Thursday, 7 May 2015

Human as a model organism

Model organisms have provided the foundation for building our understanding of life, including human disease. Homo sapiens has joined this select group, adding knowledge we can apply to our myriad companion species. But to resolve even one small part of the moving, shifting puzzle of life, we need them all.

Biology is incredibly complex. Even the simplest bacteria make intricate decisions and balance different demands, all via chemical reactions happening simultaneously in what seems like just a bag of molecules, called a cell. Larger organisms all start as a single cell and eventually become living creatures that can fly, or slither, or think – sometimes living for just a day and sometimes for centuries.

Whatever the process, whatever the outcome, it all begins with information, recorded in a tiny set of molecules (DNA) in the very first cell. How that information made it this far, and how it is now composed, comes down to the twin processes of random change (mutations) and competition between individuals, giving rise to evolution. Evolution has, quite amazingly, given rise to everything from uranium-feeding bacteria to massive sequoias and tax-filing, road-building, finger-painting humans.


Modelling life


Unpicking this complexity is hard, in part because so many things are happening all at once. We’ve been working on it for centuries, building layer upon layer of knowledge collectively, in many labs throughout the world, usually relying on specific organisms where we accumulate large amounts of knowledge on the processes of life. These ‘model’ organisms, for example the gut bacteria E. coli, are selected for their ease husbandry and other features of their biology. Interestingly, most of them have been our companions or domesticated in some way throughout our explosive growth as a species.

To create models of animal life processes at the simplest level, we use organisms like European and African yeast (used for both baking bread and making beer), which has a nucleus (like all animals, they are eukaryotes). We use the humble slime mould, which spends most of its time as a single cell but, in extremis, will band together to form a proto-organism that has given us insights into signalling. Taking it up a notch, we are helped by pests that have lived off our rubbish since our earliest days in Africa: fruit flies, mice and rats provide profound insights into animal life. Even the model worm C. elegans, which helps us understand development, could be considered ‘semi-domesticated’ (though no one really knows where ‘wild’ C. elegans might live).

Each of these models has its strengths and weaknesses: the time it takes to breed generations, the effort involved in handling them, the availability of automated phenotyping systems, the flexibility (or lack thereof) of their cellular lineage, and more exotic features, such as balancer chromosomes, RNAi ingestion, chromosomal engineering. But they all share one distinct quality: they are not human.


Using ourselves?


Using Homo sapiens as a model species to understand biology has many advantages, and some important drawbacks. Leaving aside for a moment the interaction with research into human disease, what are the benefits of using ourselves as an organism on which to model basic, fundamental life processes?

·            Humans are large, so we can acquire substantial amounts of material from consented individuals either from living persons (e.g. blood) or via autopsy;

·            The extremely large population can be accessed relatively easily, with no on-going husbandry costs;

·            Wild observational studies (i.e. epidemiology) are feasible to deploy at scale, though at considerable cost;

·            The population has good genetic properties: it is outbred, and mating is fairly random with respect to genotypes, usually with only geographic stratification;

·            Many phenotyping systems are designed explicitly for this organism, in some cases with a high level of automation;

·            An on-going, proactive screening process for rare, interesting events (i.e. ‘human clinical genetics’) are available in many parts of this population at the scale of millions of screening events each year;

·            Cells from this organism can be cultured routinely using iPSC techniques, and these cellular systems can be genetically modified and made into functional tissue-scale organoids;

·            Limited intervention studies are feasible (if expensive);

·            Research on this organism is well funded, thanks to widespread interest in human disease.

The drawbacks:

·            There are no inbred lines for Homo sapiens;

·            The large size and tissue complexity of this species, in particular the brain, presents significant challenges to understanding cellular and tissue behaviour;

·            The organism cannot be kept in a strictly defined environment (though an increasing number of aspects can be monitored in observational studies);

·            Explicit genetic crosses cannot be done (though the large number of individuals make it possible to observe many genetic scenarios in the population);

·            Genetically modified cells cannot be used to make an entire organism;

·            Intervention studies are quite limited by both safety and expense;

·            Ethical issues, which are important when studying any species, are more involved for Human – even for basic research.


An old story


Using Homo sapiens as a model species is not a new idea – it has been around since the dawn of genetics and molecular biology. Studies of human height motivated the early theory around quantitative genetics. Quite a bit of mammalian (and general eukaryotic) biochemistry and genetics was originally uncovered by discoveries of inborn errors in human metabolism in the 1960s and 1970s, and was confirmed by biochemistry studies in cow and pigeon tissue. And robust cancer-derived cell lines – most famously HeLa cells – have been used in molecular biology for decades.

