What is life? Why cells and atoms haven’t answered the question.
75 years after Erwin Schrödinger's prescient description of something like DNA, we still don't know the "laws of life."
Adam Frank is a professor of astrophysics at the University of Rochester and a leading expert on the final stages of evolution for stars like the sun. Frank's computational research group at the University of Rochester has developed advanced supercomputer tools for studying how stars form and how they die. A self-described “evangelist of science," he is the author of four books and the co-founder of 13.8, where he explores the beauty and power of science in culture with physicist Marcelo Gleiser.
- Erwin Schrödinger's 1944 book "What Is Life?" revolutionized how physicists thought about the 'laws of life.' Schrödinger anticipated how DNA would hold life's blueprints.
- In recent years, however, a new path forward has appeared that holds a unique promise. Rather than reduce biology to physics, the new direction would transform them both.
- Scientists working across domains now think that understanding life requires putting a new actor on to the stage and letting it take the lead: the flow of information.
In 1944, Erwin Schrödinger was already considered one of the greatest physicists of his generation, having discovered quantum physics' most essential equation for describing atomic-level reality. But being intellectually restless, Schrödinger was ready to take on an even more difficult subject: the nature of organisms. What was it, he asked, that makes living systems different from non-living ones? The results of his thinking became one of the most essential books in the exciting and yet dangerous territory lying between physics and biology. That book's question was also its title, "What Is Life?". Its ideas are worth looking at now because more than 75 years after its publication, there are stunning new directions opening up toward an answer that both affirms and goes far beyond Schrödinger original vision.
Left: "What is Life" by Erwin Schrödinger, Second Reprint, 1946. Right: Nobel Prize-winning Austrian physicist Dr. Erwin Schrödinger addresses the 5th World Power Conference in Vienna, Austria, 1956.
"What Is Life?" focused on the need to find the underlying physical principles that make living systems behave so differently. The hope had always been to find "laws of life" similar to what has been found for the fundamental laws of nature in other areas of physics. Looking at life from a physicists' viewpoint, Schrödinger saw that one of its most compelling properties was the defeat of the omnipresent second law of thermodynamics. The second law states that the evolution of any physical system always tends toward states of maximum disorder (i.e., maximum entropy). But at the local level of an organism's body, life manages to create and maintain staggering degrees of order. It beats back chaos, for a while at least. Thus, somehow, life manifested what Schrödinger called "negentropy" or negative entropy.
Being one of the founders of quantum mechanics, which is the science of the microworld, Schrödinger also thought deeply about life's mechanics at the molecular level. Here, he was prescient, famously conjecturing that within cells there must reside an "aperiodic crystal" that held the information needed to transmit heritable traits from one generation to the next, allowing evolution to work. By aperiodic crystal, Schrödinger meant a molecule that had a stable, regular (i.e., repeatable) structure. If it was too regular and repeatable, however, you couldn't use it to code a living organism's structure. So 'aperiodic' meant 'kinda, sorta repeating.' A decade later, Francis Crick and James Watson credited this conjecture as their inspiration for using Rosalind Franklin's X-ray data to discover DNA as the blueprint for life.
So yeah, "What Is Life?" was a really, really important book.
But as powerful as the book was, 75 years after its publication no foundational physical laws for life have ever been found. There is no F=ma or E=mc2 or even a Schrödinger's equation for living systems. In spite of decades of searching, physicists have been unable to fully "reduce" the domains of the biologist (cells and organs and ecologies) into the domains of their own (atoms and energy and forces). In recent years, however, a new path forward has appeared that holds a unique promise. Rather than reduce biology to physics, the new direction would transform them both.
The focus on networks of information flows means its laws may be emergent. Life's laws would not, therefore, be encoded in the laws of quarks.
What has become clear to scientists like Paul Davies, Sara Walker, and Lee Cronin, who are working across domains, is that understanding life requires putting a new actor onto the stage and letting it take the lead. That actor is information. Rather than focusing on the mechanics of life—meaning how the laws of atoms can be built up into a living organism—researchers are beginning to see that what really matters is how atoms and molecules become conduits for complex flows of information. Rather than just thinking about forces or energy exchanges between molecular parts, the key becomes seeing the whole; seeing how these parts can be seen as something more, something that only emerges when information becomes important to a system.
