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Jeffreys, Alec

Alec Jeffreys

University of Leicester

Southern, Edwin

Edwin M. Southern

University of Oxford

For development of two powerful technologies— Southern hybridization and DNA finger-printing — that together revolutionized human genetics and forensic diagnostics.

The 2005 Albert Lasker Award for Clinical Medical Research honors two scientists who revolutionized human genetics and forensic diagnostics. By inventing a method for detecting specific DNA sequences amidst the huge genomes of complex organisms, Edwin Southern infused genetic analysis with tremendous power. Suddenly scientists could study genetic variation in detail and decipher gene structures. Using this technology, Alec Jeffreys devised 'genetic fingerprinting', a way to distinguish every person from every other person, except an identical twin. Its ability to establish family relationships as well as individual identity has helped solve crimes, settle paternity and immigration disputes, establish the bases of inherited diseases, enhance transplantation biology, save endangered species, establish human origins and migrations, and advance countless other beneficial endeavors.

Technology has always defined the strength of genetic analysis. Until the mid-1970s, the ability to locate most genes or sequences of interest on the chromosomes of complex organisms was nearly impossible. This situation severely restricted efforts to define genetic differences that characterize species, individuals, and specific cell types, thus hampering the study of subjects as diverse as evolution and the physiological characteristics of distinct tissues.

Going with the flow

In the mid-1970s, Ed Southern (at the Medical Research Council Mammalian Genome Unit in Edinburgh) wanted to develop a method that would pinpoint a particular gene amidst the more than a billion building blocks — or basepairs — that compose the frog Xenopus laevis genome. Scientists knew that they could chop up DNA using restriction enzymes, proteins that cut DNA at particular sequences. They could then separate the resulting pieces by loading the collection onto an agarose gel and applying an electric current. The pieces would migrate at different rates, depending on size. For organisms with large genomes, however, this procedure generated a smear of DNA because of the millions of fragments. Finding a single piece of DNA that carried a specific sequence was hopeless.

Southern realized that he could accomplish his task by brute force: carving the gel into small horizontal slabs; washing the DNA out of each gel slice; attaching every portion to a separate filter; fishing for the particular DNA with a piece of matching, radioactively tagged RNA that would bind to it; and then measuring the amount of bound radioactivity. The tedium and labor involved in such a scheme spurred Southern to think of a better way.

If he could move DNA fragments from the gel to a membrane made of nitrocellulose, which grabs and clings to DNA, he knew he could then bind radioactively labeled RNA to the trapped DNA because that method was well established. However, he needed a way to transport the DNA. During pilot experiments, he realized that the trick would be to soak the DNA fragments out of the gel by forcing liquid to flow through the gel onto the nitrocellulose; he could accomplish this task by piling dry filter paper on top of the nitrocellulose, which would draw the liquid that would carry the DNA. The transfer worked. After applying radiolabeled RNA to the membrane and washing off all of it that didn’t stick to matching DNA sequences, Southern exposed the membrane to X-ray film. This procedure generated a high-resolution picture of the DNA bands that held sequences of interest.

Suddenly, scientists could detect a segment of DNA without purifying it from the rest of the genome. Researchers quickly exploited the technique of ‘Southern blotting’ for a wide variety of purposes. In 1978, they found, for example, that people with sickle cell anemia often lack the sequence for a particular restriction enzyme near the beta globin gene. Similarly, the method uncovered mutations that are associated with other ‘diseased’ versions of genes. On a large scale, it played a crucial role in mapping the human genome. Thirty years after publication, Southern’s original article holds the record for the most highly cited paper in the Journal of Molecular Biology.

Later, others developed a method for transferring and detecting RNA (as opposed to DNA) and, as a joke, called it “northern blotting.” The name stuck. Similarly, when investigators designed a related technique for proteins, they dubbed it “western blotting.” These procedures have made a huge impact on the study of genes and proteins, and have accelerated many advances in medical science.

Southern subsequently made another momentous contribution to the field of molecular biology. He conceived the notion of performing genetic analysis using tiny arrays of short DNA sequences — called DNA chips or microarrays — and he pioneered methods for building them. Because this technology allows researchers to conduct a tremendous number of experiments in parallel, it has unlocked countless realms of inquiry that biologists could only dream of 20 years ago and has already advanced the practice of medicine. For example, the use of microarrays allows cancers of the breast and blood system to be classified, which aids diagnosis and treatment.

Mini but mighty

In the mid 1970s, scientists could group people based on proteins in the blood and other bodily fluids, but these typing schemes were inadequate. For example, the ABO blood-typing system divides humans into only four groups (A, B, AB, and O). Alec Jeffreys (at the University of Leicester) wanted to find DNA that might uniquely identify individuals — variations associated with normal differences as well as those that cause disease — and he seized on the Southern blot to aid his search. He and others showed that single basepair changes at restriction sites existed, but were insufficiently informative to act as distinctive markers.

