Phylogenetic Hypotheses: Neither Testable Nor Falsifiable

Crother and Murray (Cladistics 31: 573–574, 2015) criticize the statement by Assis (Cladistics 30: 240–242, 2014) that phylogenetic hypotheses are amenable to testing but not falsification. The claims by both sets of authors are based on long-standing misconceptions about testing developed within systematics. Testing phylogenetic hypotheses confuses the inferences of those hypotheses by way of abductive reasoning with their being tested via induction. Cladograms lack the causal details of the different hypotheses implied by those diagrams to make testing feasible, and falsification has been shown to be problematic for historical sciences.     

Analysis of gene copy number changes in tumor phylogenetics

Backgound

Evolution of cancer cells is characterized by large scale and rapid changes in the chromosomal  landscape. The fluorescence in situ hybridization (FISH) technique provides a way to measure the copy numbers of preselected genes in a group of cells and has been found to be a reliable source of data to model the evolution of tumor cells. Chowdhury et al. (Bioinformatics 29(13):189–98, 23; PLoS Comput Biol 10(7):1003740, 24) recently develop a computational model for tumor progression driven by gains and losses in cell count patterns obtained by FISH probes. Their model aims to find the rectilinear Steiner minimum tree (RSMT) (Chowdhury et al. in Bioinformatics 29(13):189–98, 23) and the duplication Steiner minimum tree (DSMT) (Chowdhury et al. in PLoS Comput Biol 10(7):1003740, 24) that describe the progression of FISH cell count patterns over its branches in a parsimonious manner. Both the RSMT and DSMT problems are NP-hard and heuristics are required to solve the problems efficiently.

Methods

In this paper we propose two approaches to solve the RSMT problem, one inspired by iterative methods to address the “small phylogeny” problem (Sankoff et al. in J Mol Evol 7(2):133–49, 27; Blanchette et al. in Genome Inform 8:25–34, 28), and the other based on maximum parsimony phylogeny inference. We further show how to extend these heuristics to obtain solutions to the DSMT problem, that models large scale duplication events.

Results

Experimental results from both simulated and real tumor data show that our methods outperform previous heuristics (Chowdhury et al. in Bioinformatics 29(13):189–98, 23; Chowdhury et al. in PLoS Comput Biol 10(7):1003740, 24) in obtaining solutions to both RSMT and DSMT problems.

Conclusion

The methods introduced here are able to provide more parsimony phylogenies compared to earlier ones which are consider better choices.

     

What is behind “centromere repositioning”?

An increasing number of observations suggest an evolutionary switch of centromere position on monocentric eukaryotic chromosomes which otherwise display a conserved sequence of genes and markers. Such observations are particularly frequent for primates and equidae (for review see Heredity 108:59–67, 2012) but occur also in marsupials (J Hered 96:217–224, 2005) and in plants (Chromosome Res 25:299–311, 2017 and references therein). The actual mechanism(s) behind remained unclear in many cases (Proc Natl Acad Sci USA 101:6542–6547, 2004; Trends Genet 30:66–74, 2014). The same is true for de novo centromere formation on chromosomes lacking an active centromere. This article focuses on recent reports on centromere repositioning and possible mechanisms behind and addresses open questions.     

<Emphasis Type="Italic">Hyphodontia</Emphasis> s.l. (Hymenochaetales,Basidiomycota): 35 new combinations and new keys to all 120 current species

Phylogenetic trees indicate that Hyphodontia s.l. consists of various genera. In addition to the studies of Hjortstam and Ryvarden (Syn Fung 15:7–17, 2002; Syn Fung 26:33–55, 2009), 35 new combinations are proposed, based on morphological and/or phylogenetic information. A list of species, a phylogenetic tree with eight new sequences from holotypes and three other previously unsequenced species, emendations of the genera and new keys to all accepted species are provided.     

