A professor of Molecular, Cellular, and Developmental Biology at the University of Colorado Boulder (http://orcid.org/0000-0001-5816-9771). I have long standing research interests in phage biology, molecular structure, cytoskeletal and regulatory (signaling) systems, and the improvement of science (biology and chemistry) courses, curricula, and outcomes (see http://klymkowskylab.colorado.edu).
If there is one thing that university faculty and administrators could do today to demonstrate their commitment to inclusion, not to mention teaching and learning over sorting and status, it would be to ban curve-based, norm-referenced grading. Many obstacles exist to the effective inclusion and success of students from underrepresented (and underserved) groups in science and related programs. Students and faculty often, and often correctly, perceive large introductory classes as “weed out” courses preferentially impacting underrepresented students. In the life sciences, many of these courses are “out-of-major” requirements, in which students find themselves taught with relatively little regard to the course’s relevance to bio-medical careers and interests. Often such out-of-major requirements spring not from a thoughtful decision by faculty as to their necessity, but because they are prerequisites for post-graduation admission to medical or graduate school. “In-major” instructors may not even explicitly incorporate or depend upon the materials taught in these out-0f-major courses – rare is the undergraduate molecular biology degree program that actually calls on students to use calculus or a working knowledge of physics, despite the fact that such skills may be relevant in certain biological contexts – see Magnetofiction – A Reader’s Guide. At the same time, those teaching “out of major” courses may overlook the fact that many (and sometimes most) of their students are non-chemistry, non-physics, and/or non-math majors. The result is that those teaching such classes fail to offer a doorway into the subject matter to any but those already comfortable with it. But reconsidering the design and relevance of these courses is no simple matter. Banning grading on a curve, on the other hand, can be implemented overnight (and by fiat if necessary).
So why ban grading on a curve? First and foremost, it would put faculty and institutions on record as valuing student learning outcomes (perhaps the best measure of effective teaching) over the sorting of students into easy-to-judge groups. Second, there simply is no pedagogical justification for curved grading, with the possible exception of providing a kludgy fix to correct for poorly designed examinations and courses. There are more than enough opportunities to sort students based on their motivation, talent, ambition, “grit,” and through the opportunities they seek after and successfully embraced (e.g., through volunteerism, internships, and independent study projects).
The negative impact of curving can be seen in a recent paper by Harris et al, (Reducing achievement gaps in undergraduate general chemistry …), who report a significant difference in overall student inclusion and subsequent success based on a small grade difference between a C, which allows a student to proceed with their studies (generally as successfully as those with higher grades) and a C-minus, which requires them to retake the course before proceeding (often driving them out of the major). Because Harris et al., analyzed curved courses, a subset of students cannot escape these effects. And poor grades disproportionately impact underrepresented and underserved groups – they say explicitly “you do not belong” rather than “how can I help you learn”.
Often naysayers disparage efforts to improve course design as “dumbing down” the course, rather than improving it. In many ways this is a situation analogous to blaming patients for getting sick or not responding to treatment, rather than conducting an objective analysis of the efficacy of the treatment. If medical practitioners had maintained this attitude, we would still be bleeding patients and accepting that more than a third are fated to die, rather than seeking effective treatments tailored to patients’ actual diseases – the basis of evidence-based medicine. We would have failed to develop antibiotics and vaccines – indeed, we would never have sought them out. Curving grades implies that course design and delivery are already optimal, and the fate of students is predetermined because only a percentage can possibly learn the material. It is, in an important sense, complacent quackery.
Banning grading on a curve, and labelling it for what it is – educational malpractice – would also change the dynamics of the classroom and might even foster an appreciation that a good teacher is one with the highest percentage of successful students, e.g. those who are retained in a degree program and graduate in a timely manner (hopefully within four years). Of course, such an alternative evaluation of teaching would reflect a department’s commitment to construct and deliver the most engaging, relevant, and effective educational program. Institutional resources might even be used to help departments generate more objective, instructor-independent evaluations of learning outcomes, in part to replace the current practice of student-based opinion surveys, which are often little more than measures of popularity. We might even see a revolution in which departments compete with one another to maximize student inclusion, retention, and outcomes (perhaps even to the extent of applying pressure on the design and delivery of “out of major” required courses offered by other departments).
“All a pipe dream” you might say, but the available data demonstrates that resources spent on rethinking course design, including engagement and relevance, can have significant effects on grades, retention, time to degree, and graduation rates. At the risk of being labeled as self-promoting, I offer the following to illustrate the possibilities: working with Melanie Cooper at Michigan State University, we have built such courses in general and organic chemistry and documented their impact, see Evaluating the extent of a large-scale transformation in gateway science courses.
Perhaps we should be encouraging students to seek out legal representation to hold institutions (and instructors) accountable for detrimental practices, such as grading on a curve. There might even come a time when professors and departments would find it prudent to purchase malpractice insurance if they insist on retaining and charging students for ineffective educational strategies.(1)
Acknowledgements: Thanks to daughter Rebecca who provided edits and legal references and Melanie Cooper who inspired the idea. Educate! image from theDorian De Long Arts & Music Scholarship site.
(1) One cannot help but wonder if such conduct could ever rise to the level of fraud. See, e.g., Bristol Bay Productions, LLC vs. Lampack, 312 P.3d 1155, 1160 (Colo. 2013) (“We have typically stated that a plaintiff seeking to prevail on a fraud claim must establish five elements: (1) that the defendant made a false representation of a material fact; (2) that the one making the representation knew it was false; (3) that the person to whom the representation was made was ignorant of the falsity; (4) that the representation was made with the intention that it be acted upon; and (5) that the reliance resulted in damage to the plaintiff.”).
Insights into student thinking & course design, part of the biofundamentals project.
Something that often eludes both instructors and instructional researchers is a clear appreciation of what it is that students do and do not know, what ideas they can and cannot call upon to solve problems and generate clear, coherent, and plausible explanations. What information – thought to have been presented effectively through past instruction, appears to be unavailable to students. As an example, few instructors would believe that students completing college level chemistry could possibly be confused about the differences between covalent and non-covalent molecular interactions, yet there is good evidence that they are (Williams et al., 2015). Unless these ideas, together with their conceptual bases and practical applications, are explicitly called out in the design and implementation of instructional materials, they often fail to become a working (relevant) part of the students’ conceptual tool-kit.
To identify ideas involved in understanding biological systems, we are using an upper division undergraduate course in developmental biology (blog link) to provide context; this is a final “capstone” junior/senior level course that comes after students have completed multiple required courses in chemistry and biology. Embryonic development integrates a range of molecular level processes, including the control of gene expression, cellular morphology and dynamics, through intrinsic and extrinsic signaling systems.
A key aspect of the course’s design is the use of formative assessment activities delivered through the beSocratic system. These activities generally include parts in which students are asked to draw a graph or diagram. Students are required to complete tasks before the start of each class meeting; their responses are used to inform in-class discussions, a situation akin to reviewing game film and coaching in sports. Analysis of student drawings and comments, carried out in collaboration with Melanie Cooper and her group at Michigan State University, can reveal unexpected aspects of students’ thinking (e.g. Williams et al., 2015). What emerges from this Socratic give and take is an improved appreciation of the qualities of the tasks that engage students (as well as those that do not), and insights into how students analyze specific tasks, what sets of ideas they see as necessary and which necessary ideas they ignore when generating explanatory and predictive models. Most importantly, they can reveal flaws in how necessary ideas are developed. While at an admittedly early stage in the project, here I sketch out some preliminary findings: the first of these deal with steady state concentration and response dynamics.
