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Could We? The History of Genetics


By Michael Yudell, MPH, American Museum of Natural History
and Rob DeSalle, Ph.D., American Museum of Natural History

Gregor Mendel, pioneer of genetics and parish priest in the collegiate church at Altbrünn, located in the Czech Republic.
Gregor Mendel, pioneer of genetics and parish priest in the collegiate church at Altbrünn, located in the Czech Republic.
When Austrian monk Gregor Mendel's mid-19th century experiments led to the discovery of the basic mechanisms of heredity, the science of genetics was born and humanity took its first small steps towards deciphering the genetic code. Mendel helped set in motion a golden age as scientists around the world grappled with the biological underpinnings of heredity.

A Century of Astonishing Progress

The focus of scientific inquiry has since moved from Mendel to molecules and from genetics—the study of individual genes and the way traits pass between generations—to genomics, the study of an organism's entire complement of DNA (deoxyribonucleic acid). Today the landscape is dominated by the Human Genome Project, an international research consortium that completed the first draft of the human genetic code in June 2000. The end product—the complete sequence of all 3.1 billion base pairs of DNA contained in almost every human cell—is an encrypted blueprint for human life.

To understand the amount of data contained in the human genome, imagine 58 New York telephone books written in A's, C's, T's, and G's. ŠAMNH
To understand the amount of data contained in the human genome, imagine 58 New York telephone books written in A's, C's, T's, and G's. ŠAMNH

No one could have predicted that only a century after Mendel, scientists would begin to master the DNA molecule itself. How did we reach this point? How did science progress from thinking about the mechanisms of heredity in the broadest possible terms, to understanding that genes are the basic units of heredity, to deciphering and finally manipulating the DNA codes that underlie all life on earth? The story is one of persistence, intuition, and just plain luck.

From Pea Plants to Fruit Flies

Spurred by the publication of Charles Darwin's Origin of Species in 1859, most biological thought at the time of Mendel's discoveries was preoccupied with solving the riddles of evolution. Published in an obscure scientific journal, Mendel's work gathered dust for almost 40 years. Remarkably, it was rediscovered in 1900 by three botanists working in separate laboratories across Europe. During the first decades of the 20th century, plant genetics was superseded by research on insects and animals, and Mendel's fundamental laws—which explain how traits are passed from generation to generation—were tested across a wide range of species.

Astonishingly prolific and possessing only four pairs of chromosomes, Drosophila melanogaster (aka the fruit fly) has been the workhorse of geneticists for almost a hundred years. Beginning early last century, Thomas Hunt Morgan and his students at Columbia University began breeding fruit flies by the hundreds of thousands. At the time, the terminology of what we now call genetics was not even in place. Botanist William Bateson named the field in 1906, and three years later German biologist Wilhelm Johannsen coined the term "gene."

In 1910 a lone white-eyed male fly appeared in Morgan's laboratory. Formerly critical of Mendel's theories, Morgan came to embrace them when they were able to accurately describe the transmission of this trait across generations. He called such a trait a mutation. Morgan used mutations to move beyond the laws that managed heredity to examine the specific mechanisms—the genes themselves—that carry out the process. By finding and breeding hundreds of visible mutants, including those with variations in body color and wing shape, he and his collaborators were able to create chromosome maps that showed where on each of Drosophila's four chromosomes certain genes lay—an early map of the fruit fly genome.

Eugenics—The Dark Side of Genetic Theory
While scientific thinking about genetics was focused on the work of Morgan and his colleagues during the first three decades of the 20th century, a group of men and women known as eugenicists dominated the public discourse. Eugenics is the science of improving the qualities of humanity through selective breeding. Fed by anti-immigration sentiment and a belief in the genetic superiority of some races, the eugenics movement stoked racial hatred and led to discriminatory laws and the sterilization of approximately 30,000 allegedly "feeble-minded" Americans. Fortunately, eugenics faded from the national spotlight almost as swiftly as it had risen, a transition hastened by the horrors of the Holocaust and by advances in genetics and evolutionary and population biology.

Molecular Genetics Overtakes Classical Genetics
As some biologists established a mathematical framework for the way in which traits are passed down through generations, others struggled to determine the chemical components of whatever the hereditary material might be. Some remained wedded to the belief that proteins transmitted traits between generations, while others argued that nucleic acids were the fundamental building blocks of life. In 1944, a series of ingenious experiments conducted by three American biologists on the bacteria pneumococci (which causes pneumonia) established that genes are made up of DNA. This discovery unleashed what evolutionary biologist Ernst Mayr called a "veritable 'avalanche' of nucleic-acid research" as biochemists rushed to uncover the physical structure and chemical characteristics of DNA.

Enter the Double Helix
In the 1950s, at the Cavendish Laboratories in Cambridge, England, scientists developed X-ray crystallography, a technology that made it possible to interpret the three-dimensional structure of a crystallized molecule. It allowed Maurice Wilkins and Rosalind Franklin to take "snapshots" of DNA that were used in 1953 by James Watson and Francis Crick to build their now-famous model: they discovered that DNA was shaped like a spiral staircase, or double helix.

