Hanahan

HANAHAN — Kyle Dyson just wanted a place to call his own.

Dyson had just graduated from Charleston Southern University and gone to work at his father’s construction company. He lived in a one-bedroom apartment in North Charleston and desperately wanted more space. His father, Mike Dyson, had purchased an 800-square-foot home in the Berkeley Hills neighborhood in hopes of flipping it for a quick profit.

His son had another idea. Kyle Dyson wanted to buy the structure that was built in 1950, tear it down to its foundation, and then build a bigger, modern home in its place.

Hanahan still has that small-town feel, even though its population surpassed the 25,000 mark earlier this year. Dyson likes the idea of being able to jump into his car and be in North Charleston’s Park Circle, downtown Charleston or sitting on the beach in minutes. While his demolition project took a little longer and was more expensive than going the traditional homebuying route, Dyson, like others, has been willing to wait and spend a little more to get exactly what he wants in the city of his choice.

The idea of demolishing a structure and then building a newer, often bigger dwelling is not a new concept, especially in the more established neighborhoods that surround Hanahan High School. But it has become a trend this year as older homes built in the 1950s and 1960s are being demolished at a record pace and replaced.

The city of Hanahan has issued almost as many demolition permits since January as in the past three years combined.

“We started to see this trend at the end of last year and now it has gotten bigger,” said Mayor Christie Rainwater. “It’s an affordable option. I think buyers are seeing the value of investing in our city. There’s real potential and they are taking advantage of it.”

Demolishing a standing structure, no matter the size and replacing it with new construction can be pricey. Between the purchase of the original home and the renovations, Dyson has sunk more than $270,000 into the project. He admits it would have been cheaper just to buy a home already on the market, but the idea of starting from nothing on a bigger lot with mature trees was too much to pass up.

“You don’t get lots this big in some of the newer neighborhoods and not every house is the same,” said Dyson, who expanded his new home to almost 1,600 square feet. “Everyone knows everyone around here. People walk to places. This is a unique place to live. It’s an up-and-coming neighborhood. I know I made the right decision.”

Dyson isn’t alone in his strategy.

Matt Woodford found a home along Dennis Drive — just around the corner from Dyson’s property. The house, which hadn’t been occupied for years, backed up to Turkey Creek. He could see the potential even when others didn’t and wanted to build a home for himself and his young family.

“The lot was completely overgrown. It was a mess,” said Woodford, a general construction contractor. “There were raccoons living in the house, the floors were falling in. I wasn’t going to demo it at first, I wanted to renovate it, but the trees were growing so close to the foundation that it was just too risky. It just made more sense to tear it down and start over again.”

The new home Woodford completed in April was just a couple hundred square feet larger than the original built in 1968. Woodford has more than $650,000 invested in the property, but doesn’t feel like he overpaid for a home that he’s likely to stay in for years.

“Sure, I might have spent a little bit more, but I got exactly what I wanted and its brand new,” Woodford said. “I see it as a good option.”

Hot housing market

The Hanahan housing market has been one of the strongest in Berkeley County over the past three years.

The median price of a home in the city just three years ago was $249,000 with an average price of $254,850. This year, the median price of a home has jumped to $293,700 with an average price of $308,985. In 2017, houses were on the market for an average of 49 days, and now they last just over a month. Dyson’s house has a market value of more than $300,000.

But a hot housing market is just one of the reasons why homebuyers might be considering demolition projects in the city, said Councilman Michael Sally. One big reason for the trend has been buyers trying to avoid dealing with homeowner associations.

“There are lot of buyers that just don’t like HOAs and those older neighborhoods normally don’t have HOAs,” said Sally, a longtime real estate agent in the area.

Sally also believes the city has done a better job of enforcing its own ordinances, especially around the small downtown area.

“There are some properties that have been sitting vacant for a while,” Sally said. “We are telling owners that something has to happen, not in a strong-armed way, but more like ‘what’s going on’ and then something gets done. They sell it or get a tenant.’”

Isolated phenomenon

The demolition phenomenon has not crept into Hanahan’s neighbors in Goose Creek and North Charleston, which border the Berkeley County community.

While not common, demolition projects in North Charleston were more popular while the Park Circle area was being redeveloped several years ago. In Goose Creek, with several megadevelopments such as Carnes Crossroads and Nexton either in the city limits or on its border, the practice is almost non-existent, said city Planning and Zoning Director Mark Brodeur.

Demolitions, however, have been seen more frequently on Isle of Palms. Since Hurricane Hugo came ashore in 1989 and with the Isle of Palms connector opening in 1993, dozens of cinderblock homes were destroyed by the storm and replaced with larger homes. The practice continues to this day.

“It’s being done on a bigger scale on Isle of Palms,” Sally said. “The Isle of Palms looks completely different than it did 10 years ago because of the houses that are being built now. People think that all happened right after Hugo, but there have been more demolitions in the past decade than right after the hurricane.”

Sally said most of the demolition projects he has come across over the past couple of years have not always been investment properties.

“You certainly have people trying to flip houses, but the buyers are living in the majority of these kinds of properties,” Sally said. “Hanahan is a close-knit community. People walk to the high school football games on Friday nights. You just don’t get that everywhere in Charleston.”

While Dyson and Woodford don’t consider themselves trendsetters, they think others will follow their example.

“I think this is just starting to catch on,” Woodford said. “People are seeing the advantages of doing what I did. I think it’s going to be a lot more common.”

A few doors down from Dyson’s home, his family has already started a similar demolition project for his sister.

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Abstract

Two review articles published in 2000 and 2011 by Hanahan and Weinberg have dominated the discourse about carcinogenesis among researchers in the recent past. The basic tenets of their arguments favour considering cancer as a cell-based, genetic disease whereby DNA mutations cause uncontrolled cell proliferation. Their explanation of cancer phenotypes is based on the premises adopted by the somatic mutation theory (SMT) and its cell-centered variants. From their perspective, eight broad features have been identified as so-called ‘Hallmarks of Cancer’. Here, we criticize the value of these features based on the numerous intrinsic inconsistencies in the data and in the rationale behind SMT. An alternative interpretation of the same data plus data mostly ignored by Hanahan and Weinberg is proposed, based instead on evolutionarily relevant premises. From such a perspective, cancer is viewed as a tissue-based disease. This alternative, called the tissue organization field theory, incorporates the premise that proliferation and motility are the default state of all cells, and that carcinogenesis is due to alterations on the reciprocal interactions among cells and between cells and their extracellular matrix. In this view, cancer is development gone awry.

Keywords: Oncogenes, proliferation, somatic mutation theory, stroma, tissue organization field theory

‘…One day, we imagine that cancer biology and treatment—at present, a patchwork quilt of cell biology, genetics, histopathology, biochemistry, immunology, and pharmacology—will become a science with a conceptual structure and logical coherence that rivals that of chemistry or physics.’

–Hanahan D and Weinberg RA 2000 The hallmarks of cancer. Cell100 57–70

‘…The historical truth, for William James, is not what happened; it is what we judge that happened.’

–Borges JL 1999 Fictiones. Biblioteca Borges 53

‘…understanding how the parts relate to each other is a precondition to understanding process and understanding process is the precursor of uncovering principles.’

–Bateson P 2006 Biol. Philos.21 553–558

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1. Introduction

Almost a century after Theodor Boveri proposed the original view on what eventually became known as the somatic mutation theory of carcinogenesis (SMT), two highly influential review articles entitled ‘The hallmarks of cancer’ were published summarizing in about 27,000 words what was claimed to have been accomplished during the second half of the 20th century and what the future has in store for cancer research in the 21st one (Hanahan and Weinberg 2000, 2011). Many reviews were published before and after these, ones assessing who, what, when and why data and interpretation affected our respective views about cancer. The influential nature of these ‘Hallmarks’ reviews is, however, reflected in the over 7000 mostly laudatory citations that have accumulated in the first decade after the first of these two reviews was published, and by the fact that it spun the publication of a textbook that has been adopted by most graduate programs in the Western world (Weinberg 2006).¹ As further evidence of the influence of these reviews, a 2012 rating of the most popular articles read in the journal Cell concluded that the 2011 and the 2000 Hallmarks were first and second, respectively, among the 25 publications examined.

Because of the prominence given to these publications, they could be regarded as central to the dominant strategy applied since 1972 when the War on Cancer was formally declared with the often-referred aim of reaching the ‘mechanistic understanding of cancer’. In this regard, startling technical improvements have increased the analytical depth at which genomic mutations can be identified and transcriptional and translational modifications characterized, sequencing techniques were refined to a point that was hardly imagined in 2000 and a whole new slew of microscopic procedures were added to those already available in 1972. The explicit rationale behind the emphasis on using these technological marvels was that they would eventually uncover the lowest possible level of organization at which carcinogenesis takes place, with the clear implication that biological organization could be reduced to machines and its parts. This research program would in turn lead to effective cancer treatments. And yet, by any objective evaluation of the data collected under the Hallmarks I and II approach, the ‘mechanistic understanding of cancer’ remains elusive, as admitted by committed supporters of the SMT (Garraway and Lander 2013; Vogelstein et al. 2013).

Central to the selection of those Hallmarks has been the perception that the appearance of cancers in humans was equivalent to the process of phenotypic ‘transformation’ that was described in in culture conditions starting in the 1950s and 1960s. Among the premises adopted and conclusions drawn in these two Hallmarks reviews was the statement that (a) cancer is a genetic disease and (b) everything that cannot be now linked to a genetic origin will finally become associated to a genetic interpretation of the disease in the near future. These inferences remain central to the current explanations of cancer (Nijhawan et al. 2012).

A comprehensive critical evaluation of the content of these influential reviews has never been published according to our bibliographic searches. Nevertheless, during the period 2000–2013, several aspects of those reviews have been unambiguously criticized both on epistemological and biological grounds (Marcum 2005; Bizzarri et al. 2008; Bertolaso 2011; Soto and Sonnenschein 2011; Baker 2012, 2013). For instance, alleged unique properties of individual cancer cells ended up being shared by normal cells during diverse stages of normal development. From such an analysis, we developed ‘the death of the cancer cell’ concept (Sonnenschein and Soto 2011) and also highlighted the differences between the prevalent SMT and our own tissue organization field theory (TOFT) (Sonnenschein and Soto 1999; Soto and Sonnenschein 2011).