The ideas of steady state concentration and pathway dynamics were identified by Loertscher et al (2014)as two of five “threshold concepts” in biochemistry and presumably molecular biology as well. Given the non-equilibrium nature of biological systems, we consider the concentration of a particular molecule in a cell in dynamic terms, a function of its rate of synthesis (or importation from the environment) together with its rate of breakdown. On top of this dynamic, the activity of existing molecules can be regulated through various post-translational mechanisms. All of the populations of molecules within a cell or organism have a characteristic steady state concentration with the exception of genomic DNA, which while synthesized is not, in living organisms, degraded, although it is repaired.
In biological systems, molecules are often characterized by their “half life” but this can be confusing, since it is quite different from the way the term is used in physics, where students are likely to first be introduced to it. Echos from physics can imply that a molecule’s half-life is an intrinsic feature of the molecule, rather than of the system in which the molecule finds itself. The equivalent of half-life would be doubling time, but these terms make sense only under specific conditions. In a system in which synthesis has stopped (synthesis rate = 0) the half life is the time it takes for the number of molecules in the system to decrease by 50%, while in the absence of degradation (degradation rate = 0), the doubling time is the time it takes to double the number of molecules in the system. Both degradation and synthesis rates are regulateable and can vary, often dramatically, in response to various stimuli.
In the case of RNA and polypeptide levels, the synthesis rate is determined by many distinct processes, including effective transcription factor concentrations, the signals that activate transcription factors, rates of binding of transcription factors to transcription factor binding sites (which can involve both DNA sequences and other proteins), as well as relevant binding affinities, and the rates associated with the recruitment and activation of DNA-dependent, RNA polymerase. Once activated, the rate of gene specific RNA synthesis will be influenced by the rate of RNA polymerization (nucleotide bases added per second) and the length of the RNA molecules synthesized. In eukaryotes, the newly formed RNA will generally need to have introns removed through interactions with splicing machinery, as well as other post-transcriptional reactions, after which the processed RNA will be transported from the nucleus to the cytoplasm through the nuclear pore complex. In the cytoplasm there are rates associated with the productive interaction of RNAs with the translational machinery (ribosomes and associated factors), and the rate at which polypeptide synthesis occurs (amino acids added per second) together with the length of the polypeptide synthesized (given that things are complicated enough, I will ignore processes such as those associated with the targeting of membrane proteins and codon usage, although these will be included in a new chapter in biofundamentals reasonably soon, I hope). On the degradative side, there are rates associated with interactions with nucleases (that breakdown RNAs) and proteinases (that breakdown polypeptides). These processes are energy requiring; generally driven by reactions coupled to the hydrolysis of adenosine triphosphate (ATP).
That these processes matter is illustrated nicely in work from Harima and colleagues (2014). The system, involved in the segmentation of the anterior region of the presomitic mesoderm, responds to signaling by activating the Hes7 gene, while the Hes7 gene product act to inhibit Hes7 gene expression. The result is an oscillatory response that is “tuned” by the length of the transcribed region (RNA length). This can be demonstrated experimentally by generating mice in which two of the genes three introns (Hes7-3) or all three introns (intron-less) are removed. Removing introns changes the oscillatory behavior of the system (Hes7 mRNA -blue and Hes7 protein – green)(Harima et al., 2013).
In the context of developmental biology, we use beSocratic activities to ask students to consider a molecule’s steady state concentration as a function of its synthesis and degradation rates, and to predict how the system would change when one or the other is altered. These ideas were presented in the context of observations by Schwanhausser et al (2011) that large discrepancies between steady state RNA and polypeptide concentrations are common and that there is an absence of a correlation between RNA and polypeptide half-lives (we also use these activities to introduce the general idea of correlation). In their responses, it was common to see students’ linking high steady state concentrations exclusively to long half-lives. Ask to consider the implications in terms of system responsiveness (in the specific context of a positively-acting transcription factor and target gene expression), students often presumed that a longer half-life would lead to higher steady state concentration which in turn would lead to increased target gene expression, primarily because collisions between the transcription factor and its DNA-binding sites would increase, leading to higher levels of target gene expression. This is an example of a p-prim (Hammer, 1996) – the heuristic that “more is more”, a presumption that is applicable to many systems.
In biological systems, however, this is generally not the case – responses “saturate”, that is increasing transcription factor concentration (or activity) above a certain level generally does not lead to a proportionate, or any increase in target gene expression. We would not call this a misconception, because this is an example of an idea that is useful in many situations, but generally isn’t in biological systems – where responses are generally inherently limited. The ubiquity and underlying mechanisms of response saturation need to be presented explicitly, and its impact on various processes reinforced repeatedly, preferably by having students use them to solve problems or construct plausible explanations. A related phenomenon that students seemed not to recognize involves the non-linearity of the initial response to a stimulus, in this case, the concentration of transcription factor below which target gene expression is not observed (or it may occur, but only transiently or within a few cells in the population, so as to be undetectable by the techniques used).
So what ideas do students need to call upon when they consider steady state concentration, how it changes, and the impact of such changes on system behavior? It seems we need to go beyond synthesis and degradation rates and include the molecular processes associated with setting the system’s response onset and saturation concentrations. First we need to help students appreciate why such behaviors (onset and saturation) occur – why doesn’t target gene expression begin as soon as a transcription factor appears in a cell? Why does gene expression level off when transcription factor concentrations rise above a certain level? The same questions apply to the types of threshold behaviors often associated with signaling systems. For example, in quorum sensing among unicellular organisms, the response of cells to the signal occurs over a limited concentration range, from off to full on. A related issue is associated with morphogen gradients (concentration gradients over space rather than time), in which there are multiple distinct types of “threshold” responses. One approach might be to develop a model in which we set the onset concentration close to the saturation concentration. The difficulty (or rather instructional challenge) here is that these are often complex processes involving cooperative as well as feedback interactions.
Our initial approach to steady state and thresholds has been to build activities based on the analysis of a regulatory network presented by Saka and Smith (2007), an analysis based on studies of early embryonic development in the frog Xenopus laevis. We chose the system because of its simplicity, involving only four components (although there are many other proteins associated with the actual system). Saka and Smith modeled the regulatory network controlling the expression of the transcription factor proteins Goosecoid (Gsc) and Brachyury (Xbra) in response to the secreted signaling protein activin (↓), a member of
the TGFβ superfamily of secreted signaling proteins (see Li and Elowitz, 2019). The network involves the positive action of Xbra on the gene encoding the transcription factor protein Xom. The system’s behavior depends on the values of various parameters, parameters that include response to activator (Activin), rates of synthesis and the half-lives of Gsc, Xbra, and Xom, and the degrees of regulatory cooperativity and responsiveness.
Depending upon these parameters, the system can produce a range of complex responses. In different regimes (→), increasing concentrations of activin (M) can lead, initially, to increasing, but mutually exclusive, expression of either Xba (B) or Gsc (A) as well as sharp transitions in which expression flips from one to the other, as Activin concentration increases, after which the response saturates. There are also conditions at very low Activin concentration (marked by ↑) in which both Xbra and Gsc are expressed at low levels, a situation that students are asked to explain.
