02 December 2020

Nobelprize winner Paul Nurse: viruses are alive! and dead!

Paul Nurse 2019 lecture The Royal Institution

Sir Paul Nurse received The Nobel Prize in Physiology or Medicine 2001 for his discoveries of key regulators of the cell cycle together with Leland Hartwell and Tim Hunt. According to the Nobel committee: 

"From the beginning organisms evolve from one cell, which divides and becomes new cells that in turn divide. Eventually different types of cells are formed with different roles. For an organism to function and develop normally, cell division has to occur at a suitable pace. Paul Nurse has helped to show how the cell cycle is controlled. Through studies of yeast in the mid-1970s, he was able to show that a special gene [cdc2] plays a decisive role in several of the cell cycle's phases. In 1987 he identified a corresponding human gene [CDK1]." (Nobel prize organization)

 

Paul Nurse (2020) What is life?
Paul Nurse (2020)
What is life?

In 2020 Paul Nurse published What is Life? [1]. In the first chapters he explains biology for non-biologists: the cell, the gene, evolution, biochemistry, DNA, and control mechanisms in the cell. Almost casually Nurse tells about his discovery that led to the Nobel prize some 20 years later. These chapters constitute the foundation for the final chapter in which he develops a definition of life.  In the last chapter he defines life with 3 principles. Any entity which operates according to those three principles can be deemed to be alive.

  1. The ability to evolve through natural selection. To evolve, living organisms must reproduce, they must have a hereditary system, and that hereditary system must exhibit variability. Any entity that has these features can and will evolve.
  2. life forms are bounded, physical entities.
  3. living entities are chemical, physical and informational machines. They construct their own metabolism and use it to maintain themselves, grow and reproduce. These living machines are co-ordinated and regulated by managing information, with the effect that living entities operate as purposeful wholes. 

Whenever I encounter proposals for the definition for life, I can't help comparing them with the definition of life of the Hungarian theoretical biologist and biochemist Tibor Gánti. Years ago Gánti proposed a definition of life that stood the test of time. I refer to my description of Gánti's defitinition of life on my WDW website [2]. Reading and listening to Nurse made me thinking again about the definition of life.

The first principle, the ability to evolve, Nurse adopted from Nobelprizewinning geneticist Hermann Muller. According to Gánti evolvability belongs to the Potential life criteria. That means evolvability is not a necessary property of an entity to be alive. But Nurse does not make the distinction between actual (absolute) and potential life criteria. There are a few practical problems with his first principle. According to evolutionary biologist Szathmáry evolution is not a property of an individual, but of a population. Also, variability is not a property of an individual, but of a population. The principle also causes difficulties when applied to a somatic body cell of an animal or plant. All somatic body cells will eventually die when the organism dies, and they leave no descendants in the next generation. Nobody would deny that somatic cells are living. But at the same time one cannot say that somatic cells in your body have the evolvability property. Only germline cells are involved in reproduction. On the level of an animal there can be also a problem. Mules are infertile, so no reproduction and no evolvability, but they are alive. Finally one comment about evolvability. Nurse's first principle suggests that the only function of the hereditary subsystem is evolvability. Nurse does not state explicitly that the informational subsystem "is useful for the whole" (Gánti's 4th absolute life criterion) and controls metabolism.

His second principle is:'life forms are bounded, physical entities'. This equals Gánti's Chemical boundary system. What is the boundary? Unfortunately, the concept boundary is used in an ambiguous way. For cells the boundary is the cell membrane (animals) or cell wall (plants). But viruses have a capsid which is clearly distinct from the semi-permeable membrane of a cell. A capsid does not have the functions a cell membrane has. This has consequences.

