Portfolio Media. Inc. | 860 Broadway, 6th Floor | New York, NY 10003 | www.law360.com Phone: +1 646 783 7100 | Fax: +1 646 783 7161 | customerservice@law360.com Legal Implications Of New Cancer Causation Theories Law360, New York (August 11, 2011) -- The scientific and legal theories of carcinogenesis are intertwined, but not always synchronized. American courts are not monolithic and disagreements among judges in the same courthouse are not uncommon. Perhaps this is the reason that many courts seem to relax some of the procedural, evidentiary and substantive elements of legal causation in cancer cases. They tend to favor the status quo over acceptance of newer scientific theories of causation. Whatever the reasons — docket pressures created by thousands of similar cases, or social policies meant to shift serious medical and financial consequences from the individual to large corporations and insurers — some judges are wary of allowing new scientific principles into their courtrooms. However, judges who base their rulings on even the most altruistic societal goals, rather than on verifiable science, can err if they cling too long to obsolete, albeit widely accepted, scientific opinions, which squeeze out cutting-edge advances. Consider that as the leading theory of carcinogenesis for de ades, the “o ati Mutatio Theo “MT has se ed as the asis lia ilit fo thousa ds of lawsuits, costing hundreds of millions of dollars in litigation expenses. Along the way, the SMT-based causation testimony has led perhaps indirectly to numerous bankruptcies, even as it is increasingly questioned by many scientists. Accordingly, this article discusses a e e gi g, o peti g h pothesis, the Tissue O ga izatio Field Theo of Ca i oge esis TOFT , and poses the question of whether the SMT is heading the way of the buggy whip and the dial telephone. The Traditional Model of Carcinogenesis The “MT posits that a e is aused DNA utatio s that dis egulate a ell s itoti le. Des i i g the theo s p oposed io e ha i s, MIT iologist Robert Weinberg asserts that tumors grow when f e zied, uta t ells dis ega d the eeds of the o u it of ells, e o e selfish a d u so ia le, and only pursue "their own proliferative advantage." Robert A. Weinberg, One Renegade Cell: The Quest for the Origin of Cancer 3 (1999). I deed, Wei e g a d othe p opo e ts of the “MT ai tai that e e a si gle e egade ell ith the power of uninhibited proliferation is sufficient to give rise to a tumor mass. In asbestos litigation, this is the basis of the si gle-fi e theo of ausatio of esothelio a. Weinberg was not the first to articulate the SMT — he merely helped to package it for general consumption. The SMT first appeared in 1914, when German biologist Theodor Boveri proposed that the p o le of tu o s is a ell p o le , a d that a e o igi ates e ause of a e tai pe a e t change in the chromatin complex [that,] without necessitating an external stimulus, forces the cell, as soo as it is atu e, to di ide agai . Theodo Bo e i. The Origin of Malignant Tumors 62-63 (Cold Spring Harbor Laboratory Press 2007) (1914). Proponents of the TOFT are finding the SMT seriously flawed, even illogical. For example, the theory posits that tumors result from genetic mutations that lead to i eased p odu tio of g o th fa to s. See, e.g., Neil A. Campbell & Jane B. reece, Biology 242 (8th ed. 2007). To advocates of the TOFT, however, growth factors are a myth born out of the quest for a nutrient milieu that could keep metazoan cells alive in laboratory conditions. Carlos Sonnenschein & Ana M. Soto, The Society of Cells: Cancer and Control of Cell Proliferation 15 (1999). In the early 20th century, scientists discovered that it was possible to efficiently culture cells in serum extracted from blood plasma or lymph. See, e.g., R. Harrison, Observations on the Living Developing Nerve Fiber, 4 Proc. Soc. Exp. Biol. Med. 140 (1907); F. Peyton Rous & Frederick S. Jones, A Method for Obtaining Suspensions of Living Cells from the Fixed Tissues, and for the Plating out of Individual Cells, 23 J. Exp. Med. 549 (1916). To facilitate research on a massive scale, and to address difficulties of serum culture such as contamination, researchers sought to create a chemically defined, serum-free medium that would induce cellular proliferation. Harry Eagle & Karl A. Piez, The Utilization of Proteins by Cultured Human Cells, 235 J. Biol. Chem. 1095 (1960); H. Naim Kent & George O. Gey, Changes in Serum Proteins During Growth of Malignant Cells in Vitro, 235 Proc. Soc. Exp. Biol. Med. 205 (1957). The ensuing research was flawed, however, insofar as it rested on the premise that cell replication could be chemically induced. As plant cells and prokaryotes demonstrate, cells have a natural proliferative inclination if given the nutrients they need to stay alive. See SONNENSCHEIN & SOTO, SOCIETY OF CELLS, supra, at 14-27; see also Sonnenschein & Soto, The Tissue Organization Field Theory of Cancer: A Testable Replacement