Axial - What is Life?
Book review
What is Life?
What is Life? is one of the most important pieces of writing in life sciences. Guido Guidotti introduced me to this work when I was 18 and it transformed the way I look at the world. But more importantly, the book published in 1944 by Erwin Schrödinger influenced an entire generation of scientists to pioneer the field of molecular biology.
Based on a series of public lectures Schrödinger gave at Trinity College, Dublin, in 1943 - I have a friend who coincidentally went there and now leads one of the most exciting life sciences startups in the Bay Area - What is Life? looks at genetics at that time from a physics lens. With this framing, he introduces the concept of an aperiodic crystal that holds and transmits genetic information through covalent bonds and that life itself is characterized by its ability to resist and sometimes export entropy. These two ideas helped spur the discovery of DNA’s structure in 1953 and central dogma, which established the biotechnology industry and synthetic biology. The book sought out to understand how living systems seem to defy some aspects of physics in particular the second law of thermodynamics. Amazingly with the limited knowledge of genetics and the cell at his disposal, Schrödinger was able to hypothesize a biological code that enables heredity and selection.
From reading the book along time ago, periodically revisiting a few chapters over the years, to rereading it recently, there are 4 major results to take away:
Quite simply, having someone of the academic stature of Schrödinger publicly think about biology helped recruit many formal scientists mainly physicists to work on biology problems. This perfectly coincided with a decline of breakthroughs in quantum physics in the 1940s/1950s giving another push for physicists to bring their toolkit to a new field. For example, Crick came in and helped discover the structure of DNA and Luria helped characterize how genetic information is replicated. An aside, Linus Pauling, an incredible scientist discovery the components of protein secondary structure was a critic of the book. What is Life? was not widely accepted but brought to bear polarizing ideas that ended up being roughly true.
The book helped bring a new language to biology. For example, Schrödinger brought the concept of entropy to biology. In general, the idea of activity outside of equilibrium brought to life concepts like replication, memory, self-regulation, epigenetics, signalling.
Most importantly, the book looked at the cell as a statistical system instead of a static one. Similar to how Boltzmann brought the concept to physics decades before.
Ultimately, What is Life? supported a new framework, with a lot more formality and rules, to understand how complexity (i.e. phenotype) emerges from changes in genetics.
Background
Schrödinger won the Nobel Prize in Physics in 1933 and was exiled from his native home Austria after the nation was annexed by Nazi Germany. He moved to Ireland after he was invited to set up the Dublin Institute of Advanced Studies. This follows the past history of Ireland acting as a storehouse of knowledge during the Dark Ages. After decades of work, biology was becoming more formalized around the 1940s. Better tools were emerging to perturb various organisms and samples and the increasing number of discoveries was building out the framework of life. With the rediscovery of Mendel’s work on genetics, scientists probably most importantly Thomas Hunt Morgan and his work on fruit flies (Drosophila) set up the rules of heredity - genes located on chromosomes with each cell containing a set of chromosomes. In 1927, a seminal discovery was made that irradiation by X-rays of fruits flies can induce mutations. Just the medium was not known where Schrödinger was thinking through his ideas on biology. At the same type, organic chemistry was improving and various macromolecules in the cell such as enzymes were being identified along with the various types of bonds made. For Schrödinger, there were no tools to characterized these macromolecules (i.e. proteins, nucleic acids) such as X-ray crystallography. Really the only tool useful at the time was centrifugation. At the time, many people expected proteins to be the store and transmitter of genetic information. Luckily, Oswald Avery published an incredible paper in 1944 that found DNA as probably the store instead of proteins.
With this knowledge base Schrödinger took a beginner’s mind to biology. In some ways his naivety was incredibly useful. Instead of being anchored to some widely-accepted premise that proteins transmitted genetic information (although he had a hunch some protein was responsible), the book thought from first principles and identified a few key concepts in biology that were not appreciated but became very important. Thankfully Schrödinger was curious - he enjoyed writing poetry and reading philosophy so jumped into biology somewhat fearlessly. At the beginning of the book, he sets the main question as:
“How can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?”
Information
In the first chapter, Schrödinger argues that because organisms have orderly behavior they must follow the laws of physics. Because physics relies on statistics, life was follow the same rules. He then argues that because biological properties have some level of permanence the material that stores this information then must be stable. This material must have the ability to change from one stable state to another (i.e. mutations). Classical physics is not very useful here, but for Schrödinger his expertise in quantum mechanics helped determine that these stable states must be held together through covalent bonds (a quantum phenomena) within a macromolecule. In the early chapters, the book argues that the gene must be a stable macromolecule.
Through discussion around the stability of the gene, the book makes its most important breakthrough - an analogy between a gene and an aperiodic crystal (DNA is aperiodic but Schrödinger amazingly didn’t know that at the time): “the germ of a solid.” Simply, a periodic crystal can store a small amount of information with an infinite number of atoms and an aperiodic crystal has the ability to store a near infinite amount of information in a small number of atoms. The latter was more in line with what the current data suggested what a gene was. Max Delbrück had similar ideas along with J.B.S. Haldane, but the book was the first to connect this idea to heredity. But readers at the time and maybe even still overextended this framework to believe that genetic code contains all of the information to build an organism. This isn’t true, development requires an environment with some level of randomness.
Entropy
In the second part of the book, Schrödinger tackles how an information is transmitted and maintained through a gene. The goal is to define what life really is. He works through the problem with a thermodynamic model. Because cells are mostly at equilibrium (but not all of the time) - energetic inputs and outputs are balanced, entropy not energy must be the driving aspect for life. The Second Law of Thermodynamics proves that entropy must increase within a system. Given that, life should not exist. Schrödinger argues that life is characterized by an ability to export entropy - creating order and paying the dues of physics through heat.
This idea of entropy and life is still being worked out today. From the various interactions within a cell and between them, unique phenotypes emerge. We are just barely scratching the surface for answers. At the end of the book, Schrödinger writes more philosophically thinking how biology can inform new laws of physics and ideas around complexity and uncertainty. What is Life? created a new field, molecular biology, bridging physics and biology - at the time a transformational step - that led to new classes of medicines, products, and a lot of new problems to solve.