Mr. Pseudomonas
“A live, human-made microorganism is patentable.”
That declaration, made by Supreme Court Chief Justice Warren Burger on June 16, 1980, in the majority opinion in the case of Diamond v. Chakrabarty, upended a legal doctrine that had stood for nearly a century. The ruling was enormously important for the emerging biotechnology industry.
The United States Patent and Trademark Office (USPTO) had suspended examination of all patent applications covering engineered microorganisms. Many investors were spooked and reluctant to invest in research on technologies that might not be eligible for patent protection. The ruling in favor of patents on living things painted the future in a different color.
Facts in the case began to accumulate in 1972 when Ananda Chakrabarty, a microbiologist working for General Electric (GE), used genetic material taken from four different strains of bacteria in the genus Pseudomonas to create a novel creature capable of cleaning up oil spills. It was able to digest a range of hydrocarbons. GE filed a patent application on the bug, but the USPTO denied it on the grounds that it was a “product of nature” and could not be classified as intellectual property.
The examiner was following a precedent set in 1889, when patent commissioner Benton J. Hall rejected an application for a patent on fibers extracted from pine needles. If protection were to be granted in that instance, Hall had reasoned, “patents might be obtained upon the trees of the forest and the plants of the earth, which of course would be unreasonable and impossible.” In the commissioner’s view, nature’s bounty could be owned, but not passed off as an invention.
GE appealed the decision and won a reversal. Patent commissioner Sidney Diamond then asked the Supreme Court to review. The Court accepted the case, heard arguments on March 17, 1980, and affirmed the reversal for Chakrabarty in June (the vote was 5–4). Burger noted in the majority opinion that the US Patent Act, penned by Thomas Jefferson in 1793, defined “any new and useful art, machine, manufacture, or composition of matter” as patentable, and that by the ordinary, common meaning of these words, Chakrabarty’s bacterium qualified.
It was, Burger wrote, both a manufacture, “a useful article produced from raw or prepared materials by giving to these materials new forms, qualities, properties or combinations,” and a composition of matter, “a combination of two or more substances.”
For good measure, Burger drew on the good book, and quoted Ecclesiastes. He asserted that Congress intended statutory subject matter to include “anything under the sun made by man.” He borrowed from Shakespeare, too, to rebut the argument that a patent should be denied because genetic engineering might be dangerous. Dismissing the “gruesome parade of horribles” in Diamond’s briefs, Burger insisted that it wasn’t the Court’s job to regulate new technologies.
In summary, he wrote: “The patentee has produced a new bacterium with markedly different characteristics from any found in nature and one having the potential for significant utility. His discovery is not nature’s handiwork, but his own; accordingly it is patentable.” United States Patent No. 4,259,444, “Microorganisms Having Multiple Compatible Degradative Energy-Generating Plasmids and Preparation Thereof,” issued to GE and A.M. Chakrabarty on March 31, 1981.
Chakrabarty left GE before the decision was rendered and went on to a distinguished academic career as a professor of microbiology and immunology at the University of Illinois, Chicago School of Medicine. He carried out research programs with an eye to potential applications in environmental science and the medical treatment of cystic fibrosis and cancer. Pseudomonas was his constant companion. “All through my life, starting from my PhD thesis, it has been all about Pseudomonas,” he says. “I’m grateful to these bugs for my career.”
Chakrabarty became involved in biopharmaceutical development in 2001, when he showed that Pseudomonas aeruginosa secretes a protein that selectively kills cancer cells. His research led to the development of a peptide that is now in clinical trials. Chakrabarty expects that researchers will find more bacterial proteins with similar properties.
He supports his cancer hypothesis with an evolutionary argument: “We all host swarms of microbes — in fact their cells outnumber our own. They help digest our food, it appears that they play vital roles in booting up immune responses, and they may even be able to attack cancers directly on our behalf. Only a handful of bacterial species are virulent, and even they have a vested interest in our health. Their fate is linked to ours. If we die, they die.”
Dr. Chakrabarty Goes to Schenectady
Ananda Mohan Chakrabarty was born on April 4, 1938 in Sainthia, a small town in West Bengal, India, the youngest of seven children in a middle-class family. He enjoyed reading and attended the Ramakrishna Mission Vidyamandira, a boarding school about 100 miles away in Calcutta.
