Brown, Donald

Donald D. Brown

Carnegie Institution for Science in Baltimore

Tom Maniatis

Tom Maniatis

Columbia University

For exceptional leadership and citizenship in biomedical science—exemplified by fundamental discoveries concerning the nature of genes; by selfless commitment to young scientists; and by disseminating revolutionary technologies to the scientific community.

The 2012 Lasker~Koshland Award for Special Achievement in Medical Science honors two individuals for their exceptional leadership and citizenship in biomedical science. Donald D. Brown (Carnegie Institution for Science in Baltimore) and Tom Maniatis (Columbia University) have made numerous fundamental discoveries concerning the nature of genes and have contributed in substantial ways to the scientific community. Brown has demonstrated selfless commitment to young scientists by founding and leading the Life Sciences Research Foundation, an inventive partnership that provides postdoctoral fellowships to some of the world’s most promising researchers, and he mentored a generation of scientists at the Embryology Department at the Carnegie Institution. Maniatis created the quintessential Molecular Cloning manual — based on his own pioneering work — and thus spread revolutionary technologies into a multitude of laboratories across the world.

Brown’s interest in genes sprouted in medical school, when he began wondering how embryos develop. At the time — in the mid-1950s — scientists had mapped out that process’s anatomical features, but its molecular underpinnings remained opaque. When Brown launched his independent research program, he boldly decided to delve into the details. By studying embryos that die at a particular early developmental stage — when new ribosomes, cellular protein factories, start accumulating — Brown, in collaboration with John Gurdon (Lasker Basic Medical Research Award, 2009), discerned that a structure called the nucleolus performs a crucial job for the cell: It manufactures structural RNAs of the ribosome (ribosomal RNAs, or rRNAs).

During the first few days of development, frog embryos don’t make ribosomes; rather, they use the stockpile that the egg endowed to them. No one knew how a single cell could churn out so many protein-making factories. Brown and Igor Dawid (and, independently, Joseph Gall; Lasker Special Achievement Award, 2006) showed that frog eggs create extra rRNA genes. Thus, the researchers had unveiled the first example of gene amplification, a process that underlies events outside of embryonic development as well; for instance, it fosters runaway growth of drug-resistant cancer cells.

These amplified genes provided a plentiful source of rRNA genes that Brown could isolate and study. He supplied purified 18S and 28S rRNA genes to Herbert Boyer and Stanley Cohen for use in their classic 1974 work that opened the study of eukaryotic genes to recombinant DNA technology (Lasker Basic Medical Research Award, 1980).

When this new era arrived, Brown used the methods of recombinant DNA to analyze a small rRNA, 5S RNA. He discovered a region in the middle of its gene that unexpectedly governs production of the RNA — the first known ‘internal control region’. This observation led to Robert Roeder’s (Lasker Basic Medical Research Award, 2003) purification of a protein that binds to this sequence and thus allows the enzyme that copies DNA into RNA to choose its target — the inaugural example of a gene-specific eukaryotic transcription factor.

Brown’s isolation and purification of the 5S RNA gene relied upon the fact that it is repeated many times. In contrast, no tools existed for separating a single-copy protein-coding gene — or its corresponding messenger RNA (mRNA) — from the rest of the genome or the bulk of mRNAs.

Maniatis took key next steps to solve this problem. One way to save a genetic sequence — whether it’s RNA or DNA — is to put it into a form that can be introduced into a living cell and reproduced there. In the mid 1970s, Maniatis and collaborators Argiris Efstratiadis and Fotis Kafatos tackled this challenge. They chose the mRNA of the rabbit β-globin gene because they knew that most mRNAs in red blood cells encode this hemoglobin subunit. Then they devised ways to perform all of the enzymatic manipulations necessary to make a collection — or library — of DNA copies of mRNA molecules, called cDNAs, from the red blood cells and fish out the globin cDNAs. Unlike today, when researchers order enzymes from catalogs and they are delivered a few days later, the team had to purify all of the necessary reagents from raw materials.

Their β-globin gene was the first full-length cDNA molecule isolated. They sequenced it, and their results established that the process of cDNA cloning did not introduce genetic errors, an essential feature for using the new recombinant DNA technology in the ways scientists imagined. Maniatis had thus established generally applicable methods for constructing cDNA libraries and for retrieving any sequence of interest.

He subsequently made the first complete human ‘genomic’ DNA library — containing all of the genes in an organism — whose sequences included regulatory sequences and other DNA regions that do not provide a template for protein. In addition to supplying genomic clones for the entire biomedical research community, this monumental task yielded a standard technique that laboratories everywhere used for many years.

Maniatis then isolated the first eukaryotic genomic DNA for a protein-coding gene and identified numerous genetic defects that underlie the inherited human illness β thalassemia. Some of the changes in single DNA letters cause the cell to splice out entire chunks of protein-coding regions. He had exposed — for the first time — disease-associated ‘point’ mutations that cause aberrant splicing.

