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First Steps Toward Emergence of Life Theory

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By Stephen Sadler

What turned a primordial mixture of amino acids and proteins into the first organized, self-replicating unit? What was it that breathed the vital breath into a collection of inanimate chemical building blocks, giving rise to an unbroken chain of evolution stretching three and a half billion years into the future and culminating in us?

For many years Kauffman has studied the mathematics behind groups of molecules known as ‘autocatalytic sets’. These sets of molecules and their associated chemical reactions are special because they form self-sustaining systems which, given a ‘food source’ of simple molecules, are able to form more complex molecules which themselves catalyse, or speed up, reactions which give rise to other molecules in the set. In this way, they form “functionally closed” structures (see Figure 1) that speed up the production of the members of the set, promoting the existence of the set as a whole.

Figure 1: an example of an autocatalytic set. Black dots represent molecules in the set, whilst white boxes represent reactions. Solid arrows stand for reaction inputs and outputs, and dashed arrows indicate catalysis. Because each arrow ends on a molecule in the group, the group is said to be “functionally closed”.

To see what all this has to do with life, we must define what we mean by “life”. Whilst definitions vary, most share some common themes, for example: self-organisation, self-replication, and the ability to evolve with successive generations. Kauffman himself has defined a living organism as “an autonomous agent or a multi-agent system capable of reproducing itself or themselves, and of completing at least one thermodynamic work cycle” [1].

So could autocatalytic sets fulfil these criteria? Almost by definition their existence promotes the proliferation of their constituents, which sounds remarkably like self-replication. Their closed structure and well-defined flow of reactants and catalysts through reactions also sounds like it might fulfil the self-organisation criterion. But can they evolve? It is this question that Kauffman’s latest work addresses.

The group studied the mathematical properties of autocatalytic sets and made the remarkable discovery that any given set can be decomposed into so-called ‘irreducible autocatalytic sets’. What’s more, the number of irreducible autocatalytic sets that any larger autocatalytic set can be decomposed into rises exponentially with the size of the larger set. Since these sets overlap to some degree, they can be said to be mutually dependent, and it is not too much of a leap of faith to imagine them beginning to behave as the elements of a ‘meta autocatalytic set’.

“In other words, self-sustaining, functionally closed structures can arise at a higher level (an autocatalytic set of autocatalytic sets), i.e., true emergence,” the group say.

The combining and splitting of these functionally-closed, self-replicating entities can, according to the group’s paper, give rise to inheritance, mutation and competition. In other words: evolvability.

However, the authors don’t stop there. Is it too far fetched, they ask, to “consider a complete cell as an (emergent) autocatalytic set?” And if not, then why not think “of the collection of bacterial species in your gut (several hundreds of them) as one big autocatalytic set”? Going one step further, could the theory not be applied to ecology to describe any mutually dependent set of organisms, they ask? Could the economy not be viewed as an autocatalytic set, with its processes (reactions) assembling complex structures out of more simple ones (reactants), facilitated by tools, factory production lines and humans (catalysts)?

These are big ideas and, by the authors’ own admission, rather speculative, but with the tantalising possibility of a single theory to explain the phenomena of emergence, functional organisation and the origin of life, it seems difficult to disagree with them when they conclude: “we believe that these ideas are worth pursuing and developing further”.

A preprint version of the group’s paper can be found at http://arxiv.org/abs/1205.0584

[1] 2004, “Autonomous Agents”, in John D. Barrow, P.C.W. Davies, and C.L. Harper Jr., eds., Science and Ultimate Reality: Quantum Theory, Cosmology, and Complexity, Cambridge University Press.

 

What Is The Problem With Stem Cell Research? (Part III)

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Stem cell research leads to very strong and different opinions globally, but why? What is it about this incredible tool that allows it to be condoned and appreciated in one country, and considered immoral in others? Well, as with many issues that span the world, the local ethics play a large role in how they are received.

The main ethical argument comes down to how embryonic stem cells are taken. Because they exist around 5 days after an egg has been fertilized, the procedure involves destruction of the early embryo. Understandably, this is an unpleasant thought. However, our UK laws only allow the use of eggs spare from those who have undergone IVF (in-vitro fertilization) treatment, or from donors, it is also possible to source embryonic stem cells from fluid in the placenta and umbilical cord. The eggs from donors are fertilized outside the body, and never put back in. The artificially fertilized embryo is then grown for a maximum of 14 days. When the cells are derived (5 days after fertilisation) they are kept in culture where they can keep replicating and survive for a long time. However, new embryonic stem cells are required usually because culture conditions can lead to the cells gaining adaptations, which basically means the cells we are working with are no longer true to all stem cells. In order for all results to be standardized against other countries and labs, it is important the cells we are working with are the same anywhere else in the world, otherwise new discoveries could just be false results due to lab techniques and conditions.