Why is this new perspective so radical? What's most important is it's not reductive. That means it does not reduce life to "just" the laws governing quarks or whatever quarks are made of. Without doubt, life is a physical system, but by creating and then harnessing intricate ballets of information flows, life does something amazing: it creates. The focus on networks of information flows means its laws may be emergent. Life's laws would not, therefore, be encoded in the laws of quarks. Instead, they only emerge when enough matter is brought together in the right conditions for networks of information flows to become possible. That's when novelty enters the universe.
The other radical consequence of seeing life as a dance of information that rides matter is that this emergence continues upwards in scale. Just as new rules appear for cells, so to do they appear for collections of cells in animals or plants. And then even newer rules appear higher up on the level of ecosystems made of many animals and plants. At even higher levels still, new laws and structures must emerge in the creation of social organizations via ants, tribes of chimps, and even global technological cultures.
We'll be exploring this information flow perspective on life a lot more in the coming months, but for now it's enough to just recognize one of the key starting points. Schrödinger's "What Is Life?" was a remarkable first step because he saw information playing a central role in those aperiodic crystals. But what he could not have seen was how the focus on information flows would transform not just the answer but the very question that he posed. Because if you are going to focus on information, the next question you'll have to address is who or what knows that information. We'll leave that question for another time.
Why haven't we found aliens? Because we don't know what life is.
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Are "humanized" pigs the future of medical research?
The U.S. Food and Drug Administration requires all new medicines to be tested in animals before use in people. Pigs make better medical research subjects than mice, because they are closer to humans in size, physiology and genetic makeup.
In recent years, our team at Iowa State University has found a way to make pigs an even closer stand-in for humans. We have successfully transferred components of the human immune system into pigs that lack a functional immune system. This breakthrough has the potential to accelerate medical research in many areas, including virus and vaccine research, as well as cancer and stem cell therapeutics.
Existing biomedical models
Severe Combined Immunodeficiency, or SCID, is a genetic condition that causes impaired development of the immune system. People can develop SCID, as dramatized in the 1976 movie “The Boy in the Plastic Bubble." Other animals can develop SCID, too, including mice.
Researchers in the 1980s recognized that SCID mice could be implanted with human immune cells for further study. Such mice are called “humanized" mice and have been optimized over the past 30 years to study many questions relevant to human health.
Mice are the most commonly used animal in biomedical research, but results from mice often do not translate well to human responses, thanks to differences in metabolism, size and divergent cell functions compared with people.
Nonhuman primates are also used for medical research and are certainly closer stand-ins for humans. But using them for this purpose raises numerous ethical considerations. With these concerns in mind, the National Institutes of Health retired most of its chimpanzees from biomedical research in 2013.
Alternative animal models are in demand.
Swine are a viable option for medical research because of their similarities to humans. And with their widespread commercial use, pigs are met with fewer ethical dilemmas than primates. Upwards of 100 million hogs are slaughtered each year for food in the U.S.
In 2012, groups at Iowa State University and Kansas State University, including Jack Dekkers, an expert in animal breeding and genetics, and Raymond Rowland, a specialist in animal diseases, serendipitously discovered a naturally occurring genetic mutation in pigs that caused SCID. We wondered if we could develop these pigs to create a new biomedical model.
Our group has worked for nearly a decade developing and optimizing SCID pigs for applications in biomedical research. In 2018, we achieved a twofold milestone when working with animal physiologist Jason Ross and his lab. Together we developed a more immunocompromised pig than the original SCID pig – and successfully humanized it, by transferring cultured human immune stem cells into the livers of developing piglets.
During early fetal development, immune cells develop within the liver, providing an opportunity to introduce human cells. We inject human immune stem cells into fetal pig livers using ultrasound imaging as a guide. As the pig fetus develops, the injected human immune stem cells begin to differentiate – or change into other kinds of cells – and spread through the pig's body. Once SCID piglets are born, we can detect human immune cells in their blood, liver, spleen and thymus gland. This humanization is what makes them so valuable for testing new medical treatments.
We have found that human ovarian tumors survive and grow in SCID pigs, giving us an opportunity to study ovarian cancer in a new way. Similarly, because human skin survives on SCID pigs, scientists may be able to develop new treatments for skin burns. Other research possibilities are numerous.
The ultraclean SCID pig biocontainment facility in Ames, Iowa. Adeline Boettcher, CC BY-SA
Pigs in a bubble
Since our pigs lack essential components of their immune system, they are extremely susceptible to infection and require special housing to help reduce exposure to pathogens.