But the downsides to using humans as a model species are far fewer in number now than they were two decades ago, when the human genome was considered to be so large that a major, global consortium was required to generate it. But the human genome is dwarfed in size and complexity by bread wheat and pine, whose genomes are being untangled today. The cost of human genetics studies has plummeted so that large populations are more accessible and easily leveraged (a genotyping array now costs under €50 and sequencing under €1,000), which is a major benefit for doing statistically robust studies. The result has been a resurgence of common and rare genetic approaches. The drop in sequencing cost has allowed more scalable assays, such as RNA-seq and ChIP-seq, which let us work routinely on the scale of a whole human genome.

A decade ago there was a far wider gap between experiments that were feasible on Drosophila, C. elegans or the yeasts, but not on human beings. The landscape has changed.


Human disease


The global economy is a human concept (though it affects all species) and a big chunk of it (10% to 17% in industrialised economies) is spent on healthcare. That is a huge amount of money. A considerable amount is already spent on clinical research, but the advent of inexpensive techniques to measure DNA, RNA, proteins and metabolites presents massive, new opportunities. It is now possible to blend scientific approaches that have traditionally been separate – experimental medicine and genomics, or epidemiology and bioinformatics – to exploit these measurement techniques alongside traditional clinical approaches.

The primary motivation for all this activity and expense is to understand and control human disease. But health and disease are constantly in flux, in humans as in all species, and often the process of understanding human disease is really just the same as understanding human biology – and that’s not so different from understanding biology as a whole. Fitting all the pieces together requires taking the best from all fields, and that is in itself a huge challenge.


Traditional models, rebooted


There is justifiable excitement around new opportunities to study humans as a model organism, but it is simply not the case that the established model organisms will become less and less relevant. Placing too strong an emphasis on Human studies could lead to inadvertently hindering research on other organisms, which would be counterproductive.

‘Model’ organisms help us create ‘models’ of life processes – they do not serve as ‘models’ for human organisms. Our grasp of molecular biology is still quite basic indeed: we have a firm grasp on only just over a third of protein coding genes in humans, and this number is not much higher in simple, well-studied organisms such as yeast. Even in cases where we have ‘established the function’ of a set of genes and can tie them to a specific process, we still have huge gaps in our comprehension of how these particular molecules can create exquisitely balanced, precise processes.

Leveraging the unique properties of different model organisms provides opportunities to innovate. For example, one remarkable paper demonstrates how a worm ‘thinks’ in real time, monitoring the individual firing of each (specifically known) neuron in the animal as different cues are past over its nose. The growing set of known enhancers in Drosophila allows for the genetic ablation of many cells, and the incredible precision of mouse genetic engineering allows precise triggering of defined molecular components. None of these experiments would be even remotely feasible in Human.
We would be very foolish to take a laser-like focus on this rather eccentric bipedal primate, however obsessed might be with keeping it healthy, happy and long-lived.

Our understanding of development in organisms, of homeostasis within organs, tissues and cells, and of the intricacies of behaviour is only just starting to develop. Metaphorically speaking, we have lit a match in a vast, dark hall – the task of illuminating the processes that drive these molecules to create full systems (that go on to type blog posts) is daunting, to say the least.


Hedging our bets


There are many hard miles of molecular and cellular biology ahead to improve our understanding of biology, with leads to follow in many different models (including human!) using many different approaches. This deeper understanding of biology will directly impact our understanding of human disease in the future. We need to spread our bets across this space.

Clinical researchers might have a harder time managing this, as the necessary focus on Human to understand human disease makes it all to easy to dismiss the future impact of other organisms on understanding human biology. The majority of molecular knowledge they currently deploy in their research is built on studies of a very diverse set of organisms. Useful and surprising insights and technologies can be gleaned from any organism.

Basic researchers, on the other hand, might dismiss the advent of human biology because it places inappropriate emphasis on applied research into the specifics of human disease. All human studies are not necessarily translational, and in any case the interweaving between understanding biology and understanding disease makes it impossible to really separate these two concerns.


To Human and back again


Over the next decade, the integration of molecular measurements with healthcare will deepen. This will almost certainly have a beneficial impact on the lives and health of many people worldwide. It also provides huge opportunities for the research community – obviously for applied research but also for curiosity-driven enquiry, as this massive part of our economies will generate and manage information on ourselves.


We should exploit this to its fullest so that we can understand life, on every scale, in every part of the world we inhabit.

3 comments:

Humaun Kabir said...

Lots of Good information in your post, I favorited your blog post so I can visit again in the future, Thanks.
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andrea wang said...

Models of human disease are the animals that are built in the 3D animals model to simulate the human disease.

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