Lessons learned: Based on their responses, captured through beSocratic and revealed during in class discussions, it appears that there is a need to be more explicit (early in the course, and perhaps the curriculum as well) when considering the mechanisms associated with response onset and saturation, in the context of how changes in the concentrations of regulatory factors (through changes in synthesis, turn-over, and activity) impact system responses. This may require a more quantitative approach to molecular dynamics and system behaviors. Here we may run into a problem, the often phobic responses of biology majors (and many faculty) to mathematical analyses. Even the simplest of models, such as that of Saka and Smith, require a consideration of factors generally unfamiliar to students, concepts and skills that may well not be emphasized or mastered in prerequisite courses. The trick is to define realistic, attainable, and non-trivial goals – we are certainly not going to succeed in getting late stage molecular biology students with rudimentary math skills to solve systems of differential equations in a developmental biology course. But perhaps we can build up the instincts needed to appreciate the molecular processes involved in the behavior of systems whose behavior evolves overtime in response to various external signals (which is, of course, pretty much every biological system).
 A similar situation exists in the context of the term “spontaneous” in chemistry and biology. In chemistry spontaneous means thermodynamically favorable, while in standard usage (and generally in biology) spontaneous implies that a reaction is proceeding at a measurable, functionally significant rate. Yet another insight that emerged through discussions with Melanie Cooper.
Hammer, D. (1996). Misconceptions or p-prims. How might alternative perspectives of cognitive structure influence instructional perceptions and intentions. Journal of the Learning Sciences5, 97-127.
Harima, Y., Imayoshi, I., Shimojo, H., Kobayashi, T. and Kageyama, R. (2014). The roles and mechanism of ultradian oscillatory expression of the mouse Hes genes. In Seminars in cell & developmental biology, pp. 85-90: Elsevier.
Harima, Y., Takashima, Y., Ueda, Y., Ohtsuka, T. and Kageyama, R. (2013). Accelerating the tempo of the segmentation clock by reducing the number of introns in the Hes7 gene. Cell Reports3, 1-7.
Li, P. and Elowitz, M. B. (2019). Communication codes in developmental signaling pathways. Development146, dev170977.
Loertscher, J., Green, D., Lewis, J. E., Lin, S. and Minderhout, V. (2014). Identification of threshold concepts for biochemistry. CBE—Life Sciences Education 13, 516-528.
Saka, Y. and Smith, J. C. (2007). A mechanism for the sharp transition of morphogen gradient interpretation in Xenopus. BMC Dev Biol7, 47.
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W. and Selbach, M. (2011). Global quantification of mammalian gene expression control. Nature 473, 337.
Williams, L. C., Underwood, S. M., Klymkowsky, M. W. and Cooper, M. M. (2015). Are Noncovalent Interactions an Achilles Heel in Chemistry Education? A Comparison of Instructional Approaches. Journal of Chemical Education92, 1979–1987.
Is the coronavirus-based transition from face to face to on-line instruction yet another step to down-grading instructional quality?
It is certainly a strange time in the world of higher education. In response to the current corona virus pandemic, many institutions have quickly, sometimes within hours and primarily by fiat, transitioned from face to face to distance (web-based) instruction. After a little confusion, it appears that laboratory courses are included as well, which certainly makes sense. While virtual laboratories can be built (see our own virtual laboratories in biology) they typically fail to capture the social setting of a real laboratory. More to the point, I know of no published studies that have measured the efficacy of such on-line experiences in terms of the ideas and skills students master.
Many instructors (including this one) are being called upon to carry out a radical transformation of instructional practice “on the fly.” Advice is being offered from all sides, from University administrators and technical advisors (see as an example Making Online Teaching a Success). It is worth noting that much (all?) of this advice falls into the category of “personal empiricism”, suggestions based on various experiences but unsupported by objective measures of educational outcomes – outcomes that include the extent of student engagement as well as clear descriptions of i) what students are expected to have mastered, ii) what they are expected to be able to do with their knowledge, and iii) what they can actually do. Again, to my knowledge there have been few if any careful comparative studies on learning outcomes achieved via face to face versus virtual teaching experiences. Part of the issue is that many studies on teaching strategies (including recent work on what has been termed “active learning” approaches) have failed to clearly define what exactly is to be learned, a necessary first step in evaluating their efficacy. Are we talking memorization and recognition, or the ability to identify and apply core and discipline-specific ideas appropriately in novel and complex situations?
At the same time, instructors have not had practical training in using available tools (zoom, in my case) and little in the way of effective support. Even more importantly, there are few published and verified studies to inform what works best in terms of student engagement and learning outcomes. Even if there were clear “rules of thumb” in place to guide the instructor or course designer, there has not been the time or resources needed to implement these changes. The situation is not surprising given that the quality of university level educational programs rarely attracts critical analysis, or the necessary encouragement, support, and recognition needed to make it a departmental priority (see Making education matter in higher education). It seems to me that the current situation is not unlike attempting to perform a complicated surgery after being told to watch a 3 minute youtube video. Unsurprisingly patient (student learning) outcomes may not be pretty.
Much of what is missing from on-line instructional scenarios is the human connection, the ability of an instructor to pay attention to how students respond to the ideas presented. Typically this involves reading the facial expressions and body language of students, and through asking challenging (Socratic) questions – questions that address how the information presented can be used to generate plausible explanations or to predict the behavior of a system. These are interactions that are difficult, if not impossible to capture in an on-line setting.
While there is much to be said for active engagement/active learning strategies (see Hake 1998, Freeman et al 2014 and Theobald et al 2020), one can easily argue that all effective learning scenarios involve an instructor who is aware and responsive to students’ pre-existing knowledge. It is also important that the instructor has the willingness (and freedom) to entertain their questions, confusions, and the need for clarification (saying it a different way), or when it may be necessary to revisit important, foundational, ideas and skills – a situation that can necessitate discarding planned materials and “coaching up” students on core concepts and their application. The ability of the instructor to customize instruction “on the fly” is one of the justifications for hiring disciplinary experts in instructional positions, they (presumably) understand the conceptual foundations of the materials they are called upon to present. In its best (Socratic) form, the dialog between student and instructor drives students (and instructors) to develop a more sophisticated and metacognitive understanding of the web of ideas involved in most scientific explanations.
In the absence of an explicit appreciation of the importance of the human interactions between instructor and student, interactions already strained in the context of large enrollment courses, we are likely to find an increase in the forces driving instruction to become more and more about rote knowledge, rather than the higher order skills associated with the ability to juggle ideas, identifying those needed and those irrelevant to a specific situation. While I have been trying to be less cynical (not a particularly easy task in the modern world), I suspect that the flurry of advice on how to carry out distance learning is more about avoiding the need to refund student fees than about improving students’ educational outcomes (see Colleges Sent Students Home. Now Will They Refund Tuition?)
A short post-script (17 April 2020): Over the last few weeks I have put together the tools to make the on-line MCDB 4650 Developmental Biology course somewhat smoother for me (and hopefully the students). I use Keynote (rather than Powerpoint) for slides; since the iPad is connected wirelessly to the project, this enables me to wander around the class room. The iOS version of Keynote enables me, and students, to draw on slides. Now that I am tethered, I rely more on pre-class beSocratic activities and the Mirroring360 application to connect my iPad to my laptop for Zoom sessions. I am back to being more interactive with the materials presented. I am also starting to pick students at random to answer questions & provide explanations (since they are quiet otherwise) – hopefully that works. Below (↓) is my set up, including a good microphone, laptop, iPad, and the newly arrived volume on Active Learning.
Biological systems can be seen as conceptually simple, but mechanistically complex, with hidden features that make “fixing” them difficult.