SCID pigs are raised in bubble biocontainment facilities. Positive pressure rooms, which maintain a higher air pressure than the surrounding environment to keep pathogens out, are coupled with highly filtered air and water. All personnel are required to wear full personal protective equipment. We typically have anywhere from two to 15 SCID pigs and breeding animals at a given time. (Our breeding animals do not have SCID, but they are genetic carriers of the mutation, so their offspring may have SCID.)
As with any animal research, ethical considerations are always front and center. All our protocols are approved by Iowa State University's Institutional Animal Care and Use Committee and are in accordance with The National Institutes of Health's Guide for the Care and Use of Laboratory Animals.
Every day, twice a day, our pigs are checked by expert caretakers who monitor their health status and provide engagement. We have veterinarians on call. If any pigs fall ill, and drug or antibiotic intervention does not improve their condition, the animals are humanely euthanized.
Our goal is to continue optimizing our humanized SCID pigs so they can be more readily available for stem cell therapy testing, as well as research in other areas, including cancer. We hope the development of the SCID pig model will pave the way for advancements in therapeutic testing, with the long-term goal of improving human patient outcomes.
Adeline Boettcher earned her research-based Ph.D. working on the SCID project in 2019.
Satellite imagery can help better predict volcanic eruptions by monitoring changes in surface temperature near volcanoes.
- A recent study used data collected by NASA satellites to conduct a statistical analysis of surface temperatures near volcanoes that erupted from 2002 to 2019.
- The results showed that surface temperatures near volcanoes gradually increased in the months and years prior to eruptions.
- The method was able to detect potential eruptions that were not anticipated by other volcano monitoring methods, such as eruptions in Japan in 2014 and Chile in 2015.
How can modern technology help warn us of impending volcanic eruptions?
One promising answer may lie in satellite imagery. In a recent study published in Nature Geoscience, researchers used infrared data collected by NASA satellites to study the conditions near volcanoes in the months and years before they erupted.
The results revealed a pattern: Prior to eruptions, an unusually large amount of heat had been escaping through soil near volcanoes. This diffusion of subterranean heat — which is a byproduct of "large-scale thermal unrest" — could potentially represent a warning sign of future eruptions.
Conceptual model of large-scale thermal unrestCredit: Girona et al.
For the study, the researchers conducted a statistical analysis of changes in surface temperature near volcanoes, using data collected over 16.5 years by NASA's Terra and Aqua satellites. The results showed that eruptions tended to occur around the time when surface temperatures near the volcanoes peaked.
Eruptions were preceded by "subtle but significant long-term (years), large-scale (tens of square kilometres) increases in their radiant heat flux (up to ~1 °C in median radiant temperature)," the researchers wrote. After eruptions, surface temperatures reliably decreased, though the cool-down period took longer for bigger eruptions.
"Volcanoes can experience thermal unrest for several years before eruption," the researchers wrote. "This thermal unrest is dominated by a large-scale phenomenon operating over extensive areas of volcanic edifices, can be an early indicator of volcanic reactivation, can increase prior to different types of eruption and can be tracked through a statistical analysis of little-processed (that is, radiance or radiant temperature) satellite-based remote sensing data with high temporal resolution."
Temporal variations of target volcanoesCredit: Girona et al.
Although using satellites to monitor thermal unrest wouldn't enable scientists to make hyper-specific eruption predictions (like predicting the exact day), it could significantly improve prediction efforts. Seismologists and volcanologists currently use a range of techniques to forecast eruptions, including monitoring for gas emissions, ground deformation, and changes to nearby water channels, to name a few.
Still, none of these techniques have proven completely reliable, both because of the science and the practical barriers (e.g. funding) standing in the way of large-scale monitoring. In 2014, for example, Japan's Mount Ontake suddenly erupted, killing 63 people. It was the nation's deadliest eruption in nearly a century.
In the study, the researchers found that surface temperatures near Mount Ontake had been increasing in the two years prior to the eruption. To date, no other monitoring method has detected "well-defined" warning signs for the 2014 disaster, the researchers noted.
The researchers hope satellite-based infrared monitoring techniques, combined with existing methods, can improve prediction efforts for volcanic eruptions. Volcanic eruptions have killed about 2,000 people since 2000.
"Our findings can open new horizons to better constrain magma–hydrothermal interaction processes, especially when integrated with other datasets, allowing us to explore the thermal budget of volcanoes and anticipate eruptions that are very difficult to forecast through other geophysical/geochemical methods."
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