He leaned toward literary studies, but was steered by his father and elder brother toward the sciences. “I was a kid,” says Chakrabarty, “sixteen years old. They said, ‘We think this is what you should do.’ I agreed and never regretted it.” He soon discovered that he had no head for figures but liked biology and chemistry, particularly organic chemistry.
Chakrabarty went on to earn a PhD in 1965 under the tutelage of Sailesh Chandra Roy at the University of Calcutta. Roy studied Pseudomonas putida, a soil-dwelling bacterium that serves the great chain of life by recycling nutrients. It secretes enzymes that break down decaying organic matter into simple molecules such as sugars and amino acids. It also manufactures a brownish pigment that turns yellow when dissolved in water, and fluoresces a brilliant green when hit with ultraviolet light.
Roy asked Chakrabarty to characterize the pigment and figure out what role it played in the bacterium’s life cycle. Chakrabarty painstakingly isolated and analyzed twenty-five milligrams of it. He concluded that it was a pteridine, a class of molecules usually found in fungi, insects, and sometimes mammals, but rarely in bacteria. He performed some metabolic studies, but could not identify its function.
While Chakrabarty was getting to know P. putida in Calcutta, American biochemist Irwin Gunsalus was working with it at the University of Illinois in Urbana-Champaign. Gunsalus was a world-renowned biochemist and bacteriologist, famous for discovering lipoic acid (an essential “cofactor” that helps enzymes turn nutrients into energy) and isolating the biologically active form of Vitamin B6 (a compound called pyridoxal phosphate). Both are marketed globally as nutritional supplements.
Gunsalus had been scouring microbiomes for exotic metabolic pathways to study. In 1959, he found in a sample of sewage sludge a strain of P. putida that breaks down camphor, the waxy, noxious substance that gives mothballs their distinctive odor, and metabolizes it as a food source. When he came across a paper that Chakrabarty had written on the P. putida pigment, he wrote a letter to Roy and offered Chakrabarty a job as a postdoc in his laboratory.
Chakrabarty accepted and went to America. He worked out the camphor degradation pathway, and by 1970 had determined that the genes for the necessary enzymes were located not on the bacterium’s single chromosome, but on a plasmid — a small ring of DNA adrift in the cytoplasm.
In bacteria, chromosomal genes govern the formation of cellular structures and components of essential metabolic processes. Plasmids typically carry genes that confer adaptive traits and are readily exchanged in bacterial communities by conjugation, the transfer of genetic material between bacterial cells in direct physical contact with each other. As wide-ranging scavengers, Pseudomonas bugs must extract nutrients from many different kinds of environments. Genes that enable them to digest organic compounds enhance their ecological fitness; plasmids facilitate the distribution of these genes.
The knowledge of bacterial genetics that Chakrabarty obtained from his work with Pseudomonas shaped the course of his career for decades, but he didn’t stick around at Illinois to follow up. After five years as a postdoc, he felt it was time to move on.
He scheduled a couple of interviews with corporate recruiters, and in 1971, accepted an offer from one of Gunsalus’ former graduate students, W. Dexter Bellamy, to fill a position in a recently organized environmental biotechnology unit at the General Electric Research and Development Center in Schenectady, New York.
Bellamy, the unit’s director, assigned Chakrabarty to a team working on a way to get rid of cow manure. Manure consists largely of undigested nutrients, bacteria (mostly harmless), and a tough, fibrous material called lignocellulose, which gives leaves of grass, stalks of hay, and ears of corn their shape and stiffness.
Large feedlots used to sell manure as fertilizer, but the Environmental Protection Agency ended the practice after outbreaks of illness were linked to contaminated produce. With great heaps of manure piling up and serious environmental and economic problems looming, a group of feedlot owners appealed to GE for help.
Company scientists came up with a plan to treat the manure with a supercharged strain of actinomycetes, a filament-like soil bacterium that naturally degrades lignocellulose. The idea was to break down the manure, deactivate the bacteria, and package the residue for sale as a protein supplement in cattle feed. The project became Chakrabarty’s principal occupation at GE.
The Road to a Patent
While immersed in the feedlot project, Chakrabarty found that he missed his old friend, Pseudomonas. “I spent lots of off hours and weekends in the lab working on plasmids in Pseudomonas,” he says. “GE was like a university. So long as you did your regular work, if you wanted to do something more, it was OK.” He returned to the research he had done in Gunsalus’s lab, but with a new goal in mind.
