Thursday, December 31, 2020

20 - 029 Digitising the A Digital Human.

 So let us just remind ourselves of the objective of the Digital Human. It is to create a complete digital facsimile of a real living human. The vision I have is that you can zoom in on this digital copy going right down to the atomic level. This applies to every single component that makes up the living human. But importantly you can allow this digital human to live and therefore change with you being able to witness all these changes digitally. This includes all the things that move within the human body (eg blood, hormones etc) along with all the things that are resident within the body. (eg viruses, bacteria etc). Change includes the growth and decay phases of living and finally to death. All this to be digitally defined. From the first cells growing after conception to the final death of all the cells marking the end of that life.

You will be able to have different “lens” over this living digital human. The visual lens showing all the components the same way you would see them under a microscope and down to what you would see through an electron microscope. Another “lens” would allow you to see the human body from a purely chemical perspective. The same atoms that you can see visually but with them chemically identified. Then what I have termed the wireless “lens” where you can view everything on either side of the visual spectrum. Wireless is too simpler a term to use but because it is so easily understood it is the term we will use generically. But it covers a huge spectrum with the true wireless band only forming part of this wide spectrum. This covers a huge spectrum of impulses that run across space ranging from ultra violet through to visible light (to us) to infrared to the electric and to wireless wave bands. In addition the all the mysterious wave forms in between these defined bands. You do have to appreciate the concepts of consilience to appreciate that these “wireless” entities do form part of us as living organisms. Although scientifically they remain very unexplored and researched parts of biology. There will be the sceptics who claim these areas as being nonsense believing it to belong to pseudoscientific or occult thinking. But there are so many amazing feats in nature not fully explained that it is important to keep an open mind. Sitting her with my laptop connected via WiFi to a web server sited in California instantly communicating information would have been viewed as witchcraft in the 17th Century. Let along face timing someone sitting on an aeroplane flying over the Canadian snow covered wastelands. What will be our capabilities in 2120?

So back to basics. So whilst I can visualise this real living human I am struggling to understand how we are going to define the digital human digitally. It is going to be a visual thing. But it is also going to be a data thing in support of the visualisation. So I can see the outputs from CT scanners and electron microscopes giving me loads of visual material. I can see loads of chemical analysis giving me the chemical “lens” on these visual. I can even see the wireless “lens” superimposed on the visual and chemical “lenses”. But I want to get to the digital code. Will digital be enough? Will need something more quantum to get to the final mathematical definition of life. So the search starts of this mathematical (code) “lens” on human life. But it is not just human it is life itself.

In 2020 my digital searching for existing “digital resources” to support my digital objectives has lacked any real structure. In truth I don’t see anyone pulling it all together the way I envisage it needs pulling together. But then I am retired Information Analyst really a product of the commercial computer world just now dabbling into the life sciences. I don’t even know where to start looking to support my mental adventure. So not surprisingly I started with Wikipedia. I started to look up human genes on Wikipedia and was impressed to find that this “open systems” approach to knowledge gathering had started the process in respect of these genes in 2007. You suddenly realise you are not alone in this world. In fact thousands are just thinking like me and you if you are reading these words.

So Wikipedia became a key source of knowledge in support of building up the digital resources in respect of the Digital Human. But it obviously fails to map it all together in a structured way rather being designed to support you dipping in and out looking up facts. The links then supporting you searching linked facts allowing you to grow your understanding. But not in a zoom and out way. The search than started at looking at information stored within the biological research organisations. The research papers and the research databases. Unless I am completely missing something this is very fragmented. National boundaries come into play along with government establishments, research establishments, universities, commercial organisations and publishing organisations.

 

The one digital resource that I particularly focused upon was produced by the US National Library of Medicine and the National Center for Biotechnology Information. This is a truly amazing resource. You could search on 40 plus major information entities. It is also very information technology user friendly. Future blogs will investigate these information entities further but for now just consider one of these entities PubMed.

PubMed is a free resource supporting the search and retrieval of biomedical and life sciences literature with the aim of improving health – both globally and personally.

The PubMed database contains more than 30 million citations and abstracts of biomedical literature.