His third principle is complex. It is almost a complete definition of life because two of the three Gánti subsystems are included: a Chemical information system (for example DNA) and a Chemical motor system (metabolism). Nurse also included growth and reproduction in his third principle. According to Gánti growth and reproduction are Potential life criteria. Adults don't grow, and a non-dividing cell –for example a neuron– is not dead. That's why growth and reproduction are not necessary for being alive. They are a potential characteristic of life. The properties 'co-ordinated and regulated' and 'maintain themselves' equal Gánti's third Absolute criterion: "A living system must be inherently stable".
 

Are viruses alive? We all agree that bacteria, plants and animals are alive. Paul Nurse says viruses are alive too [7]. I disagree. The most important reason I think why viruses are not alive is that viruses are not cells and they never become cells. Not being a cell means not having a semi-permeable membrane which enables transport of molecules in and out of the cell. Viruses are a sort of stripped-down cells. Stripped down to the bare essentials: RNA or DNA with a protein coat.

Although Nurse's principles include an abstract 'boundary', in his talk he said: "the cell is the basic structural and functional unit of life" [3]. That is Robert Hooke's cell theory. Nurse is serious about the cell theory. Rightly so. In the first chapter The Cell: Biology's Atom he writes:

"What I mean by this is that cells are the smallest entities that have the core characteristic of life. (...) The cell is the simplest thing that can be said, definitely, to be alive" [5]. 

Since viruses are not cells, viruses cannot be alive. Viruses are dead RNA or DNA molecules!

In response to a question from the public Nurse says "viruses are dead outside the cell and alive inside a cell" [7]. This is an unsatisfying compromise. It reflects the fact that viruses outside a cell are chemically inert; they cannot defend themselves against outside disturbances and degradation by physical forces (UV light, heat,etc). They have no metabolism. They are passive entities subjected to physical forces. But in a cell they are active and replicate. But if Nurse wants to claim that a replicating virus (which is just a piece of RNA or DNA) is alive, than a chromosome or nucleus or mitochondrion must be alive too? [8]. It seems that the property 'being alive' belongs to a higher level than molecular level. It is a property at the level of the cell.


A car is a vehicle on wheels, with an engine, steering wheel, gas pedal, brakes, fuel tank, seats, etc. that moves autonomously. If we strip the car of everything except the wheels, what do we get? Is it a stripped-down car or a trailer? The trailer is connected to a car and has wheels and it moves when attached to the car. It does not move when not attached to a car. A car can move without a trailer, but a trailer cannot move without a car. Importantly, when the trailer moves, it does not suddenly become a car. Does it make sense to point to the fact that cars also depend on external factors (fuel)? So, there would be a continuum from car to trailer? No. But, cars and trailers share the property 'having wheels'. They are objects with wheels.


Virus: a stripped down cell?

Similarly, do we call viruses alive just because they can be viewed as stripped down versions of a cell? [6]. No. But there is one thing both have in common: DNA or RNA. Even more importantly, they use the same genetic code (the code that translates DNA sequences in to protein sequences) as all life. They need to have the same code, because otherwise their genes would be gibberish for the cell and they won't be able to replicate and produce new virus particles. Furthermore, viruses adapt to their hosts. For example the SARS-CoV-19 is perfectly adapted to the human ACE2 receptor. A perfect match. There is no doubt viruses are evolving entities. But one has to distinguish between evolving entities and living entities:

Viruses are evolving but not alive.
James Griesemer & Eörs Szathmáry [2].

When accepting the view that viruses are maximally stripped-down versions of cells, could we conclude from that that RNA or DNA are the bare essentials of evolution? The virus is a set of selfish genes. There you have it: the common property of cells and viruses is: replicating RNA or DNA. The classes of viruses and cells do not overlap, but are included in a higher class of objects with replicating RNA or DNA. Is this a rediscovery of the essence of Darwinism? I think so. It's all about replicating entities! Replicating entities that make errors and evolve. The 'units of life' are cellular. The 'units of evolution' are strings of DNA or RNA. 