Regardless of faith, most individuals consider killing humans unacceptable, but the big issue is at what point would you consider the moral status of a human being should be given to the embryo? Some religious sects believe it is at the instant the sperm fertilizes the egg, whilst others believe it is later than this. Some laws use the term ‘moment of conception’ to define the rights of a foetus, however this is ambiguous because there is no real moment, it is a progressive event that is hard to pin point.

It is almost impossible to put a definitive answer on the moral status; before implantation of the developing embryo in to the uterus wall, 14 days after fertilisation, it is common and natural for fertilized eggs to be discarded by the body if the conditions are not perfect, and also some current contraceptive devices work by preventing implantation into the uterus wall. This means early embryos are discarded both naturally and unnaturally already, so is research on them arguably more acceptable than the common wastage?

In order to determine when embryos deserve human rights, many use ideas of individuality and viability to help. In normal circumstances, the early embryo implants into the uterus at day 14. Before this, the egg only has the potential to become a person; up until 14 days, the egg can split in two to form identical twins, or two eggs (fraternal twins) can fuse to develop one person. If one egg can contribute to two people, or half a person, then it follows that the embryo isn’t truly a human with all attributed rights. After 14 days is a different matter. 20 weeks is around the last point that it is legally possible to have an abortion. Before this date it is known that the foetal tissues, including nervous system, are not developed enough for there to be any ability to survive independently. Premature babies can survive if born after around 26 weeks, so by this point their tissues are developed and connected, can respond to pain, and are they are undoubtedly human. Somewhere between individuality and viability lies the truth about when a foetus deserves human rights. We should all make our own opinions, and it is definitely a grey area with no single view right or wrong, but because embryonic stem cells are taken at 5 days, rather than 14, it is becoming increasingly acceptable to generate them for research.

Hopefully you understand this is not a deliberate provocation on the scientists’ behalf, but a necessity to improve the lives of others, and quench a certain thirst for knowledge. As scientists, we are required to be unbiased, and therefore we must accept beliefs and customs of others, and be as open to their views as our own. In my opinion, this is actually one of the most impressive aspects of our society. Britain is arguably the most multicultural, scientifically advanced nation in the world. The laws and restrictions put upon us are designed to reach a logical middle ground, and there are a number of authorities that subject research plans to heavy scrutiny before they are allowed to proceed. This, from some perspectives, may be seen as a travesty against scientific progress, but from another angle it ensures all our research is important, significant and ultimately useful. Without such rules our citizens are put at risk from promises and treatments that are unsubstantially founded. What’s more, these are precious cells and as scientists we have a responsibility to respect such a powerful tool that holds great value in every sense of the word. I personally believe that the cause justifies the means, as the goal for the research is to reduce suffering, but what do you believe?

Another controversial issue concerns a technique called somatic cell nuclear transfer. This is where the nucleus from a human cell replaces the nucleus of an egg, and the new environment changes the human nucleus to a fertilized egg-like state. This is called reproductive cloning, because if the egg were to survive it would result in an exact replica of you. This is an intriguing technique because they can use eggs from animals (e.g. cows), which are easier to get hold of, and then the nucleus that replaces the cow genetic information would be derived from the patient themselves. This leads to production of patient specific embryonic stem cells, and if we were to take the cell from a patient with a genetic disease then we can use the embryonic stem cells this technique generates to improve our understanding of how the disease is characterized, develops, and provide a model to work with for future treatments.

Born in 1996, Dolly the sheep was the first mammal to be cloned using cell nuclear transfer, showing the principle of how adult cells can be made to reverse back to a pluripotent state. However, it isn’t an easy process because often the embryos do not survive – of 239 eggs, Dolly was the only one to be successfully fertilized and live. But it still sparks debate as people worry about cloning humans. The Human Fertilization and Embryology Acts prohibit this, so there is nothing to actually worry about, but it is interesting that the principle of creating human life exists outside of sexual intercourse. Many people consider it ‘playing God’, which depending on your view, it is – but I guess the argument comes down to whether ‘playing God’ is a good or bad thing. Again, if it saves lives, and we have the power to do it (in itself an act of God?), does the cause justify the means? There were reports in 2004 that a well-known lab in Korea had cloned humans, but in hindsight this result turned out to be false and unethical on a number of grounds. Reproductive cloning is a sensitive subject as it opens a can of worms in relation to, hypothetically, whether clones have the same rights, would they be treated as equals, so on and so forth. Even the idea of engineering babies through IVF, to prevent risk of genetic disease, is a minefield of ethical, moral and financial explosives e.g. what if people create their ‘perfect’ children? How will genetically engineered children be treated? Will natural humans be treated worse? Will ‘Brave New World’ become the reality?

We know from examples throughout history, that it is controversial issues that help scientific advances break through. Controversy just implies that society is not decided on a matter, not that the matter is inherently wrong (or right). It proves how our opinions as a race have changed over time, and the mere fact that we can discuss these issues is an achievement in itself. Protesting an opinion improves research, and prevents science becoming stagnant. Science is supposed to be about searching for the unknown and explaining it, but ventures into the unknown can unearth results and predicaments that no one has the foresight to see, whether good or bad. Scientists are the modern day versions of Christopher Columbus; to discover the new world you have to sail off the edge of the map.