PubMed has been available to the public online since 1996.It was developed and is maintained by the National Center for Biotechnology Information (NCBI), at the U.S National Library of Medicine (NLM),located at the National Institutes of Health (NIH.).

In 2020 alone 100,000 articles alone were added on Covid-19.

For now I will just include the link below so you can take a look at this huge digital resource. In terms of me looking to build my Digital Human this at present appears to be the most comprehensive freely available resource. The plan in 2021 is for this Digital Human blog to try and map some of these resources into my overall Digital Human digitised map.

https://www.ncbi.nlm.nih.gov

 

Wednesday, December 30, 2020

20 - 028 Biological Coding Systems

 As someone outside of mainstream biological research this whole subject of how biological things are coded remains very confusing to this Digital Human. It does appear to be evolving but at the same time there appears many competing establishments looking to establish some standards for the coding of these biological entities. The term establishments is used in the broadest possible sense since there appear to be a number of these attempting to establish their standards as defacto. It has to be accepted that this is a very broad subject with each of the biological entities under constant change either due to deeper scientific analysis or biological evolution itself. For example consider the deeper identification of protein structures along with the annual mutation of flu viruses. So the depth of scientific investigation and analysis runs deeper whilst running in parallel with forever ongoing biological evolution. Against this is the variety of the biological entities covering genes, bacteria, viruses, hormones and antibodies for a start. Combine this with projecting these entities across species from human, monkey, mouse, bird to plants and algae you can just imagine the complexity.

Here I just want to touch the surface of this whole subject of biological, meaning living, entity definition. This whole subject has been called bioinformatics. In defining the Digital Human this is going to form one of the major foundations. It is probably no surprise that much of this work has been focussed upon understanding diseases since this gives the research a defined objective rather than it being just pure research. It also supports funding initiatives particularly when aligned with the commercial objectives of the pharmaceutical industry. Medicines and drugs themselves require their own entity definitions and classifications in parallel to the work on living entities. So just consider one database covering gene diseases.

So just take a look at the link below for a Gene Disease Database

https://en.wikipedia.org/wiki/Gene_Disease_Database

Now you can appreciate reading my Digital Human blogs that many of my links are to Wikipedia. Being an “amateur biologist” but “professional information expert” outside of the research, academic and pharmaceutical spheres of knowledge I find the simple way things are described in Wikipedia really beneficial. But you have to note that many people engaged in these establishments object strongly to the “open” nature of contributions to this Wikipedia resource where strong “peer” review and validation processes are not applied by biological academia or research experts. Being honest when I read the academic and scientific research papers that can to be easily found these days on the internet I am often confused by the content. This in in no way intended to undermine this critical and valuable work. Only to say the words written don’t steer my personal Digital Human consciousness in any sort of constructive way. I just don’t understand them. Consider this old posting (July 2008) since it does provide a good beginners insight into the subject of the Gene Wiki.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443188/

The plan is not to spend too much time on this subject here since this is one of the last Digital Human blogs of 2020 and these are areas of bioinformatics that are going to be investigated more deeply in 2021. But I wanted to include, more for myself than for your benefit, a few pointers that require further investigation by me the Digital Human in 2021.

Covid-19 has been a big driving force in terms of this Digital Human’s consciousness during 2020 and I am sure this will apply to 2021. Now wearing my Information Analyst’s hat back in March 2020 I always referred to it as the Coronavirus then the media started to label it Covid-19 which has remained its popular identifier for the last 9 months. Now this is the name of disease caused by the virus whilst the virus itself has been labelled as SARS-CoV-2.

Now a new mutant variant of this has been detected on the 20th September 2020. For some reason this has been labelled VUI-202012/01. It has been initially based upon statistical evidence which appears to show it is more easily transmitted.

For details of this use the link below.

https://en.wikipedia.org/wiki/Variant_of_Concern_202012/01

So what trains of thought did it set off in this Digital Human’s thinking? So to be more transmittable it must be more effective at entering the human cells. It propagates itself making more of itself within the cell it has entered before moving out of the destroyed cell to enter into more human cells. It repeats the propagation through the digital human body. It appears the human cells in the respiratory system are the first targets and most easily entered. But that is because these are the most easily got out having entered the nose and mouth. But once inside the lungs with access to blood circulation and the heart systems it can penetrate the gastrointestinal tract then finally to muscles, bones and joints. It becomes a true Digital Human invader. Now the body provides anti-bodies to neutralise this attack. Hopefully these successfully defeat the invader. Unfortunately the “flood” of these anti-bodies being called for by the immune system can become a problem itself. They have to have precise instructions on what to attack. If they get a set of incorrect instructions they can incorrectly identify normal human cells as being the enemy so destroying perfectly good living cells with this impacting the body’s ability to sustain life. Anti-bodies are called glycoproteins and they are a complex subject in their own right.