On March 18, 1967, the SS Torrey Canyon, a massive oil tanker, had run aground on Pollard Rock off the western tip of Cornwall, England. Fourteen of her eighteen cargo tanks ripped open, and 31 million gallons of crude leaked into the Atlantic — it was the first major spill of the supertanker era.
The spill was attacked with detergents, emulsifiers that broke up the slick into tiny globules. The slick was dispersed, but the dispersion compounded the disaster. The globules were ingestible and the detergents themselves were highly toxic. The spill devastated marine life in the region and industrial scientists around the world commenced work on new remediation technologies.
Chakrabarty joined the crowd. He had heard that Imperial Chemical Industries (ICI) of London, England, planned to breed yeast cells that would feed on hydrocarbons. But crude oil is a stew made of many different kinds of carbon-containing molecules. Chakrabarty saw that multiple enzyme sets would be required.
He hatched a plan: he would collect bacteria known to degrade hydrocarbons and check whether the enzymes were expressed by genes on plasmids. If he could locate the right set of mobile genes, he would attempt to engineer a Swiss Army bacterium.
“GE thought it was an interesting idea,” Chakrabarty says. “Nobody had ever thought of it.” The trial-and-error project got underway. It wasn’t easy. Many plasmid combinations didn’t work. One or more of the plasmids would simply shut down and stop expressing genes.
Eventually, Chakrabarty found four plasmids with genes coding for enzymes that could do the job, but two — one carrying genes for camphor-degrading enzymes, the other carrying genes for alkane-degrading enzymes — turned out to be incompatible.Chakrabarty continued to experiment.
He found that when presented with a mixture of both feedstocks, the bacteria dined exclusively (and randomly, apparently) on just one. However, when their rations were alternated between camphor and octane (an alkane with eight carbon atoms), the bugs switched metabolic pathways on and off.
Both plasmids needed to work simultaneously. Having verified that both were functional, Chakrabarty zapped the cells with ultraviolet light and fused the two plasmids into a new larger one containing both sets of genes. Chakrabarty tested and found that both pathways could be activated at once.
He had engineered a new bacterium capable of taking on an entire oil slick. He watched with delight as bacterial colonies bloomed in Erlenmeyer flasks filled with crude oil or Bunker C (a heavy fuel oil).
News of the engineered bacterium spread, and Chakrabarty was invited to speak at a microbiology conference in Tel Aviv. He submitted an abstract of his talk to GE’s management in advance — a standard practice to avoid spilling trade secrets. The abstract trickled up to Arthur Bueche, GE’s vice president for research and development, and head of the Schenectady center.
Bueche was already familiar with Chakrabarty’s pet project. “Arthur was a workaholic,” Chakrabarty says. “On weekends, he walked around the empty building and sometimes saw me in the lab. I told him what I was doing, and he got interested.”
Chakrabarty recalls the day he was summoned to Bueche’s office and asked whether his bug had been protected with a patent letter. “I said, ‘A patent letter? What’s that?’” Bueche smiled and called Chakrabarty’s boss, Ron Brooks. “He said, ‘Ron, tell Ananda about patents and please arrange to file a provisional application.’”
The application was filed with the USPTO on June 7, 1972. Bueche explained to Chakrabarty that until it was approved, nothing could be disclosed, but added that Chakrabarty could go to Tel Aviv anyway. “He promised,” Chakrabarty remembers, “that GE would pay for everything. So, I went. At the conference, I said, ‘I’m sorry, but I found out there are proprietary issues. I can’t present my paper.’”
Some time later, GE was notified that the patent application had been denied. The company decided to appeal, and the application began an eight-year journey through the judicial system.
With the hydrocarbon patent in limbo, Chakrabarty’s Pseudomonas research shifted to polychlorinated biphenyls, or PCBs. PCBs are viscous, inert oils. They are excellent insulators and can conduct a lot of heat without bursting into flame, which makes them perfect for use in high-voltage transformers. Unfortunately, they are also highly carcinogenic.
General Electric ran two capacitor factories at Hudson Falls and Fort Edward in upstate New York that had been discharging PCBs into the Hudson River since 1947. The EPA’s safe limit for PCBs exposure was five parts per million (ppm). When striped bass caught near the factories in 1975 were found to contain levels of 350 ppm, the New York State Department of Environmental Conservation (DEC) issued a health advisory and sued GE.