Maniatis devised many additional innovations that have driven key advances in molecular biology and has used them to make numerous landmark discoveries.

Exemplary citizenship

Brown’s and Maniatis’s contributions to the research enterprise have extended far beyond their seminal scientific findings. In 1979, James Watson (Lasker Basic Medical Research Award, 1960) asked Maniatis to bring his techniques to the community by teaching a course at Cold Spring Harbor Laboratory — and Maniatis generously agreed. Its tremendous success spurred Maniatis and postdoctoral fellow Edward Fritsch to turn the course manual into a book. With Joseph Sambrook, they did so. Soon people all over the globe who studied myriad cellular processes were using it. Their Molecular Cloning manual, first published in 1982, sold 62,000 copies, and that number jumped to 95,000 in the second edition.

Images of publications

In different ways, Brown stimulated and bolstered biological research. He conceived and founded the Life Sciences Research Foundation (LSRF), an organization that honors excellence and potential in young investigators by awarding them prestigious postdoctoral fellowships. With the advent of recombinant DNA technology, Brown realized that biology would play a central role in pharmaceutical research and reasoned that companies would want to give something back to the system that enabled their success. Through his relentless efforts on an annual basis over the past 30 years, Brown has persistently tapped into this funding source as well as foundations and philanthropists to sustain the program. LSRF boasts 450 current fellows and alumni, many of whom have gone on to highly successful scientific careers.

In addition to helping seed the world with bright young scientists, Brown built a top-notch biology research program at his home institution. As Director of the Department of Embryology at the Carnegie Institution between 1976 and 1994, he created a scientifically diverse and stimulating environment, the quality of which is especially impressive given the department’s small size. When Brown left the directorship, five of eight laboratory heads were members of the US National Academy of Sciences. Two of the remaining three would later join that society and one of them would win the Nobel Prize.

by Evelyn Strauss

Key publications of Donald D. Brown

Brown, D.D. and Dawid, I.B. (1968). Specific gene amplification in oocytes: Oocyte nuclei contain extrachromosomal replicas of the genes for ribosomal RNA. Science. 160, 272-280.

Brown, D.D., Wensink, P.C., and Jordan, E. (1971). Purification and some characteristics of 5S DNA from Xenopus laevis. Proc. Natl. Acad. Sci. USA. 68, 3175-3179.

Brown, D.D. (1973). The isolation of genes. Sci. Am. 229, 21-29.

Sakonju, S., Bogenhagen, D.F., and Brown, D.D. (1980). A control region in the center of the 5S RNA gene directs specific initiation of transcription: I. The 5′ border of the region. Cell. 19, 13-25.

Pelham, H.R.B. and Brown, D.D. (1980). A specific transcription factor that can bind either the 5S RNA gene or 5S RNA. Proc. Natl. Acad. Sci. USA. 77, 4170-4174.

Brown, D. D. and Cai, L. (2007). Amphibian metamorphosis. Dev. Biol. 306, 20-33.

Key publications of Tom Maniatis

Maniatis, T., Kee, S.G., Efstratiadis, A., and Kafatos, F.C. (1976). Amplification and characterization of a β-globin gene synthesized in vitro. Cell. 8, 163-182.

Maniatis, T., Hardison, R.C., Lacy, E., Lauer, J., O’Connell, C., Quon, D., Sim, G.K., and Efstratiadis, A. (1978). The isolation of structural genes from libraries of eucaryotic DNA. Cell. 15, 687-701.

Ruskin, B., Krainer, A.R., Maniatis, T., and Green, M.R. (1984). Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro. Cell. 38, 317-331.

Palombella, V.J., Rando, O.J., Goldberg, A.L., and Maniatis, T. (1994). The ubiquitin-proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB. Cell. 78, 773-785.

Thanos, D. and Maniatis, T. (1995). Virus induction of human IFN-β gene expression requires the assembly of an enhanceosome. Cell. 83, 1091-1100.

Maniatis, T., Fritsch, E.F., and Sambrook, J. (1982). Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

Award presentation by Michael Brown

Award presentation by Michael BrownThe Lasker~Koshland Special Achievement Award is “special” because great science is only the ante. The winner must have done something special to advance science itself, hopefully by helping young scientists.

This year, the Lasker Jury was deadlocked. Two candidates soared high above the rest. Both deserved the award. Even Joe Goldstein couldn’t break the deadlock. So we will break tradition instead. Today we present two Special Achievement Awards — to Don Brown and Tom Maniatis.

I begin with Don Brown. After graduating from medical school in Chicago, Don was seduced by the siren of science. What better place for seduction than Paris, where Don studied with the legendary Jacques Monod. In 1960, Don joined the Department of Embryology at the Carnegie Institution in Baltimore, and he never left. He directed the department for 19 years.