Now it is well publicised that it is the spikes on the SARS-CoV-2 virus that are the tools whereby they force entry into the human cell. Now the question to be answered - Is this entry by a chemical or a mechanical process? Does the spike touch the cell with a chemical that results in the human cell wall dissolving so the virus can gain access into the cell? Or is the spike equipped at its end with the equivalent of a “beak” where by it can mechanically beck its way into the cell membrane to gain access. To make it more transmittable either the attack chemical has been made more potent or the mechanical beak has been redesigned to make it cut into the cell more effectively. These are evolutionary changes. The digital code within the virus must have changed to allow these changes to be implemented. But there is no intelligence within a virus to trigger this redesign. Does it just happen randomly? If random a change could be for the better or it could be worse. A random decision making it worse could lower transmission rates and the virus could then just die out. 

You sort of enter the discipline of game theory. When to innovate against when to remain unchanged. Innovation could improve success or lead to failure. Remaining unchanged would uphold the status quo. This is against a backdrop of anti-bodies choosing to make similar decisions with hopefully vaccines improving the odds for the success of anti-bodies. The intellectual issue remains. What triggers the decision by the virus to change and how is the process undertaken to establish the new DNA code to support the change. One line of thought could be a battle raging inside someone with Covid-19 with the virus fighting the anti-bodies whilst trying to gain access to a human cell. In this battle the Covid-19 virus by chance effects a change that allows it to succeed in battle. The virus RNA is modified to reflect this change. Then reproduction is based upon this these new RNA instructions. These new mutant versions then proceed to succeed in all future battles thereby becoming the new dominant virus whilst the old virus just dies away. This is life played out at its very basic lower level almost emulating the basics that lead to the very start of life.These basic processes are what we need to understand if we are tio fully define the Digital Human.   

From an Information Analysts perspective (rather than a biologists) it is going to be vital that a standardised global resource is established so we can effectively deal with future global pandemics as well as all other diseases effecting our lives. Just as the internet has established local and global standardised communication networks (5G,Wifi, IP,Bluetooth etc) and the world wide web (WWW) has established global standardised information processing (HTML,XML,CSS,JS etc) along with all the supporting digital file structures (eg PDF,JPEG, MPEG etc) to define what goes on in the silica. Then similarly bioinformatics have to go through a process of establishing in a similar way all the biological standards necessary covering the living part of our world. It will be a lot more complicated that our current Information Technologies (IT) based upon silica but it is these technologies we will be using to get started.

 

Tuesday, December 29, 2020

20 - 027 Covid-19 and Human Genes

 Reading the headline that “Genes Linked to the Worst Cases” in the Times on Saturday the 12th December 2020 was really no surprise to this Digital Human. Just like computer viruses are dependent upon the underlying source code they attack on your computer then it is no surprise that human viruses adopt a similar strategy when attacking the human body. Computer viruses look for weaknesses to find their way into your computer. Human viruses must adopt a similar strategy. But they also can cause different levels of increased havoc dependent on your genetic makeup which is your equivalent to your computers source code. Your genetic makeup is the luck of the draw with it being established at the time of your conception. You are on then established on the roulette wheel of life. So what has been established so far in respect of Covid-19?

Scientists have identified mutations in five genes as having links to the disease becoming a life threatening illness for patients. The article goes on to say the Roslin Institute, Edinburgh University compared the genes of 2,244 critically ill British coronavirus patients with those of healthy volunteers. Variations in five genes – IFNAR2, TYK2, OASI, DPP9 and CCR2 – were associated with severe Covid-19 complications. These genes point to the importance of using antiviral and anti-inflammatory treatments to lower the illness experienced in these patients. In terms of risk of death they are not significant factors, but still worth addressing, with age and the underlying health of the patient still remaining the key risk of death determinates.