In 1976, the DEC prohibited all fishing in the upper Hudson and all commercial fishing downstream. By 1977, when the EPA banned PCBs, well over a million pounds had found their way into the river. The plume stretched from Hudson Falls to the southern tip of Manhattan, 200 miles downstream.
Chakrabarty considered making a PCB-degrading bug. He had a lead to follow — he had taken water samples near the factories and isolated “a consortium of microorganisms” that was pulling chlorine atoms off biphenyl molecules. Bueche encouraged him to apply for a $100,000 National Science Foundation (NSF) grant to carry the work forward.
Chakrabarty remembers the response when the proposal went to GE’s corporate offices: “The lawyers laughed. They said, ‘When GE applies for a government contract, it’s for no less than $500 million.’ They rejected it.” Chakrabarty went back to Bueche. “He smiled,” says Chakrabarty. “His secretary called someone, and it went through. I’m told it was the first grant the NSF ever gave to industry.”
The sediments on the riverbed and the surrounding floodplains continued to disgorge accumulated toxins. The Hudson was added to the EPA’s Superfund list in 1984. By that time, the EPA had abandoned bioremediation strategies involving genetic engineering.
Twenty-five years later, in 2009, General Electric began implementing the EPA’s cleanup plan. The project is scheduled to wrap up this year. The company has dredged three million cubic yards of sediment along forty miles of waterway below Fort Edward. The price tag is hard to pin down, but estimates run from half a billion to a billion dollars, most of it coming from GE.
Amicus Curiae
The Supreme Court decision in Diamond v. Chakrabarty launched the victor on a sideline career as an expert witness and consultant on science policy and intellectual property law. Chakrabarty says his primary mission is educating the judiciary.
To this end, he began working in the 1990s with Franklin Zweig, founder of the Einstein Institute for Science, Health, and the Courts in Bethesda, Maryland. The institute was set up by the Department of Energy as an adjunct to the Human Genome Project, to inform judges about the moral and legal issues surrounding the ready availability of personal genetic information.
The Institute disbanded in 2003 as the Human Genome Project wound down, but Chakrabarty still teaches genetics to jurists. “I’ve been to courts all over the country,” he says. “I’ve been to the International Court of Justice at The Hague. It’s important to have scientifically literate judges. In the United States, Congress hardly ever overrules a Supreme Court decision. It’s too much work, and by the time a case has gotten to the Supreme Court, it’s too controversial. They won’t touch it.”
In 2013, Chakrabarty filed an amicus curiae brief with the US Supreme Court on behalf of Myriad Genetics in the case that revisited the patentability of genes. Myriad had discovered two genes, BRCA1 and BRCA2, a mutation in either increases a woman’s odds of getting breast cancer from about 12 percent to 50 percent.
The company developed a test based on these genes, and patented both test and genes. The court ruled unanimously that although the cancer screens were patentable, the DNA, mutated or otherwise, was not, because all that had been done to isolate it was to break a few chemical bonds. The decision echoed the “product of nature” standard from 1889.
Chakrabarty thinks it was a mistake: “BRCA1 and BRCA2 are chemically isolated products of nature. If they aren’t patentable then neither are protein-based drugs. If a protein sequence is a product of nature, then so too are smaller peptide fragments.” Chakrabarty has investigated bacterial proteins and peptides with therapeutic properties. He is afraid that the AMP v. Myriad Genetics decision will reduce incentives to invest in the development of promising biological drugs: “It’s an absolutely terrible precedent, and I think we will start seeing its effects in a few years.”
From Industry to Academia
As the trouble with PCBs was becoming known, the manure recycling project was nearing completion. The process worked in the lab with small batches, so in 1978, GE built a pilot plant in Casa Grande, Arizona, twenty miles south of Phoenix. When the plant went operational, a major planning flaw became apparent.
With large batches that take days to process, GE’s fast-growing actinomycetes worked for a few hours, but then suddenly quit. That turned out to be the interval it took a host of native microbes to catch up, overwhelm the corporation’s alien bugs, and sequester available nutrients.
“Cow manure is not sterile,” Chakrabarty says ruefully. “We should have thought of that, but we didn’t. And you can’t sterilize mountains of it. It’s not economical.” The pilot plant was a failure. “At that point,” says Chakrabarty, “I decided it was time to quit.”