 

Concluding: Nurse is absolutely right that the cell is the simplest unit that can be said to be alive. We now understand why the cell is the smallest life form: only a cell can integrate the three necessary components of life: a semi-permeable boundary, a hereditary information system and a metabolism. A logical consequence is that a virus cannot be said to be alive, neither inside nor outside a cell. I disagree that this is an arbitrary decision. It just follows from the cell theory. Furthermore, Nurse is absolutely right about the profound interconnectedness of all life. And, I fully agree, viruses are intimately and necessary connected to life. They speak -so to say- the same language. But that does not make them living. I also fully agree with Nurse that the ability to evolve is important. There would not be a single human on this planet without evolvability. But evolvability is a property of populations of DNA/RNA based units.

I thank Paul Nurse for writing such a stimulating book!


 

Update 13 Dec: small edit and note 8 added.


Notes

  1. Paul Nurse (2020) What is Life. Understand Biology In Five Steps, David Fickling Books. It is a popular science book without footnotes, index, and literature list. -I don't know whether the hardback is illustrated, but my e-book is not. Here is a short interview with Paul Nurse about the book. I could not contact the publisher via the contact form on their website, there isn't any confirmation that the message have been send successfully (only a blanc screen!);  and the email address info@davidficklingbooks.com does not exist (mailer-daemon: "we were unable to deliver your message").
  2. The Principles of Life. superior insights into the nature of life is about Tibor Ganti's definition of life on my WDW website.
  3. What is Life? Sir Paul Nurse - 2020 James Martin Memorial Lecture youtube 6 Mar 2020. Please note that being a cell is not included in his three principles.
  4. Biography of Paul Nurse at Nobel website. Contains many interesting details about his life. Recommended. Not in the book.
  5. Paul Nurse: "What I mean by this is that cells are the smallest entities that have the core characteristic of life. This is the basis of what biologists call cell theory: to the best of our knowledge, everything that is alive on the planet is either a cell or made from a collection of cells. The cell is the simplest thing that can be said, definitely, to be alive". (22/360 e-book)
  6. Stripped-down cell: everything is removed from the cell: all proteins, amino acids, ATP, water, cytoplasm, mitochondria, ribosomes, nucleus envelope, etc.
  7. In the book he wrote: "You could almost say that viruses cycle between being alive, when chemically active an reproducing in hosts cells, and not being alive, when existing as chemically inert viruses outside a cell." 328/360. He adds: almost all other forms of life are also dependent on other living beings. Added: 11 Dec 2020
  8. Mitochondria are an interesting test case for the definition of life. They have semi-permeable membranes, have metabolism, produce energy and have DNA. That should suffice for being alive. They cannot exist independently outside a cell. But almost all other forms of life are also dependent on other living beings according to Nurse. Just as a virus and other obligate intracellular parasites. Added: 13 Dec 2020

 

See also:

Paul Nurse: The Royal Institution 2019 lecture What is Life? (youtube)


8 comments:

  1. Gert,

    thanks a lot for your thorough exposé. It has a very high information density. Much to digest. So lots of questions!

    To start with caution, but I hope it'll trigger you enough...!

    “evolution is not a property of an individual, but of a population. Also, variability is not a property of an individual, but of a population”

    But isn’t that exactly the core of Darwinism since Fisher (1930), especially where he compares his theorem with the second law and lists the (5) differences with biology? In short: Populations are not like molecules in an ideal gas –they aren't just some conglomerate or aggregate. And the same is true, of course, for organisms, cells.

    Which brings me to this wild idea - for the sake of argument: try to turn things around. When does a cell, you may take the 'minimal cell', just become an aggregate of dead molecules? How do you define the difference? In what terms? What about states, levels? Information?

    I am afraid you'll find that there are simply too many ways to describe an aggregate of dead molecules. Yet there’s only one way to live! (cfr the title of doi: 10.1016 / j.tig.2013.03.001)- I think....