Consider these genes in detail.

For IFNAR2 look at :-

https://en.wikipedia.org/wiki/IFNAR2

For TYK2 look at :-

https://en.wikipedia.org/wiki/tyrosine_kinase_2

For OAS1 look at :-

https://en.wikipedia.org/wiki/OAS1

For DPP9 look at :-

https://en.wikipedia.org/wiki/DPP9

For CCR2 look at :-


If nothing else reading through these will introduce to the complexity of the genes of the Digital Human. In fact the Covid-19 virus is very simple compared with the complexity of the human body and the human cells it enters. Now if you just consider that it can all be defined in digital code then broken down to this basic level it can be easily analysed. The genes are small blocks of digital code. Genes link to genes like having hyperlinks. A virus entering the body is a piece of code that will establish its own links whilst the body will react by using anti-bodies to break these links. It can all be logically and digitally defined. Remember the work of Edward O. Wilson on Consilience. It is digitisation that is going to fully validate the concept of consilience.

20 - 026 - Protein Folding and Deep Mind

 The possibility of creating a the Digital Human just got very much closer with the DeepMind artificial intelligence research organisation, owned by Google, managing to digitise the protein folding process. So what does this all mean?

The human body is made of real tangible things. At an organ level (eg heart, liver, brain etc) these are easily visualised and you have probably seen the equivalents in animals at the local butcher. Now imagining zooming into these using an electron microscope which has the power to make a human hair look a mile wide. You going to come across structures made up from atoms and molecules so tiny they could never be handled by us as humans but they exist in the same way that organs exist but they are just a whole lot smaller.

These are the components that make up your human body. All be it very small components. They can be viewed under an electron microscope at the lowest level as tiny spheres, tubes and random three dimensional shapes that wriggle and move around. Importantly they have structures so they maybe strips that are straight or folded or tubes that are straight or bent or blobs that are any shape. They can float independently or have differing attachments to each other. They make up a very random and surreal world and to say it is abstract would be an understatement. Now to represent this real moving world of the body digitally has become the objective of DeepMind. It’s a case of getting what you can view under an electron microscope to be created digitally. Just like digital games reflect real life situations then DeepMind maps digitally represent the working of these really tiny biological components.

You are going to zoom down from human body to a human organ to cluster of human cells to a human cell and then to the molecules and atoms within this cell. Then no doubt in the future into the atom itself. It is the clusters of human cells forming their own unique structures where many new facets of life are to be uncovered. Being real physical structures the way they move and interact within the body can be investigated. Even using Computer Aided Manufacture (CAM) vastly enlarged models can be made of these structures. These can be handled and the way they lock together with other cell structures can be assimilated to learn how things work. By applying the same techniques to humans suffering illness and disease the faulty structures can be examined to determine how the condition is causing illness. But possibly most significantly the same processes can be applied after the introduction of medical interventions (eg drugs) to determine how they change these structures. Dismantling the human body, all be it digitally, like you would dismantle a car to locate the component that is the root cause of a medical problem. Digitisation is the key to this approach.