Biological systems are evolving, bounded, non-equilibrium reaction systems. Based on their molecular details, it appears that all known organisms, both extinct or extant, are derived from a single last universal common ancestor, known as LUCA. LUCA lived ~4,000,000,000 years ago (give or take). While the steps leading to LUCA are hidden, and its precursors are essentially unknowable (much like the universe before the big bang), we can come to some general and unambiguous conclusions about LUCA itself [see Catchpole & Forterre, 2019]. First LUCA was cellular and complex, probably more complex that some modern organisms, certainly more complex than the simplest obligate intracellular parasite [Martinez-Cano et al., 2014]. Second, LUCA was a cell with a semi-permeable lipid bilayer membrane. Its boundary layer is semi-permeable because such a system needs to import energy and matter and export waste in order to keep from reaching equilibrium, since equilibrium = death with no possibility of resurrection. Finally, LUCA could produce offspring, through some version of a cell division process. The amazing conclusion is that every cell in your body (and every cell in every organism on the planet) has an uninterrupted connection to LUCA.
So what are the non-equilibrium reactions within LUCA and other organisms doing? building up (synthesizing) and degrading various molecules, including proteins, nucleic acids, lipids, carbohydrates and such – the components needed to maintain the membrane barrier while importing materials so that the cell can adapt, move, grow and divide. This non-equilibrium reaction network has been passed from parent to offspring cells, going back to LUCA. A new cell does not “start up” these reactions, they are running continuously through out the processes of growth and cell division. While fragile, these reaction systems have been running uninterruptedly for billions of years.
There is a second system, more or less fully formed, present in and inherited from LUCA, the DNA-based genetic information storage and retrieval system. The cell’s DNA (its genotype) encodes the “operating system” of the cell. The genotype interacts with and shapes the cell’s reaction systems to produce phenotypes, what the organism looks like and how it behaves, that is how it reacts to and interacts with the rest of the world. Because DNA is thermodynamically unstable, the information it contains, encoded in the sequences of nucleotides within it, and read out by the reaction systems, can be altered – it can change (mutate) in response to its environmental chemicals, radiation, and other processes, such as errors that occur when DNA is replicated. Once mutated, the change is stable, it becomes part of the genotype.
The mutability of DNA could be seen as a design flaw; you would not want the information in a computer file to be randomly altered over time or when copied. In living systems, however, the mutability of DNA is a feature – together with the effects of mutations on a cell’s reproductive success mutations lead to evolutionary change. Over time, they convert the noise of mutation into evolutionary adaptations and diversification of life.
Organisms rarely exist in isolation. Our conceptual picture of LUCA is not complete until we include social interactions (background: aggregative and clonal metazoans). Cells (organisms) interact with one another in complex ways, whether as individuals within a microbial community, as cells within a multicellular organism, or in the context of predator-prey, host-pathogen and symbiotic interactions. These social processes drive a range of biological behaviors including what, at the individual cell level, can be seen as cooperative and self-sacrificing. The result is the production of even more complex biological structures, from microbial biofilms to pangolins and human beings, and complex societies. The breakdown of such interactions, whether in response to pathogens, environmental insult, mutations, politicians’ narcissistic behaviors and the madness of crowds, underlie a wide range of aberrant and pathogenic outcomes – after all cancer is based on the anti-social behavior of tumor cells.
The devil is in the details – from the conceptual to the practical: What a biologist/ bioengineer rapidly discovers when called upon to fix the effects of a mutation, defeat a pathogen, or repair a damaged organ is that biological systems are mechanistically more complex that originally thought, and are no means intelligently designed. There are a number of sources for this biological complexity. First, and most obviously, modern cells (as well as LUCA) are not intelligently designed systems – they are the product of evolutionary processes, through which noise is captured in useful forms. These systems emerge rather than are imposed (as is the case with humanly designed objects). Second, within the cell there is a high concentration of molecules that interact with one another, often in unexpected ways. As examples of molecular interactions that my lab has worked on, the protein β-catenin – originally identified as playing a role in cell adhesion and cytoskeletal organization, has a second role as a regulator of gene expression (link). The protein Chibby, a component of the basal body of cilia (a propeller-like molecular machine involved in moving fluids) has a second role as an inhibitor of β-catenin’s gene regulatory activity (link), while centrin-2. another basal body component, plays a role in the regulation of DNA repair and gene expression (link). These are interactions that have emerged during the process of evolution – they work, so they are retained.
More evidence as to the complexity of biological systems is illustrated by studies that examined the molecular targets of specific anti-cancer drugs (see Lowe 2019. Your Cancer Targets May Not Be Real). The authors of these studies used the CRISPR-Cas9 system to knock out the gene encoding a drugs’ purported target; they found that the drug continued to function (see Lin et al., 2019). At the same time, a related study raises a note of caution. Smits et al (2019) examined the effects of what were expected to be CRISPR-CAS9-induced “loss of function” mutations. They found expression of the (mutated) targeted gene, either by using alternative promoters (RNA synthesis start sites) or alternative translation start sites. The results were mutant polypeptides that retained some degree of wild type activity. Finally, in a system that bears some resemblance to the CRISPR system was found in mutations that induce what is known as non-sense mediated decay. A protection against the synthesis of aberrant (toxic) mutant polypeptides, one effect of non-sense mediated decay is to lead to the degradation of the mutant RNA. As described by Wilkinson (2019. Genetic paradox explained by nonsense) the resulting RNA fragments can be transported back into the nucleus where they interact with proteins involved in the regulation of gene expression, leading to the expression of genes related to the originally mutated gene. The expression of these related genes can modify the phenotype of the original mutation.
Biological systems are further complicated by the fact that the folding of polypeptides and the assembly of proteins (background: polypeptides and proteins) is mediated by a network of chaperone proteins, that act to facilitate correct, and suppress incorrect, folding, interactions, and assembly of proteins. This chaperone network helps explain the ability of cells to tolerate a range of genetic variations; they render cells more adaptive and “non-fragile”. Some chaperones are constitutively expressed and inherited when cells divide, the synthesis of others is induced in response to environmental stresses, such as increased temperatures (heat shock). The result is that, in some cases, the phenotypic effects of a mutation on a target protein may not be primarily due to the absence of the mutated protein, but rather to secondary effects, effects that can be significantly ameliorated by the expression of molecular chaperones (discussed in Klymkowsky. 2019 Filaments and phenotypes).
As one more, but certainly not the last, complexity, there is the phenomena by which “normal” cells interact with cells that are discordant with respect to some behavior (Di Gregorio et al 2016).1 These cells, termed “fit and unfit” and “winners and losers”, clearly socially inappropriate and unfortunate terms, interact in unexpected ways. The eccentricity of these cells can be due to various stochastic processes, including monoallelic expression (Chess, 2016), that lead to clones that behave differently (background: Biology education in the light of single cell/molecule studies). Akieda et al (2019) describe the presence of cells that respond inappropriately to a morphogen gradient during embryonic development. These eccentric cells are “out of step” with their neighbors are induced to die. Experimentally blocking their execution leads to defects in subsequent development. Similar competitive effects are described by Ellis et al (2019. Distinct modes of cell competition shape mammalian tissue morphogenesis). That said, not all eccentric behaviors lead to cell death. In some cases the effect is more like an ostracism, cells responding inappropriately migrate to a more hospitable region (Xiong et al., 2013).
All of which is to emphasize that while conceptually simple, biologically systems, and their responses to mutations and other pathogenic insults, are remarkably complex and unpredictable – a byproduct of the unintelligent evolutionary processes that produced them.