Several research groups had noticed highly variable regions present at diverse spots in the human genome. In each case, the spans — or ‘minisatellites’ — consisted of short repeated DNA sequences; different people carried different numbers of repeats.

When Jeffreys was analyzing the human myoglobin gene for other reasons, he found a minisatellite consisting of a 33-base-pair repeat. To determine whether related sequences exist, he probed the entire genome with a piece of radioactively labeled single-stranded DNA that contained multiple copies of this sequence. It bound at several sites, four of which varied greatly from person to person, differing in length by an integral number of repeat units. The repeats differed somewhat in sequence, but all carried a common core.

Jeffreys engineered a piece of single-stranded DNA that contained multiple copies of this shared core and tagged it with radioactivity. He then used this DNA to scour the human genome for additional minisatellites, reasoning that each person’s constellation of minisatellites should identify him or her because lengths vary from individual to individual. Together, they comprise a unique genetic fingerprint. Jeffreys showed that members of a family can be distinguished — and that each offspring carries only bands from the parents — half from the mother and half from the father, except in the occasional case where a new mutation crops up.

Illustration of Information transfer

Information transfer. In the technique that Southern devised, a solution flows through the gel and onto the nitrocellulose membrane, carrying DNA with it. Once the DNA is immobilized, the membrane is immersed in liquid that contains a radioactive DNA or RNA probe that adheres to sequences of interest. After washing away unbound probe, the membrane is placed next to X-ray film,thus generating ‘bands’ that correspond to DNA fragments that stuck to the probe.

Satellites land in the real world

Jeffreys soon applied his technique to a number of practical problems. The first such use, in 1985, involved the immigration case of a UK citizen who was returning to join his mother and siblings after a long visit to his original home of Ghana. Officials said that this boy’s passport was forged and, as a consequence, he faced deportation. The authorities thought he might be a nephew or unrelated. But DNA fingerprint analysis showed that all of the boy’s DNA bands matched either those of the mother or one of her undisputed children (and by inference, the father), and the family was reunited.

Jeffreys improved and adapted the technology so it would work on tiny amounts of forensic biological samples and lend itself to computer database manipulation, which facilitates DNA comparisons. In 1986, he used the related method of DNA profiling in a confounding case of two brutal rape and murder attacks in Leicestershire, UK. Eventually the police instigated the first DNA-based manhunt, asking for voluntary samples from all men of a certain age in the area’s villages. After a convoluted series of events, which included a false confession, the murderer persuading a colleague to act as a proxy for the blood test, and an overheard conversation in a pub, the police tracked down the killer, who is serving a life sentence for each murder. Forensic teams worldwide now routinely use DNA profiling. It has not only convicted many criminals, but has also absolved innocent people who were wrongly accused. Furthermore, DNA is quite stable and remains relatively intact after death. As a result, scientists could take advantage of the method to name disaster victims, including those of 9/11, and Jeffreys could confirm the identity of an exhumed body thought to be the Nazi war criminal Josef Mengele.

Applications of DNA fingerprinting and related techniques are endless. In bone marrow transplants, for example, the circulating blood cells should carry donor, not recipient, DNA patterns. Scientists can ferret out DNA signatures of inherited diseases and cancers. The method has addressed problems in international smuggling, conservation biology, and molecular anthropology as well. Investigators can establish, for instance, that a wildlife trophy came from the corpse of a protected animal. Furthermore, they can use it to avoid mating close relatives while trying to save an endangered population. Molecular ecologists have harnessed the strategy to figure out which individuals have spawned the most offspring. It has advanced the fields of evolutionary and population biology, enabling detailed genetic comparisons of various groups. For example, Jeffreys and others showed that the breadth of human variation in Africa was considerably greater than that in non-African populations. These observations supported the theory that people originated in Africa.

Southern invented a technology that made complex genomes accessible to meticulous analysis, and Jeffreys capitalized on this method to uncover the huge diversity of genetic variation. The effects of these innovations have been profound — reverberating over a wide range of sociological, medical, scientific, and forensic arenas.

by Evelyn Strauss

Key publications of Alec Jeffreys

Jeffreys, A.J., Wilson V., and Thein, S.L. (1985). Hypervariable “ministatellite” regions in human DNA. Nature. 314, 67–73.

Jeffreys, A.J., Wilson, V., and Thein, S.L. (1985). Individual-specific “fingerprints” of DNA. Nature. 316, 76–79.

Jeffreys, A.J., BrookField, John F.Y., and Semeonoff, R. (1985). Positive identification of an immigration test-case using human DNA fingerprints. Nature. 317, 818–819.