So let us try and visualise how this digitisation is achieved. There are similarities to computer gaming and computer aided design (CAD). So think of large rectangular box that the human body can be placed inside possibly lying down flat like being in a coffin but not coffin shaped being just rectangular box shaped. Now visualise ruler markings along the edges of this rectangular box. Using three of these edges with their marking points can allow you to locate any point within this box. So the tip of your nose can have an X reading and a Y reading and a depth from the top of the box being the Z reading. The classic three co-ordinates necessary to locate anything in space. Now image the ruler markings going down to the thousandth of a hair width so you can locate a point to a very exact molecular and even lower atomic level. You can define a living cell at the end of your nose. A large number of co-ordinates can define the shape of this cell as each point on the surface of the cell are defined by X-Y-Z co-ordinates. You can even define things within the cell itself along with their location and shape. The outer cell membrane can be defined by both its inner and outer surfaces thereby defining its thickness or even variations in this thickness over its surface. Now you can zoom both in and out. Out from a cell to the part of an organ, then the organ itself and then the organs place within the human body. It is Google Maps for the human body. This covers what I term the physical mapping. Now at every one of these points the chemical makeup of the point can be defined based upon the Periodic Table so you achieve chemical mapping. This allows you to create a chemical map if you like layered over the physical like in Google maps viewing something as a map or a satellite image. The same thing viewed in a physical and a chemical dimension. This creates the fact that within the physical shape the chemical makeup may adopt a different pattern. Seeing the human body in this layered way makes investigating the body’s changes and processes a multi-dimensional experience. The physical shape might change whilst the chemical makeup does not. Whilst the chemical makeup maybe changing whilst the physical remains unchanged. One of the commonest processes, a process representing change, would be for the chemical makeup within a cell to change with this subsequently resulting in a physical change. The key medically would be to spot theses chemical changes early with possibly a drug intervention before the problem presents itself as a physical change. True preventative medicine. It is important to reiterate the fact that the physical structures are created as a digital map and the chemical makeup is recorded as a separate digital map. These are then overlaid over each other. Now this overlaying of different what I have termed dimensions is important. The physical dimension and the chemical dimension. This lends itself to the addition of other dimensions if they can be scientifically be defined by capturing data on them. So for example the electrical activity within the body or other dimensions not previously scientifically identified. These maybe considered unreal at present but subjects like radiesthesia and telepathy come to mind being what I and others (but only a few of us) term the “wireless aspects of life”. Subjects to be explored later in this book.

But what becomes really important is when you can run these digital maps over time so you can view all the changes in the human body both physically and chemically. You can watch tumours grow and drugs destroy them digitally. This leads to the important ability to re-run scenarios over and over again with this forming one of the important tenets of artificial intelligence (AI). The ability to build up digital pathways that can represent reality. Adjustments can be made to data along these pathways and the changes can be recorded. This approach can then be used to build up a whole holistic view as thousands of different pathways are simulated and stored. So intelligence on a subject is grown until it shown to accurately represent a reality.

So what you can see under a digital microscope can now be digitally represented with the human body emulating a moving computer game. These are digital 3D shapes all interacting like they would within a real living biological body. In fact what you get to see digitally is a visual representation of what you would see under a powerful digital microscope. The significance of it being digital is that it can be analysed in terms of its internal structures then by using artificial intelligence processing different scenarios can be run through thousands of times with various adjustments being made to the objects under scrutiny. Essentially you can make changes, possibly by applying a drug, into the equation and then run through a sequence to determine the impact of the drug. Like playing strategy games where decision tree style thinking is important where at each node new decisions can be made about the way forward based upon new data. These biological digital models allowing for many thousands if not millions of different scenarios to be tested leading to different final results. Once a positive result is achieved you can reverse back over the decision tree to analyse all the different node point inputs.

Whilst being really comfortable with these digital models essentially replicating what can be seen using a digital microscope it is when it comes to the underlying chemistry of the model where this adds a new very powerful scientific dimension. Think of hovering a pointer over a particular point within the digital model and then the chemical makeup is displayed at a molecular level. Essentially the elements as defined in the Periodic Table. These can be painted as colours within the digital model so you can visually see the chemical makeup and importantly changes to this make up over time. You can see things going wrong both visually and chemically at the same time. A new tumour developing with cell multiplication with these cells changing in their chemical makeup. Then hopefully the reverse effect after the application of treatments. The thought that one day you could see all this happening in your body real time on your smartphone. Possibly the most significant aspect being the very early identification of these changes so they can be treated well before the patient is aware of any symptoms.

DeepMind is applying both Gaming and Computer Aided Design (CAD) principles to biological components down at a nanometre sizes. The CAD is important because it is simple step to Computer Aided Manufacture (CAM) where the three dimensional printing of components has become a standardised industrial practice. So it is a simple step to create physical three dimensional models of these biological components. Now significantly there is a school of thought that being able to create physical models of these tiny biological components will give us a totally new insight into how our bodies are assembled from the very smallest building blocks of atoms and molecules up to cells and cellular structures up to organs. So this is true biological engineering. The creation of these tiny cells, viruses and bacterium as real models produced through Computer Aided Manufacturing (CAM) but in sizes where they can be handled which allow us to see how they interact manually. The way viruses gain entry into human cells can be witnessed through the workings of these enlarged models. It is important to appreciate that although many of the processes within a human body are chemical it is also the mechanical designs that evolve from these chemical processes that undertake purely mechanical activities. They are interlocking mechanical processes like keys opening a lock or pick axes breaking into the wall of a cell. These are real mechanical activities taking place within the human body and their assessment as such it important as a tenet of medical investigation.