Around the same time, an unsolicited letter showed up announcing a vacancy in the College of Medicine at the University of Illinois, Chicago (UIC). Gunsalus had arranged for the letter to be sent to GE, and he encouraged Chakrabarty to apply for the open position. Chakrabarty did so with no expectations, but his bioengineering work had garnered a lot of publicity. He believes that may have helped his cause. In any event, he joined the medical school as a full professor in April 1979.
The NSF allowed him to transfer the PCB grant, and he broadened his research to include Agent Orange, the defoliant dropped by US warplanes on the jungles of Vietnam. Agent Orange is laced with dioxins, which resemble PCBs in certain respects and are just as carcinogenic. Chakrabarty subsequently carried on for twenty-five years with government-funded basic research on metabolic pathways utilized by bioremediating bacteria.
On March 17, 1980, during his second year at UIC, Chakrabarty was in Washington DC to hear GE-appointed attorney Ed Mackie argue his case before the Supreme Court. Three months later he received a phone call from a reporter who asked whether he had heard the ruling. He hadn’t. He says, “I was delighted to have won the case, but I had already left GE and was concentrating on my teaching and research at UIC, so I took the decision in stride at that moment.”
After that initial call, Chakrabarty’s phone rang continuously for days, but he admits that he didn’t realize the importance of the patent in the larger scheme of things: “Many biotech and pharmaceutical companies had written amicus curiae briefs to the court in support of my position, but I could not quite appreciate the implications of the ruling in terms of its significance for the biotechnology industry.”
Back at UIC, Chakrabarty felt obliged, as a medical school professor, to adopt a research topic in human health. In 1981, he began working with cystic fibrosis (CF) patients, who have a genetic mutation that causes thick, sticky mucus to accumulate in their lungs. The mucus makes an ideal habitat for another Pseudomonas species — P. aeruginosa, which is ubiquitous in aquatic, terrestrial, and atmospheric environments, in part because it can utilize at least seventy-five different organic compounds as nutrients for growth.
Unlike its mild-mannered cousin putida, P. aeruginosa is a malevolent invader. It’s the leading cause of life-threatening infections in CF patients, because once it enters the lungs it forms a “biofilm,” a slimy mat designed to keep the body’s natural defenses at bay. The immune response relies on antibodies to identify pathogens by their chemical fingerprints. The slime is the biological equivalent of latex gloves — it prevents detection by antibodies, and it also insulates bacteria from the effects of antibiotics.
Chakrabarty spent the next two decades elucidating the mechanics by which P. aeruginosa evades the immune system in the lungs and forms biofilms. Cystic fibrosis was an ideal experimental setting. Most P. aeruginosa infections in human beings are opportunistic, appearing in people with weakened immune systems. But CF patients are not immunocompromised.
“It seemed that something else was promoting this specific infection,” Chakrabarty says. “We reasoned that the bacterium might have a weapon that kills the foot soldiers of the immune system — the macrophages, the neutrophils, the killer cells, and so on.”
In 1999, Olga Zaborina, a postdoc in Chakrabarty’s lab, grew Pseudomonas colonies taken from CF patients in a nutrient soup, removed the bacteria, and fed the purified broth to off-the-shelf immune cells, J774 macrophages. The macrophages died. “We got very excited,” Chakrabarty recalls. “If you’re a biochemist, it’s not too difficult to take the growth medium, fractionate it, and test each fraction for cytotoxic activity.” The cytotoxic effect was a property of a fraction without bacteria.
The group eventually isolated the toxin, and, as in any good whodunit, the killer’s identity came as a complete surprise. It was a protein called azurin, named for its sky blue color. A copper atom situated at the core of the molecule produces the hue, and conducts the electrons that power chemical reactions.
A great deal is known about azurin, including its structure and its known functions in electron transfer, but there was nothing in the literature to suggest that it served any other purpose. Chakrabarty was at a loss to explain Zaborina’s extraordinary finding, and soon lost confidence in it when she tested azurin on macrophages extracted from mouse bellies, and nothing happened. “We were distraught,” says Chakrabarty, “but Olga verified by a number of experiments that azurin was cytotoxic against J774 cells.”
