In Silico Is Not a Lonely Option: In Vitro Organoids Test New Pharmaceuticals

In 2014, I remarked here about in silico modeling for digital biology. The relationship between AI-driven digital and in vitro modeling in systems biology is developing to some extent in synch and in a mutually cross-fertilizing manner for the purpose of minimizing both clinical and animal testing while expediting, improving and reducing cost of biomedical innovation. Here is a sketch of how this might work in a more organized fashion:

Organoids are artificial organ-like structures a few millimeters in size bred in vitro that show realistic micro-anatomy. They are developed to perform medical tests for which otherwise animal testing would have to be used, that, ethical issues aside, is neither a very close nor highly reliable approximation of human organs. Such partial models of the brain, heart or kidneys have already been created in recent years for narrowly-tailored specific purposes. Compared to in silico models, they involve genuine human tissue and higher levels of complexity in some respects.

Researchers working with Josef Penninger at the Institute of Molecular Biotechnology (IMBA) in Vienna, Austria now report that they took a further step: they established 3D tissue cultures that permit testing blood vessels on the micro scale. Among additional future uses, their model presented in Nature serves to simulate diabetic vascular damage.

Diabetics frequently face vascular diseases as a consequence of their systemic condition. In the case of major blood vessels, potential consequences include faster occurrences of atherosclerosis resulting in myocardial infarction, stroke, and amputation of the lower limbs. However, diabetic damage affecting small vessels, micro-vasculopathy, can have similarly catastrophic results as it triggers diabetic kidney disease that requires many diabetics to undergo regular dialysis, and/or causes diabetic retinopathy. Work on a 3D vascular organoid model was finalized by a team of Reiner Wimmer, who created 1-2-millimeter sized models of human capillaries, complete with endothelial cells as a cavity lining layer as well as pericytes as supporting cells.

To create a vascular model of capillaries, the researchers induced human stem cells to differentiate into functional blood vessels of a micro-format. These human blood vessel organoids were then implanted into the kidneys of immunodeficient mice that do not reject human cell tissue. The organoids grew to form a stable, perfused vascular tree including arteries, arterioles and venules. In 95 percent of cases, the organoids survived longer than six months. This experimental design also appears to be well suited for research on microvascular disease resulting from diabetes mellitus type 2. In this type of microvascular disease, one essential feature is the thickening and onion-like structure of these vessels’ basement membrane and loss of vascular cells. The endothelial cell layer “leaks,” and such leakage leads in diabetics to retinal disease that causes a typical damage to the ocular fundus ending in blindness. Diabetes impairs the functions of endothelial cells and disturbs communication between the endothelium and pericytes.

The experiment imitated type 2 diabetes in the lab by exposing the blood vessel organoids to hyperglycemia by inducing high concentrations of sugar and inflammatory messengers (cytokines), which in vitro induces thickening of the vascular basement membrane. Down to the level of electron microscopy, all the typical pathological changes to the capillaries became visible.  The authors derived a first set of results from tests in which the diabetic organoids were treated with a wide range of conventional antidiabetic medications aimed at lowering blood sugar levels. None of them showed any effect on the changes occurring in the vascular organoids. Perhaps the best result came from an inhibitor of gamma-secretase enzyme (DAPT). DAPT reduced the formation of vascular thickening type IV collagen and normalized the emergence of endothelial cells. According to the results of first impression, this is apparently due to an effect attributed to the expression of the NOTCH3 gene. Gamma-secretase inhibitors have so far been tested as potential Alzheimer drugs. This may yet prove important to future search for new strategies for prevention and treatment of diabetic vascular disease.

The exciting part about this research is that the authors were able to produce genuine human blood vessels out of stem cells. These organoids show very high similarity to human capillaries, which permits conducting meaningful studies of vascular diseases directly in live human tissue. This study in experimental biology proved that organoids derived from human stem cells faithfully reproduce the structure and function of human blood vessels and are useful systems for modelling and identifying the regulators of diabetic vasculopathy, a disease that affects hundreds of millions of patients worldwide. To the extent the data from such models can be fed into AI to improve in silico modeling, a significant acceleration of pharmacological testing cycles seems to be within reach.


It Now Becomes Impossible to Lose Face in China: Faceless Face Recognition

As Chinese authorities seek cradle-to-grave surveillance in the world’s largest market for surveillance camera technology, AI algorithms take over where cameras cannot film faces.