Spinicaudata (“Conchostraca,” Crustacea) from the Middle Keuper (Upper Triassic) of the southern Germanic Basin,with a review of Carnian–Norian taxa and suggested biozones

The Coburg Sandstone member of the Hassberge Formation, Middle Keuper, Carnian, Upper Triassic, in the Germanic Basin of Central Europe contains spinicaudatan branchiopods which considerably broaden the known spectrum and provide important data on the phylogenetic history and intercontinental correlation of this systematic group. The spinicaudatan fauna for this lithostratigraphic unit is described in detail and includes Euestheria kozuri sp. nov., E.? sp. nov. A, Gregoriusella striatula sp. nov., Laxitextella freybergi Kelber and Kozur in Kozur and Weems, 2007, L. dorsorecta (Reible, 1962), and Laxitextella? sp. A. Additional discussions deal with Euestheria multicostata (Geyer, 1987), E. winterpockensis (Bock, 1953a), Laxitextella laxitexta (Sandberger in Jones, 1890), Laxitextella multireticulata (Reible, 1962), and “Laxitextella? hausmanni (Schmidt, 1938),” as well as problems with (sub)global zonations that are based on spinicaudatans and suggested to be of Carnian and Norian age.     

The phylotypic stage as a boundary of modular memory: non mechanistic perspective

The concept of the phylotypic stage has been strongly integrated into developmental biology, thanks mostly to drawings presented by Haeckel (Anthropogenie oder Entwicklungsgeschichte des Menschen, 1874). They are printed in every textbook as proof of the existence of the phylotypic stage and the fact of its conservation, albeit many times criticized as misleading and simplifying (Richardson in Develop Biol 172:412–421, 1995, Richardson et al. in Anat Embryo 196:91–106, 1997; Bininda-Emons et al. in Proc R Soc Lond 270:341–346, 2003). Although generally accepted by modern biology, doubt still exists concerning the very existence or the usefulness of the concept. What kind of evolutionary and developmental horizons does it open indeed? This article begins with the history of the concept, discusses its validity and draws this into connotation with the idea of a memory activated throughout the development. Barbieri (The organic codes. An introduction to semantic biology, 2003) considers the phylotypic stage to be a crucial boundary when the genetic program ceases to suffice for further development of the embryo, and supracellular memory of the body plan is activated. This moment clearly coincides with the commencing of the modular development of the embryo. In this article the nature of such putative memory will be discussed.     

Segmental isotopic labeling of HIV-1 capsid protein assemblies for solid state NMR

Recent studies of noncrystalline HIV-1 capsid protein (CA) assemblies by our laboratory and by Polenova and coworkers (Protein Sci 19:716–730, 2010; J Mol Biol 426:1109–1127, 2014; J Biol Chem 291:13098–13112, 2016; J Am Chem Soc 138:8538–8546, 2016; J Am Chem Soc 138:12029–12032, 2016; J Am Chem Soc 134:6455–6466, 2012; J Am Chem Soc 132:1976–1987, 2010; J Am Chem Soc 135:17793–17803, 2013; Proc Natl Acad Sci USA 112:14617–14622, 2015; J Am Chem Soc 138:14066–14075, 2016) have established the capability of solid state nuclear magnetic resonance (NMR) measurements to provide site-specific structural and dynamical information that is not available from other types of measurements. Nonetheless, the relatively high molecular weight of HIV-1 CA leads to congestion of solid state NMR spectra of fully isotopically labeled assemblies that has been an impediment to further progress. Here we describe an efficient protocol for production of segmentally labeled HIV-1 CA samples in which either the N-terminal domain (NTD) or the C-terminal domain (CTD) is uniformly ¹⁵N,¹³C-labeled. Segmental labeling is achieved by trans-splicing, using the DnaE split intein. Comparisons of two-dimensional solid state NMR spectra of fully labeled and segmentally labeled tubular CA assemblies show substantial improvements in spectral resolution. The molecular structure of HIV-1 assemblies is not significantly perturbed by the single Ser-to-Cys substitution that we introduce between NTD and CTD segments, as required for trans-splicing.     

Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged

Multiple investigators have reported thepresence of defects in the immune response of the elderly [Castle In: Clin Infect Dis 31:578, 2000; Ortqvist et al. In: Eur Respir J 30:414–422, 2007; Saurwein-Teissl et al. In: J Immunol 168:5893, 2002; Haynes et al. In: Proc Natl Acad Sci USA 100:15053–15058, 2003]. These defects reduce the magnitude of the immune response to infection and to vaccination. In individuals greater than 55 years of age, the probability of developing a fully protective neutralizing antibody response to the yearly multivalent particle inactivated influenza vaccine is less than 20% [Jefferson et al. In: Lancet 264:1165–1174, 2005; Goodwin et al. In: Vaccine 24:1159–1169, 2006; Jackson et al. In: Lancet 372:398–405, 2008; Simonsen and Taylor In: Lancet 7:658–666, 2007]. The defects in the aged immune system that are responsible for this limited response to vaccination in the older age groups include functional defects of the antigen presenting cells, functional defects in CD4 helper CD4 T cells and monocytes, and an altered microenvironment [Eaton et al. In: J Exp Med 200:1613–1622, 2004; Dong et al. In: J Gen Virol 84:1623–1628, 2003; Deng et al. In: Immunology 172:3437–3446, 2004; Cella et al. In: J Exp Med 184:747–752, 1996]. Starting at puberty, the involution of the thymus and the consequent reduction of the export of naïve T cells specific to neo-antigens leads to the reduction of the ratio of antigen naïve to memory cells as chronological age advances [Prelog In: AutoimmunRev 5:136–139, 2006; McElhaney et al. In: J Immunology 176:6333–6339, 2006]. Changes in glycosylation of T cells and target antigens acquired during the aging process and the antibodies to these new glycopeptides and glycoproteins may also contribute to a reduction in the functioning of the adaptive immune response [Ishii et al. In: J Clin Neurosci 14:110–115, 2007; Shirai et al. In: Clin Exp Immunol 12:455–464, 1972; Adkins and Riley In: Mech AgeingDev 103:147–164, 1998; Ben-Yehuda and Weksler In: Cancer Investigation 10:525–531, 1992]. One of the more interesting examples of the functional defects in the cells of the adaptive immune response is a reduced level of expression in the surface cytoadhesion and activation receptor molecules on CD4 helper T cells undergoing activation during vaccination. Upon infection or vaccination, CD40L is typically increased on the surface of CD4 helper T cells during activation, and this increased expression is absolutely essential to the CD40L promotion of expansion of antigen-specific B cells and CD 8 effector T cells in response to infection or vaccination [Singh et al. In: Protein Sci 7:1124–1135, 1998; Grewal and Flavell In: Immunol Res 16: 59–70, 1997; Kornbluth In: J Hematother Stem Cell Res 11:787–801, 2002; Garcia de Vinuesa et al. In: Eur J Immunol 29:3216–3224, 1999]. In aged human beings and mice, the reduced levels of expression of CD40 ligand (CD40L) in activated CD4 helper T cells is dramatically reduced [Eaton et al. In: J Exp Med 200:1613–1622, 2004; Dong et al. In: J Gen Virol 84:1623–1628, 2003]. To circumvent the reduction in CD40L expression and the subsequent reduction in immune response in the elderly, we have developed a chimeric vaccine comprised of the CD40L linked to the target antigen, in a replication incompetent adenoviral vector and in booster protein. This review will discuss the implementation the potential use of this approach for the vaccination of the older populations for cancer and infection.     

Zooplankton abundance in the pelagic region of Lake Kasumigaura (Japan): monthly data since 1980

Microscopic crustaceans (cladocerans and copepods) and rotifers are the principal zooplankton components of the pelagic food webs in lakes. They play important ecological roles, functioning as essential links between primary producers and planktivorous fish. Individuals zooplankton are important nodes of matter flow in pelagic ecosystems. The zooplankton community structure can provide useful indicators of top–down processes, such as the magnitude or strength of planktivorous predators and the extent of zooplankton grazing. Here we report the abundance of zooplankton taxa (crustaceans and rotifers) that were recorded monthly, from January 1980 to September 2015, at two stations on Lake Kasumigaura, a shallow eutrophic lake that is the second largest lake in Japan. The data include information on 12 copepod species (taxa), 20 cladoceran species (taxa), 40 rotifer species (taxa), and the opossum shrimp (Neomysis intermedia). In the 1980s, the plankton of the lake were characterized by cyanobacterial blooms and the co-dominance of Bosmina and Diaphanosoma in the summer. In addition, the two cladoceran genera, Daphnia galeata and Chydorus sphaericus were often prominent. The plankton profile changed dramatically in the middle (1997–2004) of the present long-term monitoring period, when cyanobacteria disappeared and diatoms became dominant even in the summer; concurrently, only the Diaphanosoma cladocerans were evident. However, in the past 10 years, cyanobacterial blooms, the co-dominance of Bosmina and Diaphanosoma, and D. galeata have re-emerged. Zooplankton monitoring forms part of the Lake Kasumigaura Long-Term Environmental Monitoring Program, which has been conducted by the National Institute for Environmental Studies (NIES) since 1977. Data on other planktonic components (phytoplankton and the elements of microbial food webs) noted during monitoring and on primary production were published in Takamura and Nakagawa (Ecol Res 27:839 2012a, Ecol Res 27:837 2012b, Ecol Res 31:287 2016). Lake Kasumigaura is a core site of the Japan Long-term Ecological Research Network, a member of the International Long-term Ecological Research Network. Our quantitative dataset spanning several decades is unique in terms of the work on lakes and the plankton therein, and is freely available. The dataset has been used in ecological and environmental programs, as well as in studies on lake management.     