One of Watson and Crick's original models for the structure of DNA, displayed in AMNH's exhibit 'The Genomic Revolution.' Roderick Mickens ŠAMNH
One of Watson and Crick's original models for the structure of DNA, displayed in AMNH's exhibit "The Genomic Revolution." Roderick Mickens ŠAMNH

Watson and Crick's greatest strength lay in their ability to reconcile their model with existing science. As late as 1933 Thomas Hunt Morgan pointed out that there was "no consensus opinion amongst geneticists as to what the genes are—whether they are real or purely fictitious." Working on instinct, Morgan couldn't be sure that his gene maps were more than a wild goose chase. But beginning with the 1944 discovery that DNA was indeed the "stuff" of heredity, the existence of genes became less and less theoretical. Watson and Crick's discovery of the actual physical structure of DNA finally created a consensus among geneticists that genes were real. With the basics of heredity now worked out, their successors began to examine and manipulate genetic processes at the molecular level.

Delving Deeper Into the Cell

The other major players at the molecular level are proteins—structures that are made of amino acids and that govern cell function. In the 1950s, chemist Fred Sanger figured out how to determine the order of amino acids in a given protein. That proteins consist of linear arrays of twenty amino acids and genes consist of linear arrays of four nucleic acids, or bases (DNA), could mean only one thing. Some kind of code connected the information in the DNA to the production of proteins. The rigorous thinking and experimentation required to solve the puzzle attracted some of the greatest scientific minds at work in mid-century.

In the 1960s, Crick and chemist Sydney Brenner determined how DNA instructs cells to make specific proteins: a different triplet of bases in the DNA—called codons—codes for each of the twenty amino acids, chains of which build the various proteins. More and more codons were identified over the next few years, and the code eventually turned out to be the same in all organisms, from ferns to flamingos.

Meanwhile, biochemists were taking the cell apart to determine how DNA was replicated, how proteins were synthesized, and what role enzymes played. In 1958 Arthur Kornberg and Severo Ochoa were the first to synthesize DNA molecules in a test tube. They went on to discover a broad array of enzymes and proteins important in DNA replication and the translation of proteins. Others were busy manipulating bacteria to expedite analysis of DNA and genes. A technology called recombinant DNA—cutting DNA from one organism and inserting it into the DNA of another—was invented in 1972, creating the field of genetic engineering. This enormously important development made it possible to clone and modify genes, establishing a foundation for modern biotechnology. For example, colonies of bacteria are now being used to economically manufacture insulin and human growth hormone.

The newest PCR machine, the DNA Engine Tetrad, amplifies a target sequence of DNA into more than a million copies in just a few hours. Meg Carlough ŠAMNH
The newest PCR machine, the DNA Engine Tetrad, amplifies a target sequence of DNA into more than a million copies in just a few hours. Meg Carlough ŠAMNH

Technologies that enabled scientists to see and manipulate specific DNA sequences also evolved. A crucial breakthrough was the invention of polymerase chain reaction (PCR) by Kary Mullis in 1983, a process that generates trillions of copies of a specified segment of DNA in a matter of hours. PCR transformed molecular biology by making genetic material in quantities large enough to allow experimentation.

All these discoveries set the stage for the first sequencing of an entire genome, that of a tiny virus called PhiX0174, in 1977. The sequence itself unveiled many unknowns about genes and gene structure, a theme that played out over and over as more genomes were sequenced: a bacterium in 1995; the first higher organism, the roundworm C. elegans, in 1998; the fruit fly in March 2000; and three months later, the human being.

Moving Beyond the Genome

Now that the human genome has been sequenced, the emphasis is shifting to proteomics: the study of all the proteins for which genes code. The approximately 30,000 genes defined by the Human Genome Project translate into 300,000 to 1 million proteins. While a genome is relatively fixed, the proteins in any particular cell change dramatically as genes are turned on and off in response to their environment, directing an astonishing range of biological functions with exquisite precision.

Molecular biologists are now beginning to unravel the complex ways in which genes interact with each other and with the environment to produce a multiplicity of outcomes. We continue to gather and analyze information about both human and non-human genomes at an astonishing pace.

The Risks and Rewards of Genetic Technologies

The ability to manipulate DNA makes us capable of doing immense harm to ourselves and our environment, just as it holds out vast promise for improving our lives in ways as yet unseen. Emerging technologies may increase the potential for genetic discrimination and the invasion of genetic privacy. Some worry about the environmental consequences of altering the genomes of various plants and animals. As our skills and knowledge grow, we need to think hard about dealing with such potential consequences.

There is no doubt, however, that genomic technologies will change our lives for the better. Comparative genomics, which compares whole genome sequences from a range of organisms, will advance our understanding of the natural world and the role genes play in complex human diseases. Mice, for example, have many gene sequences identical to humans, yet gene functions often differ. By comparing gene function between mice and humans, or between humans and other species, we will begin to unravel many genetic mysteries. Microarray technology, which enables scientists to compare tens of thousands of genes at once, promises to unlock the genetic roots of diseases and to enhance our ability to treat them. The new field of pharmacogenomics will usher in an era of personalized medicine. Cancer patients, for example, will receive therapies tailored to their specific conditions rather than undergoing ineffective and debilitating treatments. There may even come a time when geneticists begin to manipulate our genes to increase human life spans, creating a veritable fountain of youth. Finally, as we sequence the genomes of more and more species, our understanding of the tree of life and our place in the natural world will deepen.

Contemplating the mechanisms and meaning of heredity, scientists a century ago wondered, "Could we?" We could, and we did. And the sequencing of the human genome is another milestone on the age-old quest to understand our origins and decode our biological destiny.





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