The Carnegie Department of Embryology was formed at Johns Hopkins in 1913. For 50 years, the department was known for descriptive studies of primate development, but there was no mechanistic insight. While being seduced in Paris, Don realized that genes were the keys to embryology. Soon, genes would be understood not as abstract mathematical entities, but as living strands of nucleic acids that could be dissected with the tools of chemistry. At Carnegie, Don hand-picked a young faculty that shared his mechanistic view. His tiny faculty never numbered more than 11, yet they produced much of our current molecular understanding of development. Nearly all of Don’s recruits earned worldwide recognition. In turn, they trained hundreds of fellows. Already, many are household names.

Don’s own science led the way. Even before recombinant DNA, Don isolated the first animal gene (from a frog), and he showed how it is turned on and off during development. He isolated the first protein that controls this expression, opening the field of transcriptional regulation. He also told us how hormones cause a tadpole to lose its tail when it turns into a frog. Don Brown is universally recognized as among the most pioneering of 20th-century biologists.

But Don did much more. Heroically, single-handedly, and selflessly, he created the Life Sciences Research Foundation, a national fellowship program that has financed the training of 456 of the most accomplished scientists of our era. In 1982, Don realized that pharmaceutical companies rely on biologists trained in universities. Don said, “It is time that companies put money into the pot.” They should pay to train the next generation. But companies don’t part with their dollars easily. So Don took up his tambourine and his tin cup and he began to beg for donations.

I can attest to Don’s persistence. In 1996, I joined the board of Pfizer. The first person to call with congratulations was Don. Quickly he said that I was now able to insist that Pfizer funds at least one fellowship every year. And Don didn’t stop there. Each year for the next 16 years, he called and prodded me to renew my efforts. If he called me so often, Don must have called at least a 100 people each year, selflessly begging for donations — not on his own behalf — but only to support the next generation.

The Life Sciences Research Foundation has little overhead. Don does not take a penny in salary. Nor do the fellowships support his institution. Selection as an LSRF fellow is one of the highest honors a young scientist can earn. Don Brown is the Mother Teresa of American science, and he clearly merits the Special Achievement Award.

Don’s co-recipient is Tom Maniatis, whose scientific credentials also reign supreme. As a post-doc, Tom joined a young whiz kid, Mark Ptashne, at Harvard, where he showed how regulatory proteins can bind to DNA and block its transcription into messenger RNA. Later, Tom rose to the top of faculty ranks at Harvard.

I view Tom as the obstetrician of recombinant DNA. Like most obstetricians, Tom wasn’t present at the conception, but he did manage the delivery. Conception occurred in California, when Herb Boyer and Stan Cohen inseminated a frog gene into bacteria. Incidentally, the frog gene was the one that was isolated by Don Brown. For this seminal achievement, Boyer and Cohen shared the the Lasker Basic Science Award in 1980. But this technology could not deliver on its promise until human genes could be isolated. This was where Tom delivered. First, he isolated the first full-length DNA copy of a human messenger RNA — the one encoding the beta-globin component of hemoglobin. He surpassed his own triumph when he created the first bacterial library of human genes. Whereas Boyer and Cohen had inserted just one frog gene, Tom inserted the entire human genome. Then he showed how to fish out specific genes from this library. He showed how globin genes are arranged in tandem on human chromosomes and how genomic rearrangements give rise to hereditary anemias. All of this was breakthrough stuff that mesmerized the scientific community.

Tom went on to make many other paradigm-shifting discoveries, particularly in RNA splicing and innate immunity. Suffice it to say that Tom’s pure scientific contributions would qualify him for any award.

But the Special Achievement award requires something else. Tom made two special contributions. The first involves his gene library. With consummate generosity, Tom gave his library freely to any scientist who wished to isolate a human gene. Just think of it. Tom had the whole human genome in his freezer. He could easily have kept it to himself, using it to patent large chunks of the human genome. Instead, he gave it away. Indeed, Tom’s library was the ultimate source for nearly all of the human genes that were isolated over the next 10 years.

Tom’s final special achievement was even more generous. The methods for introducing genes into bacteria were complex. Only a handful of scientists could do it. Tom realized that the new methods could be disseminated only by training young scientists. So he took two approaches. First, he organized courses at Jim Watson’s summer camp on the Sound. Tom lectured prolifically, providing detailed instructions. But the courses were limited to a few dozen students. To disseminate his methods, Tom and two colleagues wrote a guidebook: Molecular Cloning: A Laboratory Manual. Published in 1982 by the Cold Spring Harbor Press, it was a molecular biologist’s cookbook. It outlined all of the procedures to isolate genes and produce their products. In the 1980s, a visitor to any molecular biology laboratory anywhere in the world would find a well-worn copy of this manual opened on the desk of every graduate student and postdoctoral fellow. If Don Brown is the Mother Teresa of science, then Tom Maniatis is Julia Child.

Now I hope you can see why the Lasker Jury could not distinguish between Don and Tom. They both made revolutionary discoveries. But they did more. Each of them sacrificed himself to pave a path for young scientists to follow. Don and Tom are both special, and they both deserve the Lasker~Koshland Special Achievement Award.

Acceptance remarks

Interview with Donald D. Brown and Tom Maniatis

Video Credit: Susan Hadary