Two main arguments should be offered when criticizing a theory. First, why has the theory failed, and second, what does the competing theory offer that would resolve the unknowns left by the failing theory. The main reason why H&W’s views and ours differ substantially is because each of us adopts significantly different premises and, therefore, the methodology used and the conclusions we respectively draw will be necessarily different. Herein, we aim at rebutting the value of the specific Hallmarks identified by H&W as being crucial to the explanation of the cancer process.

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2. Background

H&W have aligned themselves with the SMT by stating that ‘…cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis’ and sided with those who consider cancer as a cell-based disease caused by DNA mutations. In fact, H&W have been among the most ardent theoretical and pragmatic architects of this view of cancer (Weinberg 1998).

In Hallmarks I, H&W pointedly linked six essential alterations in cell physiology to malignant growths. It is relevant to list verbatim those putative alterations as they were defined in the text. The ‘six essential alterations in cell physiology that collectively dictate malignant growth are… self-sufficiency in growth signals, insensitivity to growth-inhibitory (antigrowth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis…’ These alterations ‘…are shared in common by most and perhaps all types of human tumors…’ As recalled above, these conclusions were drawn by H&W under the assumption of equivalence between in culture and in animal data that uses genetically modified mice and the process of carcinogenesis in human beings. In Hallmarks II, H&W re-evaluated and expanded their 2000 assessment and increased by two their six original Hallmarks incorporating ‘reprogramming of energy metabolism and evading immune destruction’.

During the last decade, many have pondered about the explanations for the initiation and progression of cancers and reached alternative conclusions to those offered by H&W. By using mathematical modeling, Enderling et al. (2009) challenged the conclusion reached by H&W whereby evading apoptosis represents a hallmark of cancer (Weinberg 1998). Separately, Lazebnik concluded that H&W fell short in dealing with the complexity of cancer at large by ignoring that benign tumors share five of the six putative 2000 Hallmarks while failing to be associated with the crucial differentiating quality of cancers, i.e. their malignancy (Lazebnik 2010). This latter particular objection relates to a non-trivial aspect of the subject given the toll that this disease has taken along the last half a century especially in the industrialized countries. It is likely that this is, in fact, the main reason why cancer has acquired such social prominence to the point that about two million publications have accumulated over a century and well over 200 billion dollars have been invested into a gargantuan effort to explain, accurately diagnose, prognosticate and, most importantly, eventually ‘cure’ the disease. The impact of this research contribution on treatment is summarized in a public document drawn by a panel of experts convened by the U.S. Institute of Medicine (a branch of the U.S. National Academy of Sciences) toward the end of 2012 that, among other things, concluded that ‘…Despite progress in reducing cancer death rates, disparities in cancer outcomes persist, problems of overuse and misuse contribute to a lack of evidence-based cancer screening and treatment, and many patients do not experience patient-centered cancer care, such as access to palliative care and use of treatment plans to help with patient–clinician communication and decision making…’ (Institute of Medicine 2013).

Before examining in detail the Hallmarks of Cancer, it is worth clarifying some issues prominently alluded to in these two reviews, namely, (a) cell proliferation and its relationship with carcinogenesis and (b) the methodological tools and models used to explore the SMT. The relationship between control of cell proliferation and carcinogenesis stems from the claim that, ‘the most fundamental trait of cancer cells involves their ability to sustain chronic proliferation.’ Objectively, cell proliferation is a straight forward process whereby two daughter cells are generated from a (single) ‘mother’ cell. If exceptions to this rule exist, cancer cells have not been recorded as being one of them. Thus, the alleged ‘sustained chronic proliferation’ abides by the rule that a ‘mother’ cancer cell always delivers two ‘daughter’ cells no matter what may be happening within the ‘mother’ cancer cell carrying the mutated DNA sequence. In short, regardless of whether the proliferation is episodic or chronic, the end product of the event is the generation of two cells out of one. Equally important, this binary process of proliferation can be easily monitored in culture conditions using electronic particle counting. Accrual of cells as a function of time allows for measuring population doubling times during the exponential phase of cell proliferation (Luria 1975; Sonnenschein and Soto 1980; Sonnenschein and Soto 1999). Cells in a tumor have not been shown to proliferate at a faster rate than normal enterocytes or blastomeres (Baserga 1976). Of note, the common practice of using tritiated thymidine incorporation, an indicator of DNA synthesis, as a surrogate parameter of cell proliferation yields or rates is inadequate (see below).

The relevance of using two-dimensional cell culture experiments and genetically modified mice approaches has not been extensively and explicitly debated given that these methods of generating cancer growths are not representative of the way cancers arise in humans or in naïve experimental animals exposed to carcinogens (Durum and Muegge 1998; Pitot 2002; Cardiff et al. 2008).

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3. The six (plus two) essential alterations in cell physiology that allegedly dictate malignant growth

In Hallmarks I, it is stated that normal cells remain in a state of passive quiescence and that they require growth signals to stimulate them to enter the cycle. Additionally, in that review, growth factors and oncogenes are attributed the role of stimulators of proliferation in cancer cells. Further, it is concluded that (a) tumor cells become autonomous due to the dominant character of oncogenes, b) tumor cells proliferate because of their capacity to produce their own growth factors, c) tumor cells over-express growth factor receptors and (d) over-expression of oncogenes stimulate cell proliferation. These conclusions can be challenged on two fronts: first, as explained elsewhere, an important point in this regard is to make explicit which is the premise adopted regarding the default state of cells. Based on evolutionary theory, proliferation as the default state is a sine qua non pre-requisite for life (Sonnenschein and Soto 1999). Thus, it becomes puzzling to explain how data could have been generated and eventually published claiming just the opposite, that is, that quiescence was instead the default state of cells in metazoa. Notwithstanding, despite its implausibility from an evolutionary perspective, explicit references that quiescence is the ‘default state’ of cells in metazoa are still being widely disseminated in the scientific literature (Alberts 2010) and in textbooks of biology (Cooper 1997; Lodish et al. 2000; Alberts et al. 2008). And second, and equally disturbing, no objective published experimental data shows the alleged direct stimulatory effect on cell proliferation of any growth factor and/or of any oncogene (Sonnenschein and Soto 2000). In addition, no knock-out experiments document a proliferative phenotype due to a putative stimulatory effect by a single or a combination of growth factors (Durum and Muegge 1998). In sum, as mentioned above, no cancer cell proliferates faster than normal early embryonic cells, and more chronically than, for an instance, enterocytes in the small intestine, or hemopoietic cells in the bone marrow.

Growth factors have been operationally defined while using an artifactual, far-from-physiological, two-dimensional tissue culture methodology. The vast majority of these models have equated serum starvation with physiological quiescence. Under these non-physiological starving conditions that usually lead to cell death, the effect of putative growth factors was measured as an increase of thymidine incorporation into DNA; sensu stricto, this is not equivalent to increased cell proliferation (Drach et al. 1981;Wolff and Bodycote 1986). Alternatively, when ‘bioassays’ were used to characterize growth factors (like in the case of nerve growth factor (NGF) or epidermal growth factor (EGF), the relationship between the bioassay and cell proliferation was equivocal. For example, the purification of EGF was monitored by observing a shortening of the age of eyelid opening and teeth eruption in newborn mice, phenomena that are rather linked to cell death and stromal breakdown, and not to cell proliferation per se (Sharov et al. 2003). Remarkably, the original seminal founding papers published by Rita Levi-Montalcini and Stanley Cohen, working at Washington University in St Louis, MO, in the 1950s and 1960s suggest that neither growth factor directly stimulated the proliferation of alleged target cells, or any cell for that matter. In fact, these Nobel Prize winners unambiguously reached this conclusion themselves (Cohen and Elliot 1962; Cohen 1965; Levi-Montalcini 1986).

Because cell proliferation and motility are so central to a comprehensive understanding of all aspects of living organisms, clarification of the above-referred issues represent important priorities in developmental biology and carcinogenesis. In sum, based on epistemological and experimental grounds, proliferation remains as the default state of all cells. Thus, the need to stimulate cells does not exist in order for them to enter the cycle and generate their respective two daughter cells (Sonnenschein and Soto 1999; Harris 2004; Soto and Sonnenschein 2004; Sonnenschein and Soto 2011). Recently, the concept of a proliferative default state re-emerged in the fields of stem cell biology and immunology. In the former, it is referred to as the ‘ground state’, by analogy to the concept used in physics to signal the state of lowest energy, and the opposite of the ‘excited state’. Thus, embryonic stem cells ‘have an innate programme for self-replication that does not require extrinsic instruction’ (Ying et al. 2008). In immunology, the study of lymphocyte quiescence revealed that it is an induced phenomenon, and thus, it implies that proliferation is the default or ground state (Yusuf and Fruman 2003). In conclusion, the regulation of cell proliferation or of motility can only be effectively implemented by inhibiting the expression of these default states.

Comparable conclusions are relevant when considering oncogenes. During the Oncogene Revolution (1975–1985), it was emphatically claimed that these genes or their gene products directly stimulated the proliferation of cells either in culture or in animal experiments. In fact, no such direct stimulation has been verified (Scully and Edwards 1991; Jacobsen et al. 2002). Even one of the pioneers in the field of oncogenes admitted two decades ago that ‘… we have learned very little about the causes of cancer from the study of proto-oncogenes and tumor suppressor genes’ (Bishop 1991). Thus, as research on oncogenes expanded, the evidence pointing to the pleiotropic nature of gene effects blurs the assumed specificity of oncogenes as inducers of cell proliferation and neoplastic transformation.

Review articles about carcinogenesis follow a familiar trend whereby they refer to publications that would have documented the alleged oncogene-mediated proliferative stimulation of cells. For the most part, these references are made in review articles, which, in turn, refer to previously published review articles in which the promised evidence keeps being referenced but the actual data are hard to retrieve (for examples of this practice, see Podlaha et al. 2012 and Visvader 2011).

