Notes on Engineering Health, July 2021: Some Notes on Model Organisms

In 1859, Charles Darwin published the first edition of his seminal work On the Origin of Species By Means of Natural Selection or the Preservation of Favoured Races in the Struggle for Life, which laid out the theory of natural selection. As people reckoned with the ideas of heredity and a common lineage for all organisms suggested by Darwin, the question of how to study these phenomena arose.

Unbeknownst to most of the scientific world at that time, while Darwin was unveiling his revolutionary theory, Gregor Mendel and his (now) famous pea plants were simultaneously laying down the foundations of modern genetics, and providing an answer to the question of how to acquire new biologic knowledge proving the incredible power and importance of “model organisms” in understanding biology.

What Mendel somehow intuited well ahead of the rest of the field was that if every organism has a shared origin, then there must be some basic biological principles that are at play in humans as well as in much “simpler” organisms. The idea that certain organisms can be studied and used to acquire knowledge on other organisms led the way to new fields of research and the development of a myriad of the models (zebrafish, yeasts, bacteria, phages, and, of course, mice and monkeys to name a few) that drive much of modern biology.

Three models have had an outsized impact on research (note, we absolutely acknowledge the importance and the contribution of other models and do not mean to insult our readers with a passion for other organisms).

The fruit fly, or Drosophila melanogaster, became a lab animal in 1901 at Harvard University as scientists were looking for an animal they could keep easily in the lab and reproduce in large numbers. These flies were key for Thomas Hunt Morgan, considered the father of all drosophilists and inspired by Mendel’s experiments, to establish that chromosomes were the basis of heredity, for Eric Wieschaus and Christiane Nüsslein-Volhard to discover genes controlling embryonic development (those same genes are conserved in humans!) and, more recently, Michael Rosbash to uncover some of the mechanisms controlling the circadian rhythm. In a 2001 survey, it was shown that 75% of known human disease genes had an identifiable match in Drosophila and the immense set of genetic tools developed for this model continue to make it an essential part of many biologists’ experimental arsenal.

The round worm, or Caenorhabditis elegans, was the first multicellular organism to have its whole genome sequenced (a partial genome in 1998 and a complete one in 2002). With leadership from Sydney Brenner beginning in the 1970s, the round worm became a perfect screening tool where every gene could be knocked down using silencing RNA (siRNA) and thereby reveal its function. Silencing genes using this techniques has worked remarkably well in worms as they absorb the siRNA through their food and bodies in their normal living environment. Thanks to large screening efforts over the years, many discoveries were made via the worm including elucidating mechanisms in areas as diverse as programmed cell death (apoptosis), aging (development of Alzheimer’s disease, role of oxidative stress and lifespan) and sleep. Overall flies and worms have been tremendous models to study cell cycle and developmental processes.

The mouse, or Mus musculus, combines features that make them the perfect proverbial lab workhorse—ease of maintenance and handling, high reproduction rate, and proximity to human biology. If fruit flies are humans’ first cousins, then mice are their brothers sharing 99% of protein-coding genes. Mice are thus far better models than yeasts, worms, and flies to interrogate the immune, endocrine, nervous, cardiovascular, skeletal and other complex mammalian physiological systems. Mice get sick with many similar diseases as humans do, and researchers have managed to create models for diseases that normally do not affect the rodent. The Jackson Laboratory has played a crucial role in the development of the mouse into the leading model for biomedical research developing breeds to study conditions as diverse as multiple types of cancers, Down syndrome, Cystic Fibrosis, diabetes, and many more.

While many, many mice have been cured of all sorts of inflicted ailments, the translation to human biology and disease has often been more haphazard than is optimal. No model is perfect and, as useful a tool mice have been, there are species differences that have been hard to reconcile. As one example, although Dr. Valina Dawson managed to create a parkin knockout mouse, mimicking a mutation that causes some cases of Parkinson’s disease, the mice did not display the disease’s hallmark features - no trembling limbs, no rigid body movements, no unsteady gait.

Despite the glorious past (and noted shortcomings) of these model organisms, one can wonder about their future. From peas to flies to mice, is the next frontier of the model organism its complete virtualization? Some argue that the increasing use of AI will replace the need to experiment on animals, going directly from in vitro to in silico without the burdensome in vivo step. It is true that, while they enabled truly remarkable biological discoveries, many of these models fall short of clearly predicting how a drug will behave in humans. A complementarity of approaches however seems to yield more promising results, with this massive effort aiming at improving the translation from mouse to human an interesting effort in this direction.