J774 cells may act like macrophages, Chakrabarty says, “But I eventually found a 1975 report in Nature that indicated they are cancer-derived. That’s why they’re always growing. And it occurred to me, ‘Does azurin work against J774 cells because they’re really tumor cells?’”
Chakrabarty shifted the focus of his work from cystic fibrosis to cancer. He wanted to test the hypothesis that azurin attacks cancer cells while sparing normal cells. If it did, he would have a biotherapy with very low toxicity.
Chakrabarty needed to test matched samples of cancer cells and healthy cells to find out. He contacted Tapas K. Das Gupta, head of the medical school’s Department of Surgical Oncology. Das Gupta had such tissues in his possession.
When surgeons excise tumors, surrounding tissue is biopsied to confirm that the cancer hasn’t spread, and samples are frozen for future reference. Das Gupta tested Chakrabarty’s azurin extract and confirmed it had no effect on normal cells but was murderously effective on cancer cells.
“Talk about serendipity,” Chakrabarty says. “I found an interesting new property of a protein from my favorite bug. It was worth pursuing to find out its potential.” He began to speculate that the protein, and others like it, had evolved in Pseudomonas aeruginosa in order to protect the bacterium’s host organisms from other, more virulent invaders — because if its hosts died, so would P. aeruginosa.
Chakrabarty and Das Gupta began working together to investigate azurin’s potential as a cancer therapy. The National Institutes of Health (NIH), which had supported Chakrabarty’s CF research, declined to fund the project. When the CF grants expired in 2001, Chakrabarty and Das Gupta cofounded a private company, CDG Therapeutics, and carried on with funding from angel investors. A string of patents followed that cover the use of azurin and similar compounds in cancer therapy.
The road from a patent to a pharmaceutical product is long, and clinical trials are enormously expensive. In the case of azurin, purity standards imposed by the US Food and Drug Administration (FDA) were an additional hurdle. Cloning and expressing the protein in bacteria was not an option because the extract would likely be contaminated with cell wall liposaccharide, a deadly toxin. The FDA had indicated that CDG would be required to file a Biologics License Application (BLA) and follow a very stringent regulatory path.
The only alternative was to synthesize the protein chemically, but azurin is composed of 128 amino acid residues. At that time, assembling a molecule of that size lay at the boundary of technical feasibility. Chakrabarty and Tohru Yamada, a postdoc in his laboratory, tried to identify active segments of the protein and found one, just twenty-eight amino acids in length, that would enter and destroy cancer cells unaided while ignoring normal cells.
A sequence of that length could be manufactured at a reasonable cost. The drug, called p28, passed an initial early-stage test in May 2012. Ten of fifteen terminal cancer patients stabilized or improved while receiving the drug, and one went into remission, without serious adverse side effects. A second trial is scheduled to wrap up in December 2015, and a proof-of-concept study with pediatric brain-tumor patients is in the works.
As a full-time faculty member at the university, Chakrabarty is not allowed to serve as a company officer. Das Gupta, however, is retired and directly engaged in planning the clinical program. Tohru Yamada, Chakrabarty’s former postdoc and a co-inventor of the drug, serves as CDG’s director of drug development.
The Father of Immunotherapy
There are medical precedents supporting Chakrabarty’s approach to anticancer therapy. Back in 1891, William B. Coley at Memorial Hospital in New York (now Sloan-Kettering Memorial Hospital) injected preparations of live streptococcus bacteria into patients with inoperable tumors, and witnessed full recoveries.
Coley was a young physician. He had been deeply affected by the loss of one of his first patients the previous year. Seventeen-year-old Bessie Dashiell had entered his care with a swollen hand, which he diagnosed as a probable malignant tumor in one of the metacarpal bones. He amputated her forearm to prevent the cancer from spreading, but was too late — within ten weeks she was dead.
Convinced that there must be a better approach, Coley began poring over the hospital’s records and found a patient, a German immigrant named Strauss, who had been admitted seven years earlier with a malign, inoperable neck tumor. The tumor vanished when Strauss came down with erysipelas, a streptococcal skin infection. After recovery and discharge from the hospital, he disappeared. Coley attempted to find him. Without a lead to follow, Coley spent weeks scouring the tenements of lower Manhattan. His efforts were ultimately rewarded — when he caught up with Strauss, the man was still cancer-free.
