Tom Maniatis: A Deep Sense that Science Must Be Shared

History books are filled with the technical advances that made genetic engineering possible, from the discovery of enzymes that cut and paste DNA to the development of techniques for reading the sequence of genes.

But perhaps more than any other advance in molecular biology, it was a centuries-old technology – ink on paper, in the form of Tom Maniatis’ 1982 Molecular Cloning manual – that was responsible for igniting the revolution of recombinant DNA.

The manual – often referred to as “the Bible” by students and researchers -- contained practically every technique biologists needed to know in order to manipulate DNA. With these techniques scientists could identify genes that cause disease and they could produce new drugs such as human insulin. Later, the techniques proved indispensable for the success of the Human Genome Project. Maniatis’ laboratory developed many of the techniques in the manual, and they were so clearly explained that complete novices to molecular biology could pick up the manual and get instant results.

“It’s impossible to overstate the impact this manual had on a rapidly expanding field,” wrote the publisher on the manual’s 25th anniversary. “Molecular Cloning was the book that really put the techniques in every lab’s hands. It opened a door for many researchers into the world of recombinant DNA technology and played a significant role in spreading these approaches through the scientific community.”

Maniatis, now the chairman of the Department of Biochemistry and Molecular Biophysics and Isidore S. Edelman Professor of Biochemistry, still seems surprised at the impact the manual has had around the world.

“I got an email the other day from Huda Zoghbi, who discovered the gene that causes a severe form of autism in young women [Rett Syndrome],” he said. “It’s amazing to me. Here’s this powerhouse researcher, a member of the National Academy of Sciences and a Howard Hughes investigator, who said she knew nothing about recombinant DNA when she got her first research position. But she told me she used the manual to write her first NIH grant (which was awarded).”

The manual (co-written with his postdoc Ed Fritsch and Joe Sambrook, then the scientific director of Cold Spring Harbor Laboratory) appeared at a tipping point in the history of molecular biology.

NEXT:  Suddenly Everyone Had the Tools to Study How Cells Work

Suddenly Everyone Had the Tools to Study How Cells Work

The fundamental molecules of life – DNA (genes), RNA, and proteins – were being studied in simple organisms such as bacteria and viruses, but it was not possible to study these molecules in more complex organisms, most importantly in humans. Human genes were still buried within DNA’s 3 billion base pairs, and the details of how certain genes lead to disease were completely concealed. Experts in the field expected slow, incremental growth in new knowledge.

But the invention of new recombinant DNA techniques, which allowed researchers to cut DNA from an organism, and paste it into a DNA molecule capable of replicating in bacteria (cloning vector), made it possible for the first time to isolate and study human genes and the proteins they encode. Major steps in this direction were provided by the development of methods for generating cDNA and genomic DNA libraries in the Maniatis lab.

However, these methods were technically complex, and required expertise that most biologists did not have. “The techniques were difficult for people who had never used them before,” Maniatis admits. “Most of this technology came out of labs in Boston or the San Francisco area. It was fine if you were there and could walk down the hall to get help, but otherwise the technology was hard to master.”

Jim Watson, director of Cold Spring Harbor Laboratory, asked Maniatis to teach the techniques during a summer course at CSHL, and afterward, produce a manual.

“At first I was reluctant [to write a manual]. I couldn’t really even imagine the value,” Maniatis said in a video produced by CSHL. “I thought, well, maybe it could be used by labs that do this work to train new students.”

But the manual quickly spread far beyond those few labs: partly because even complete novices, like a young Huda Zogbhi, could get the techniques to work. And partly because researchers in other fields, from medicine to agriculture, saw how they could benefit from the techniques.

Richard Axel, MD, Nobel laureate and University Professor in the Departments of Biochemistry & Molecular Biophysics and Neuroscience, and a good friend of Maniatis, sums up what happened next: “Molecular biology just took off. Suddenly everyone had the tools to study how cells work.”

NEXT:  Fundamental Discoveries of the Nature of Genes

Fundamental Discoveries of the Nature of Genes

Molecular Cloning had a tremendous impact on science, but Maniatis’ scientific discoveries are also being honored by the Koshland-Lasker Award.

As a young researcher first at Cold Spring Harbor and later Cal Tech, Maniatis wanted to understand how genes are switched on and off in the cell. All cells in the body possess the gene for hemoglobin, for example, so why is hemoglobin only produced in red blood cells?

Using the genetic engineering techniques developed in his lab, and propagated in Molecular Cloning, Maniatis was the first to isolate a human gene (human β-globin) and the first to use the cloned genes to identify mutations in a human gene that causes disease. β-globin is one part of the hemoglobin protein complex, and the mutations Maniatis identified cause an inherited blood disease called beta thalassemia.