Over-expression of so-called oncogenes relied on phenotypic changes on cells in culture conditions, a phenomenon described as ‘transformation.’ Carefully conducted experiments aimed at rigorously defining the ‘transformation’ phenomenon concluded that a mere change in culture conditions (changes in serum concentration under which cells were maintained) reliably mimicked those phenotypic changes (for a comprehensive review, see Rubin 2011a). This evidence implied that ‘transformation’ was an unspecific, trivial in culture artifact that could hardly be extrapolated to the complex process of carcinogenesis happening in living organisms (Rather 1978; Pitot 2002).

In Hallmarks I and II, it was claimed that, in addition to being self-sufficient in growth signals, cells might also be under the active influence of endogenous and exogenous inhibitory or anti-proliferative signals that would prevent them from expressing either their autonomous and/or their acquired proliferative capacity. This interpretation implies that an effective way to regulate proliferation in multicellular organisms is by actively inhibiting such cells from proliferating. In this context, where no rejection of an alleged stimulatory option is stated, inhibitors of cell proliferation would represent just a balancing act (the yin) to neutralize the ‘positive’ arm of the metaphorical balance represented by growth factors and oncogenes (the yang).

Moreover, according to H&W, in order to ‘prosper’, incipient cancer cells would acquire the capacity to evade these hypothetical inhibitory signals, a process inferred to be mostly funneled through the TP53 proteins and the retinoblastoma protein (pRb) and its two relatives, p107 and p130. Despite acknowledging a lack of consistency regarding the alleged inhibitory function of these proteins, H&W have called them ‘canonical suppressor(s) of cell proliferation’. Although in 2000 the mode of action of these molecules was elusive, since then several groups have linked pRb to TGFβ signalling and to either or both cell proliferation and inhibition. Consequent with the premise favoured by H&W that cancer is a cell-based disease, the action of TGFβ and other alleged inhibitors is placed at the intracellular signaling circuitry level. In 2011, the mode of action of TP53 and TGFβ on cell proliferation still remained obscure (Levine 2011; Senturk and Manfredi 2012). What has received much attention in this regard, however, is the participation of TP53, TGFβ and pRb in ‘signal transduction’ pathways and networks. For example, H&W further inferred that ‘…the existence of an antigrowth signaling circuitry is clear (Figure 2), as is the necessity for its circumvention by developing cancers’ (Hanahan and Weinberg 2000 p 61). No reference was made either in 2000 or in 2011 that this alleged ‘anti-growth signaling circuit’ is an inferential entity which requires empirical verification. As remarked above when we referred to unsubstantiated claims that growth factors stimulated cell proliferation, what is being challenged is the existence of evidence for an unequivocal proliferative or anti-proliferative effect of these alleged stimulators or inhibitors of cell proliferation and not whether growth factors or the anti-proliferative factors affect signal transduction during either normal organogenesis and/or carcinogenesis. Our objections are aimed, instead, at the unsubstantiated inferences made when these sub-cellular biochemical reactions are considered relevant to a discrete, meaningful proliferative effect due to direct stimulation by either growth factors or oncogenes, or an inhibitory one by inhibitors of cell proliferation, showcased by TGFβ.

During normal development, apoptosis is an important feature of organogenesis (Gilbert 2010). During carcinogenesis, on the other hand, explaining a net local accrual of cells requires either an increased cell proliferation rate and/or inhibition of cell death. In this latter regard, however, the alleged ‘acquired resistance toward apoptosis’ as ‘a hallmark of most and perhaps all types of cancers’ becomes nothing more than another unsubstantiated inference unless experimental evidence is quoted to document such a claim in in vivo carcinogenesis models. Once again, as it was remarked above when referring to growth factors, oncogenes and suppressor genes, no challenge is being leveled at the reliability and reproducibility of the multiple biochemical reactions that involve Bcl-2, pTen, c-Myc, FAS, caspases and other proteins together with the hundreds of molecules with which these putative participants interact during the apoptotic process. Criticisms are leveled, instead, at the inference that ‘evasion of programmed cell death (apoptosis)’ can be reliably linked to the tissue-based events that characterize the initiation and progression of cancer. In fact, Enderling and Hahnfeldt using mathematical modeling and computer simulation found that increasing the rate of apoptosis, while obviously reducing tumor size in the short-term, actually enhances growth in the long-term. They show that tumors can remain dormant for a long time while stimulation of apoptosis can cause the tumor cell population to aggressively invade. Their work suggests that the widely regarded ‘evading cell death’ as a hallmark of cancer needs to be revisited (Enderling and Hahnfeldt 2011).

Regarding this fourth acquired capability, in Hallmarks I, H&W are rather reserved about a significant role, if any, played by senescence in carcinogenesis. After making strong arguments, nuanced by their usual pre-emptive caveats, regarding the rounds of proliferation by human cell populations and the putative role of telomerases in aging and in cancer, H&W made the sobering statement that senescence could be an artifact of cell culture that may not represent an impediment to tumor progression in vivo. This represents a significant concession when considering that immortalization was previously viewed as a crucial event in carcinogenesis (Elenbaas et al. 2001;Lundberg et al. 2002). In Hallmarks I, it was anticipated that, within the following 10 years, research might clarify this subject. In 2011, however, H&W estimated that ‘replication-induced senescence as a general barrier (of the neoplastic state) requires refinement and reformulation’. They conclude that ‘…cell senescence is emerging conceptually as a protective barrier to neoplastic expansion that can be triggered by various proliferation-associated abnormalities, including high levels of oncogenic signaling and, apparently, subcritical shortening of telomeres’. After referring to a number of publications arguing for and against a significant role played by telomeres on carcinogenesis, H&W concede that ‘… The realization that impaired telomere function can actually foster tumor progression has come from the study of mutant mice that lack both p53 and telomerase function. The proposition that these two defects can cooperatively enhance human tumorigenesis has not yet been directly documented’. Thus, the role of telomerases during carcinogenesis remains to be fully elucidated, which questions their characterization as a bona fide Hallmark of cancer.

This fifth acquired capability together with the sixth one (tissue invasion and metastasis) belong to features that take place at the tissue level of biological organization during stages of cancer occurring much later than those of initiation (‘progression’). This particular ‘acquired capability’ appears as a means to merge the notion of cancer as a cell-based phenomenon (SMT) with features of the tissue-based theories of carcinogenesis. In other words, this appears as a ‘synthesis’ (a premature one at that) or a ‘compromise’ between the SMT and the premise of the TOFT that states that carcinogenesis is a tissue-based disease (Sonnenschein and Soto 1999, 2008; Baker 2012, 2013; Soto and Sonnenschein 2004).

In Hallmarks I, it was already acknowledged that ‘induction of angiogenesis will prove to be an early to mid-stage event in many human cancers’, and thus it represents a phenomenon that, like ‘tissue invasion and metastasis,’ i.e. the sixth induced capability of cancers, is triggered once the initial stages of tumor formation have been well underway. Significantly, this angiogenic capability was considered to be the result of a balance between pro-angiogenic (VEGF, acidic and basic fibroblast growth factors or FGF i/2) and anti-angiogenic factors (trombospondin-1, among them). The switch toward angiogenesis would have been triggered by the tumor itself through mechanisms that were not quite obvious in 2000. Nevertheless, a decade before 2000 and since then, the strategies aimed at therapeutically managing angiogenesis during cancer progression were being prominently and successfully hailed to an eager investment community. Critical assessments were published regarding the rationale to offer promises and their impact on the reality of the market, and more importantly in the bodies and minds of patients, their relatives, the medical community and public health officials (Ebos and Kerbel 2011). In 2011, bevacizumab (Avastin) was withdrawn from the market of effective therapeutic drugs for breast cancer (http://www.cancer.gov/cancertopics/druginfo/fda-bevacizumab).

From an evolutionary perspective, motility, like proliferation, is the other default state of all cells. On the other hand, ontogenetically, cell and tissue motility and migration are part of a vast array of processes that make normal organogenesis possible (Gilbert 2010). The alleged exceptionality of a hypothetical cancer cell to abide by its constitutive ability to move and to proliferate together with other proposed cancer cells singularities has been a prevalent but misguided notion for a century now. Notwithstanding, aggressive efforts to find what is unique in a cancer cell when compared with its normal counterparts have been unproductive (Sonnenschein and Soto 2011). In other words, if a cancer cell exists as a discrete entity distinguishable from a normal cell, it has certainly been very uncooperative in revealing what it has ‘invented’ to deserve the fame it has acquired. More to the point, cells isolated from cancers revert to normalcy when placed in a normal microenvironment (Illmensee and Mintz 1976; Maffini et al. 2005; Hendrix et al. 2007; Bussard et al. 2010)

In Hallmarks II, the ‘epithelial-mesenchymal transition’ (EMT) was attributed to be the means by which ‘transformed epithelial cells can acquire the abilities to invade, to resist apoptosis, and to disseminate’. H&W inferred that EMT-inducing transcription factors (including Snail, Slug, Twist and Zeb1/2) can orchestrate most steps of the invasion-metastasis cascade save the final step of colonization. The induction of phenotypic changes on individual cells would be due to ‘heterotypic interactions of cancer cells with adjacent tumor-associated stromal cells’ and that, next, they would ‘be choreographed by one or more of these transcriptional regulators’. By using this metaphorical language, H&W invite the reader to consider the participation of a ‘choreographer’ during carcinogenesis.² Regardless, it remains unexplained how hypothetical ‘micro-environmental stimuli distinct from those received by cancer cells located in the cores of these lesions’ would fit within the SMT as conceived by H&W. Incidentally, whether EMT plays a role in carcinogenesis and metastases has been compellingly challenged by experienced cancer pathologists (Tarin et al. 2005). The narrative in this segment of Hallmarks II is fraught with contradictory statements that baffle a reader interested in discerning whether, on the one hand, much progress has been made since 2000 as the text declares and, on the other, the admitted failure of this alleged progress to be translated into meaningful improvements in treatment as shown statistically in the Institute of Medicine report, referred to above (Institute of Medicine 2013).

