Normal human cells engineered to become malignant
1
k ^g^^glll J. \Λ*)1Α~ vestors in its takeover bid-counterbid confrontation with TotalFina (C&EN, July 26, page 9). These actions include a no-layoff pledge by Elf designed to gain union support. The takeover proposals from the two companies are very similar when it comes to both parties' oil operations. But there is a conflict of philosophies in the proposals concerning the treatment of the combined chemicals operations. TotalFina argues that the chemicals unit should stay with an oil company in order to maximize synergies. Elf Aqui- taine proposes the more drastic split of oil and chemical operations into two separate companies with the working ti- tles of Oilco and Chemco. The question seems to come down to where chemical synergies are rooted: at the refinery, in which case TotalFina's proposal is the more economically sound, or at the cracker, which both Elf Atochem and TotalFina have. Elf Aqui- taine executives question refinery- chemical synergies; for example, the concept of feedstocks at below market prices, they contend, is a myth. Puéchal argues that for a chemical company to exist on its own it needs to be "responsible, in control of its destiny, judged on its own merits, like BASF and Dow, and enjoying the same assets." The new Chemco would be an indepen- dent entity, not an "adjustment variable" for a larger parent company. TotalFina has already suggested that if it wins the takeover battle, it will sell some chemi- cal assets to help support oil and gas projects. Puéchal also envisions the integrated TotalFina and Elf Atochem chemical op- erations making up a well-balanced chemical portfolio, with nearly $16 bil- lion in sales per year—a move that would catapult Chemco into the top five global players. Basic chemicals would account for about 30% of the business; specialty chemicals, 29%; performance polymers and derivatives, 27%; and fine chemicals, 14%. He points to the fine chemicals operations as the bridge be- tween the specialty and commodity chemicals operations contributed by the two parties, holding everything together. Elf Aquitaine's argument has not convinced everyone. Some senior exec- utives at other chemical companies as well as long-time industry observers in the press see major difficulties in creat- ing such a large, free-standing compa- ny. Elf s and TotalFina's chemical oper- Puéchal: seeking Independent chemicals ations seem to have little cohesiveness, they say. And, of course, the Elf Aqui- taine proposal flies in the face of the cur- rent fashion for "pure-play" companies focusing exclusively on, say, polyolefins or specialty chemicals. Elf Atochem staffers privately say they are resigned to a merger. What they fear is that, in the course of a nego- tiated settlement of the bid, TotalFina will insist upon a compromise that ac- cepts the splitting off of most of the chemical businesses into a new compa- ny, but keeping petrochemicals with the oil company. That, says one staffer, would be the worst outcome of all since the full chain of chemical products would be needed to attain all potential synergies from the deal. Patricia Layman Normal human cells engineered to become malignant During life, human cells sometimes ac- quire mutations that make them turn into cancer cells. Despite long-standing efforts, researchers have not been able to identify the precise combination of molecular and genetic changes needed to make human cells cancerous. But a collaborative group headed by cancer researcher Robert A. Weinberg of the Whitehead Institute for Biomedi- cal Research, Cambridge, Mass., has now found a formula for doing just that [Nature, 4 0 0 , 464 (1999)]. The group's work supports new ideas about ap- proaches to cancer chemotherapy. In earlier work, scientists had found ways to transform normal mouse cells into malignant cells. And human tumor cells have been created by treating nor- mal human cells with carcinogenic sub- stances or X-rays, or by inserting the whole genome of a tumor-inducing vi- rus into such cells. But the Whitehead Institute study is the first in which nor- mal human cells have been made can- cerous by the deliberate activation of a set of specific cellular pathways. Weinberg and coworkers find that several cellular pathways must be al- tered if malignant transformation of nor- mal cells is to occur. The SV40 large-T antigen oncogene, which turns off two tumor-suppressor gene pathways, must be present. The ras oncogene, which di- rectly induces the transformation pro- cess, must be activated. And the en- zyme telomerase—which can immortal- ize cells and lead to tumor formation by maintaining the length of telomeres (chromosome end-caps)—must be ex- pressed. The researchers have success- fully transformed human epithelial and fibroblast cells by incorporating these activities into the cells. The findings are significant because they suggest that scientists are begin- ning to understand enough about the molecular biology of the cell to be able to turn cancer on—and potentially off— at will. The cellular pathways used by Weinberg and coworkers have all been known to be cancer-related. It is the group's selection of the correct path- ways and their combination into an ef- fective cancer-inducing methodology that makes the work truly novel. "This result is a landmark for the field because a minimal defined set of genetic changes has been shown to con- vert normal mortal cells into cells that can form tumors and proliferate indefi- nitely," comments David R. Corey, asso- ciate professor of pharmacology and biochemistry and a Howard Hughes Medical Institute assistant investigator at the University of Texas Southwestern Medical Center, Dallas. "While it will be interesting in the future to learn what other combination of genetic alterations will produce the same result, the essen- tial requirement for maintaining telo- mere length is clear. The results sup- port the hypothesis that interfering with telomeres should be a valid approach to chemotherapy." Stu Borman 8 AUGUST 2,1999 C&EN
Transcript of Normal human cells engineered to become malignant
k ^ g ^ ^ g l l l J. \Λ*)1Α~ vestors in its takeover bid-counterbid confrontation with TotalFina (C&EN, July 26, page 9). These actions include a no-layoff pledge by Elf designed to gain union support.