It is common to think of teaching as socially and politically beneficial, or at least benign, but Donovan et al. (2019. ” Toward a more humane genetics education” Science Education 103: 529-560)(1) raises the interesting possibility, supported by various forms of analysis and a thorough review of the literature, that conventional approaches to teaching genetics can exacerbate students’ racialist ideas. A focus on genetic diseases associated with various population groups, say for example Tay-Sachs disease within Eastern European Jewish populations of sickle cell anemia within African populations, can result in more racialist and racist perspectives among students.
What is meant by racialist? Basically it is an essentialist perspective that a person is an exemplar of the essence of a group, and that all members of a particular group “carry” that essence, an essence that defines them as different and distinct from members of other groups. Such an essence may reflect a culture, or in our more genetical age, their genome, that is the versions of the genes that they possess. In a sense, their essence is more real than their individuality, an idea that contradicts the core reality of biological systems, as outlined in works by Mayr (2,3) – a mistake he termed typological thinking.
Donovan et al. go on to present evidence that exposure of students to lessons that stress the genomic similarities between humans can help. That “any two humans share 99.9% of their DNA, which means that 0.1% of human DNA varies between individuals. Studies find that, on average, 4.3% of genetic variability in humans (4.3% of the 0.1% of the variable portion of human DNA) occurs between the continental populations commonly associated with US census racial groups (i.e., Africa, Asia, Pacific Islands, and The Americas, Europe). In contrast, 95.7% of human genetic variation (95.7% of the 0.1% of variable portion of human DNA) occurs between individuals within those same groups” (italics added). And that “there is more variability in skull shape, facial structure, and blood types within racially defined populations … than there is between them.” Lessons that emphasized the genomic similarities between people and the dissimilarities within groups, appeared effective in reducing racialist ideation – they can help dispel racist beliefs while presenting the most scientifically accurate information available.
This is of particular importance given the dangers of genetic essentialism, that is the idea that we are our genomes and that our genomes determine who (and what) we are. A pernicious ideology that even the co-discover of DNA’s structure, James Watson, has fallen prey to. One pernicious aspect of such conclusions is illustrated in the critique of a recent genomic analysis of educational attainment and cognitive performance by John Warner (4).
An interesting aspect of this work is to raise the question of where, within a curriculum, should genetics go? What are the most important aspects of the complex molecular-level interaction networks that connect genotype with phenotype that need to be included in order to flesh out the overly simplified Mendelian view (pure dominant and recessive alleles, monogenic traits, and unlinked genes) often presented? A point of particular relevance given the growing complexity of what genes are and how they act (5,6). Perhaps the serious consideration of genetic systems would be better left for later in a curriculum. At the very least, it points out the molecular and genomic contexts that should be included so as to minimize the inadvertent support for racialist predilections and predispositions.
Donovan, B. M., R. Semmens, P. Keck, E. Brimhall, K. Busch, M. Weindling, A. Duncan, M. Stuhlsatz, Z. B. Bracey and M. Bloom (2019). “Toward a more humane genetics education: Learning about the social and quantitative complexities of human genetic variation research could reduce racial bias in adolescent and adult populations.” Science Education 103(3): 529-560.
Mayr (1985) The Growth of Biological Thought: Diversity, Evolution, and Inheritance. Belknap Press of Harvard University Press ISBN: 9780674364462
Mayr (1994) Typological versus population thinking. In: Conceptual issues in evolutionary biology. MIT Press, Bradford Books, 157-160. Sober E (ed)
Why we shouldn’t embrace the genetics of education. Warner J. Inside Higher Ed blog, July 26 2018 Available online (accessed Aug 22 2019)
When a building is named after a scientist, it is generally in order to honor that person’s scientific contributions. The scientist’s ideological opinions are rarely considered explicitly, although they may influence the decision at the time. In general, scientific contributions are timeless in that they represent important steps in the evolution of a discipline, often by establishing a key observation, idea, or conceptual framework upon which subsequent progress is based – they are historically important. In this sense, whether a scientific contribution was correct (as we currently understand the natural world) is less critical than what that contribution led to. The contribution marks a milestone or a turning point in a discipline, understanding that the efforts of many underlie disciplinary progress and that those contributors made it possible for others to “see further.” (2)
Since science is not about recognizing or establishing a single unchanging capital-T-Truth, but rather about developing an increasingly accurate model for how the world works, it is constantly evolving and open to revision. Working scientists are not particularly upset when new observations lead to revisions to or the abandonment of ideas or the addition of new terms to equations.(3)
Compare that to the situation in the ideological, political, or religious realms. A new translation or interpretation of a sacred text can provoke schism and remarkably violent responses between respective groups of believers. The closer the groups are to one another, the more horrific the levels of violence that emerge often are. In contrast, over the long term, scientific schools of thought resolve, often merging with one another to form unified disciplines. From my own perspective, and not withstanding the temptation to generate new sub-disciplines (in part in response to funding factors), all of the life sciences have collapsed into a unified evolutionary/molecular framework. All scientific disciplines tend to become, over time, consistent with, although not necessarily deducible from, one another, particularly when the discipline respects and retains connections to the real (observable) world.(4) How different from the political and ideological.
The historical progression of scientific ideas is dramatically different from that of political, religious, or social mores. No matter what some might claim, the modern quantum mechanical view of the atom bears little meaningful similarity to the ideas of the cohort that included Leucippus and Democritus. There is progress in science. In contrast, various belief systems rarely abandon their basic premises. A politically right- or left-wing ideologue might well find kindred spirits in the ancient world. There were genocidal racists, theists, and nationalists in the past and there are genocidal racists, theists, and nationalists now. There were (limited) democracies then, as there are (limited) democracies now; monarchical, oligarchical, and dictatorial political systems then and now; theistic religions then and now. Absolutist ideals of innate human rights, then as now, are routinely sacrificed for a range of mostly self-serving or politically expedient reasons. Advocates of rule by the people repeatedly install repressive dictatorships. The authors of the United States Constitution declare the sacredness of human rights and then legitimized slavery. “The Bible … posits universal brotherhood, then tells Israel to kill all the Amorites.” (Phil Christman). The eugenic movement is a good example; for the promise of a genetically perfect future, existing people are treated inhumanely – just another version of apocalyptic (ends justify the means) thinking.
Ignoring the simpler case of not honoring criminals (sexual and otherwise), most calls for removing names from buildings are based on the odious ideological positions espoused by the honored – typically some version of racist, nationalistic, or sexist ideologies. The complication comes from the fact that people are complex, shaped by the context within which they grow up, their personal histories and the dominant ideological milieu they experienced, as well as their reactions to it. But these ideological positions are not scientific, although a person’s scientific worldview and their ideological positions may be intertwined. The honoree may claim that science “says” something unambiguous and unarguable, often in an attempt to force others to acquiesce to their perspective. A modern example would be arguments about whether climate is changing due to anthropogenic factors, a scientific topic, and what to do about it, an economic, political, and perhaps ideological question.(5)
So what to do? To me, the answer seems reasonably obvious – assuming that the person’s contribution was significant enough, we should leave the name in place and use the controversy to consider why they held their objectionable beliefs and more explicitly why they were wrong to claim scientific justification for their ideological (racist / nationalist / sexist / socially prejudiced) positions.(6) Consider explicitly why an archeologist (Flinders Petrie), a naturalist (Francis Galton), a statistician (Karl Pearson), and an advocate for women’s reproductive rights (Marie Stopes) might all support the non-scientific ideology of eugenics and forced sterilization. We can use such situations as a framework within which to delineate the boundaries between the scientific and the ideological.