3.6.1 Plasticity in the invasive growth program

In Hallmarks II, it is acknowledged that (a) ‘phenotypes of high grade malignancy do not arise in a strictly cell-autonomous manner, and that their manifestation cannot be understood solely through analyses of tumor cell genomes’ and that (b) ‘the ability to negotiate most of the steps of the invasion-metastasis cascade may be acquired in certain tumors without the requirement that the associated cancer cells undergo additional mutations beyond those that were needed for primary tumor formation’. Moreover, ‘the notion that cancer cells routinely pass through a complete EMT program is likely to be simplistic, if plausible at all’. Notwithstanding, plasticity due to the yet-to-be identified ‘contextual signals’ allegedly responsible for inducing invasive growth (often via an EMT) can, in H&W’s view, act also in reverse and become responsible for a reversibility that a mutational event is unlikely to ‘negotiate’. Thus, in another ad hoc accommodation to empirical evidence, H&W propose that the complex EMT process can be going backward in an equally complex way and become a mesenchymal-epithelial transition (MET). This nimble plasticity argument is used to explain the ‘formation of new tumor colonies of carcinoma cells exhibiting a histopathology similar to those of carcinoma cells in the primary tumor that never underwent an EMT’. H&W resort to a dexterous vocabulary to cover all possibilities, even contradictory ones, to explain the same phenomenon, in this case the generation of metastases and curiously the ‘reverse migration’ of metastatic cells from metastatic sites to the their primary tumor site. These propositions, where no hypotheses are ruled out, make finding explanations an untraceable and unverifiable process incompatible with the aims of scientific discovery (Ayala 1968; Soto and Sonnenschein 2012) (see below).

3.6.2 The daunting complexity of metastatic colonization

In Hallmarks II, H&W ignore the fact that motility is the other important dominant, constitutive property of all cells (see above). Thus, whether metastatic cells adapt to ectopic tissue microenvironments in which they either colonize and thrive by forming a tumor or are, instead, prevented from proliferating and remain dormant or die in situ, represents a relevant question in stages of cancer progression. In this regard, metastatic efficiency is significantly enhanced by the co-migration of cancer-associated stromal fibroblasts that join migratory epithelial cancer cells (Duda et al. 2010). The presence of these mixed emboli reinforces the notion that cancer metastases, as their primary cancers, are not cell-based events but represent, instead, tissue-based phenomena (Sonnenschein and Soto 1999; Soto and Sonnenschein 2011).

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4. Emerging hallmarks

When introducing their 7th and 8th Hallmarks of Cancer, H&W qualified them as ‘emerging’ under the commentary that there are still ‘unresolved issues surrounding its (their) functional independence from the core hallmarks’. The new Hallmarks are: ‘reprogramming energy metabolism’ and ‘evading immune destruction.’

H&W go on to state that ‘[T]he chronic and often uncontrolled cell proliferation that represents the essence of neoplastic disease involves not only deregulated control of cell proliferation but also corresponding adjustments of energy metabolism in order to fuel cell growth and division’. Thus, in H&W’s view, energy metabolism comes to represent a condition necessary to fuel the proliferative process. This notion may be easily extended by stating the obvious, i.e. if there is no fuel or energy source, there will be no proliferation. The architectural tissue dislocation resulting from those initial steps enables an increased proliferation rate of the cells within the tumor which, in order to survive and ‘prosper’ will require what H&W call the ‘reprogramming of energy metabolism’. A simpler and still accurate way to sum up this situation may be by stating that the ‘reprogramming of energy metabolism’ is one more of the consequences and not one of the causes of carcinogenesis.

The involvement of energy metabolism in carcinogenesis has been predicated initially by Otto Warburg who claimed that, unlike normal adult tissues, a cancer cell produces energy mainly by aerobic glycolysis instead of oxidative phosphorylation. For over half a century, this argument has been cyclically resurrected and abandoned, a common pattern followed by other failed theories and hypotheses of carcinogenesis (see below). The most recent episode in the Warburg effect saga is highlighted by the demonstration that normally proliferating embryonic Xenopus retina cells in vivo use glycogen to fuel aerobic glycolysis (Agathocleous et al. 2012). Again, the locus of energy metabolism resides inside cells. And, as mentioned all along, there has been nothing qualitatively novel inside a cancer cell that would distinguish it from what happens inside a normal cell (Sonnenschein and Soto 2011). The differences, if any, are of a quantitative nature: a cell metabolizes more or less of a given substrate, or a signalling pathway might be more active in a cell within a cancer than in a normal cell (cells may proliferate more often that in ‘normal’ tissues). However, these quantitative differences show the plasticity of all cells and are not unique to their being part of a tumor. The proliferative and gene expression repertoire of a so-called ‘cancer cell’ has been proven similar to that of normal cells during one or more stages of normal development. At some of these stages, certain cells proliferate more frequently than others and as a result they require additional sources of energy substrates; these normal cells use the same energy resources that cells within a tumor use when they proliferate.

Given that H&W view carcinogenesis through a reductionist, oncogene-centered perspective, they consider that ‘aerobic glycolysis is simply another phenotype that is programmed by proliferation-inducing oncogenes’ and because of it would merit being an additional Hallmark of Cancer. However, given the elusive impact that oncogenes have had in explaining carcinogenesis, it might be high time to relegate the Reprogramming of Energy Metabolism to the dust bin of failed hypotheses.

In Hallmarks II, it is stated that ‘the role that the immune system plays in resisting or eradicating formation and progression of incipient neoplasias, late-stage tumors, and micrometastases’ is still an unresolved issue. Notwithstanding, as done with Reprogramming Energy Metabolism, H&W introduced Evading Immune Destruction as the 8th Hallmark of Cancer. Ever since the immunological surveillance theory of carcinogenesis was introduced in the late 1950s, a cyclical dismissal and revival has characterized the fate of this controversial theory (Stutman 1974; Fuchs and Matzinger 1996; Dunn et al. 2004). In sum, as with the Warburg effect, the H&W narrative provides a merely lukewarm endorsement to this topic as the 8th Hallmark of Cancer.

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5. Miscellaneous topics covered in Hallmarks II

In addition to the analysis of the six plus two Hallmarks of Cancers dealt with in 2011, H&W commented on various subjects tangentially related to the core of cancer initiation and progression. In our own analysis of the H&W reviews we have selected a few topics that we consider relevant to the controversies surrounding interpretations of those reports and analysis.

H&W and others have characterized ‘cancer stem cells’ as entities that have been defined operationally. As with other operationally defined entities inhabiting the subject of cancer research, such as growth factors and oncogenes (see above), cancer stem cells are an elusive and controversial subject that nonetheless generates an extensive body of literature. H&W’s narrative on stem cells and cancer stem cells define stemness vaguely. Cancer stem cells easily morph in and out of their stemness at the whim of any convenient situation conceived by H&W. Admittedly, as has happened with oncogenes, another operationally defined participant in carcinogenesis, they may be mutated in certain loci within their DNA sequence, they can be present in a fraction of some cancers, they can play a role in either cell proliferation and in carcinogenesis; however, in all these instances the experimental evidence is rather weak. Despite those blanks and uncertainties in the experimental record, we will be looking forward to the now traditional, yearly-renewed ‘future ten-year’ period(s) when more experimental evidence might solidify conclusions about the true impact of CSC in carcinogenesis.

Theoretical propositions have not been subjected to a rigorous analysis in Hallmarks I and II. For instance, in the latter, H&W proposed to complement the already crowded intracellular circuitry with ‘similar diagrams charting the complex interactions between the neoplastic and stromal cells within a tumor and the dynamic extracellular matrix that they collectively erect and remodel’. Objectively, this proposition runs counter to the notion that, according to the SMT, a single cell originated the neoplasm. Nevertheless, regarding their Figure 5, H&W state that ‘(A) a reasonably complete graphic depiction of the network of micro-environmental signaling interactions (that) is still far beyond our reach, as the great majority of signaling molecules and pathways remain to be identified. We [H&W, that is] provide instead a hint of such interactions in Figure 5, upper. These few well-established examples are intended to exemplify a signaling network of remarkable complexity that is of critical importance to tumor pathogenesis’. H&W openly acknowledge that the melding of their proposed signaling interaction circuitry between cancer cells and their supporting stroma ‘clearly complicate the goal of fully elucidating the mechanisms of cancer pathogenesis’. However, they now discharge on systems biologists the task of charting ‘the crucial regulatory networks that orchestrate malignant progression’. And as usual, ‘it seems likely that understanding these dynamic variations will become crucial to the development of novel therapies designed to successfully target both primary and metastatic tumors’.

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6. Therapeutic targeting

Finally, in Hallmarks II, H&W deal with the controversial issue of whether ‘[T]he introduction of mechanism-based targeted therapies to treat human cancers has been heralded as one of the fruits of three decades of remarkable progress of research into the mechanisms of cancer pathogenesis’. Not everyone in positions to know shares the optimistic views of H&W (Institute of Medicine 2013;Kaiser 2012;Miklos 2005;Tarin 2011). Even H&W acknowledge that their optimism is based on evidence yet to be collected, that is, ‘the myriad therapies that are under development or have been introduced of late into the clinic.’ While from the SMT perspective, it may be considered a virtue to have aimed at molecular targets, the bedside reality suggests that the ‘resulting clinical responses have generally been transitory, being followed by almost-inevitable relapses’. Thus, explanations for the perceived failures are in order and, they happen to be the collection of usual suspects, namely, ‘partially redundant signaling pathways’, ‘alternative forms of drug resistance’, etc. Thus, regarding therapeutic gains, we also prefer to allow for time to provide the unbiased verdict of whether ‘personalized targeted medicine’ and additional therapies based on the SMT will become as effective as these Hallmarks reviews anticipate.

