Tag: science

Molecular bumper cars (RNA polymerase-ribosomal interactions): their (unexpected) functional effects and how to control them

Cells are extremely complex.1 Much of their “core” complexity appears to have been present in their last (universal) common ancestor, known as LUCA. We find it in the “conserved” molecular mechanisms and machines active in modern cells. LUCA and its offspring are membrane-bounded, non-equilibrium systems that import free energy and export entropy to maintain and repair themselves, to grow, behave, and reproduce (and all the other things living things do). One problem, however, with LUCA is that it makes speculation on the steps that preceded it impossible to know with certainty. Not withstanding claims of breakthroughs (e.g. ‘Monumental’ experiment suggests how life on Earth may have started“), it is likely that we will never know the actual steps involved; after all, the origin of life occurred billions of years ago and under rather different conditions than exist today.

Living systems “work” based on inherited, pre-existing molecular machines and mechanisms (1). The actions of these machines are fueled through coupling to thermodynamically favorable reactions taking place under non-equilibrium conditions, i.e. the living state. Looking at the details of these interactions reveals interesting and unexpected behaviors. Unfortunately, the “simple” physical-chemical underpinnings of these processes, key to understanding them, are not always presented to students effectively (2).  At the same time, the complexity of cellular systems means that in practice, the link between “simple” molecular mechanisms and the behavior of a biological systems can be obscure (see 3).  That said, key insights are illuminated when molecular mechanisms are examined, as illustrated by Wee et al., (2023)(4).  

Emerging from LUCA, biological populations have diverged into distinct “prokaryotic” lineages: the bacteria and archaea.2 Both are defined by a protein-lipid boundary layer, the plasma membrane. Within this membrane is a single internal compartment, the cytoplasm. Information is stored in cells in two forms, first in the on-going LUCA-derived living system and the second, information in the sequence of double-stranded DNA molecules. These two types of information are interdependent: the information in DNA makes sense only within a cell and the on-going cellular processes depend upon and utilize the information in DNA. In bacteria and archaea, these are circular double-stranded DNA molecules. Here we restrict our discussion to the common unicellular bacterium Escherichia coli (E. coli), one of the workhorse systems that led to an understanding of core molecular mechanisms.  

E. coli hasa single circular genomic DNA molecule of ~5 million nucleotide base pairs in length; it contains about 5000 distinct genes that encode polypeptides and functional “non-coding” RNA molecules (if you are interested in numbers, check out bionumbers).  An E. coli cell is rod-shaped and ~1 micrometer (10-6 meters) long. Its genomic DNA molecule is ~1000 times longer than the cell that contains it, and a rapidly dividing cell can contain multiple copies of the genome. Genes typically contain two distinct functional regions. Regulatory regions interact with various proteins that determine whether a gene is “expressed” or not. Coding regions specify what is expressed. The first step is the synthesis of an RNA molecule; such a molecule can encode a polypeptide or a non-coding RNA.3 Non-coding RNAs can have structural, catalytic, or regulatory functions.  

The first step in gene expression in all cell types is the binding of proteins to a gene’s regulatory sequences. Typically a complex of proteins leads to the binding and activation of a DNA-dependent, RNA polymerase. The RNA polymerase complex unwinds a specific region of the DNA and uses the complementary nature of nucleotide base pairing: A binding to T in DNA and U in RNA, and C binding to G in both, to synthesize an RNA molecule based on DNA sequence. Synthesis of RNAs that encode polypeptides, known as messenger RNAs (mRNAs) starts with the 5′ end of the molecule and moves toward the 3′ end (replaced ↓ soon).

In prokaryotic cells, both DNA and mRNA synthesis reactions occur in the cytoplasm. A ribosome, a molecular machine composed of multiple proteins and RNAs, can engage the 5′ end region of an mRNA as soon as it appears – before the synthesis of the mRNA is complete. The cytoplasm of a cell contains lots of ribosomes; in E. coli there are ~70,000 ribosomes per cell (more or less). This leads to some interesting and functionally significant interactions.  One thing to consider, not always stressed, is that these synthetic processes are not error proof.  DNA replication (DNA-directed, DNA synthesis), transcription (DNA-directed, RNA synthesis), and polypeptide synthesis (RNA-directed, polypeptide synthesis) all have an error rate, typically 1 error per ~106 addition events for DNA replication and transcription. Errors can lead to mutations in the DNA, RNAs that encode abnormal proteins, or abnormal and potentially toxic polypeptides.

