Albert Lasker
Clinical Medical Research Award

In the last 50 years, the world has been radically changed by three inventions—burgers, chips, and genes. Let me explain. First, the burger. I ate my first Big Mac in 1966 while I was a resident at the Massachusetts General Hospital in Boston. I vividly remember telling Michael Brown, a fellow house officer at the time, about my fabulous epicurean experience, and for the past 37 years Mike and I have had many exciting discussions about cholesterol while devouring "Big Macs."

Since the early 1960s, McDonalds has grown from a few restaurants in California to 30,000 restaurants in 120 countries.

Everyday, 10 percent of Americans eat at McDonalds. McDonalds owns more real estate than any other entity in the world—the Catholic church included. Ray Kroc founded McDonalds. His ingenious idea was that people wanted to be served in 60 seconds. McDonalds is a cogent illustration of how one good idea by one person can change the way we live—for better or worse! Or, to paraphrase Woody Allen, "This is the transmutation of life—by a lowly hamburger."

So much for burgers. Now for the chips, not the Frito-Lay type, but the silicon type that power our cell phones, our personal computers, and the Internet. In the early 1960s, Jack Kilby, a newly hired engineer at Texas Instruments, had the ingenious idea that all the components of an electrical circuit could be integrated onto a single flake of silicon. The first practical application of Kilby's integrated circuit came rapidly. Within two years, Texas Instruments introduced the first pocket calculator with all the electronic transistors squeezed onto a single wireless chip the size of a matchbox. But that was not small enough. Within a few months, scientists at Intel figured out how to shrink the integrated circuit to the size of a pinhead. The result was a microcomputer on a chip—the so-called memory chip. The rest is history.

Intel's co-founder, Gordon Moore, says that there are more microchips made every year than raindrops in California. In the last 20 years, microchips and computers accounted for 40 percent of U.S. industrial growth.

Now for the genes—the newest transmutation that is changing the way we deal with human beings just as McDonalds changed the way we deal with food and chips changed the way we deal with information. Watson and Crick discovered the structure of DNA in 1953. For the next three decades, DNA led a cloistered existence, coiled comfortably in the nucleus of the cell. There were a very few people in the world who understood the power of DNA, and this handful of DNA aficionados went on to make major discoveries —the genetic code in 1966, gene cloning in 1973, and DNA sequencing in 1977. But, unlike the case with burgers and chips, none of these discoveries had any immediate impact on society. The practical applications of DNA have only become apparent in the last 10 years—thanks in large part to the insight of the two scientists, Edwin Southern and Alec Jeffreys, whom we honor today with the 2005 Lasker Award for Clinical Medical Research.

The first chapter in our story begins in 1975. Recombinant DNA and gene cloning had just come on the scene, and the human genome was a jumble of tens of thousands of fragments of DNA. No one knew how to identify a single gene amongst this morass of DNA until Ed Southern developed a powerful new technology. The key to Southern's technology was a brilliant insight that in retrospect is deceptively simple, but somehow it had never occurred to anyone other than to Southern. Southern's technique depended on the prior discovery of bacterial enzymes that cut DNA at certain sequences, chopping the genome into thousands of tiny fragments. Southern realized that these fragments could be separated by electrophoresis on an agarose gel, after which each of the fragments could be transferred through the pores of the gel to a nylon membrane in the same way that blotting paper absorbs ink. The nylon membrane is then incubated with a radioactive probe that latches onto the specific gene fragments of interest, which are detected by placing an X-ray film on top of the membrane. The probed DNA fragments become visible on the film as bands that resemble a supermarket barcode. I will spare you all the other technical details. Suffice to say, Southern's transfer technique for detecting the fragments of a single gene, called Southern blotting, inspired the development of other transfer protocols for detecting single species of RNA and protein, which scientists waggishly dubbed "northern" and "western" blotting—even though there is no Dr. Northern and no Dr. Western.

The ability to transfer DNA from a gel to a membrane paved the way, literally, for the transfer of DNA from the theoretical to the practical, from the bench to the bedside. Southern blotting unlocked the human genome so that all of our genes could now be mapped, and human genetic diseases could be diagnosed and screened with a precision that was previously unthinkable. Southern blotting also enabled the development of gene knockout technology for creating mouse models of human disease, and it laid the groundwork for the second chapter in our story, the discovery of DNA fingerprinting.

In 1977, Alec Jeffreys became a passionate practitioner of Southern's newly invented technique and used it to study the evolution of gene families. Jeffreys noticed that the myoglobin gene from different individuals produced a different pattern of DNA fragments on Southern blots. He went on to show that this difference resulted from a tandem repeat of DNA, called a minisatellite, where a short sequence of DNA is repeated many times in a row and varies in length from person to person. At the same time, other scientists studying other genes were observing a similar phenomenon in their favorite gene. But, unlike all the other scientists who remained highly focused on their own particular gene, Jeffreys made a conceptual leap. In 1984, he figured out that the minisatellites in all these different genes shared a nearly identical core sequence of DNA that could be used as a probe to latch onto many minisatellites at the same time. When the DNAs from different people were run on a Southern gel and then probed with the consensus minisatellite sequence, the result was astounding: Every person's DNA showed a unique pattern of bands just like every person's fingers show a unique pattern of skin ridges. The analogy to digital fingerprinting was so striking that Jeffreys named his procedure DNA fingerprinting. The DNA fingerprint of every person on the planet can be distinguished from every other person—except for his or her identical twin.