Chemical Analysis of a “Miller-Type” Complex Prebiotic Broth

In a famous experiment Stanley Miller showed that a large number of organic substances can emerge from sparking a mixture of methane, ammonia and hydrogen in the presence of water (Miller, Science 117:528–529, 1953). Among these substances Miller identified different amino acids, and he concluded that prebiotic events may well have produced many of Life’s molecular building blocks. There have been many variants of the original experiment since, including different gas mixtures (Miller, J Am Chem Soc 77:2351–2361, 1955; Oró Nature 197:862–867, 1963; Schlesinger and Miller, J Mol Evol 19:376–382, 1983; Miyakawa et al., Proc Natl Acad Sci 99:14,628–14,631, 2002). Recently some of Miller’s remaining original samples were analyzed with modern equipment (Johnson et al. Science 322:404–404, 2008; Parker et al. Proc Natl Acad Sci 108:5526–5531, 2011) and a total of 23 racemic amino acids were identified. To give an overview of the chemical variety of a possible prebiotic broth, here we analyze a “Miller type” experiment using state of the art mass spectrometry and NMR spectroscopy. We identify substances of a wide range of saturation, which can be hydrophilic, hydrophobic or amphiphilic in nature. Often the molecules contain heteroatoms, with amines and amides being prominent classes of molecule. In some samples we detect ethylene glycol based polymers. Their formation in water requires the presence of a catalyst. Contrary to expectations, we cannot identify any preferred reaction product. The capacity to spontaneously produce this extremely high degree of molecular variety in a very simple experiment is a remarkable feature of organic chemistry and possibly prerequisite for Life to emerge. It remains a future task to uncover how dedicated, organized chemical reaction pathways may have arisen from this degree of complexity.     

Plant individuality: a solution to the demographer’s dilemma

The problem of plant individuality is something which has vexed botanists throughout the ages, with fashion swinging back and forth from treating plants as communities of individuals (Darwin 1800; Braun and Stone 1853; Münch 1938) to treating them as organisms in their own right, and although the latter view has dominated mainstream thought most recently (Harper 1977; Cook 1985; Ariew and Lewontin 2004), a lively debate conducted mostly in Scandinavian journals proves that the issues are far from being resolved (Tuomi and Vuorisalo 1989b; Fagerström 1992; Pan and Price 2001). In this paper I settle the matter once and for all, by showing which elements of each side are correct.     

A state-by-state comparison of middle school science standards on evolution in the United States

The focus of this study is a state-by-state comparison of middle school science standards on evolution in the United States. In 2009, Louise Mead and Anton Mates reviewed the high school science standards on evolution, giving each state a grade based on multiple factors including the number of times the word “evolution” is mentioned, the types of evolution covered, and the inclusion of creationist jargon (Mead and Mates in Evol Educ Outreach 2:359, 2009). Their study was a replication of an earlier one completed in 2000 by Lawrence Lerner and the Thomas B. Fordham Foundation (Lerner in Good science, bad science: teaching evolution in the states. Thomas Fordham Foundation, Washington, 2000). Mead and Mates indicated that, on average, the quality of the standards had increased over the decade between studies. This study concludes that this positive trend is now evident in the middle school science standards across the nation. We propose that early evolutionary education will be an excellent indicator of future acceptance of evolution across the United States and strongly encourage that evolution be introduced as the underlying theme of biology early in a student’s academic career.     