– Jonathan Friedlander, PhD & Geoffrey W. Smith



First Five
First Five is our list of essential media for the month which spans a range of content including scientific papers, books, podcasts, and videos. For our full list of interesting media in health, science, and technology, updated regularly, follow us on Twitter or Instagram.

1/ Problem Solving
When it comes to solving problems, humans seem to favor addition over subtraction, even when taking something away is a better solution.
Nature > Washington Post >

2/ Digital Inclusion As A Social Determinant Of Health
As digital tools and telehealth become more central to the delivery of care, disparities in access to broadband Internet and computing devices are highlighting the fact digital access is now a crucial social determinant of health.
Nature Digital Medicine > AHRQ >

3/ Weird Biochemistry
The canonical understanding of life on Earth is that it involves a four-letter genetic alphabet that encodes “three-letter words” which produce 20 amino acids. Three recent papers in Science show, however, that at least in some viruses, one of the four standard bases in their DNA is swapped out for a novel fifth one. These findings lead one biologist to comment “[We need to] stop taking the components of molecular biology as we know them for granted. Purely because our instrumentation has gotten better and we’ve looked harder, everything that we thought was standard and universal is just falling away.”
Science 1 > Science 2 > Science 3 > Quanta >

4/ Gluten Intake Not Associated With A Decrease In Cognitive Function
As more people in the U.S. switch to a gluten-free diet, popular belief has linked a low-gluten diet to increased cognitive benefit. But a new study finds no evidence of such an association. Scientists looked at more than 20 years of data from more than 13,000 women who didn't have a history of celiac disease. The analysis found no statistically significant differences in cognitive scores - including learning and working memory - between those who had the lowest daily gluten intake and those with the highest. As is often the case with nutritional studies, though, there were caveats: the study only included women who were of middle age, and the findings thus may not be generalizable.
JAMA Network Open >

5/ Obesity
While the world has understandably been focused on the Covid-19 pandemic for the past year, the global obesity pandemic has not gone away, and nor have the scientists who are trying to understand and solve it. Interesting recent work in the area includes:

– A study of the molecular pathways behind acquired obesity which found that the pathways responsible for mitochondrial metabolism in adipose tissue were greatly reduced by obesity.
Cell Reports Medicine >
– A life-course longitudinal study of body mass index (BMI) that probed the temporal dynamics of BMI as individuals age and how social status defines disparities in lifetime obesity risk. The results show that adolescence and young adulthood are critical life stages when excess weight can rapidly accumulate and racial/ethnic or educational disparities emerge.
PNAS >
– A study suggests that increasing a protein concentrated in brown fat appears to lower blood sugar, promote insulin sensitivity, and protect against fatty liver disease by remodeling white fat to a healthier state.
Nature Communications >
– Perhaps not surprisingly, another study shows that our brains process taste information before factoring in health information. One of the study’s authors comments, “We've always assumed people make unhealthy choices because that's their preference or because they aren't good at self-control. It turns out it's not just a matter of self-control. Health is slower for your brain to estimate -- it takes longer for you to include that information into the process of choosing between options."
Nature Human Behaviour >



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Public-Interest Technologies for Better Health

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The Columbia University DICE Program
It is regrettably all too clear that certain populations remain underrepresented in health-related sciences on a national basis. Underrepresentation of these groups in the field overall trickles down to their underrepresentation in the life sciences commercialization and entrepreneurship community and ultimately in the amount of money that companies led by members of these underrepresented groups receive from venture capitalists.

In December of 2020, Columbia Technology Ventures, with support and sponsorship from Digitalis Commons, launched Columbia's Program for Diversity & Inclusion in Commercialization & Entrepreneurship (DICE). The program supports early-career individuals who identify as being from traditionally underrepresented groups in life science entrepreneurship and commercialization as defined by the NIH. DICE provides eligible Columbia graduate students and postdocs with educational programming, mentorship, networking, and funding opportunities to prepare participants for careers in bringing life science innovation to market, with a focus on therapeutics, diagnostics, medical devices, and enabling technologies.

In its highly successful inaugural cycle, 17 students across 12 departments participated in DICE. Students completed a Life Science Accelerator Bootcamp, were mentored by experienced life science entrepreneurs, industry executives, and venture capitalists from traditionally underrepresented populations, and were provided stipends for professional development. As the program moves into its second cycle it looks to expand its reach in myriad ways.

The Columbia DICE Report for Spring 2021 can be read here.

To learn more about the program, including details of the program structure, eligibility, awards & grants, and timelines, please visit techventures.columbia.edu/DICE.