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7. General comments about theories of carcinogenesis and the role of the microenvironment in them

In Hallmarks I, H&W repeatedly referred to what the future of cancer research in the following decade was going to be. In 2000, H&W forecasted that cancer research was going to resemble a science more akin to physics or chemistry. A short aside is justified here. A recent Editorial in Nature magazine evaluated the impact of an experiment conducted at CERN, near Geneva, Switzerland, aimed at finding evidence for or against the existence of the then elusive Higgs boson (Brumfiel 2012). The evidence collected from this experiment so far favors the notion that, indeed, the Higgs boson does exist. The Nature magazine commentator concluded that a number of alternative possibilities will have to be re-evaluated and, in all likelihood, some of the theories on the subject will have to be abandoned. This conclusion reinforces a practice in the exact sciences (in this case, physics) where it is acknowledged that not everyone has a piece of ‘the truth’. In physics, at least, the tradition of testing theories and dropping them when proven inadequate has been applied and accepted by all players. A welcomed novelty would be the adoption in cancer biology of this centuries-old practice that has been so beneficial to the progress and the prestige of physics and even branches of biology, with the exception of cancer research (Soto and Sonnenschein 2012).

In Hallmarks II, H&W proposed to hybridize their long-held reductionist approach to an organicist one, where the complex microenvironment with its multiplicity of cell types plays a role in carcinogenesis as illustrated in their Figure 4. H&W also introduced a provocative caveat in this hybridizing compromise whereby this combination of reductionism (represented by the SMT and their always cell-based variations) and the participation of the microenvironment would be only operative in carcinomas, which happen to represent over 90% of the cancers that bring patients to the clinic. The other 10% of cancers are represented by connective tissue cancers (sarcomas and blood cancers). It is noteworthy however, that the oncogene pioneers, among which Weinberg featured prominently, focused their efforts on so called ‘viral carcinogenesis’ while using chicken and mouse fibroblasts in culture conditions (Rubin 2011b). The sarcomas resulting from the local inoculation of millions of fibroblast-like cells did not justify their inclusion in this generalization in the genesis of carcinomas, i.e. tumors that have a significantly different histogenesis and histopathology (Cardiff et al. 2008).

In Hallmarks I and II, the mounting evidence for a causal role of the stroma in carcinogenesis is incorporated within the oncogene theory by proposing that ‘incipient neoplasias begin the interplay by recruiting and activating stromal cell types that assemble into an initial pre-neoplastic stroma, which in turn responds reciprocally by enhancing the neoplastic phenotypes of the nearby cancer cells.’ Thus, the increasing participation of the microenvironment in carcinogenesis, an alternative originally unworthy of being considered within the SMT scenario, is now morphed into the problem of how mutated genes recruit otherwise normal neighboring stroma cells. H&W, as noted by J Marcum, ‘believe cancer is ultimately and fully explainable in terms of mutated genes’. The increasingly popular compromise of unifying the SMT with events localized in the microenvironment ignores the fact that the premises on which the SMT and the TOFT are founded are incommensurable because (a) they occur at different levels of biological organization and (b) they are diametrically opposed to each other (Soto and Sonnenschein 2011; Baker 2012, 2013).

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8. An alternative view on carcinogenesis

Our analysis of the alleged Hallmarks of Cancer lead us to conclude that they are not the hallmarks H&W assumed them to be and that their adoption as such are unlikely to remedy, first, the stagnation of current SMT-based cancer research and, second, equally important, the frustrating experiences of patients and doctors in the therapeutic front. But… are there alternatives that may offer a more promising outlook to the failure of the SMT, its variants and the hybridized theories (SMT plus the micro-environmental component of the TOFT)?

A conceptually and pragmatically significantly different strategy to explain carcinogenesis has been based on the premises adopted by the TOFT. To repeat, those premises are (a) cancer is a tissue-based disease, and (b) proliferation and motility are the default states of all cells. The rationale for why these premises are reliable and evolutionarily relevant to biological theory has been explicitly described and debated, and more importantly, the theory has been successfully tested at the laboratory bench using in animal approaches (Soto and Sonnenschein 1987; Sonnenschein and Soto 1999; Maffini et al. 2004; Maffini et al. 2005; Soto and Sonnenschein 2011). Briefly, the experimental protocol we designed gave equal chances to both the SMT and TOFT to provide a comprehensive explanation for the generation of mammary gland tumors in rodents. When rats of the susceptible WF strain are injected with the mutagenic carcinogen N-nitrosomethyl urea (NMU) at 50 days of age, they develop mammary carcinomas with an incidence of 80–100%. Under the SMT the results are interpreted as an effect of the mutagen in the DNA of epithelial cells; in this view, the epithelial cells are the target of the carcinogen. From the TOFT perspective, the target is the reciprocal interactions between stroma and epithelium; these are the interactions that mediate normal mammogenesis. According to the TOFT, alteration of this reciprocal interaction would lead to carcinogenesis. From this perspective, the stroma could have been the primary target of the carcinogen. Thus, isolated epithelial cells were exposed to the carcinogen or to its vehicle in vitro, while the stroma, represented by the epithelium-free cleared fat pad, was exposed in vivo. The half-life of NMU is 20 min. Five days after exposure epithelial cells were injected into the cleared fat pads to produce 4 types of recombinants. Cancer only developed in the recombinants whose stroma was exposed to carcinogen. Exposure of the epithelium did not result in cancer outcomes, instead, normal ducts developed from them when recombined with vehicle-exposed stroma.

The generation of adenocarcinomas by the epithelial cells that were never directly exposed to mutagenic agents is compatible with the expectations of the TOFT and incompatible with the predictions of the SMT. Similar conclusions are drawn from the outcome of the groups of rats that received epithelial cells that, while exposed to NMU, did not develop tumors when injected into fat pads that were not exposed to the mutagen (Maffini et al. 2004). The overall results from these experiments favour rejecting the SMT while satisfactorily explaining carcinogenesis based on the evolutionary-relevant premises adopted by the TOFT.

Consistent with the notion that carcinogenesis results from the faulty interaction between stroma and epitheliium is evidence generated in other experimental models like the one whereby the fate of transplanted pre-neoplastic hepatocytes depends on whether they are incorporated into either normal or in retrorsine (a naturally occurring pyrrolizidine alkaloid)-exposed livers: in the latter, those hepatocytes generate hepatocellular carcinomas while they become ‘normalized’ when implanted into livers of untreated hosts (Laconi 2007).

In order to buttress the arguments supporting the adoption of the TOFT, we explored an additional possibility anticipated by this theory, i.e. that cancer is a reversible developmental disease. This notion opposes the inference drawn from the SMT that being a genetic disease due to the accumulation of stable somatic mutations, cancer becomes irreversible. When testing whether cancer is a reversible process, we devised an experimental protocol where epithelial cells from the type of rat mammary adenocarcinomas induced by NMU would revert to normalcy. The results of this experiment showed that the mammary epithelial tumor cells injected in cleared fat pads of older rats and in twice-pregnant mothers became normalized and formed normal ducts at the site of inoculation (Maffini et al. 2005). These data strengthen conclusions drawn from experiments conducted during the last four decades while the SMT was becoming the prevalent theory of carcinogenesis. There are multiple examples of normalization of cells that once belonged to a cancer: from teratocarcinoma cells that when injected into blastocysts populate all tissues and even develop into normal gametes (Mintz and Ilmensee 1975; Illmensee and Mintz 1976), to melanoma cells normalized when injected into embryos before the neural crest cells migrated (Hendrix et al. 2007), to teratocarcinoma and mammary carcinoma cells that form normal structures when placed into the mammary gland of mice (Bussard et al. 2010; Booth et al. 2011).

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9. Reactions from the scientific community and the public to the failure of the prevalent theory of carcinogenesis

An increasing proportion of the scientific community and the public at large are becoming aware that the well-meant but misguided efforts started in the 1970s are unlikely to render the desirable outcomes. Almost imperceptibly, probably due to this realization, both researchers who have pursued the research strategies of the SMT and organizations that represent cancer patients are sensibly switching the emphasis of their future efforts in the direction of cancer prevention (Interagency Breast Cancer & Environmental Research Coordinating Committee 2013; Vogelstein et al. 2013). Lately, this goal is being viewed as more realistic, socially responsive and financially sound when compared to the aggressive therapeutic options of chemotherapy, surgery and radiation. Nonetheless, despite recognizing the shortcomings of a failed research option, the current international consensus continues to emphasize an agenda consistent with the SMT (Varmus and Kumar 2013). Based on this conceptual disconnect, the need to go back to the metaphoric blackboard and re-evaluate objectively and dispassionately what has been done, what has been useful, and what has been superfluous and wasteful is becoming imperative. Searching for pragmatic answers to resolve the cancer puzzle by plodding on the same unproductive ideas advanced by the SMT is unlikely to satisfy the wide array of stakeholders firmly committed to find a solution (Baker 2012, 2013).

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10. Conclusions and future vision

Our analysis substantiates the fact that the so-called Hallmarks of Cancer, a byproduct of the century-old SMT, has failed when assessed by the two main pragmatic criteria used to evaluate the success of any theory, namely, (a) it has not contributed to an increased understanding of the phenomenon under study, in this case cancer and (b) there has not been a meaningful beneficial translation of this research program at the site where it counts, that is, in the cancer ward.

The stated purpose of writing the 2011 version of the Hallmarks has been ‘to revisit, refine, and extend the concept of cancer hallmarks, which has provided a useful conceptual framework for understanding the complex biology of cancer’. A cursory analysis of these highly selectively referenced reviews becomes perplexing when comparing claims and contradictions with the reality of the cancer ward. A new conceptual approach is in order. We have provided a blueprint on which to execute such novel approach based on the tissue organization field theory. To implement this blueprint, the reductionist philosophy at the core of the SMT and its exclusive focus on bottom-up causation should be abandoned. Its continuous invocation of ‘programs’ and ‘mechanisms’ is a reflection of inadequate metaphors borrowed respectively from computer sciences and outdated physics; organisms are neither computers nor machines (Longo et al. 2012; Tallbot 2013).³ Instead, an organicist approach whereby causation occurs in all directions, namely bottom-up, top-down and reciprocal, will best illuminate the complexity of cancer. In this perspective, there are no privileged causes; mechanical forces, electrical fields and molecules all contribute to the formation of a biological structure, be it normal or a cancer (Soto et al. 2008). Additionally, rather than looking at complexity as if it was a hindrance, we should embrace it by developing the appropriate theories and tools to study it. Systems biology offers such a possibility. Mathematical modelling and computer simulation offer great heuristic value, and may help practitioners to separate promising hypotheses from the bad ones (Soto and Sonnenschein 2012).