for the Somatic Mutation Theory, 33 BIOESSAYS 332 (2011). The misguided notion that certain molecules could trigger cell replication, however, precipitated a sea h a o g a e iologists fo the ge eti a d ole ula o igi s of a e i g o th fa to s. Id. Secondly, a deceptively simple evolutionary observation eliminates considerable support for the notion that cancer is caused by mutated renegade cells. See Weinberg, supra. To attribute cellular replication to mutations and overproduction of growth factors, one must assume that the default state of cells is not proliferation, but quiescence. Proponents of the TOFT, however, point out that this assumption lacks merit. Proliferation is an established fundamental characteristic of our ancestor cells — prokaryotes — and there is no evidence that, somewhere along the course of evolution into more complex biological systems, cells lost their replicative predisposition. Bruce Alberts, et al., Molecular Biology of the Cell 891 (3d ed. 1994). Finally, the idea that a single renegade cell can give rise to a tumor is inconsistent with an accumulating body of evidence. For example, countless experiments have shown that cells conform to their surrounding tissue, even to the point of reversing cancer, and that cancer is predictably induced by disrupting the metazoan tissue architecture. Stuart G. Baker et al., Research on Early-Stage Carcinogenesis: Are We Approaching Paradigm Instability?, 28 J. Clin. Oncology 3215, 3217 (2010); John D. Potter, Morphostats, Morphogens, Microarchitecture and Malignancy, 7 Nat. Rev. Cancer 464 (2007); Sonnenschein & Soto, The Somatic Mutation Theory of Cancer: Growing Problems with the Paradigm?, 26 Bioessays 1097 (2004); Sonnenschein & Soto, Theories of Carcinogenesis: An Emerging Perspective, 18 Semin. Cancer Biol. 372 (2008). Mutations, moreover, occur from a variety of known and unknown causes, including something as atu al a d i e o a le as g o i g olde , a d fo usi g o hat auses utatio s i stead of hat reverses them, the SMT is missing the point. Accordingly, the scientific debate about cancer causation is i easi gl fo usi g o the od s sudde i a ilit to o t ol a o al ells, ega dless of hethe these ells a o alities esult f o the atu al p o ess of li i g o f o ge eti utatio s. Why should cancer researchers care? Because, if the SMT is no longer good science in the laboratory, adherence to outdated, erroneous causation theories will delay, if not prevent, curing cancer. Why should lawyers care? Because, if judges allow outdated, erroneous causation theories into the courtroom in mass and toxic tort trials, those flawed opinions may lead to misplaced liability. The Tissue Organization Field Theory of Carcinogenesis The TOFT posits that cancer is a tissue-based disease caused by the disruption of the normal intercellular and stromal/epithelial interactions at the site of a tumor. Sonnenschein & Soto, Somatic Mutation Theory of Carcinogenesis: Why It Should Be Dropped and Replaced, 29 Mol. Carcinogenesis 205, 208 . The TOFT s st e gth stems from the fact that, unlike the SMT, the TOFT is universally consistent with evolutionary and developmental biology, and free from the epistemological contradictions that render the SMT inapposite absent a myriad of ad hoc exceptions. The ability of organized tissue to control the genetic expression of its component cells lends the TOFT o side a le edi ilit . “tudies ha e sho that o ga ized tissue a ep og a a e ells to a t as normal cells, or even transform malignant cells into healthy ones by inducing normal differentiation and conformity. See, e.g., Karen M. Bussard & Gilbert H. Smith, The Mammary Gland Microenvironment Directs P oge ito Cell Fate I Vi o, I t. J. Cell Bio., A t. Id As a di e t e a ple of the microenvironment controlling progenitor cells, our laboratory recently demonstrated that ... both adult testicular cells and bona fide neural stem cells could be reprogrammed by the mouse mammary gland to eha e as a a epithelial ells. ; B ia W. Booth, et al., The Normal Mammary Microenvironment Suppresses the Tumorigenic Phenotype of Mouse Mammary Tumor Virus-Neu-Transformed Mammary Tumor Cells, 30 Oncogene 679 (2011); William B. Coleman, et al., Regulation of the Differentiation of Diploid and Aneuploid Rat Liver Epithelial (Stem-Like) Cells by the Liver Microenvironment, 67 Cancer: Princ. & P a . of O ol. 99 Ou esults ... suggest that the hepati i oe i o e t egulates the differentiation of some neoplastically transformed hepatic stemlike cells, thereby eliminating or edu i g thei tu o ige i pote tial. . In light of these scientific observations, the TOFT presents a quantifiable, persuasive and more reliable theory of carcinogenesis than the SMT. See Baker, et al., Paradigm Instability?, supra at 3215-16 o te plati g the eed fo a pa adig shift ased o o se atio s su h as Potte s, that t a spla ti g normal cells into another ... stromal environment [e.g., testis cells to kidney capsule] is