The takeover proposals from the two companies are very similar when it comes to both parties' oil operations. But there is a conflict of philosophies in the proposals concerning the treatment of the combined chemicals operations. TotalFina argues that the chemicals unit should stay with an oil company in order to maximize synergies. Elf Aquitaine proposes the more drastic split of oil and chemical operations into two separate companies with the working titles of Oilco and Chemco.
The question seems to come down to where chemical synergies are rooted: at the refinery, in which case TotalFina's proposal is the more economically sound, or at the cracker, which both Elf Atochem and TotalFina have. Elf Aquitaine executives question refinery-chemical synergies; for example, the concept of feedstocks at below market prices, they contend, is a myth.
Puéchal argues that for a chemical company to exist on its own it needs to be "responsible, in control of its destiny, judged on its own merits, like BASF and Dow, and enjoying the same assets." The new Chemco would be an independent entity, not an "adjustment variable" for a larger parent company. TotalFina has already suggested that if it wins the takeover battle, it will sell some chemical assets to help support oil and gas projects.
Puéchal also envisions the integrated TotalFina and Elf Atochem chemical operations making up a well-balanced chemical portfolio, with nearly $16 billion in sales per year—a move that would catapult Chemco into the top five global players. Basic chemicals would account for about 30% of the business; specialty chemicals, 29%; performance polymers and derivatives, 27%; and fine chemicals, 14%. He points to the fine chemicals operations as the bridge between the specialty and commodity chemicals operations contributed by the two parties, holding everything together.
Elf Aquitaine's argument has not convinced everyone. Some senior executives at other chemical companies as well as long-time industry observers in the press see major difficulties in creating such a large, free-standing company. Elf s and TotalFina's chemical oper-
Puéchal: seeking Independent chemicals
ations seem to have little cohesiveness, they say. And, of course, the Elf Aquitaine proposal flies in the face of the current fashion for "pure-play" companies focusing exclusively on, say, polyolefins or specialty chemicals.
Elf Atochem staffers privately say they are resigned to a merger. What they fear is that, in the course of a negotiated settlement of the bid, TotalFina will insist upon a compromise that accepts the splitting off of most of the chemical businesses into a new company, but keeping petrochemicals with the oil company. That, says one staffer, would be the worst outcome of all since the full chain of chemical products would be needed to attain all potential synergies from the deal.
Patricia Layman
Normal human cells engineered to become malignant
During life, human cells sometimes acquire mutations that make them turn into cancer cells. Despite long-standing efforts, researchers have not been able to identify the precise combination of molecular and genetic changes needed to make human cells cancerous.
But a collaborative group headed by cancer researcher Robert A. Weinberg of the Whitehead Institute for Biomedical Research, Cambridge, Mass., has now found a formula for doing just that [Nature, 400 , 464 (1999)]. The group's
work supports new ideas about approaches to cancer chemotherapy.
In earlier work, scientists had found ways to transform normal mouse cells into malignant cells. And human tumor cells have been created by treating normal human cells with carcinogenic substances or X-rays, or by inserting the whole genome of a tumor-inducing virus into such cells. But the Whitehead Institute study is the first in which normal human cells have been made cancerous by the deliberate activation of a set of specific cellular pathways.
Weinberg and coworkers find that several cellular pathways must be altered if malignant transformation of normal cells is to occur. The SV40 large-T antigen oncogene, which turns off two tumor-suppressor gene pathways, must be present. The ras oncogene, which directly induces the transformation process, must be activated. And the enzyme telomerase—which can immortalize cells and lead to tumor formation by maintaining the length of telomeres (chromosome end-caps)—must be expressed. The researchers have successfully transformed human epithelial and fibroblast cells by incorporating these activities into the cells.
The findings are significant because they suggest that scientists are beginning to understand enough about the molecular biology of the cell to be able to turn cancer on—and potentially off— at will. The cellular pathways used by Weinberg and coworkers have all been known to be cancer-related. It is the group's selection of the correct pathways and their combination into an effective cancer-inducing methodology that makes the work truly novel.
"This result is a landmark for the field because a minimal defined set of genetic changes has been shown to convert normal mortal cells into cells that can form tumors and proliferate indefinitely," comments David R. Corey, associate professor of pharmacology and biochemistry and a Howard Hughes Medical Institute assistant investigator at the University of Texas Southwestern Medical Center, Dallas. "While it will be interesting in the future to learn what other combination of genetic alterations will produce the same result, the essential requirement for maintaining telomere length is clear. The results support the hypothesis that interfering with telomeres should be a valid approach to chemotherapy."
Stu Borman
8 AUGUST 2,1999 C&EN
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