The implications of DNA fingerprinting for society are enormous. It is the biggest breakthrough in forensic science since the digital fingerprint technique was put into practice 120 years ago. Courts throughout the world now use DNA fingerprinting to solve crimes, to convict culprits, and to exonerate innocent people who have been wrongfully convicted. Since 1972, in the U.S. alone, 161 persons have been freed from prison, many of whom served for years, some on death row.

As Jeffreys originally showed, DNA fingerprinting has numerous other practical applications. It can be used to settle immigration disputes; to identify victims from fragments of tissues following disasters, such as hurricane Katrina; to monitor donor and recipient cells following bone marrow and organ transplantation; to trace the origin of humans and other species; and to save endangered species by avoiding the mating of close relatives. Speaking of mating, the most common use of DNA fingerprinting today is to settle paternity disputes. In the U.S., more than 300,000 paternity tests are done each year, with the frequency of false paternity varying from 5 to 30 percent, depending on whether you live in Forest Hills or Beverly Hills.

As a historical tool, DNA fingerprinting has been remarkably revealing: it proved that Thomas Jefferson fathered a child with his slave; it confirmed the identity of an exhumed body thought to be the Nazi war criminal, Josef Mengele; it proved that Dolly the sheep was indeed a true clone; it provided decisive evidence in the case of the stain on the blue dress—a seminal event if ever there were one; and it also provided decisive evidence in the O.J. Simpson case. Unfortunately, the jury ignored the DNA evidence and instead sided with Johnnie Cochran's anti-scientific argument: "If the glove don't fit, you must acquit."

Southern and Jeffreys are revered by their scientific colleagues as exceptional experimentalists and inspiring mentors. Both are respected for their superb communication skills and their strong sense of public service, and both have been knighted by the Queen. Like all true Brits, both are fond of their puddings, especially Yorkshire pudding, bread pudding, blood pudding, and (befitting their allegiance to Queen Elizabeth) the Raspberry Queen of Puddings.

Speaking of puddings, most Americans are not connoisseurs of the countless varieties of British Puddings, but we are all familiar with the nickname "Puddn'head," to refer to a simpleton or a fool. The first "Puddn'head" was created by Mark Twain in his novel Puddn'head Wilson. Twain wrote his novel in 1894, only one year after Charles Darwin's cousin Francis Galton published his book on the individuality of fingerprints. Galton was the father of eugenics, and he viewed fingerprints as a way to classify people by race.

Concerned with the racial injustice of slavery, Mark Twain used the Galtonian concept of fingerprints in a brilliantly imaginative way to construct the plot of his novel, Puddn'head Wilson. The main character is a young New York City lawyer named David Wilson, who wandered west to seek his fortune. Soon after arriving in the Missouri town of Dawson's Landing, Wilson acquired the nickname "Puddn'head" because he fooled around collecting fingerprints on all of the 2000 citizens of Dawson's landing. Every time a new baby was born or a new person moved to town, Puddn'head would get the fingerprints. His extensive fingerprint collection is arguably the first complete data base ever assembled. For 20 years, Puddn'head's fellow citizens never paid him much attention until one day he astonished them in the courtroom. Puddn'head used his fingerprint expertise to solve a double mystery involving a case of switched identities of two babies exchanged at birth, a white baby and a light-skinned slave baby, one of whom had grown up to murder the town judge. Puddn'head's courtroom logic explaining the value of fingerprints was spellbinding. Here's his summary statement to the jury, which he made 110 years ago:

"Every human being carries with him from his cradle to his grave certain physical marks which do not change their character… …these marks are his signature, his physiological autograph, so to speak, and this autograph cannot be counterfeited, nor can he disguise it or hide it away, nor can it become illegible by the wear and the mutations of time. This signature is not his face—age can change that beyond recognition; it is not his hair, for that can fall out; it is neither his height nor his form, for duplicates of those exist. This signature—the fingerprint—is each man's very own. There is no duplicate of it among the swarming populations of the globe!"

It's a real tragedy that Puddn'head Wilson was not in the courtroom to rebut Johnnie Cochran.

To their British colleagues, Ed Southern and Alec Jeffreys are now referred to, affectionately, as Sir Edwin and Sir Alec. To those of us in the U.S., these nicknames are a bit stuffy. So it might be more appropriate to change them to "Puddn'head Southern" and "Puddn'head Jeffreys" in honor of the two Brits who solved the double mystery of identifying the gene and detecting its DNA fingerprint.