of the blue, war broke out. The American geneticist and entrepreneur, J. Craig Venter and his for-profit company Celera promised to map a complete genome faster and cheaper than all the academic groups combined. Venter had established a veritable sequencing factory in Rockville, Maryland, just down the road from NIH, and filled it with a new generation of sequencing machines and a phalanx of supercomputers rigged to put together the genetic jigsaw puzzle. The initiative was not welcomed. Venter was called a maverick in the newspaper headlines, and Watson, in his typical style, came out and called his competitor “Hitler.”
The acrimony ended with a compromise, in which Celera and the Human Genome Project exchanged vital data. This convenient union worked together to produce the first rough outline of the human genome in 2001, four years earlier than planned. The sequence was launched with grandiose rhetoric. The US President, Bill Clinton, and the UK Prime Minister, Tony Blair, appeared hand in hand on television, speaking of the“Book of Life.”
But the book contained some surprises. Researchers were stunned at how little content there seemed to be. The scientific consensus had predicted that there must be around a hundred
thousand genes in the human genome, but the analysis indicated that it was closer to twenty thousand to thirty thousand – shockingly few.
Genes constitute only about two percent of the whole genome, appearing like pearls threaded on a long string. Each gene corresponds to a sequence that twines between a start signal and a stop signal; in between the genes lies a sea of DNA that never produces protein. The remaining ninety-eight percent of the genome is a mixed bag of components that are, as yet, only poorly explored and understood.
The genes themselves are flanked by regions that help regulate how active the gene is. You can compare it to a speed regulator, which can boost the production of RNA or gear it down, according to need. But these regulatory regions don’t take up much space, and most of the rest, by far, is what is sometimes called junk DNA, simply trash. A part of it – in fact, eight percent of the total genome – looks like nothing more than a virus graveyard, containing sequences stemming from a motley crew of viruses that, at various points far back in the depths of evolution, have latched on as stowaways and lost their ability to make us sick.
Other “junk,” though, is beginning to reveal its genuine function. It turns out this mess is not just passive – it gives rise to huge quantities of RNA molecules that are never translated into protein, but travel around the cell on their own. Scientists have already discovered that some of these RNA molecules help regulate how active “real” genes are; others are still waiting to have their role clarified.
So, from the genetic material of a few hundred anonymous individuals, hundreds of thousands of lab-hours, and four billion dollars, the Human Genome Project gave us the first biological map of humanity. The technological developments that made it possible also now mean that things are moving at an incredibly rapid pace. Today, the cost of sequencing DNA is almost in free fall, to the point where the fall is faster than would be predicted by Moore’s law (which says that the price of calculating power of microchips will drop fifty percent every year and a half). Between 1999 and 2009, the price shrank by the factor of a whopping fourteen thousand, and in 2010 – barely a decade after the first genome was sequenced – companies such as Illumina and Complete Genomics could sequence a person’s genome for six thousand dollars. The work is done by a single machine and takes a single day.