 

So why is this suddenly so significant in respect of the work at DeepMind on proteins?

Life is dependent on proteins. Proteins are made up from chains of organic compounds known as amino acids. These bond together into long chains to make proteins, which in turn create different types of tissue that perform all sorts of functions within the human body. Proteins, the building blocks of life, adopt complex three-dimensional shapes which determine what they do and how they do it. They make up good cells, bad cancer cells, viruses, bacteria and antibodies. If something is alive it will be made up of proteins. Proteins are the machinery of both life and unfortunately death. Failures in the production of these proteins will lead to death. Proteins which are collections of compounds called amino acids are the machinery of life. Machinery is the right term to use because it implies they are physical, which they are, so we need to know what they look like. They cannot just be considered as a chemical compound listing the molecules that make them up since life is about movement and this is the machinery that supports this movement. It is about biological engineering and not pure chemical engineering. At the atomic level biology works by the interlocking structures of atoms in a physical way. We need to know how the one dimensional sequence of atoms we get from chemistry “folds” in a 3D image. Into a real physical component.

Protein molecules can coil around themselves in all sorts of different ways. They can be tangled in a normal way. But also they can be tangled in a way that is abnormal leading to conditions like Alzheimer’s and Parkinson’s. Tangling is a really strong force in natural for good and for bad. I think of how the Christmas tree lights or power cables to electrical appliances or water hoses or blind cords can get so horrendously tangled together. There seems to be some natural forces of nature that sit behind the tangling of rope or strip like materials particularly if they have protrusions like the lights on Christmas tree lights. Going back to the primeval soups of life it is these tangling processes that allowed the build-up of more complex life forms. Algae deposits and damp algae twisting and turning until by chance something more sophisticated is created. The complexity of sperm swimming to the egg to penetrate it to generate the start of a cell reproduction cycle. These basic building blocks of life need to be digitally analysed both physically and chemically to understand when and how life itself sparks into a continuous process of growth and decay. In the case of decay protein malformation and malfunction maybe behind many of the unpleasant conditions associated with the aging process.

 

 

Now deriving the chemical formula of a protein is scientifically relatively straightforward but determining its physical appearance was a long laborious process called crystallography. Prior to this digital break by DeepMind this was the standard way of “seeing” a protein by a process of crystallisation. That is lock it in a stasis in a repeating pattern then you fire x-rays at it in all different directions and from the image they form you can infer its shape. What DeepMind did was create some specific chemical knowledge and then apply this to those proteins where x-ray images existed from the above crystallography process. By constantly adjusting the underlying algorithm they started to get the protein chemical makeup to equal the created x-ray images. So the model was built upon crystallised protein x-ray pictures. So having trained the algorithm to link the protein amino acid structure to the corresponding specific crystallographic image it could then be applied to tens of thousands of proteins that had never been mapped using crystallography. Some of these previously unmapped proteins could then have the crystallographic process applied and this could be compared to the DeepMind image. The success rate of this DeepMind mapped image against the actual crystallographic image showed that the process was a real success. But importantly the algorithm could continue to be adjusted as new crystallographic images became available further refining its accuracy. To the point that the digital only processes were deemed as accurate as crystallography. But the digital approach had another major advantage.

Now in the body proteins are not crystallised but they are free moving structures that warp and bend continually. This makes the modelling of this real world behaviour a lot more difficult. But real success will follow on from when the digital modelling mirrors real life. The computer model equals what you can see under an electron microscope. But then significantly digital model will have captured the underlying logic to these biological processes. Once this structure is a “calculated” one based upon this logic we can then run in a “live” model emulating life within the human body. Knowing this we can go onto design the experiments that make drugs and enzymes and all the molecular tools we need to improve the human condition. These medical interventions can also be modelled real time so we can monitor how they interact with the faulty proteins. So create a sick digital human then test the best medical interventions to make it better.