Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News
Flaws in Science, Business Model Spoil Calgene’s Genetically Modified Tomatoes
The story of the Flavr Savr™ tomato, the first genetically modified (GM) food crop to be marketed commercially following FDA approval in 1994, all started with tomato soup.
Flavr Savr’s developer, a California company named Calgene, had a million-dollar contract with Campbell Soup Co. to study whether the gene of an enzyme normally found in tomatoes, polygalacturonase (PG), could be isolated from the fruit and reintroduced in reverse or “antisense” orientation. PG breaks down cell wall pectin, a setting agent in ripe fruits such as tomatoes, resulting in a more fluid tomato paste.
Campbell’s was looking at cutting costs by keeping newly made tomato paste thicker through Calgene’s technology as an alternative to the traditional method of heating the paste high enough to kill the pectin. Calgene reasoned that because PG enhanced viscosity, it would also slow the rotting of a tomato, which it did.
But while Calgene’s antisense copy of the PG gene suppressed production of the enzyme, the company couldn’t overcome Campbell’s’ reluctance to tinker with its recipe for the tomato soup it introduced to market in 1897—or, ultimately, translate its discovery into a lucrative business.
“Calgene was publicly traded, and there were expectations about how much Calgene was going to earn. We had to have some relatively big businesses in order to justify our stock price. And fresh market tomato was a pretty big business,” William Hiatt, a scientist at Calgene from 1981 to 1997 who headed the company’s tomato research, told GEN. “We decided instead to try to apply that in the fresh market, and see if we couldn’t create a business there. The idea was that if we provide good fruit to the grocery store, it will sit there longer. And then, as the consumer buys it, the consumer will have longer to eat it.”
Calgene won FDA approval for Flavr Savr on May 18, 1994. Three days later, Flavr Savr was introduced under the brand name MacGregor at a pair of grocery stores—one in Davis, CA, the other in Northbrook, IL—each of which sold more than 3,000 pounds of the GM tomatoes. Despite objections raised by some GM critics, the launch of Flavr Savr generated mostly favorable publicity and initially brisk sales, even after being priced 70 cents more per pound than conventionally grown tomatoes.
Pushed It Too Hard
Calgene envisioned Flavr Savr as an alternative to traditionally grown tomatoes, which are picked while green and hard, then ripened artificially through treatment with ethylene gas. The process reddens the tomatoes, often at the expense of their flavor. Instead, the company waited until its modified tomatoes were vine ripe before picking them. Calgene reasoned that the PG enzyme would not only stave off rotting but also prevent softening of the tomatoes during ripening, allowing them to be transported hundreds of miles across the U.S. without bruising, while retaining their vine-ripe taste.
In addition to the antisense PG gene, contained within a bacterial plasmid, Calgene’s modified tomatoes included the kanamycin-resistance (kanr) gene, which encoded the enzyme aminoglycoside-3'-phosphotransferase II [APH(3')II]. The enzyme was used as a marker for identifying plant cells carrying the antisense PG gene.
“We hoped that they would stand up to the shipping, but in reality, they really didn’t. That was kind of the downfall of that effort,” Hiatt acknowledged. “We pushed it too hard.”
The modified tomatoes’ lack of durability forced the fledgling Calgene to produce its crop year-round and deliver it more widely nationwide, adding to an already costly production process. Flavr Savr tomatoes cost $10 per pound to produce, but were being sold for only $1.99 per pound at the market, a fact that Calgene researcher Belinda Martineau shared in her 2001 book First Fruit: The Creation of the Flavr Savr Tomato and the Birth of Biotech Food.
“Flavr Savr failed because it made a minimal impact on shelf life/fruit softening, and the transgene was put into some very poor germplasm,” Harry J. Klee, Ph.D., Monsanto’s chief tomato scientist two decades ago, told GEN.
“Calgene chose an old-at-the-time variety that they could access with FTO,” added Dr. Klee, using the initials for “freedom to operate,” the ability to proceed with R&D and/or commercial production with minimal risk of infringing IP or property rights. “It was a terrible variety with relatively poor yields. It simply cost them more to make the tomatoes than they could sell them for.”
Dr. Klee now studies fruit flavor quality as a professor at University of Florida, where his lab is working to produce a better tasting tomato, as well as understand the chemical and genetic make-up of flavor in fruits and vegetables.
In a paper published last year in the journal Molecular Plant, Dr. Klee and colleagues found that qualitative differences in esters within tomato fruits (Solanum lycopersicum) and a closely related wild tomato species (Solanum pennelli) resulted from differences in enzymatic activity of a ripening-related alcohol acyltransferase (AAT1): “Our consumer results indicate that it is desirable to decrease the content of esters in tomato fruits and identification of AAT1 as the most important anabolic enzyme is an important step to reach that goal. It will be particularly interesting to identify knock-out mutations in AAT1 to quantitatively assess the specific contributions of esters to consumer liking and introduce such mutations into breeding programs.”
A Boutique Product
Faced with a cost gap it could not close, a stock price that plunged from $25 to $4 a share, and growing competition, Calgene had little choice but to sell. Thirteen months after the modified tomatoes were brought to market, Monsanto agreed to acquire a 49.9% stake in Calgene for $30 million, and transfer to Calgene its 50% stake in tomato distributor Gargiulo, a deal designed to expand Flavr Savr distribution into more supermarkets and concluded in March of 1996.
Eight months later, Monsanto raised its stake to a controlling 54.6% for $50 million more. And in April 1997, Monsanto agreed to buy Calgene’s remaining assets for $240 million. Following the takeover, Calgene’s chairman and CEO Roger H. Salquist led an exodus of employees; Hiatt remained with the new owner as a project manager until retiring in 2010.
