UAB Alumnus Revolutionizes Tuberculosis Research

By Meghan Davis

1013 jacobs1UAB alumnus Bill Jacobs has earned a place in the prestigious National Academy of Sciences for his efforts to understand and eradicate tuberculosis.Bill Jacobs cracked one of the great problems in infectious disease research using a mathematician's heart, a molecular biologist's training, and a helpful handful of dirt.

Jacobs, a professor of immunology, microbiology, and genetics at the Albert Einstein College of Medicine in New York City, earned one of the top honors in American science when he was elected to the National Academy of Sciences in 2013. He won the honor, in part, for identifying new ways to target tuberculosis, which is still one of the world's great public health threats. But Jacobs, who earned his Ph.D. in molecular cell biology at UAB in 1985, says it all might not have happened apart from a fateful letter to Birmingham.

While studying math at Edinboro State College near Erie, Pennsylvania (actress Sharon Stone was a classmate), Jacobs took a microbiology course that sparked his interest. He applied to several microbiology graduate programs, but few even bothered to answer his inquiry letters. Then Roy Curtiss, Ph.D., founder of UAB's molecular cell biology graduate program, invited him to Birmingham for an interview and tour.

"I told Roy that I didn't know much biology," Jacobs says. "And he told me, 'There is no sin in being ignorant. The sin is to remain ignorant.' I decided that from that day forward, I wasn't going to be ashamed to ask questions in seminars."

Jacobs says he still uses Curtiss's quote to encourage his own students.

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Mycobacteriophages deliver a fluorescent marker gene to Mycobacterium tuberculosis, the bacterium that causes tuberculosis, in this microscope video from Jacobs's lab. Scientists can then use that fluorescent marker in tests to rapidly determine bacterial resistance to various drug treatments.

One Bacterium to Another

Jacobs loved UAB's cross-disciplinary emphasis on genetics. He rotated through several labs before settling in with Curtiss and his wife, Josephine Clark-Curtiss, Ph.D., who were studying leprosy. In their lab, Jacobs helped establish the first library of the Mycobacterium leprae genome.

Intrigued by the process of bacterial genetics and intent on tackling problems affecting the developing world, Jacobs decided to focus his career on tuberculosis. A close relative of leprosy, tuberculosis persists as a widespread epidemic. As of 2012, one in three people on Earth were believed to be carriers of Mycobacterium tuberculosis, the bacterium that causes the disease. After HIV/AIDS, TB is the greatest killer worldwide. The incidence of drug-resistant TB is spreading and often coincides with HIV infection.

Pioneering researcher Robert Koch proved that tuberculosis was caused by bacteria in 1882. But by the time Jacobs left UAB in 1985 for a position at the Albert Einstein College of Medicine, scientists were frustrated in their attempts to reveal the underlying genetics of the TB bacterium.

Jacobs says his own molecular research has always been guided by Koch's reasoning process, enshrined in his famous "Koch's postulates," which establish a causal relationship between a microbe and a disease. In order to prove this relationship, Jacobs explains, a microbe must be found in diseased organisms and absent in healthy ones, it must be isolated from those diseased organisms and grown in pure culture, it must cause disease when introduced to a healthy organism, and it must be isolated once again from the experimental host and confirmed to be identical to the original microbe.

"To prove that a phenotype—virulence—is caused by a particular genotype, you have to have a mutant, you have to clone it, and you have to transfer it to a healthy cell to reproduce," Jacobs says. "Nowadays we would sequence those genes, find a good copy, and put back only the good parts of the sequence. In the 1980s we could clone genes, but nobody had figured out how to transfer the DNA. That's what I did."

Down and Dirty

To do it, Jacobs recalled the bacteriophages—viruses that infect bacteria—he had used in the Curtiss lab. He didn't have phages at his new lab in New York, but he knew where to find some. He started with the dirt in his backyard, isolating a useful phage he named the Bronx Bomber, or Bxb1. Then, on a trip to the Bronx Zoo, he had a flash of inspiration and grabbed a handful of dirt and dung from the zebra cage. From that auspicious clod, Jacobs isolated Bxz1, which he used to introduce foreign DNA into Mycobacterium tuberculosis for the first time. His technique is now used by TB researchers worldwide.

w1013-jacobs-phagesafariFor the past 20 years, Jacobs and his twin sister, Debbie, have inspired high school and university students to dig in to the challenge of microbiology in "No Phage Left Behind" workshops."I used to think the Bronx Zoo was cool for the animals, but it's really cool for the microbes," Jacobs says. When he leads microbiology workshops for high school and university students, Jacobs often has them begin by digging up dirt, he says. For the past 20 years, his twin sister, Debbie, has helped him run a program called "No Phage Left Behind" for high school students at the University of Pittsburgh.

Using those first phages, and many more that he and his students have collected since then, Jacobs has made TB easier to study by genetically manipulating the mycobacterium. He has helped create faster diagnostic tests to determine if a patient's strain of TB is drug-resistant. And he is working to develop a better TB vaccine.

Jacobs also believes that fighting the disease means being on the ground where it is most prevalent. In 2009, he helped launch the KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) in Durban, South Africa. K-RITH is a collaboration between the University of KwaZulu Natal and the Howard Hughes Medical Institute, where Jacobs serves as an investigator. (UAB investigators and students also have a significant presence at K-RITH.) While he is in South Africa, Jacobs takes students to a game park to find new phages to continue his research.

"I'm very fortunate to be able to do what I've done," he says. "Now we can discover all this knowledge about TB and come up with new drugs, new vaccines, and new diagnostic tests." But even though he has made great contributions to the fields of microbiology and immunology, Jacobs says he still identifies with his first intellectual love: "In my heart I'm still a mathematician."

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