 

Dolly’s Cell Nuclear Transfer – I.S.

Nucleus from egg is removed

and replaced with a nucleus of a normal adult cell from Dolly,

the egg can then develop inside uterus as normal, to generate a clone of Dolly

∞

Why Should We Study Stem Cells? (PART II)

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Well, the more they are studied the more they tell us about how our body functions in normal and diseased states, showing amazing potential in a therapeutic sense. In the US, 2009 and 2010 saw the first use of human embryonic stem cells in clinical trials, but they were turned into neural support cells before they were implanted in spinal cord injury patients. This research was performed on animal models first to ensure its safety, and stands as a landmark in stem cell therapy. Currently, this is largely how such therapies are developing; taking an embryonic stem cell and turning it into a more committed cell type that can then be implanted.

Other notions of directly injecting embryonic stem cells into patients to treat disease and degeneration are a premature and scary thought, putting patients at high risk of cancer, and thankfully are not allowed in most countries. As stem cell scientists, we don’t want to promise miracle cures, but we are very much aware of how they can help current strategies against many illnesses. For example, embryonic stem cells can divide forever and create two new cells each time. These divisions are tightly controlled, but cancer shows the same ability without the control. So, as you may see, learning what controls and restricts division improves our understanding of what goes wrong in a normal cell that allows it to switch to a cancerous state, and how we may set about stopping this. Some respected theories even suggest that cancer occurs when an adult stem cell loses control of its ability to replicate. Indeed, it appears that cancer is a natural part of life.

Of course, adult stem cells have been used for decades without being isolated, for example in bone marrow transplants for patients with leukeamia. Because the patient has reduced ability to make white blood cells, they cannot fight infection, so donor bone marrow replaces their own. In the new bone marrow exist adult stem cells – hematopoietic stem cells – that can make all the blood cells necessary to repopulate the body. In recent years, more and more funding has gone into studies on adult stem cells. The main reasons for this are because it does not require taking the early embryo, and bypasses a biological problem that embryonic stem cells have. If we were to take such a cell, and then inject it into another person – either as itself or a more restricted cell type – the human body would mount an immune reaction because it has molecules from a source that it cannot recognize. By manipulating the stem cells that are already within us, the body doesn’t have to cope with an immune reaction at the same time. Many of these studies, despite relatively early, provide a convincing approach towards new therapies, improve our understanding of how our bodies maintain themselves, what can go wrong, and possibly identify stem cell populations as new drug targets.

Mesenchymal stem cells are another type of adult stem cell taken from bone marrow, but another good source is fat tissue. It was found that they could be easily grown in culture, and have the ability to become a wide variety of cells. Due to their lack of ethical controversy, and ease in sourcing, they have become an integral part of tissue engineering and current regenerative therapies, for example there are clinical trials on patients with MS (multiple sclerosis) and coronary heart disease, and have been proved successful in many other diseases and injuries. This fact could mean that mesenchymal stem cells could soon be widely used, for a host of reasons, and in many places. Perhaps you will one day rely on a mesenchymal stem cell based therapy.

Induced pluripotent stem cells are also a new hope for regenerative therapy. These cells would be derived from the individual patient, and then directed into whatever cell types were necessary. Unfortunately, this process is still very inefficient and has a very long way to go before you see any science fiction like organs being transplanted back into us to replace our old ones! However, they do provide a way to generate tissues and systems that can be used as a model for an organ. With this, it is possible to use them to test new drugs and are potentially an alternative therapeutic strategy to embryonic stem cells. They do not stimulate the same intensity of ethical debate, and are currently being used by many labs to see whether they can aid in regeneration of different parts of the body and to understand more about cell fate decisions. Again, these studies can be thought of as preliminary, as scientists are still learning about their differences and problems that are encountered when using cells that have been forced to become stem cells.

This description has barely touched the surface of the research that is out there, but even so, it is obvious and amazing to see just how much power these cells hold and how our fate is inextricably linked with stem cells, both embryonic and adult. They are an essential part of our biological development, and hold key responsibilities in maintaining life. Understanding their influence on our biological world is the next step towards improving it, but Nature does not give up its secrets easily, and has a unique way of dangling the truth behind the smoke and mirrors.

Simple Steps to a Neuron – I.S.

Adult neural stem cell; must give rise to a neural progenitor before being committed to a neuron

Embryonic stem cell; must give rise to a neural progenitor before being committed to a neuron

Induced pluripotent stem cell; fibroblast must be turned into a pluripotent cell, which then needs to gives rise to a neural progenitor before being committed to a neuron

Immature neurons, or support cells, could be targeted (Adult NSC) or transplanted (ESC, IPS) to required regions of the central nervous system

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