As for cancer being an exceptional disease, a pretentious ‘emperor of all maladies’, we are looking forward, instead, to seeing cancer research and cancer biology disappear as independent branches of biology and become, instead, an integral part of an enlarged field of developmental biology. A rational discussion of the merits of this alternative to the SMT will provide a refined understanding of normal and neoplastic alterations of development based on reliable evolutionarily-relevant premises. A productive debate within this context may then contribute to a realistic approach to cancer therapy.

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Acknowledgments

We thank Cheryl Schaeberle for her help in the editing and the preparation of this manuscript. The work was supported by the Avon Foundation grant no. 02-2011-095 as well as by the National Institute of Environmental Health Sciences, Award Number R01ES08314. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Institutes of Health.

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Footnotes

¹To avoid repetitions of the names of Hanahan and Weinberg and ‘The hallmarks of cancer’ articles from 2000 and 2011, we will use the acronyms H&W, and Hallmarks I and Hallmarks II, respectively.

²In Longo et al. (2012), we criticize the use of metaphors in biology.

³The success of molecular biology techniques when sequencing the human and other genomes exposed the unsustainability of reductionistic, of linear thinking, genetic determinism and additional failed ideologies. These issues are analysed in the book Genetic explanations: Sense and nonsense (eds) S Krimsky and J Gruber 2013 (Cambridge, MA: Harvard University Press).

Note added in proof

In a recent article, researchers committed to the SMT conclude that most mutations in genes proposed to be ‘drivers’ of carcinogenesis, as originally described by The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium, represent instead false positives. This conclusion gleaned from sophisticated data-mining computer models suggests that those alleged driver genes remain elusive and their nature is subject to the premises of the model used to find them (Lawrence MS et al. 2013 Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. doi:10.1038/nature12213).

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Heartland was at the top of the list followed by Midland Health and Rehabilitation Center in Columbia with 29 cases, and Greer Rehabilitation and Healthcare Center in Greer with 22 cases.

“We communicate directly with employees, patients and their families if they are affected or if there is a risk of exposure in our facility,” Heartland officials said. “This information is constantly changing and for us to report that information publicly may just add concern and fear rather than allay it.”

Heartland officials said they are in the process of contacting families with additional information, and doing everything they can to minimize risks associated with COVID-19 in their facility.

According to state health officials, the spread of respiratory illnesses like COVID-19 is common in nursing homes, assisted living facilities, and similar congregate facilities due to shared living and dining areas as well as limitations for social distancing.

On March 13, Gov. Henry McMaster issued an executive order that stopped public visitation to these types of facilities in order to help protect the vulnerable population of residents, the staff who care for them, and outside visitors.

“DHEC is compiling and verifying this information to help present a fuller picture of COVID-19’s impact on these types of congregate facilities,” state officials said.

When we first realized that the novel Coronavirus reached the United States earlier this year, we began putting precautions in place such as checking and monitor for symptoms of the novel Coronavirus for all visitors, patients and employees. Then on March 14, we added more precautions such as eliminating group activities and most visitors except for end of life reasons. We also implemented universal masking of our employees.

The Department of Health notified Heartland Health Care Center - Hanahan, a not-for-profit, mission-focused skilled nursing and rehabilitation center, that we have confirmed positive cases of the novel Coronavirus. We know that the frail and elderly are especially susceptible to this virus. That’s why we are in close communication with our local health department, CDC and CMS to ensure we have the latest information and resources available. The health and well-being of our patients and employees remains our top priority.

We have taken significant additional precautions to minimize risk to patients and employees and have had systems and processes in place to help reduce the risks associated with the novel Coronavirus. We have precautionary measures designed to protect the safety and health of patients, employees and authorized visitors. We are:

• Holding new admissions.
• Taking regular symptom and temperature checks of all residents. We have reduced our temperature threshold to 99 degrees so we can address any change in condition rapidly.
• Reviewing all inventory for personal protective equipment, such as masks and gowns, and educating staff on proper use and disposal.
• Working with the Department of Health, CDC and the community to minimize any additional risk.
• Regular updates and in-servicing of our care team.

• We will designate an isolation unit for patients who meet our isolation criteria (higher risk patients).
• The unit will have barriers installed to protect other residents and employees and keep higher risk patients in a focused treatment area.
• As much as possible, we will have dedicated staff on the unit in CDC-approved Personal Protective Equipment (PPE). This means respiratory masks, gowns, face shields or goggles and gloves.
• Special cleaning, disposal, laundry and sanitizing measures will be enforced.

We communicate directly with employees, patients and their families if they are affected or if there is a risk of exposure in our facility. This information is constantly changing and for us to report that information publicly may just add concern and fear rather than allay it. We are happy to address any concerns or questions employees, patients and families have directly with them. Since CMS is allowing us to release more information, we are in the process of contacting families with additional information. We will then keep this information updated on our website.

We are doing everything we can to minimize risks associated with the novel Coronavirus in our facility. We are in very close communication with our medical director, clinical support team, and local and state health officials about the appropriate steps to serve the best interests of our patients, employees and visitors. We are instructing our staff and patients to follow the recommended preventative actions. We appreciate the Department of Health’s support in identifying and addressing this issue as well. We continue to take every precaution to prevent the spread of the infection and keep families informed.

A Lowcountry nursing home with a poor federal rating and a recent six-figure fine over safety violations is now host to one of the largest known coronavirus outbreaks in the state, records show.

The 57 cases confirmed by health officials Tuesday at Heartland Health and Rehabilitation Care Center in Hanahan account for 40 percent of the known cases in all of Berkeley County. Infections at the 135-bed facility also dwarfed other totals from the state’s hundreds of nursing homes and other long-term care facilities.

Lawyers who handle litigation against nursing homes said the news came as no surprise. They pointed to the Hanahan facility’s poor health inspection record. That includes a one-star federal rating — the lowest possible — and a recent $234,000 fine stemming from a 2018 inspection that cited, among other issues, infectious disease control violations.

A spokeswoman for HCR Manor Care, the home’s Ohio-based corporate owner, said the Hanahan facility moved quickly to protect residents and staff. That includes halting visitors, regularly checking residents’ temperatures and equipping staff with special protective gear.

Information on the outbreaks at nursing homes had been kept from South Carolinians for weeks. In states like Washington, early reports of cases clustered among vulnerable elderly residents helped spur health authorities into action to combat the virus.

South Carolina health officials said they needed time to compile the reports, and the S.C. Department of Health and Environmental Control released the data Tuesday night.

It revealed traces of the virus in nursing homes and other long-term care facilities in virtually every corner of the state. Among them: Greenville-area homes, a skilled nursing facility on Hilton Head and a rehab center in Rock Hill.

Of the 46 facilities with reported cases, as of April 21, five had more than 10. The Midland Health and Rehabilitation Center, an 88-bed facility in Columbia, reported the second-highest total of cases with 29.

But, according to the data, which DHEC began collecting April 3, no facilities face an outbreak like the one in Hanahan.

Julie Beckert, the spokeswoman for Heartland’s owner, also stressed that the Hanahan facility is working closely with state and local officials to monitor the outbreak.

Hanahan Mayor Christie Rainwater, for her part, said she was unaware the nursing home’s cases totaled in the 50s until news outlets reported it Tuesday. City officials were first flagged to the home’s outbreak a few weeks ago, Rainwater said, through an anonymous tip.

“I’m very grateful to the brave person who came forward because she realized something had to be done before it was too late,” Rainwater said.

Since then, the facility has stayed in close contact with the city, she said.

Several factors regarding the outbreak in Hanahan remain unclear. DHEC’s total includes both staff and patients who have tested positive, and Beckert said providing a more detailed breakdown presents challenges.

Fifteen employees have tested positive, and five have recovered, Beckert said. The facility is now treating 38 patients with COVID-19, she said. Since March, three residents have died, though the facility doesn’t know if those deaths were related to the virus.

“This information is constantly changing and for us to report that information publicly may just add concern and fear rather than allay it,” Beckert said.

Kenneth Jones, a resident of the Hanahan home, told The Post and Courier he and families of residents have also been kept in the dark. After Jones tested positive for COVID-19 last week, he said no one at the facility notified his wife or three children.

He decried several other key aspects of the home’s preparation for the outbreak.

Nurses have attended to him without wearing masks, Jones said. Some residents have been free to roam the halls. And though the facility has been locked down to visitors, it allowed unnecessary exceptions on more than one occasion, he said.

Prior to the outbreak, the 60-year-old former electrician had planned on leaving the facility. Jones needed just a few more weeks of therapy after multiple surgeries and rehabilitation of a bad knee.

Now stricken with the virus, though not showing symptoms, Jones is largely confined to his bed in a ward full of COVID-19 patients that’s cordoned off from the rest of the facility. He shares a small, hospital-like room with another man who also tested positive, Jones said.

“It’s really been like a nightmare,” Jones said. “We’re all stacked on top of each other down here.”

Beckert said COVID patients may share rooms under federal guidelines. Staffers are required to wear masks, she said, including face shields in the isolation unit.

After The Post and Courier contacted Beckert, she said she relayed Jones’ concerns to the Hanahan facility.

The cluster in Hanahan came as less of a shock to Nathan Hughey, a Mount Pleasant lawyer who handles litigation against nursing homes.

“It has a history,” he said.

The facility is one of 34 in the state with the lowest one-star rating from the federal Centers for Medicare and Medicaid Services, federal data shows.

Most of Heartland’s five other facilities in South Carolina carry more decent ratings. Its other Lowcountry facility, Heartland of West Ashley Rehab and Nursing Center, also carries a one-star rating.

Inspectors flagged a laundry list of violations at the Hanahan home in 2018, and the federal government refused to pay the facility for the care it provided to Medicare and Medicaid recipients for about a month until they were fixed.