enough to induce carcinoma predictably and that, despite the abnormal phenotype of the subsequent cancer cells, t a spla ti g the a k to thei p ope e i o e t e su es that the etu to o al. iti g Potter, Morphostats, Morphogens, Microarchitecture and Malignancy, supra, 7 Nat. Rev. Cancer 464). Revisiting Carcinogenesis in a Post-Daubert World It likely will be just a matter of time before the TOFT gains even greater acceptance as the operative theory of carcinogenesis in the scientific world. Again, why should lawyers care? The answer is that scientific progress does not operate in a vacuum, and its effects extend far beyond medical libraries and laboratories. As the TOFT replaces the SMT, the focus of cancer causation would shift from genetic mutagens (e.g., sunlight) to the ause fo the eakdo of tissue ho eostasis a d the tissue s a ilit to i du e a a e ell s ediffe e tiatio a k to o al . I the ou t oo , the efo e, the TOFT a p o ide g ou ds to revisit causation with a more critical eye to what constitutes good s ie e a d hat should e excluded from evidence. Consider how the TOFT might replace the SMT in Daubert jurisdictions. Daubert was a product liability action in which the plaintiffs alleged that the morning sickness pills their mothers took caused them to develop birth defects. Daubert v. Merrell Dow Pharmaceuticals Inc., 509 U.S. 579 (1993). The Ninth Ci uit affi ed the dist i t ou t s g a t of su a judg e t fo defe da t, o g ou ds that plai tiffs expert testimony did not meet the standard of general acceptance articulated in Frye v. United States, 293 F 1013 (D.C. Cir. 1923). Id. at 579. The U.S. Supreme Court reversed and remanded, holding that Federal Rule of Evidence 702 governed the admissibility of expert testimony — not Frye. Id. Pu sua t to ‘ule , the ou t added, ge e al a epta e is ot a p e e uisite to the ad issi ilit of s ie tifi e ide e, a d the t ial judge is ha ged with ensuring that expert testimony rests on a reliable foundation and is relevant to the subject matter at issue before being admitted in evidence. Id. at 596-98. Disse ti g i pa t, Chief Justi e Willia ‘eh uist e p essed o e that, he eas ‘ule o fides to the judge some gatekeeping responsibility in deciding questions of the admissibility of proffered expert testimony ... I do not think it imposes on them either the obligation or the authority to become a ateu s ie tists i o de to pe fo that ole. 9 U.“. at -01. On remand, Judge Alex Kozinski of the Ninth Circuit endorsed Justi e ‘eh uist s app ehe sio , la e ti g that f ede al judges uli g o the ad issi ilit of e pe t s ie tifi testi o ... i a postDau e t o ld ust dete i e othi g less tha hethe the e pe ts' testi o efle ts s ie tifi k o ledge, hethe thei fi di gs a e de i ed the s ie tifi ethod, a d hethe thei o k p odu t a ou ts to good s ie e. F. d , 99 . A plai tiff s lai ust state e ough fa tual allegatio s to aise a ight to elief a o e the spe ulati e le el. Bell Atla ti Co p. . T o l , U.“. , . Fu the o e, it is the plai tiff s u de to support these factual allegations with relevant, admissible evidence. See F. R. Evid. 402-03. Federal Rule of Evidence 104 gives the court exclusive discretion to determine witness qualifications and the admissibility of proffered evidence. Because expert testimony based on obsolete science is neither reliable nor relevant, the court must exclude it from evidence pursuant to F. R. Evid. 702. Daubert, 509 U.S. at 591. Thus, Daubert provides forward-thinking litigators with a roadmap to supplant the principles found admissible yesterday with the more reliable theories of today. Due Process and Rule 702 require that only reliable sources of information be admitted into trial evidence. When scientific evidence no longer supports a cause of action, however, the party disadvantaged by the obsolete model has a great incentive to convince the court why a paradigm shift is necessary. Reliable scientific data increasingly show that cancer is more than renegade cells created by mutagenic agents. As modern research demonstrates the implausibility of the SMT, judges in Daubert jurisdictions will undoubtedly be called upon to decide whether SMT-based expert testimony still has a place in the courtroom. Justice Rehnquist and Judge Kozinski may have been right, and to make these determinations judges will have to become amateur scientists. In the courtroom, however, it is surely better for judges to play amateur scientists than for scientists to play amateur judges. --By Roberto Vela and F. Ford Loker, Miles & Stockbridge PC Roberto Vela is an associate and Ford Loker is a pri ipal with Miles & Sto k ridge i the fir ’s Balti ore office. The opinions expressed are those of the authors and do not necessarily reflect the views of the firm, its clients, or Portfolio Media, publisher of Law360. This article is for general information purposes and is not intended to be and should not be taken as legal advice. All Content © 2003-2011, Portfolio Media, Inc.