Jeffreys, A.J., Neumann, R., and Wilson, V. (1990). Repeat unit sequence variation in minisatellites: a novel source of DNA polymorphism for studying variation and mutation by single molecule analysis. Cell. 60, 473.

Jeffreys, A.J., MacLeod, A., Tamaki, K., Neil, D.L., and Monckton, D.G. (1991). Minisatellite repeat coding as a digital approach to DNA typing. Nature. 354, 204–209.

Jeffreys, A.J. (1993). 1992 William Allan Award Address. Am. J. Hum. Genet. 53, 1–5.

Key publications of Edwin Southern

Southern, E.M. (1975). Detection of specific sequences among DNA fragments separated by gel electrophoresis. J. Mol. Biol. 98, 503–517.

Arnhein, N. and Southern, E.M. (1977). Heterogeneity of the ribosomal genes in mice and men. Cell. 11, 363–370.

Southern, E.M. (1982). Application of DNA analysis to mapping the human genome. Cytogenet. Cell Genet. 32, 52–57.

Southern, E.M., Maskos, U., and Elder J.K. (1992). Analyzing and comparing nucleic acid sequences by hybridization to arrays of oligonucleotides: evaluation using experimental models. Genomics. 13, 1008–1017.

Case-Green, S.C., Mir, K.U., Pritchard, C.E., and Southern, E.M. (1998). Analysing genetic information with DNA arrays. Curr. Opin. Chem. Biol. 2, 404–410.

Southern, E.M. (2000). Blotting at 25. TIBS. 25, 585–588.

Award presentation by Joseph Goldstein

Joe Goldstein Presenting awardIn 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.

Every day, 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 US 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 United States 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 United States, 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 United States, 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.

Acceptance remarks

Alec Jeffreys accepting award

Nature Medicine Essay

Acceptance remarks, 2005 Lasker Awards Ceremony

The Foundation has done me a great, and I have to say wholly unexpected, honor today, and I am delighted to accept this award not only for myself but also on behalf of all my colleagues who helped turn my dream of DNA identification 20 years ago into a technology that has reached out and directly touched the lives of millions of people worldwide.

Our discovery of DNA fingerprinting was of course totally accidental — what we were really trying to do at the time was to find highly informative DNA markers for basic genetic analysis in humans.

But at least we had the sense to realize what we had stumbled upon. At the time, 20 years ago, we saw the potential for DNA maybe in the occasional specialist forensic or civil law case. What has staggered me is just how dramatic the spread of DNA testing has become. Let me just give two examples. First, the United Kingdom National DNA database now contains the DNA profiles of 3 million UK citizens, which on a proportionate basis would mean that, were we in the United Kingdom, then a dozen or so people in this room would be on that database. Second, I recently had lunch with senior judges at the Old Bailey courts in London and met one judge who was really excited as he was trying a case which, for a change, did not involve any DNA evidence. And it’s not just crime — for example, DNA is clearly going to play a major role in identifying the victims of the Hurricane Katrina disaster.

The impact of DNA fingerprinting has been extraordinary in terms of sheer numbers of people tested. But these bald numbers hide countless personal stories — some squalid, some touching, some tragic. Perhaps one of the most inspiring is that of Kirk Bloodsworth, a truly courageous man whom I am proud to count as a personal friend. He was convicted of a terrible murder back in 1984 and served nine years in a US penitentiary, including two years on death row, before DNA testing exonerated him and led to the identification of the true murderer. Kirk is now a tireless campaigner for post-conviction DNA testing, one of the most important aspects of DNA fingerprinting.

I am very proud of DNA fingerprinting and of the effect that it has had on society and criminal justice. My baby has come of age and I am pleased to say it’s flourishing. I thank you all for honoring it.

Edwin Southern accepting Award

Nature Medicine Essay

Acceptance remarks, 2005 Lasker Awards Ceremony

My big contribution to science was the discovery that blotting paper could be used to soak liquid out of jelly. I wouldn’t be here today if others had not found clever applications for this simple discovery and I’m delighted to share this prestigious award with Alec Jeffreys who used the method to make the most important discovery that genes have a split structure — the introns in eukaryotic genes — and he also developed his famous fingerprinting method from it. But there have been others. I get a little bit of credit for each application, as there have been many, colleagues have been generous in their acknowledgement, and the credit has mounted up over the years. I hope that anyone who has used the method, learning of this award, will feel that they have earned a share in it.

The molecular sciences have brought wonderful progress to biology and medicine in recent decades. It has been a privilege to have lived through this period and to have played a part in it. But this is a beginning. There is much to be done now that we have easy means to read gene sequences and to exploit them. Progress will need new methods, but methods development is not always given the recognition it deserves. I hope that this prestigious award from the Lasker Foundation will encourage others to engage in this most rewarding aspect of science.

Interview with Alec Jeffreys and Edwin Southern