    ReplyDelete
  2. Hi Harry, may I ask first: did the car cartoon help your understanding of the point I tried to make? Do you agree/disagree with the main conclusions at the end?
    Which brings me to your wild idea: I would say your minimal cell becomes very soon an aggregate of molecules when one or more of the 3 subsystems of your cell (information system, semi-permeable boundary, metabolism) is missing (assuming there is food and no external disturbances).
    Does that make sense to you?
    Thanks for your comment.

    ReplyDelete
  3. Gert,

    This really is a very big topic. So, much has been said about it already. Hence a few comments

    1. Reproduction, variation and heredity, in short differential reproduction, is a fortiori not the same as evolution through natural selection, or Darwinian evolution. In other words, the ability to evolve, and indeed to live, also exists without natural selection: drift (and draft), CNE etc.

    2. This second principle applies to almost everything - including viruses. But are they alive? That just seems to beg the question.

    3. I think any definition of life should start with the 2nd law: entropy increases as long all states of a system are equally probable. Since von Neumann (1932; see also Shannon Weaver (1949)) entropy has been related to information (bits) and since 1961 we know the equivalence of energy and information from Landauer. So, the first question seems to me: where do those improbable states - or those bits, for that matter - come from? (cfr Kaufman) Where do they start, in what kind(s) of system. Did, may be, these quantum fluctuations make the difference? Could we, perhaps, may be, have gotten those first bit (s) for free? �� Or did it all get started with gradients? Because, in combination with higher entropy you have less energy, also known as the principle of least effort.

    5. A typical 'life principle' seems to me, are all these repair mechanisms - or do they fall under point 3?

    A final remark: S. Hossenfelder asserts we are just a pile of elementary particles. So we can describe life ‘in principle' by filling in all the equations that physicists have on offer. But then, how do we get all the data we need, don't we need additional data and/or additional equations? Or additional concepts? Aren’t we missing any information, bits? And above all: what do we actually buy for all those equations if they don't really have much to tell us about ourselves? Or do they?

    ReplyDelete
  4. Harry, thanks for your interesting comments.
    By coincidence an article appeared today in Nature describing a definition of life nearly 100% similar to Ganti's definition and very similar to Paul Nurse's definition:

    "Although there is no standardized definition of life, most researchers agree that it needs several components. One is information-carrying molecules — DNA, RNA or something else. (...) Furthermore, the first organisms must have had a way to feed and maintain themselves, perhaps using protein-based enzymes. Finally, something held these disparate parts together, keeping them separate from their environment".
    These are the 3 subsystems of Ganti (altough by other names)!

    https://www.nature.com/articles/d41586-020-03461-4

    (to be continued)

    ReplyDelete
  5. Harry,
    1) in evolution one does not get from bacterium to human with drift, isn't it?
    2) all the 3 principles must be true at the same time to be alive!
    3) Famous second law: OK. Interesting. But how do you make that in to a practical test? Infrared thermometer? but computers produce also heat, so how to discriminate between dead and alive? how do you apply it to bacteria and viruses?
    5) fair. repair mechanisms is included in maintaining the system.
    6) dead or alive challenge: are viruses alive because they can reproduce inside a host cell, contain RNA/DNA and have a boundary???

    ReplyDelete
  6. Gert,

    "one does not get from bacterium to human with drift, isn't it?"

    Natural selection does?


    ReplyDelete
  7. https://www.youtube.com/watch?v=9euW5iCjKDo&feature=emb_logo

    remember my rule: the more (detail) we can set eyes on, the less we see of Darwin- the devil is in the detail;-)

    ReplyDelete
  8. Harry, this blog is about WHAT IS LIFE? and whether viruses are alive or dead or according to Nurse sometimes alive when inside a cell. What do you think?
    PS
    Thanks for the amazing and important video! Recommended! That machine can teach biologists a lot! f.e. how a virus enters a cell. Very relevant for SARS-COV-2.

    ReplyDelete

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