To deal with physical realities, these synthetic processes employ various “error correction” strategies.  In the case of DNA and RNA synthesis, the polymerases involved have what is known as “proof-reading” activities. If the incorrect nucleotide is inserted into a growing DNA or RNA chain, it can be recognized; the polymerase can then “reverse” (move backward along the DNA), remove the mistakenly inserted nucleotide, and then move forward again, adding the correct nucleotide. Key here is that the polymerase is moving back and forth along the DNA strand. The result of proof-reading is to reduce the error rate of DNA-dependent DNA and RNA synthesis substantially, down to 10-8 to 10-10 per base pair in the case of DNA synthesis.  

In the case of the RNA polymerase, the newly synthesized RNA can fold back on itself, forming what is known as a “hairpin”. This hairpin “can stabilize an elemental pause (in RNA synthesis) an allosteric interaction with the β-flap tip helix of RNAP”. What Wee et al (4) report is as the mRNA-associated ribosome moves along the RNA it unfold the hairpin and “bumps” into the polymerase, inhibiting this “pause” which increases the rate of mRNA synthesis and inhibits the polymerase’s error correction function. The resulting mRNA population has more frequent base pair changes, errors that can influence the polypeptides synthesized. While cells of all types have various  “chaperone” systems that can deal with misfolded proteins that arise in response to various stresses or errors, these can be overwhelmed. The resulting misfolded (damaged) proteins can lead to cellular defects and long term effects on viability (discussed in 5).  

About 1.5 billion years later (give or take), a new type of cell appeared, the result (apparently) of a symbiotic interaction between an archaeal-like “host” and a O2-utilizing bacterium.  This synthetic organism, the progenitor of the eukaryotes, differed from either type of prokaryote in that it sequestered its genome, now composed of linear DNA molecules, within a double membrane bounded “nuclear” compartment. In this hybrid cell type, DNA and RNA synthesis was confined to the nucleus, while ribosomes and polypeptide synthesis were confined to the cytoplasm. Eukaryotic cells are typically much larger that prokaryotic cells, reproduce more slowly, and are more complex in terms of the numbers of genes, and the amount of genomic DNA they contain. It is tempting to speculated that while rapidly dividing, relatively simple prokaryotic cells may be able to tolerate more mistakes in terms of the synthesis of their polypeptides, larger, more complex eukaryotic cells would be vulnerable. A plausible result would be a selection pressure to separating RNA from polypeptide synthesis.

literature cited

  1. Alberts, B. (1998). The cell as a collection of protein machines: preparing the next generation of molecular biologists. Cell, 92, 291-294.
  2. de Lorenzo, V., 2024. The principle of uncertainty in biology: Will machine learning/artificial intelligence lead to the end of mechanistic studies?. Plos Biology, 22, p.e3002495.
  3. Klymkowsky, M.W., 2021. Making mechanistic sense: are we teaching students what they need to know? Developmental Biology, 476, pp.308-313.
  4. Wee et al., 2023. A trailing ribosome speeds up RNA polymerase at the expense of transcript fidelity via force and allostery. Cell, 186, pp.1244-1262.
  5. Klymkowsky, M.W., 2019. Filaments and phenotypes: cellular roles and orphan effects associated with mutations in cytoplasmic intermediate filament proteins. F1000Research, 8.

Footnotes

  1. if you want brush up on you molecular biology, check out chapter 7 of biofundamentals  ↩︎
  2. Image from Govindjee – doi:10.3389/fpls.2011.00028, CC BY 3.0.  Given the diversity of biological systems, these are general descriptions – often there a exceptions, but recognizing them all makes generating a coherent narrative difficult (and beyond me).  Mea culpa.    ↩︎
  3. bioliteracy link: When is a gene product a protein when is it a polypeptide? ↩︎

Is it possible to teach evolutionary biology “sensitively”?

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.   

  1. Apologies to “Good Omens”
  2. 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.” 

From the Science March to the Classroom: Recognizing science in politics and politics in science

Jeanne Garbarino (with edits by Mike Klymkowsky)

Purely scientific discussions are hallmarked by objective, open, logical, and skeptical thought; they can describe and explain natural phenomena or provide insights into a broader questions. At the same time, scientific discussions are generally incomplete and tentative (sometimes for well understood reasons). True advocates of the scientific method appreciate the value of its skeptical and tentative approach, and are willing to revise even long-held positions in response to new, empirically-derived evidence or logical contradictions. Over time, science’s scope and conclusions have expanded and evolved dramatically; they provide an increasingly accurate working model of a wide range of processes, from the formation of the universe to the functioning of the human mind. The result is that the ubiquity of science’s impacts on society are clear and growing. However, discussing and debating the details of how science works, and the current consensus view on various phenomena, such as global warming or the causes of cancer or autism, is very different from discussing and debating how a scientific recommendation fits into a societal framework. As described in a recent National Academies Press report on Communicating Science Effectively  [link], “the decision to communicate science [outside of academia] always involves an ethical component. Choices about what scientific evidence to communicate and when, how, and to whom, are a reflection of values.”