Understanding this distinction is critical and is one of the primary justifications for why people not necessarily interested in science or science-based careers are often required to take science courses. Yet all too often these courses fail to address the constraints of science, the difference between political and ideological opinions, and the implications of scientific models. I would argue that unless students (and citizens) come to understand what constitutes a scientific idea or conclusion and what reflects a political or ideological position couched in scientific or pseudo-scientific terms, they are not learning what they need to know about science or its place in society. That science is used as a proxy for Truth writ large is deeply misguided. It is much more important to understand how science works than it is to remember the number of phyla or the names of amino acids, the ability to calculate the pH of a solution, or to understand processes going on at the center of a galaxy or the details of a black hole’s behavior. While sometimes harmless, misunderstanding science and how it is used socially can result in traumatic social implications, such as drawing harmful conclusions about individuals from statistical generalizations of populations, avoidable deaths from measles, and the forced “eugenic” sterilization of people deemed defective. We should seek out and embrace opportunities to teach about these issues, even if it means we name buildings after imperfect people.
The location of some of my post-doc work.
In the words of Isaac Newton, “If I have seen further than others, it is by standing upon the shoulders of giants.”
Unless, of course, the ideas and equations being revised or abandoned are one’s own.
Perhaps the most striking exception occurs in physics on the subjects of quantum mechanics and relativity, but as I am not a physicist, I am not sure about that.
Perhaps people are “meant” to go extinct.
The situation is rather different outside of science, because the reality of progress is more problematic and past battles continue to be refought. Given the history of Reconstruction and the Confederate “Lost Cause” movement [see PBS’s Reconstruction] following the American Civil War, monuments to defenders of slavery, no matter how admirable they may have been in terms of personal bravery and such, reek of implied violence, subjugation, and repression, particularly when the person honored went on to found an institution dedicated to racial hatred and violent intimidation [link]. There would seem little doubt that a monument in honor of a Nazi needs to be eliminated and replaced by one to their victims or to those who defeated them.
Michael Reiss, a professor of science education at University College London and an Anglican Priest, suggests that “we need to rethink the way we teach evolution” largely because conventional approaches can be unduly confrontational and “force religious children to choose between their faith and evolution” or to result in students who”refuse to engage with a lesson.” He suggests that a better strategy would be akin to those use to teach a range of “sensitive” subjects “such as sex, pornography, ethnicity, religion, death studies, terrorism, and others” and could “help some students to consider evolution as a possibility who would otherwise not do so.” [link to his original essay and a previous post on teaching evolution: Go ahead and teach the controversy].
There is no doubt that an effective teacher attempts to present materials sensitively; it is the rare person who will listen to someone who “teaches” ideas in a hostile, alienating, or condescending manner. That said, it can be difficult to avoid the disturbing implications of scientific ideas, implications that can be a barrier to their acceptance. The scientific conclusion that males and females are different but basically the same can upset people on various sides of the theo-political spectrum.
In point of fact an effective teacher, a teacher who encourages students to question their long held, or perhaps better put, familial or community beliefs, can cause serious social push-back – Trouble with a capital T. It is difficult to imagine a more effective teacher than Socrates (~470-399 BCE). Socrates “was found guilty of ‘impiety’ and ‘corrupting the young’, sentenced to death” in part because he was an effective teacher (see Socrates was guilty as charged). In a religious and political context, challenging accepted Truths (again with a capital T) can be a crime. In Socrates’ case”Athenians probably genuinely felt that undesirables in their midst had offended Zeus and his fellow deities,” and that, “Socrates, an unconventional thinker who questioned the legitimacy and authority of many of the accepted gods, fitted that bill.”
So we need to ask of scientists and science instructors, does the presentation of a scientific, that is, a naturalistic and non-supernatural, perspective in and of itself represent an insensitivity to those with a super-natural belief system. Here it is worth noting a point made by the philosopher John Gray, that such systems extend beyond those based on a belief in god(s); they include those who believe, with apocalyptic certainty, in any of a number of Truths, ranging from the triumph of a master race, the forced sterilization of the unfit, the dictatorship of the proletariat, to history’s end in a glorious capitalist and technological utopia. Is a science or science instruction that is “sensitive” to, that is, uncritical of or upsetting to those who hold such beliefs, possible?
My original impression is that one’s answer to this question is likely to be determined by whether one considers science a path to Truth, with a purposeful capital T, or rather that the goal of scientists is to build a working understanding of the world around and within us. Working scientists, and particularly biologists who must daily confront the implications of apparently un-intelligent designed organisms (due to ways evolution works) are well aware that absolute certainty is counterproductive. Nevertheless, the proven explanatory and technological power of the scientific enterprise cannot help but reinforce the strong impression that there is some deep link between scientific ideas and the way the world really works. And while some scientists have advocated unscientific speculations (think multiverses and cosmic consciousness), the truth, with a small t, of scientific thinking is all around us.
Photograph of the Milky Way by Tim Carl photography, used by permission
A science-based appreciation of the unimaginable size and age of the universe, taken together with compelling evidence for the relatively recent appearance of humans (Homo sapiens from their metazoan, vertebrate, tetrapod, mammalian, and primate ancestors) cannot help but impact our thinking as to our significance in the grand scheme of things (assuming that there is such a, possibly ineffable, plan)(1). The demonstrably random processes of mutation and the generally ruthless logic by which organisms survive, reproduce, and evolve, can lead even the most optimistic to question whether existence has any real meaning.
Consider, as an example, the potential implications of the progress being made in terms of computer-based artificial intelligence, together with advances in our understanding of the molecular and cellular connection networks that underlie human consciousness and self-consciousness. It is a small step to conclude, implicitly or explicitly, that humans (and all other organisms with a nervous system) are “just” wet machines that can (and perhaps should) be controlled and manipulated. The premise, the “self-evident truth”, that humans should be valued in and of themselves, and that their rights should be respected (2) is eroded by the ability of machines to perform what were previously thought to be exclusively human behaviors.
Humans and their societies have, after all, been around for only a few tens of thousands of years. During this time, human social organizations have passed from small wandering bands influenced by evolutionary kin and group selection processes to produce various social systems, ranging from more or less functional democracies, pseudo-democracies (including our own growing plutocracy), dictatorships, some religion-based, and totalitarian police states. Whether humans have a long term future (compared to the millions of years that dinosaurs dominated life on Earth) remains to be seen – although we can be reasonably sure that the Earth, and many of its non-human inhabitants, will continue to exist and evolve for millions to billions of years, at least until the Sun explodes.
So how do we teach scientific conclusions and their empirical foundations, which combine to argue that science represents how the world really works, without upsetting the most religiously and politically fanatical among us? Those who most vehemently reject scientific thinking because they are the most threatened by its apparently unavoidable implications. The answer is open to debate, but to my mind it involves teaching students (and encouraging the public) to distinguish empirically-based, and so inherently limited observations and the logical, coherent, and testable scientific models they give rise to from unquestionable TRUTH- and revelation-based belief systems. Perhaps we need to focus explicitly on the value of science rather than its “Truth”. To reinforce what science is ultimately for; what justifies society’s support for it, namely to help reduce human suffering and (where it makes sense) to enhance the human experience, goals anchored in the perhaps logically unjustifiable, but nevertheless essential acceptance of the inherent value of each person.