The facility’s six-figure fine that year — about $234,000 — was among the biggest penalties assessed in South Carolina in recent years.

Among other infractions, that inspection found issues that could limit Heartland’s ability to control the spread of disease, though they were relatively minor. The nursing home had failed to test for the bacteria that causes Legionnaires disease, and a nurse was seen taking a resident’s blood sample without wearing gloves.

The facility started testing for Legionnaires and monitoring its staff’s hand hygiene later that year, inspection records show.

Beckert said those issues are now resolved and the facility is now compliant with state and federal regulations.

Thad Moore contributed to this report.

Fresh from intensive care, Aaron Lorick struggled to speak as COVID-19’s signature cough buffeted his words. Yet he was determined to issue a warning.

The Hanahan nursing home where he worked was putting staff and residents in danger, he said. Missteps let the virus prey on the frailest people in their care.

Lorick wanted to help them. He also feared for his coworkers at Heartland Health and Rehabilitation Care Center, not to mention their families. His own wife and toddler were already sick with the virus.

So on April 23, a few days after his discharge from a hospital, he risked his employment to speak with a Post and Courier reporter and lay out a series of failures that, he feared, had put countless people at risk.

The 44-year-old’s job as a certified nursing assistant required close contact with the patients he bathed, changed and hand fed. He knew of at least two who’d been infected by the virus. Yet, he said, nobody at Heartland had bothered to inform the staff.

“They didn’t tell us anything,” he explained. “They told us we didn’t have an outbreak at our facility.”

In reality, Lorick witnessed the dawn of one of South Carolina’s largest and deadliest nursing home outbreaks, one that ultimately would cost at least 15 residents their lives and point to deeper problems within an industry catering to the state’s most vulnerable residents.

Yet all he’d had to protect himself was a thin surgical mask — far from the layers of gear recommended by health experts. His supervisors had forced staff to reuse their lone masks for weeks, he said.

Given most residents were unable to move around the 135-bed facility, risk came largely from staff spreading it. Yet, workers, including him, cared for those with — and without — COVID-19, going back and forth, back and forth.

Then there was the lag in testing. State officials would trace the first case to March 26, but the entire facility was not tested until a month later. Neither staff nor residents knew who was infected.

The day Lorick issued his warning, just one other facility in the entire state had more reported cases.

Over the months since, gaps in oversight have left the public in the dark about nursing home outbreaks, at Heartland and other facilities across South Carolina. In most cases, whether or not they have current infections, or how many, is anybody’s guess. State health officials don’t require nursing homes to test their residents and staff — even though they house the very people most at risk from the virus.

Yet outbreaks like the one at Heartland teach critical lessons.

After Lorick’s appeal, The Post and Courier began to retrace the outbreak there to learn what went wrong — and to see how facilities can avoid future missteps. Reporters interviewed current and former staff, residents and residents’ family members. They also reviewed more than 500 pages of emails, state health department records, and police and fire reports.

In response to inquiries from the newspaper, representatives of the facility stressed that safety was, and remains, their top priority.

After the initial outbreak, they ramped up testing and now keep on hand an adequate supply of protective gear, said Julie Beckert, a spokeswoman for the facility’s Ohio-based owner.

“It is easy to Monday morning quarterback from the safety of one’s home, but it doesn’t help the cause or recognize that our employees and leadership team have been true heroes working on the frontlines learning and altering the way we deliver care,” she said.

Recent measures have brought Heartland’s count of new infections to zero, she added. But for many it came too late.

“I don’t even know how I’m alive,” Lorick said that day in April, still coughing, struggling for a deep breath.

He wondered if he’d ever be well enough to return to Heartland and the residents he adored.

First signs of danger

In early March, back before Lorick got sick, a Leprechaun green wreath hung on the door to Elizabeth Carroll’s room inside Heartland. St. Patrick Day’s was approaching, but the festive spirit did little to assuage her daughter’s concerns as she eased the door open.

Carroll, a 78-year-old with dementia, had moved into the nursing home just two months earlier. Since then, her daughter, Sharon Smith, had spotted bruises on her mother’s body along with new, severe skin deterioration.

The novel coronavirus was in the news, and someone had checked Smith’s temperature on the way in, but she was more worried about her mother’s care.

She knew the facility had a poor health inspection record. That included a one-star federal rating, the lowest possible. After a 2018 inspection, Heartland got slammed with a $234,000 fine — one of the largest handed out in the state in recent years — for problems like regularly being short staffed. (A spokeswoman insists the facility has since addressed these issues).

Smith stepped into the room, cramped with two beds.

First, she greeted her mother, a devoted Christian with a warm smile who loved birds and gospel music.

Then she said hello to her mom’s new roommate. Her family had connections to the woman, a longtime Hanahan resident who had arrived a week or two earlier, in late February.

When the woman first arrived, she seemed fine. Then she developed a cough. Smith heard she had pneumonia.

Now, Smith watched her cough and cough. The woman’s chest heaved with rapid, shallow breaths. She coughed with such force that she began to throw up.

Smith felt terrible for her. She hit the call bell, grabbed a pan and hurried over, standing beside the woman to catch her vomit. When the coughing ebbed a bit, Smith left to clean the pan, then returned to wipe the woman’s face and comfort her.

Eventually, an employee came to help. But the nursing assistants each had so many patients it was hard to get to everyone right away.

Aaron Lorick was among those working that day. As midnight approached, almost an hour after his shift ended, he messaged his wife.

He’d be late; his replacement had not yet arrived. It wasn’t unusual.

A single mask

A few weeks later, Lorick’s wife noticed a face mask in her husband’s car. It was cotton, blue with pleats.

“What is this?” Gamilah Lorick said, reaching for it.

“Don’t pick it up!”

Aaron Lorick had worked all weekend. Among his patients was Vikki O’Driscoll, a 62-year-old former bus driver who was disabled after a vehicle accident. Around that time, O’Driscoll contracted the virus, although Lorick had no way of knowing that.

The nursing home had just begun testing patients. O’Driscoll would eventually be tested, but the results would take a week. A nationwide lack of materials was causing critical delays.

Lorick explained to his wife that the staff had received one mask each. They were told to keep it for two weeks because Heartland had no more supplies. The facility did not have a stockpile of protective gear, like gowns and N95 respirators, prior to the outbreak.

Gamilah pointed at one of the mask’s strings, which had popped off. Her husband said he planned to tape it or staple it.

He’d have to make do.

First cases emerge

As March faded into April, Sharon Smith learned that her mother’s roommate, the woman with the severe cough, had been hospitalized with a confirmed COVID-19 infection.

Smith had little idea what was going on inside Heartland. Neither did many other residents’ loved ones.

By then, the governor had declared a state of emergency and restricted visitation at nursing homes.

Smith didn’t know that a staff member had tested positive. She didn’t know that other residents were showing symptoms, too. And she didn’t know how much her mother had suddenly weakened, that the older woman mostly stared straight ahead now, her mouth open.

Smith did know that her mother had not received a test for the virus. Without known symptoms like coughing, she wasn’t immediately in line for one.

‘I’ve never felt this way’

Not long after his wife found his mask, Lorick slept most of the day.

It was a Monday, and he’d worked that weekend. Given he had been helping with a large-scale move of residents from around the facility into one hall, pushing their beds down the long corridors, she figured he’d just worn himself out.

He’d told her that nobody explained to him why they were moving certain people into one area.

The next day, Lorick awoke still exhausted, now with a fever.

A day later, he barely could stand. Everything hurt. His back in particular was killing him.

“I’ve never felt this way before,” he told Gamilah.

She rubbed his back, pounded it, warmed it with a compress. When she looked up common symptoms of COVID-19, she saw: “extreme fatigue.”

Gamilah prepared to take him for a coronavirus test.

A wildfire’s spread

The same day that Gamilah researched symptoms, Vikki O’Driscoll died. Her brother wouldn’t learn the virus had killed her until he read her death certificate, five days later.

Late the following day, Sharon Smith got a phone call: She and her siblings needed to go to Heartland. Their mother’s condition had been deteriorating rapidly and now was so grave they should say goodbyes. They could enter the facility one at a time.

When Smith arrived, she remembered her mother’s former roommate and how she had coughed so badly she vomited. Now, as she stepped into the room, she watched her mother, Elizabeth Carroll, pant heavily in her bed.

Carroll died the next morning.

Around the same time, Gamilah Lorick sat at the desk in her home office with a runny nose, eyes burning. She logged off work and found her husband on the phone, his tone somber.

His test had come back positive.

Gamilah began to cry. She didn’t feel well, and they slept with their toddler in bed every night.

The Loricks didn’t know it, but the state Department of Health and Environmental Control had already begun gathering information about Heartland’s outbreak. Health officials had found 24 residents and 10 staff had tested positive — so far.

Spreading threat

On Easter Sunday, one week after Lorick first felt exhausted, Gamilah drove him to Summerville Medical Center. His condition had worsened each day.

By then, Gamilah had tested positive, too. Their toddler also showed symptoms.

At the hospital, Lorick’s oxygen saturation sank dangerously low. A key indicator for blood clots had skyrocketed. He had pneumonia in both lungs.

The medical team admitted him to a hospital room.

As Lorick battled the virus, Heartland began testing residents who showed symptoms. One whom Lorick especially liked, Ken Jones, tested positive. The whole hall where Jones lived was hard hit.

The 60-year-old was moved to another hall now set aside for residents with COVID-19. He heard that 45 to 50 other residents were housed there, too.

Staff were supposed to wear masks, and most did. But some let them hang around their necks.

The next day, Hanahan fire officials showed up for an inspection.

Assistant Chief Michael Bargeron noticed some staff weren’t wearing face coverings. When done tending to a patient, some slipped their masks off their faces while still in the COVID ward, which Bargeron dubbed the “hot zone.”

The situation wasn’t entirely dire. To Bargeron, staffing levels seemed decent. And he welcomed the fact that the COVID ward had its own air system, which meant that potentially contagious particles weren’t being pumped to other parts of the building.

Most concerning to him was the reuse of gowns that were meant to be disposable.