Over the last ~150 years, the accelerating pace of advances in science and technology have enabled future sustainable development, but they have also disrupted traditional social and economic patterns. Closing coal mines in response to climate predictions (and government regulations) may be sensible when viewed broadly, but are disruptive to those who have, for generations, made a living mining coal. Similarly, a number of prognosticators have speculated on the impact of robotics and artificial intelligence on traditional socioeconomic roles and rules. Whether such impacts are worth the human costs is rarely explicitly considered and discussed in the public forum, or the classroom. As members of the scientific community, our educational and outreach efforts must go beyond simply promoting an appreciation of, and public support for science. They must also consider its limitations, as well as the potential ethical and disruptive effects on individuals, communities, and/or societies. Making policy decisions with large socioeconomic impacts based on often tentative models raises risks of alienating the public upon which modern science largely depends.

Citizens, experts or not, are often invited to contribute to debates and discussions surrounding science and technology at the local and national levels. Yet, many people are not provided with the tools to fully and effectively engage in these discussions, which involves critically analyzing the scope, resolution, and stability of scientific conclusions. As such, the acceptance or rejection of scientific pronouncements is often framed as an instrument of political power, casting a shadow on core scientific principles and processes, framing scientists as partisan players in a political game. The watering down of the role of science and science-based policies in the public sphere, and the broad public complacency associated with (often government-based, regulatory) efforts, is currently being challenged by the international March For Science effort. The core principles and goals of this initiative [link] are well articulated, and, to my mind, representative of a democratic society. However, a single march on a single day is not sufficient to promote a deep social transformation, and promote widespread dispassionate argumentation and critical thinking. Perspectives on how scientific knowledge can help shape current and future events, as well as the importance of recognizing both the implications and limits of science, are perspectives that must be taught early, often, and explicitly. Social or moral decisions are not mutually exclusive from scientific evidence or ideas, but overlap is constrained by the gates set by values that are held.

In this light, I strongly believe the sociopolitical nature of science in practice must be taught alongside traditional science content. Understanding the human, social, economic and broader (ecological) costs of action AND inaction can be used to highlight the importance of framing science in a human context. If the expectation is for members of our society to be able to evaluate and weigh in on scientific debates at all levels, I believe we are morally obligated to supply future generations with the tools required for full participation. This posits that scientists and science educators, together with historian, philosophers, and economists, etc., need to go beyond the teaching of simple facts and theories by considering how these facts and theories developed over time, their impact on people’s thinking, as well as the socioeconomic forces that shape societies. Highlighting the sociopolitical implications of science-based ideas in classrooms can also motivate students to take a greater interest in scientific learning in particular, and related social and political topics in general. It can help close the gap between what is learned in school and what is required for the critical evaluation of scientific applications in society, and how scientific ideas can and should be evaluated when it comes to social policy or person beliefs.

A “science in a social context” approach to science teaching may also address the common student question, “When will I ever use this?” All too often, scientific content in schools is presented in ways that are abstract, decontextualized, and can feel irrelevant to students. Such an approach can leave a student unable or unwilling to engage in meaningful and substantive discussions on the applications and limitations of science in society. The entire concept of including cost-benefit analyses when considering the role of science in shaping decisions is often over-looked, as if scientific conclusions are black and white. Furthermore, the current culture of science in classrooms leaves little room for students to assess how scientific information does and does not align with their cultural identities, often framing science as inherently conflicting or alien, forcing a choice between one way of seeing the world over the other, when a creative synthesis seems more reasonable. Shifting science education paradigms toward a strategy that promotes “education through science” (as opposed to “science through education”) recognizes student needs and motivations as critical to learning, and opens up channels for introducing science as something that is relevant and enriching to their lives. Centered on the German philosophy of Allgemeinbildung [link] that describes “the competence for participation in critical dialogue on currently important matters,” this approach has been found to be effective in motivating students to develop the necessary skills to implement empirical evidence when forming arguments and making decisions.