Mathematical Model of Bone Remodeling Captures the Antiresorptive and Anabolic Actions of Various Therapies

A better understanding of the molecular pathways regulating the bone remodeling process should help in the development of new antiresorptive regulators and anabolic regulators, that is, regulators of bone resorption and of bone formation. Understanding the mechanisms by which parathyroid hormone (PTH) influences bone formation and how it switches from anabolic to catabolic action is important for treating osteoporosis (Poole and Reeve in Curr Opin Pharmacol 5:612–617, 2005). In this paper we describe a mathematical model of bone remodeling that incorporates, extends, and integrates several models of particular aspects of this biochemical system (Cabal et al. in J Bone Miner Res 28(8):1830–1836, 2013; Lemaire et al. in J Theor Biol 229:293–309, 2004; Peterson and Riggs in Bone 46:49–63, 2010; Raposo et al. in J Clin Endocrinol Metab 87(9):4330–4340, 2002; Ross et al. in J Disc Cont Dyn Sys Series B 17(6):2185–2200, 2012). We plan to use this model as a bone homeostasis platform to develop anabolic and antiresorptive compounds. The model will allow us to test hypotheses about the dynamics of compounds and to test the potential benefits of combination therapies. At the core of the model is the idealized account of osteoclast and osteoblast signaling given by Lemaire et al. (J Theor Biol 229:293–309, 2004). We have relaxed some of their assumptions about the roles of osteoprotegerin, transforming growth factor \(\upbeta \), and receptor activator of nuclear factor \(\upkappa \)B ligand; we have devised more detailed models of the interactions of these species. We have incorporated a model of the effect of calcium sensing receptor antagonists on remodeling (Cabal et al. in J Bone Miner Res 28(8):1830–1836, 2013). We have also incorporated a basic model of the effects of vitamin D on calcium homeostasis. We have included a simple model of the mechanism proposed by Bellido et al. (2003), Ross et al. (J Disc Cont Dyn Sys Series B 17(6):2185–2200, 2012), of the influence of PTH on osteoblast apoptosis, a mechanism that accounts for the anabolic response to pulsatile PTH administration. Finally, we have devised a simple model of the administration and effects of bisphosphonates. The biomarkers in the model are procollagen type 1 amino-terminal propeptide and C-terminal telopeptide. Bone mineral density is the model’s principal endpoint.     

Weak radicals,weak suppletion,and phonological indices in Semitic

Paster (2014) has argued that grammar does not distinguish between weak and strong suppletion. This claim is countered in this paper, in an analysis of allomorphic effects in several Semitic languages. What has been traditionally called “root” is broken down into three levels: the formless index (Harley 2014), the phonological index (Borer 2005, 2009, 2013) and its underlying representation. The distinction between the first two leads to a principled structural difference between weak and strong suppletion. Several test cases are presented that require a distinction between the latter two. Two general conclusions are drawn: (1) allomorphy at the different levels has different functions, and (2) in the Semitic root-and-pattern system, weakly suppletive allomorphy never targets the root as a whole; there is no root allomorphy in Semitic.     

Verb-noun compounds in Italian from the 16th century onwards: an increasing exploitation of an available word-formation pattern

Verb-noun compounds are typically considered to be one of the most important innovations in the domain of Romance word-formation (cf. Bauer 2011, among many others). This morphological innovation can also be seen as part of a general tendency in Romance languages to prefer head-initial structures across different levels of the language system (cf., e.g., Ledgeway 2012: 225). However, the question of the productivity of VN compounds arises immediately as there is evidence that the pattern has become extremely productive only recently. This paper investigates the question of the productivity of the VN compounds starting out with a distinction between availability of a word-formation pattern and its profitability (cf., e.g., Bauer 2001). This article shows that the structural presence—availability—of VN compounding seems to be diachronically constant, but that the quantitative exploitation of the pattern—its profitability—turns out to be a recent phenomenon. Following recent research on compounding in Spanish (Moyna 2011) and French (Rosenberg 2007, 2008, 2011), this paper takes one concrete example of the Italian VN compounds and proceeds to show its diachronic evolution from the 16th to the 19th century on the basis of data drawn from diachronic corpora as well as from major historical dictionaries. It demonstrates that the “dramatic increase” alluded to by Bauer (2011: 543) is not to be taken as a sign of a new structural innovation, but rather as a fortuitous exploitation of a well-settled word-formation pattern.     