Apologies to “Good Omens”
For example, “We hold these truths to be self-evident, that all men are created equal, that they are endowed by their creator with certain unalienable rights, that among these are life, liberty and the pursuit of happiness.”
Montaigne concludes, like Socrates, that ignorance aware of itself is the only true knowledge” – from “forbidden knowledge” by Roger Shattuck
A month or so ago we were treated to a flurry of media excitement surrounding the release of the latest Pew Research survey on Americans’ scientific knowledge. The results of such surveys have been interpreted to mean many things. As an example, the title of Maggie Koerth-Baker’s short essay for the 538 web site was a surprising “Americans are Smart about Science”, a conclusion not universally accepted (see also). Koerth-Baker was taken by the observation that the survey’s results support a conclusion that Americans’ display “pretty decent scientific literacy”. Other studies (see Drummond & Fischhoff 2017) report that one’s ability to recognize scientifically established statements does not necessarily correlate with the acceptance of science policies – on average climate change “deniers” scored as well on the survey as “acceptors”. In this light, it is worth noting that science-based policy pronouncements generally involve projections of what the future will bring, rather than what exactly is happening now. Perhaps more surprisingly, greater “science literacy” correlates with more polarized beliefs that, given the tentative nature of scientific understanding –which is not about truth per se but practical knowledge–suggests that the surveys’ measure something other than scientific literacy. While I have written on the subject before it seems worth revisiting – particularly since since then I have read Rosling’s FactFullness and thought more about the apocalyptic bases of many secular and religious movements, described in detail by the historian Norman Cohn and the philosopher John Gray and gained a few, I hope, potentially useful insights on the matter.
First, to understand what the survey reports we should take a look at the questions asked and decide what the ability to chose correctly implies about scientific literacy, as generally claimed, or something simpler – perhaps familiarity. It is worth recognizing that all such instruments, particularly those that are multiple choice in format, are proxies for a more detailed, time consuming, and costly Socratic interrogation designed to probe the depth of a persons’ knowledge and understanding. In the Pew (and most other such surveys) choosing the correct response implies familiarity with various topics impacted by scientific observations. They do not necessarily reveal whether or not the respondent understands where the ideas come from, why they are the preferred response, or exactly where and when they are relevant (2). So is “getting the questions correct” demonstrates a familiarity with the language of science and some basic observations and principles but not the limits of respondents’ understanding.
Take for example the question on antibiotic resistance (→). The correct answer “it can lead to antibiotic-resistant bacteria” does not reveal whether the respondent understands the evolutionary (selective) basis for this effect, that is random mutagenesis (or horizontal gene transfer) and antibiotic-resistance based survival. It is imaginable that a fundamentalist religious creationist could select the correct answer based on plausible, non-evolutionary mechanisms (3). In a different light, the question on oil, natural gas and coal (↓) could be seen as ambiguous – aren’t these all derived from long dead organisms, so couldn’t they reasonably be termed biofuels?
While there are issues with almost any such multiple choice survey instrument, surely we would agree that choosing the “correct” answers to these 11 questions reflects some awareness of current scientific ideas and terminologies. Certainly knowing (I think) that a base can neutralize and acid leaves unresolved how exactly the two interact, that is what chemical reaction is going on, not to mention what is going on in the stomach and upper gastrointestinal tract of a human being. In this case, selecting the correct answer is not likely to conflict with one’s view of anthropogenic effects on climate, sex versus gender, or whether one has an up to date understanding of the mechanisms of immunity and brain development, or the social dynamics behind vaccination – specifically the responsibilities that members of a social group have to one another.
But perhaps a more relevant point is our understanding of how science deals with the subject of predictions, because at the end of the day it is these predictions that may directly impact people in personal, political, and economically impactful ways.
We can, I think, usefully divide scientific predictions into two general classes. There are predictions about a system that can be immediately confirmed or dismissed through direct experiment and observation and those that cannot. The immediate (accessible) type of prediction is the standard model of scientific hypothesis testing, an approach that reveals errors or omissions in one’s understanding of a system or process. Generally these are the empirical drivers of theoretical understanding (although perhaps not in some areas of physics). The second type of prediction is inherently more problematic, as it deals with the currently unobservable future (or the distant past). We use our current understanding of the system, and various assumptions, to build a predictive model of the system’s future behavior (or past events), and then wait to see if they are confirmed. In the case of models about the past, we often have to wait for a fortuitous discovery, for example the discovery of a fossil that might support or disprove our model.
It’s tough to make predictions, especially about the future – Yogi Berra (apparently)
Anthropogenic effects on climate are an example of the second type of prediction. No matter our level of confidence, we cannot be completely sure our model is accurate until the future arrives. Nevertheless, there is a marked human tendency to take predictions, typically about the end of the world or the future of the stock market, very seriously and to make urgent decisions based upon them. In many cases, these predictions impact only ourselves, they are personal. In the case of climate change, however, they are likely to have disruptive effects that impact many. Part of the concern about study predictions is that responses to these predictions will have immediate impacts, they produce social and economic winners and losers whether or not the predictions are confirmed by events. As Hans Rosling points out in his book Factfullness, there is an urge to take urgent, drastic, and pro-active actions in the face of perceived (predicted) threats. These recurrent and urgent calls to action (not unlike repeated, and unfulfilled predictions of the apocalypse) can lead to fatigue with the eventual dismissal of important warnings; warnings that should influence albeit perhaps not dictate ecological-economic and political policy decisions.
Footnotes and literature cited: 1. As a Pew Biomedical Scholar, I feel some peripheral responsibility for the impact of these reports
2. As pointed out in a forthcoming review, the quality of the distractors, that is the incorrect choices, can dramatically impact the conclusions derived from such instruments.
3. I won’t say intelligent design creationist, as that makes no sense. Organisms are clearly not intelligently designed, as anyone familiar with their workings can attest
Drummond, C. & B. Fischhoff (2017). “Individuals with greater science literacy and education have more polarized beliefs on controversial science topics.” Proceedings of the National Academy of Sciences 114: 9587-9592.
Embryogenesis is based on a framework of social (cell-cell) interactions, initial and early asymmetries, and cascading cell-cell signaling and gene regulatory networks (DEVO posts one, two, & three). The result is the generation of embryonic axes, germ layers (ectoderm, mesoderm, endoderm), various organs and tissues (brains, limbs, kidneys, hearts, and such) and their characteristic cell types, their patterning, and their coordination into a functioning organism. It is well established that all animals share a common ancestor (hundreds of millions of years ago) and that a number of molecularmodules were already present in that common ancestor.
At the same time evolutionary processes are, and need to be, flexible enough to generate the great diversity of organisms, with their various adaptations to particular life-styles. The extent of both conservation and flexibility (new genes, new mechanisms) in developmental systems is, however, surprising. Perhaps the most striking evidence for the depth of this conservation was supplied by the discovery of the organization of the Hox gene cluster in the fruit fly Drosophila and in the mouse (and other vertebrates). In both, the Hox genes are arranged and expressed in a common genomic and expression patterns. But as noted by Denis Duboule (2007) Hox gene organization is often presented in textbooks in a distorted manner (↓).