In extending the idea of the perceived value of science in sociopolitical debates, students can build important frameworks for effectively engaging with society in the future. A relevant example is the increasing accessibility of genome editing technology, which represents an area of science poised to deeply impact the future of society. In a recent report [link] on the ethics of genome editing, assembled by an panel of clinicians and scientists (experts), it is recommended that the United States should proceed — cautiously — with genome editing studies on human embryos. However, as pointed out [link], this panel failed to include ANY public participation in this decision. This effort, fundamentally ignores “a more conscious evaluation of how this impacts social standing, stigma and identity, ethics that scientists often tend to cite pro forma and then swiftly scuttle.” As this discussion increasingly shifts into the mainstream, it will be essential to engage with the public in ways that promote a more careful and thoughtful analysis of scientific issues [link], as opposed to hyperbolic fear mongering (as seen in regard to most GMO discussions)[link] or reserving genetic engineering to the hyper-affluent. Another, more timely example, involves the the level at which an individual’s genome be used to predict a future outcome or set of outcomes, and whether this information can be used by employers in any capacity [link]. By incorporating a clear description of how science is practiced (including the factors that influence what is studied, and what is done with the knowledge generated), alongside the transfer of traditional scientific knowledge, we can help provide future citizens with tools for critical evaluation as they navigate these uncharted waters.

It is also worth noting tcorrupted sciencehat the presentation of science in a sociopolitical contexts can emphasize learning of more than just science. Current approaches to education tend to compartmentalize academic subjects, framing them as standalone lessons and philosophies. Students go through the school day motions, attending English class, then biology, then social studies, then trigonometry, etc., and the natural connections among subject areas are often lost. When framing scientific topics in the context of sociopolitical discussions and debates, stu
dents have more opportunities to explore aspects of society that are, at face value, unrelated to science.

Drawing from lessons commonly taught in American History class, the Manhattan Project [link] offers an excellent opportunity to discuss the fundamentals of nuclear chemistry as well as sociopolitical implications of a scientific discovery. At face value, harnessing nuclear fission marked a dramatic milestone for science. However, when this technology was pursued by the United States government during World War II — at the urging of the famed physicist Albert Einstein and others — it opened up the possibility of an entirely new category of warfare, impacting individuals and communities at all levels. The reactions set off by the Manhattan Project, and the consequent 1945 bombing of Hiroshima and Nagasaki, are ones that are still felt in international power politics, agriculture, medicine, ecology, economics, research ethics, transparency in government, and, of course, the Presidency of the United States. The Manhattan Project represents an excellent case study on the relationship between science, technology, and society, as well as the project’s ongoing influence on these relationships. The double-edged nature often associated with scientific discoveries are important considerations of the scientific enterprise, and should be taught to students accordingly.

A more meaningful approach to science education requires including the social aspects of the scientific enterprise. When considering a heliocentric view of the solar system, it is worthwhile recognizing its social impacts as well as its scientific foundations (particularly before Kepler). If we want people to see science as a human enterprise that can inspire rather than dictate decisions and behaviors, it will require resifting how science — and scientists — are viewed in the public eye. As written here [link]. we need to restore the relationship between scientific knowledge and social goals by specifically recognizing how

'So... cutting my funding, eh? Well, I've got a pair of mutant fists that say otherwise!'
‘So… cutting my funding, eh? Well, I’ve got a pair of mutant fists that say otherwise!’

science can be used, inappropriately, to drive public opinion. As an example, in the context of CO2-driven global warming, one could (with equal scientific validity) seek to reduce CO2 generation or increase CO2 sequestration. Science does not tell us which is better from a human perspective (although it could tell us which is likely to be easier, technically). While science should inform relevant policy, we must also acknowledge the limits of science and how it fits into many human contexts. There is clearly a need for scientists to increase participation in public discourse, and explicitly consider the uncertainties and risks (social, economic, political) associated with scientific observations. Additionally, scientists need to recognize the limits of their own expertise.

A pertinent example was the call by Paul Ehrlich to limit, in various draconian ways, human reproduction – a political call well beyond his expertise. In fact, recognizing when someone has gone beyond what science can legitimately tell us [link] could help rebuild respect for the value of science-based evidence. Scientists and science educators need to be cognizant of these limits, and genuinely listen to the valid concerns and hesitations held by many in society, rather than dismiss them. The application of science has been, and will always be, a sociopolitical issue, and the more we can do to prepare future decision makers, the better society will be.

Jeanne Garbarino, PhD, Director of Science Outreach, The Rockefeller University, NY, NY

Jeanne earned herJGarbarino Ph.D. in metabolic biology from Columbia University, followed by a postdoc in the Laboratory of Biochemical Genetics and Metabolism at The Rockefeller University, where she now serves as Director of Science Outreach. In this role, she works to provide K-12 communities with equitable access to authentic biomedical research opportunities and resources. You can find Jeanne on social media under the handle @JeanneGarb.