Maniatis’ laboratory also made the first complete human “genomic” DNA library -- a collection of DNA fragments containing every human gene – this made it possible to isolate any gene, study its regulation and produce the encoded protein. This was a major step forward in the identification of disease genes and in the understanding of disease mechanisms. And as he did with genetic engineering techniques, Maniatis freely shared this library with other researchers.

Other discoveries made by Maniatis and his students have uncovered important details in how information in genes is turned into proteins, including the mechanisms by which DNA is transcribed to produce RNA, and the process called RNA splicing.

Not content to see discoveries contained in the basic science community, Maniatis also helped launch one of the first biotech companies. In 1980, he co-founded Genetics Institute (eventually bought by Wyeth), which developed blood clotting factors, the blood stimulating protein erythropoietin used to treat anemia, and bone morphogenic proteins used in the treatment of severe fractures and other orthopedic indications. ProScript, which he co-founded in 1994, developed a cancer drug based on discoveries made in his lab and others. The drug, Velcade, is now the most effective treatment for multiple myeloma, and is the first in its class of so called “proteasome inhibitors” that are being tested in a wide range of cancers.

“The years I’ve been involved with biotech have exposed me to human biology and medicine in a way that would not have been possible otherwise,” Maniatis says. “I became a scientist because of the excitement of making discoveries, but to see the impact these discoveries have on the treatment of human disease is particularly gratifying.”

NEXT:  New Frontiers: Columbia, Genomes and Personalized Medicine

New Frontiers: Columbia, Genomes and Personalized Medicine

From the days of sharing the techniques of recombinant DNA with the world, to improving human health through biotech ventures, “Tom has had a deep sense that science must be shared,” Axel says.

That commitment is now moving in new directions at Columbia, where Maniatis moved in 2010 after spending 30 years at Harvard.

One reason for relocating, Maniatis says, is the transforming impact his sister’s death in 1993 from ALS had on his life. Initially, he helped the ALS Association as a consultant, but he later jumped into ALS research himself, devoting half of his lab’s time to the search for the causes of ALS.

“The Motor Neuron Center at Columbia was a huge attraction,” Maniatis says. “I was going in the direction of molecular neuroscience, and there is no better place in the world to do that than Columbia.”

As chair of Biochemistry and Molecular Biophysics, Maniatis is also shaping the future of the department, which underwent a seismic shift a few years ago when its neuroscientists formed a new Department of Neuroscience. Although these faculty members remained in the Department with joint appointments, it was clear that future appointments in neuroscience would be focused in the new department.

“It was clear that in addition to the traditional strength in structural biology, the Biochemistry department would take on new directions, so I took the opportunity to strengthen our department in systems biology,” Maniatis says. “All aspects of biology are moving toward a system-wide approach, and we have worked closely with Prof. Andrea Califano and Barry Honig to recruit outstanding young system biologists to Columbia.”

Systems biologists can’t function without data, however, and that set Maniatis on another public service mission: establishing a genome center for all of New York City.

“It’s amazing, but New York was left out of the picture at the start of the genomics revolution in the 90s,” Maniatis says. “It is difficult for individual institutions to maintain cutting edge genomic facilities because of the cost and rapid obsolescence of the technology”. In addition, the interpretation of the massive amount of sequence data requires major advances in bioinformatics and systems biology, which is best accomplished through cooperation between multiple institutions.”

To help Columbia and the City, Maniatis teamed up with Nancy Kelley (the current executive director of the center) to co-found the New York Genome Center (NYGC). The NYGC is an unprecedented collaborative effort in New York that brings together 11 scientific and medical institutions, including Columbia and New York-Presbyterian, to collaborate and share genomic infrastructure.

Once it is up and running at full capacity in 2013, the center will be one of the largest sequencing and analysis facilities in the country. Maniatis and Lee Goldman, MD, dean of the faculties of health sciences and medicine at CUMC, serve on the Board of Directors of the NYGC, and Maniatis chairs the Scientific Steering Committee.

“The potential of personalized medicine is a big driver behind the idea of the center,” Maniatis adds. “Unfortunately, personalized medicine was overhyped when the human genome was sequenced in 1999, and right now, sequencing DNA outpaces our ability to analyze the data and find drugs. However, it’s now starting to happen. We will be able to mine the data for medical breakthroughs, but more slowly than initially predicted.”

“I have enjoyed working on initiatives that have a broad impact on science and medicine throughout my career, and I believe that the New York Genome Center will have such an impact on human genetics and genomics and the treatment of cancer and genetic diseases”.