The Hox gene clusters of vertebrates are compact, but are split, disorganized, and even “atomized” in other types of organisms. Similarly, processes that might appear foundational, such as the role of the Bicoid gradient in the early fruit fly embryo (a standard topic in developmental biology textbooks), is in fact restricted to a small subset of flies (Stauber et al., 1999). New genes can be generated through well defined processes, such as gene duplication and divergence, or they can arise de novo out of sequence noise (Carvunis et al., 2012; Zhao et al., 2014 – see Van Oss & Carvunis 2019. De novo gene birth). Comparative genomic analyses can reveal the origins of specific adaptations (see Stauber et al., 1999).The result is that organisms as closely related to each other as the great apes (including humans) have significant species-specific genetic differences (see Florio et al., 2018; McLean et al., 2011; Sassa, 2013 and references therein) as well as common molecular and cellular mechanisms.
A universal (?) feature of developing systems – gradients and non-linear responses: There is a predilection to find (and even more to teach) simple mechanisms that attempt to explain everything (witness the distortion of the Hox cluster, above) – a form of physics “theory of everything” envy.But the historic nature, evolutionary plasticity, and need for regulatory robustness generally lead to complex and idiosyncratic responses in biological systems.Biological systems are not “intelligently designed” but rather cobbled together over time through noise (mutation) and selection (Jacob, 1977)(see blog post).
That said, acommon (universal?) developmental process appears to be the transformation of asymmetries into unambiguous cell fate decisions. Such responses are based on threshold events controlled by a range of molecular behaviors, leading to discrete gene expression states. We can approach the question of how such decisions are made from both an abstract and a concrete perspective. Here I outline my initial approach – I plan to introduce organism specific details as needed.I start with the response to a signaling gradient, such as that found in many developmental systems, including the vertebrate spinal cord (top image Briscoe and Small, 2015) and the early Drosophila embryo (Lipshitz, 2009)(↓).
We begin with a gradient in the concentration of a “regulatory molecule” (the regulator).The shape of the gradient depends upon the sites and rates of synthesis, transport away from these sites, and turnover (degradation and/or inactivation). We assume, for simplicity’s sake, that the regulator directly controls the expression of target gene(s). Such a molecule binds in a sequence specific manner to regulatory sites, there could be a few or hundreds, and lead to the activation (or inhibition) of the DNA-dependent, RNA polymerase (polymerase), which generates RNA molecules complementary to one strand of the DNA. Both the binding of the regulator and the polymerase are stochastic processes, driven by diffusion, molecular collisions, and binding interactions.(1)
Let us now consider the response of target gene(s) as a function of cell position within the gradient. We might (naively) expect that the rate of target gene expression would be a simple function of regulator concentration. For an activator, where the gradient is high, target gene expression would be high, where the gradient concentration is low, target gene expression would be low – in between, target gene expression would be proportional to regulator concentration.But generally we find something different, we find that the expression of target genes is non-uniform, that is there are thresholds in the gradient: on one side of the threshold concentration the target gene is completely off (not expressed), while on the other side of the threshold concentration, the target gene is fully on (maximally expressed).The target gene responds as if it is controlled by an on-off switch. How do we understand the molecular basis for this behavior?
Distinct mechanisms are used in different systems, but we will consider a system from the gastrointestinal bacteria E. coli that students may already be familiar with; these are the genes that enable E. coli to digest the mammalian milk sugar lactose.They encode a protein needed to importlactose into a bacterial cell and an enzyme needed to break lactose down so that it can be metabolized.Given the energetic cost to synthesize these proteins, it is in the bacterium’s adaptive self interest to synthesize them only when lactose is present at sufficient concentrations in their environment.The response is functionally similar to that associated with quorum sensing, which is also governed by threshold effects. Similarly cells respond to the concentration of regulator molecules (in a gradient) by turning on specific genes in specific domains, rather than uniformly.
Now let us look in a little more detail at the behavior of the lactose utilization system in E. coli following an analysis by Vilar et al (2003)(2).At an extracellular lactose concentration below the threshold, the system is off.If we increase the extracellular lactose concentration above threshold the system turns on, the lactose permease and β-galactosidase proteins are made and lactose can enter the cell and be broken down to produce metabolizable sugars.By looking at individual cells, we find that they transition, apparently stochastically from off to on (→), but whether they stay on depends upon the extracellular lactose concentration. We can define a concentration, the maintenance concentration, below the threshold, at which “on” cells will remain on, while “off” cells will remain off.
The circuitry of the lactose system is well defined(Jacob and Monod, 1961; Lewis, 2013; Monod et al., 1963)(↓).The lacI gene encodes the lactose operon repressor protein and it is expressed constituately at a low level; it binds to sequences in the lac operon and inhibits transcription.The lac operon itself contains three genes whose expression is regulated by a constituatively active promoter.LacY encodes the permease while the lacZ encodes β-galactosidase.β-galactosidase has two functions: it catalyzes the reaction that transforms lactose into allolactone and it cleaves lactose into the metabolically useful sugars glucose and galactose. Allolactone is an allosteric modulator of the Lac repressor protein; if allolactone is present, it binds to lac epressor proteins and inactivates them, allowing lac operon expression.
The cell normally contains only ~10 lactose repressor proteins. Periodically (stochastically), even in the absence of lactose, and so its derivative allolactone, the lac operon promoter region is free of repressor proteins, and a lactose operon is briefly expressed – a few LacY and LacZpolypeptides are synthesized (↓).This noisy leakiness in the regulation of the lac operon allows the cell to respond if lactose happens to be present – some lactose molecules enter the cell through the permease, are converted to allolactone by β-galactosidase.Allolactone is an allosteric effector of the lac repressor; when present it binds to and inactivates the lac repressor protein so that it no longer binds to its target sequences (the operator or “O” sites).In the absence of repressor binding, the lac operon is expressed.If lactose is not present, the lac operon is inhibited and lacY and LacZ disappear from the cell by turnover or growth associated dilution.
The question of how the threshold concentration for various signal-regulated decisions is set often involves homeostatic processes that oppose the signaling response. The binding and activation of regulators can involve cooperative interactions between molecular components and both positive and negative feedback effects.
In the case of patterning a tissue, in terms of regional responses to a signaling gradient, there can be multiple regulatory thresholds for different genes, as well as indirect effects, where the initiation of gene expression of one set of target genes impacts the sensitive expression of subsequent sets of genes.One widely noted mechanism, known as reaction-diffusion, was suggested by the English mathematician Alan Turing (see Kondo and Miura, 2010) – it postulates a two component system. One component is an activator of gene expression, which in addition to its own various targets, positively regulates its own expression. The second component is a repressor of the first.Both of these two regulator molecules are released by the signaling cell or cells; the repressor diffuses away from the source faster than the activator does.The result can be a domain of target gene expression (where the concentration of activator is sufficient to escape repression), surrounded by a zone in which expression is inhibited (where repressor concentration is sufficient to inhibit the activator).Depending upon the geometry of the system, this can result in discrete regions (dots or stripes) of primary target gene expression (see Sheth et al., 2012).In real systems there are often multiple gradients present; their relative orientations can produce a range of patterns.
The point of all of this, is that when we approach a particular system – we need to consider the mechanisms involved.Typically they are selected to produce desired phenotypes, but also to be robust in the sense that they need to produce the same patterns even if the system in which they occur is subject to perturbations, such as embryo/tissue size (due to differences in cell division / growth rates) and temperature and other environmental variables.
note: figures returned – updated 13 November 2020.
While stochastic (random) these processes can still be predictable.A classic example involves the decay of an unstable isotope (atom), which is predictable at the population level, but unpredictable at the level of an individual atom.Similarly, in biological systems, the binding and unbinding of molecules to one another, such as a protein transcription regulator to its target DNA sequence is stochastic but can be predictable in a large enough population.