A competitive arm’s race has been set off among Chinese companies. Similar to the “Sputnik shock” that set off the 1960s space race, this one seeks to generate the best surveillance technologies to meet the growing demand of police authorities in the country. Companies recently began to use software that recognizes people no longer by their face – which may be too easily fooled – but solely based on their body shape and gait. Algorithms are used whenever cameras cannot record faces. Gait recognition software is already being used by police on the streets of Beijing and Shanghai, but also, and potentially giving rise to more concern, for population control of Uighurs in the Western province of Xinjiang.

Virtually all surveillance products in use are made by Chinese companies in China. Foreign companies hardly play any role in monitoring the Chinese population as it has long exceeded a billion. In terms of gait recognition, startup Watrix has made a name for itself. CEO Huang Yongzhen said his system can identify people up to 50 meters away, even with their backs to the camera or with their face covered. Current European legislation banning facial or full-body veiling may be approaching obsolescence. Of course, the ancient trope of all Big Brothers in history surfaces again: “if you have nothing to hide, you have nothing to fear.”[1] Right – East Germany’s Ministry of State Security was built entirely on that sound principle. Similarly, China is less concerned with protecting citizens – and indeed surveillance can be shown to have potential benefits to that end – than it is with protecting the governing elite’s monopoly on power. Of course, human assets are becoming rapidly superfluous with surveillance technology based on pattern recognition, even though the computing power needed for gait recognition is far greater that what is required for face recognition, since it requires not one but a multitude of pictures to identify an unmistakable pattern. But watertight surveillance is essential to China’s massive experiment with ranking and monitoring citizens for purposes of social credits and demerits (very much worth a separate in-depth look – another day). The other pillar, of particular significance in China, is “trust your government.” Well… If Western societies that can freely elect and remove their governments cannot bring themselves to trust them, how trustworthy can be the Communist Party of China, an unelected monopoly that cannot be removed from power by lawful means and knows no term limits?

The increasingly sophisticated surveillance techniques have led human rights advocates to fear that Chinese people have very little privacy left. Robots resembling Star Wars’ "R2-D2" come equipped with dozens of sensors and cameras as well as red glowing "ears" and can identify individuals within a large crowd. Specialized police goggles can scan passersby and compare a person’s profile directly with a large database of fugitive suspects.

Of course, it is far from reasonable or even justifiable to view gait recognition as a “Chinese issue” that raises concern for individual liberties and human rights. The U.K., Japan, Israel and the U.S. Defense Information Systems Agency have worked on gait recognition software since more than a decade and certainly not without results, even if results have not been commercialized as they were by Watrix.

The Watrix software isolates an individual’s silhouette from video footage and analyzes its movement. Then it creates a model of individual gait. At this time, the algorithm is not capable of making positive identification of individuals in real time yet. It requires uploading of footage for purposes of analysis that can condense searching through an hour of surveillance footage to about ten minutes. However, no special cameras are required and footage from ordinary CCTV surveillance cams suffices to produce 94% accuracy. 

Purported uses of biometric recognition outside of social control purposes to maintain social stability and to manage society include the ability to spot people in distress, such as elderly individuals after a fall. But the closer one looks at claims that this technology can make life safer and more convenient, the more findings are reduced to fool-proof identification that cannot be derailed by limping, walking with splayed feet or hunching over because more extensive footage will invariably analyze all features of an entire body beyond commonly perceived visual traits. It would appear that gait is at least as unique to an individual as fingerprints or cornea patterns but features fewer abilities to escape detection. It is clear that Big Brother feeds on Big Data, and that the real danger lay in data preservation and storage, a fact that far exceeds legitimate purposes of near-real-time safety surveillance, such as monitoring a public space for elderly people after a fall.

Rewarding or punishing individuals for behavioral traits is hardly new and hardly a Chinese discovery. The key distinction is between criminal law – which, for good reason, has substantial barriers to system activation, such as burden of proof and presumption of innocence – and merely non-criminal if socially arguably less desirable choices. It is by that standard that China’s social credit ranking is likely to descend into an Orwellian dynamic.

[1] Daniel J. Solove, Nothing to Hide: The False Tradeoff Between Privacy and Security (2011).