Coley began digging, and found scattered reports going back to the 1700s of chance infections beating cancer. There were even documented cases of syphilis preventing it. Apparently these ailments somehow kicked the immune system into overdrive, and enabled it to wipe out cancer cells as well as microbes. Encouraged, Coley injected live streptococci into three patients with inoperable tumors. Two of the three showed significant tumor shrinkage. Unfortunately, two also succumbed to the infection. Coley later heat-treated his inoculant to kill the bacteria, and over the next four decades he injected some 1,000 terminal patients with what is now known as Coley’s toxin. His lifetime success rate was about two out of three.
Biotechnology for the Third World
Chakrabarty has long been involved in commercial science in another way. As new molecular biology firms sprouted in the United States in the early 1980s, the United Nations Industrial Development Organization (UNIDO) began considering investments in biotech R&D as a possible path to prosperity for developing nations. In 1984, Chakrabarty attended a UNIDO meeting in Vienna that led to the formation of the International Center of Genetic Engineering and Biotechnology (ICGEB).
The ICGEB began operations in 1987, with Chakrabarty’s old mentor Irwin Gunsalus as its first director. Chakrabarty served on the organization’s original council of scientific advisors. The group established a research facility in Trieste, Italy, which doubled as the organization’s headquarters. Vigorous promotion by Indira Gandhi led to the formation of a second research unit in New Delhi, India, and Nelson Mandela added a third center in Cape Town, South Africa in 2007.
The organization currently lists sixty-four member nations and another twenty-two petitioning to join. The United States is not one of them, having pulled out of UNIDO in 1996. Chakrabarty lobbied for support in Washington, but was received with a chill: “The vibrations I got were, ‘Why do you create a competitor? We would like to sell our products to developing countries. We don’t want them to make their own.’”
The ICGEB’s principal business is training students and scientists. The goal is to produce a generation of knowledge workers capable of establishing and nurturing biotechnology industries in member nations. The research side of the organization remains operational as well, and has effected seventy technology transfers through licensing arrangements and other mechanisms.
There are a few success stories. ICGEB engineers, for example, have invented a high-yield process for expressing a precursor of human insulin in Pichia pastoris, a species of yeast. The organization has licensed it to a Chinese drug maker. And an Indian company currently manufactures rapid diagnostic kits developed by ICGEB scientists for HIV, hepatitis B & C, and dengue fever. The products are sold in more than forty countries.
In addition to lending assistance to the ICGEB, Chakrabarty is carrying out a personal Third World biotechnology mission. After severing formal ties with CDG in 2006, he cofounded a new biopharmaceutical company, Amrita Therapeutics, with Susan K. Finston, an attorney and former vice president of the Pharmaceutical Manufacturers Association of America.
The company, located in India, in the western state of Gujarat, is developing anticancer and antiviral drugs. Like CDG, Amrita extracts peptide fragments from bacterial proteins and screens them for the ability to target and destroy diseased cells while ignoring healthy ones. Its lead drug candidate, called ATP-01, is active against HIV and the protozoal parasites that cause leishmaniasis.
Chakrabarty has recently gone off in yet another direction, with colleagues from the ICGEB. He is working with Mexican plant biologist Miguel Gomez Lim and Portuguese cancer researcher Arsenio Fialho to grow genetically altered foodstuffs with tissues that express azurin and other potentially beneficial proteins.
The team has established proof of principle: they engineered tomatoes that produce interleukin-2, an anti-tumor drug, and fed them to mice with artificially induced cancers. The mice returned to health. In March 2015, Chakrabarty, Lim, and Fialho submitted provisional patent applications covering genetically modified foods with anticancer activity.
“You never stop dreaming,” Chakrabarty says. “Today it’s mice. Tomorrow it might be monkeys. The day after tomorrow it will be people getting their cancer drugs in cream of tomato soup, spinach salad, and carrot sticks. I want to reach out to the Third World, where there’s no access to pricey drugs. People think it’s a dream, but I think there’s a good chance it will pan out.”
— article by Douglas Smith
To see more stories like this, visit us at biotechhistory.org
photo credits:
Ananda Chakrabarty in front of Supreme Court. Getty.
GE Schenectady research laboratory. Matt H. Wade. Wikimedia.
Hudson Falls GE Factory. The Center for Land Use Interpretation.
William B. Coley. Global Advances in Health and Medicine.
Ananda Chakrabarty. Biswarup Ganguly. Wikimedia.