Staff also donned and doffed the gowns in the same room, which meant that potentially soiled gear was being brought into an area that was supposed to stay virus-free. A nurse also told Bargeron that staff had been pulling gowns off, over their heads, without cleaning them.

Bargeron saw high risk of cross-contamination.

Beckert, the Heartland spokeswoman, said the facility quickly addressed the concerns. She said the fire department used safety standards that were more strict than state health guidelines, and that DHEC’s own inspection of the facility flagged no serious violations.

Either way, when Bargeron offered to train staff on properly handling its protective gear, he said he didn’t hear back. Heartland officials felt it was important for staff to stick with their in-house training, to remain consistent across the company’s other facilities.

The fire department attempted the training anyway and sent a crew to the facility after a few days passed, Bargeron would later say.

Heartland turned them away.

Empty rooms, quiet hallways

April was awful. Residents died, often back to back. Nurses called devastated families to deliver bad news. Other times, they dialed the coroner.

As staff walked the hardest-hit hallways, they passed room after room where residents once called out to them, now empty.

Residents’ families suffered, too, from afar. They included loved ones of Maretha Martin, a 94-year-old former hairdresser who was bedridden. Partially paralyzed by a stroke, she was among the oldest residents at Heartland. Lorick called her “momma.”

Her family had long been unhappy with her care at Heartland. Now, with the nursing home shut down to visitors, their worry turned to anguish.

On April 20, a nurse called them. Martin’s blood pressure had plummeted, and staff were rushing her to the hospital. There, she tested positive for the coronavirus.

A doctor said Martin had suffered a heart attack and a stroke — most likely a week earlier. Her son, Lorenza Bell, pictured her suffering all that time. How had nobody noticed?

Back at Heartland, the death toll rose. It became common to see coworkers break down crying, exhaustion and anger lining their faces.

Some staff quit in fear of contracting the virus. Others were quarantined at home battling COVID-19 themselves. Those who remained worked harder than ever.

Housekeepers cleaned soiled laundry not knowing who had COVID and who didn’t. Many staff, especially nursing assistants who provide the most hands-on care, were close to the residents falling ill and dying.

And they all worried about Lorick, their colleague who grew sicker every day.

Fight for life

Three days after Lorick was admitted to the hospital, he got transferred to the intensive care unit, where he stayed for about a week battling pneumonia.

Then, he began to improve.

Everyone felt relieved. On April 21, he went home.

That same day, DHEC released its first tallies of COVID-19 infections at each of the state’s nursing homes and other long-term care facilities.

The data showed a cluster at Heartland: 57 known cases among staff and residents at the 135-bed facility. It did not reveal how many had died.

Residents’ loved ones learned of the cluster when the data hit the news.

Sharon Smith thought back to her mother’s roommate who had tested positive. She recalled her mom’s strange breathing, her rapid deterioration before dying.

Her mother’s death certificate said she died of a stroke, but Smith knew that COVID-19 could cause dangerous blood clots. Because Heartland never tested her mother, Smith figured she might never know if the coronavirus played a role.

In the press, Heartland defended its handling of the virus, saying the facility moved quickly to protect residents and staff. That included creating an isolation unit with barriers to separate it from other parts of the building. In that unit, ideally staff should have been wearing full protective gear, including gowns and face shields.

Beckert, the spokeswoman, said the facility did not have a stockpile of gear, other than surgical masks and gloves, prior to the outbreak. But she stressed that Heartland was able to quickly gather better protective gear once administrators confirmed the virus was in the building.

She also insisted there was no proof that Lorick contracted the virus on the job.

“The community is where employees are getting infected,” Beckert told The Post and Courier.

Yet by mid-April, 10 employees had confirmed infections, and that tally would swell to one of the state’s highest.

Lorick was home from the hospital when a coworker messaged him complaining about negative news coverage of the cluster.

The woman also typed, “We are so worried about you.”

“I just got out of hospital last week,” he responded. He asked how the residents were doing.

They were dying, she answered, “a lot of them.”

She listed three, then three others she figured would pass away soon. Another wouldn’t eat. One “was in a bad way.” Another was dying, “and we are all getting sick too.”

“Are the positive workers still working?” Lorick asked.

“I dont think so but i am confused about that,” she typed.

When she’d asked the administrator if he expected them to work while sick, she added, he got mad “and said no but keep in mind i cant replace you all.”

‘This is not your ending’

Around the same time, Martin, the former hairdresser who’d been hospitalized, was sent back to Heartland. She was placed in the facility’s hospice unit. The state’s visitors ban had an exemption for when deaths were imminent, so that allowed her family a special visit.

Bell, her 71-year-old son, could say goodbye in person.

He entered the facility a final time on May 1. Before, during his daily visits, he brought Martin her favorite plates of catfish, cornbread and greens, or crackers and chocolate.

This time, he wore gloves, a gown, a mask and a face shield. His mother was not responsive, but he felt sure she could hear him.

“We love you,” he told her. “This is not your ending. This is just your beginning.”

She died that evening.

Start of the end

Two days later, Lorick woke with chills. No amount of Tylenol helped.

Gamilah drove him back to Summerville Medical Center and dropped him off, given visitation was banned there, too.

His fever continued to rise, and a scan showed the pneumonia had worsened. A doctor readmitted him to the hospital.

By then, the situation at nursing homes across the state had become so dire that health officials announced they would test residents and staff members at every facility in the state. At least five weeks had passed since the first staff and residents at Heartland had tested positive.

Four days after his readmission, Lorick called Gamilah to describe a crushing pain in his chest.

Alarmed, she asked, “Have you ever felt that before?”

“No.”

He told her a test showed he likely was having a heart attack. Pain wracked his chest.

“I don’t know how long I can hold on.”

Someone told Gamilah that he needed a stent, and soon an ambulance sped him to the larger Trident Medical Center.

He arrived just after 5 p.m. That night, he managed to talk to Gamilah on the phone. They spoke almost every hour at first. Then the calls slowed.

At 2 a.m., he told Gamilah goodbye, that he loved her.

“Remember that you have to come home,” she warned.

He just answered with “mmmhmmm.”

“Aaron, you have to get some rest,” she urged. “You’re going to wear yourself out.”

“Mmmhmmm.”

In the morning, her phone rang again. The voice on the other end wasn’t his. Instead, a stranger said her husband’s heart had stopped. They’d gotten him back, but he was on a ventilator.

Lorick remained on the breathing machine for 31 days. He’d suffered brain damage.

On June 9, a nurse called Gamilah. By then, the Lowcountry had opened back up. People returned to beaches and bars, not always wearing masks.

The woman urged Gamilah to come.

Gamilah raced to the hospital. When she arrived, nurses met her in the hallway, so she peered into her husband’s room. The curtain was drawn.

Aaron Lorick had already died.

Back at Heartland, word seeped from text to text, from one coworker to another, along the forlorn hallways. Staff broke down crying. Many felt like walking zombies.

Would this nightmare ever end?

Life ends, life re-opens

Lorick’s funeral was held on June 19, a sunny Friday, at Hilton’s Mortuary. The North Charleston funeral home sits at the bustling crossroads of Montague Avenue and the railroad tracks.

Mourners gathered outside under the carport. Four rows of foldout chairs, draped in crisp white cloths, sat spaced 6 feet apart.

From a stroller parked among them, two tiny tennis shoes appeared, white ones with a dash of sparkle. The Loricks’ toddler, 19-month-old Erin, watched cartoons on a cell phone, too young to know they were here to say goodbye to her father.

Nobody hugged; nobody kissed.

But some things remained unchanged. People read Scripture. A priest prayed. Loved ones shared memories of Lorick.

When it was Gamilah’s turn, she remembered his 22 years of nursing assistant work.

“He loved his patients,” she said.

When she sat down, a hymn played, “It is well, it is well with my soul ...”

Just then, a freight train barreled down the tracks, carrying the day’s commerce, its horn blaring over the hymn’s reassurance.

At that point, Lorick’s passing wasn’t reflected in the latest update from Heartland. But the enormity of its outbreak was clear: No fewer than 15 dead.

No clear answers

Two months after Lorick’s funeral, gaps in the state’s testing and reporting requirements keep the public in the dark about outbreaks at the state’s nursing homes.

While Heartland’s cluster illuminates just how crucial rigorous testing is to controlling the virus’ spread, state health officials don’t mandate testing at any nursing home. While DHEC offers some guidelines, the agency largely relies on nursing homes to test as they see fit and self-report their cases.

In its weekly summary data, DHEC also does not clearly indicate whether outbreaks at nursing homes are current, despite federal guidance for how to make those determinations.

Delays in testing results pose an issue. But either way, other reporting models are more revealing.

North Carolina’s state health agency identifies long-term care facilities considered to have their outbreaks under control, based on test results. Even a private South Carolina provider, Pruitt Health, on its website reveals more information, such as the number of nursing home patients who have been tested.

And there’s been almost no way for families of nursing home residents in South Carolina to see for themselves if situations have improved.

In-person visits have been banned since March. On Friday, Gov. Henry McMaster called on DHEC to issue guidelines that nursing homes can use for limited visitation. But there’s still no telling when doors can actually reopen.

While Heartland continues to monitor for symptoms, it has not tested all patients and staff since mid-June, spokeswoman Beckert said. However, she added, the situation has greatly improved in recent weeks, insisting the facility has “recovered” from COVID-19.

Several facilities with early clusters, including Heartland, have reported scant new infections to DHEC. Some have reported none at all. But because DHEC releases nothing about how many tests, if any, have been performed at these facilities, it’s nearly impossible to verify.

Caleb Connor, an Aiken attorney, said it’s critical for state health officials to disclose more information to families, so they can act as watchdogs against neglect. He and other lawyers who litigate issues with nursing homes said they’ve been fielding calls from every corner of the state.

“People are assured there’s nothing wrong, everything’s under control,” he said. “The next thing they know, they get a call that their loved one is in the hospital.”

As of Wednesday, more than 4,800 people have been infected at 165 South Carolina nursing homes. The virus killed 704 of them.

Among employees, the group of 33 who tested positive at Heartland remains among the state’s highest. The numbers from the facility now also show a 16th death: Aaron Lorick.