Monsanto had set its research sights on biotechnology in 1981, and in 1987 conducted the first U.S. field trials of plants with biotech traits. The same year Calgene launched Flavr Savr, Monsanto introduced to the U.S. its first biotech product Posilac, bovine somatotropin (bST) for dairy cows.
While sewing up ownership of Calgene and soon after, Monsanto launched Roundup Ready versions of crops that included soybeans, cotton, canola, and corn, featuring in-seed tolerance to glyphosate-based herbicides that included the company’s Roundup.
“Flavr Savr is almost like a unique experiment that ushered in the GM world. But Flavr Savr was a boutique product. It was not a commodity product,” Jon Entine, executive director of the Genetic Literacy Project, and senior fellow at the World Food Center Institute for Food and Agricultural Literacy at University of California, Davis, told GEN. “What made GM successful is farmer adoption, and commodity crops—cotton, soybeans, alfalfa, corn, sugar beets. Things like that were embraced immediately by farmers because of yields going up, and costs going down dramatically.”
As much as GM technologies were embraced by farmers, Hiatt said, consumers didn’t perceive the same benefit to genetically modified foods that Calgene tried to promote with Flavr Savr.
“Every time they heard about genetic engineering in food, it had something to do with spraying pesticides or spraying Roundup. If a trait actually did nothing but encourage spraying more Roundup, even though it’s a better herbicide than the other ones that were used, you can see why the consumer wouldn’t be all excited about it,” Hiatt said.
“That kind of changed the tenor of industry,” he added. “I tell you, if Flavr Savr would have succeeded, the whole biotech industry would be different today.”
Flavr Savr’s Regulatory Legacy
Despite its scientific and commercial shortcomings, Flavr Savr succeeded in helping establish FDA’s approach to regulating genetically modified crops and foods.
Calgene first approached the U.S. Department of Agriculture (USDA), persuading it to remove Flavr Savr from agency regulation by declaring that the genetic sequences used in producing Flavr Savr did not cause the tomatoes to become a plant pest risk and thus were not harmful to the environment. Calgene also approached the FDA with two separate requests for advisory opinions. One addressed the safety of the kanr gene as a selectable marker in food; the other, offered a detailed safety review of the Flavr Savr tomatoes.
Following consultations with Calgene, the FDA in 1992 first developed its “Statement of Policy—Foods Derived from New Plant Varieties,” intended to apply the same regulatory standards to transgenic and conventional crops and foods. Calgene and other companies were required to consult with the FDA on safety issues, as well as thoroughly evaluate food safety pertaining to allergenicity, toxins, nutrition, and any newly produced substances.
Calgene reformatted the Environmental Assessment data it submitted when it sought the advisory opinions to support a formal petition to the agency. Calgene submitted Food Additive Petition, No. 3A4364, which the FDA formally accepted for review on June 21, 1993. The petition covered the use of the kanr gene as a processing aid in the development of genetically engineered plant varieties of tomato, as well as oilseed rape and cotton.
Calgene also came up with the FDA’s substantial equivalence standard used for assessing Flavr Savr and later GM crops: “In most cases, the substances expected to become components of food as a result of genetic modification of a plant will be the same as or substantially similar to substances commonly found in food, such as proteins, fats and oils, and carbohydrates.”
Unlike many GM food developers today, Calgene openly promoted the genetic modifications made to its tomatoes, with a label stating: “Grown from Genetically Modified Seeds.” That didn’t stop several groups—including Consumers Union, the Environmental Defense Fund, the Union of Concerned Scientists, and Pure Food Campaign—from opposing Flavr Savr and demanding that the FDA require GM food labeling. They contended that other companies wouldn’t be as forthcoming as Calgene and that consumers had a right to know what they were eating, an argument that succumbed to industry-funded opposition in California in 2012, but succeeded 2 years later in Vermont when it passed its mandatory GM food labeling law, Act 120.
Act 120 takes effect July 1, 2016. A coalition of industry groups—Grocery Manufacturers Association (GMA), Snack Food Association, International Dairy Foods Association, and National Association of Manufacturers—challenged the law in a federal lawsuit. They argued the law was unconstitutional and imposes burdensome new speech requirements on food manufacturers and retailers by requiring GM food labeling, and sought a preliminary injunction in a motion that was denied, allowing the law’s implementation.
Since 2002, the European Union has implemented a centralized, process-based framework for regulating GM foods, following the 1990s bovine spongiform encephalopathy (mad cow disease) epidemic in the U.K. All foods containing 0.9% GM material require labeling, and all GM food requires evaluation by the European Food Safety Authority, followed by approval from the European Commission or a committee of member states. By contrast, as of March 31, the FDA has disclosed 170 consultations with GM food growers since 1995, all resolved without requiring premarket approval.
Last November, over the objections of GM food opponents, the FDA concluded 20 years of review with approval of AquAdvantage® Salmon, a genetically modified Atlantic salmon developed in 1989 by AquaBounty Technologies to reach market size in less time than conventionally farmed Atlantic salmon.
FDA regulates GE animals under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act, because the recombinant DNA (rDNA) construct introduced into the animal—in this case, a trait that makes the AquAdvantage Salmon grow faster—meets the agency’s definition of a drug. That approval has been challenged by a coalition of consumer, environmental, and fishing groups jointly represented by the Center for Food Safety and Earthjustice, which on March 31, 2016, sued the FDA seeking to overturn the approval.