Strong Comma-Free Codes in Genetic Information

Comma-free codes constitute a class of circular codes, which has been widely studied, in particular by Golomb et al. (Biologiske Meddelelser, Kongelige Danske Videnskabernes Selskab 23:1–34, 1958a, Can J Math 10:202–209, 1958b), Michel et al. (Comput Math Appl 55:989–996, 2008a, Theor Comput Sci 401:17–26, 2008b, Inf Comput 212:55–63, 2012), Michel and Pirillo (Int J Comb 2011:659567, 2011), and Fimmel and Strüngmann (J Theor Biol 389:206–213, 2016). Based on a recent approach using graph theory to study circular codes Fimmel et al. (Philos Trans R Soc 374:20150058, 2016), a new class of circular codes, called strong comma-free codes, is identified. These codes detect a frameshift during the translation process immediately after a reading window of at most two nucleotides. We describe several combinatorial properties of strong comma-free codes: enumeration, maximality, self-complementarity and \(CF^3\)-property (comma-free property in all the three possible frames). These combinatorial results also highlight some new properties of the genetic code and its evolution. Each amino acid in the standard genetic code is coded by at least one strong comma-free code of size 1. There are 9 amino acids \(S=\{Asn,Asp,Gln,Gly,Lys,Met,Phe,Pro,Trp\}\) among 20 such that for each amino acid from S, its synonymous trinucleotide set (excluding the necessary periodic trinucleotides \(\{AAA,CCC,GGG,TTT\}\)) is a strong comma-free code. The primeval comma-free RNY code of Eigen and Schuster (Naturwissenschaften 65:341–369, 1978) is a self-complementary \(CF^3\)-code of size 16. Furthermore, it is the union of two strong comma-free codes of size 8 which are complementary to each other.     

Inheritance by recruitment

Doolittle (Biol Philos 28(2):351–378, 2013) and Ereshefsky and Pedroso (Proc Natl Acad Sci 112:10126–10132, 2013) argue that selection can act at the level of biofilms and other microbial communities. Clarke (Biol Philos 191–212, 2016) is skeptical and argues that selection acts on microbial cells rather than microbial communities. Her main criticism is that biofilms lack one of the ingredients required for selection to operate: heritability. This paper replies to her concern by elaborating how biofilm-level traits can be inheritable     

Levels of selection in biofilms: multispecies biofilms are <Emphasis Type="Italic">not</Emphasis> evolutionary individuals

Microbes are generally thought of as unicellular organisms, but we know that many microbes live as parts of biofilms—complex, surface-attached microbial communities numbering millions of cells. Some authors have recently argued in favour of reconceiving biofilms as biological entities in their own right. In particular, some have claimed that multispecies biofilms are evolutionary individuals (Doolittle in Biol Philos 28:351–378, 2013; Ereshefsky and Pedroso in PNAS USA 112(33): 10126–10132 2015). Against this view, I defend the conservative consensus that selection acts primarily upon microbial cells.     

Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM)

Objectives

In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions.

Introduction

All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. in Omics 15:173–182, 2011; Fan et al. in Metabolomics 7(2):257–269, 2011a, in Pharmacol Ther 133:366–391, 2012a, in Metabolomics 8(3):517–527, b; Xie et al. in Cell Metab 19:795–809, 2014; Ren et al. in Sci Rep 4:5414, 2014; Sellers et al. in J Clin Investig 125(2):687–698, 2015). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by Warburg (Biochem Z 142:317–333, 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014). As the microenvironment of the target human tissue is retained and individual patient’s response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical trials or treatments

Conclusions

Development of ex vivo human tissue and animal models with humanized organs including bone marrow and liver show considerable promise for analyzing drug responses that are more relevant to humans. Similarly using stable isotope tracer methods with these improved models in advanced stages of the drug development pipeline, in conjunction with tissue biopsy is expected significantly to reduce the high failure rate of experimental drugs in Phase II and III clinical trials.