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p. 1228. The future of cell researchlocked

  • Terence Allen
  •  and Graham Cowling

Abstract

‘The future of cell research’ examines new directions and how they might evolve. Some involve the understanding of how cellular behaviour can change so dramatically after subtle changes at the level of genes and proteins. Other approaches use cells to cure a disease, for extraction of metals, the breakdown of petroleum products, or to harness light to produce biofuels. Other efforts are to create synthetic life and understand the biology behind ageing. New approaches are needed to investigate ‘systems biology’ or ‘biocomplexity’, where the challenge is to understand the collective interactions of multiple molecular processes, not only within the cell itself, but also at the tissue, organ, and organism level.

The whole cell is considerably more than the sum of the working parts. The same can also be said about the genome, where the identification of the blueprint for individual molecular components of the cell is undertaken in the expectation that a rigorous characterization of all of the parts separately will lead to an understanding of the whole. This is a system of investigation called reductionism, which has been a dominant philosophy in biological investigation for decades. However, just to identify the molecular parts of the puzzle is not going to tell us how the whole works if we do not understand the rules for their assembly. This requires the development of approaches to investigate ‘systems biology’ or ‘biocomplexity’, and represents a paradigm shift (i.e. ‘thinking outside the box’) in biological research, wherein the challenge is to understand the collective interactions of multiple molecular processes, not only within the cell itself, but also at the tissue, organ, and organism level. The bottom line is ‘do the molecules drive the cell to drive the organism, or does the organism drive the cell and its molecules?’ In reality, such interactions lie somewhere between the cell responding to its immediate environment, balanced against the controls of gene expression.

There are many new exciting areas of research into cells. Some involve the understanding of how cellular behaviour can change p. 123so dramatically after subtle changes at the level of genes and proteins. Other approaches use cells to cure a disease, for extraction of metals, the breakdown of petroleum products, or to harness light to produce biofuels. Equally fascinating are our efforts to create synthetic life and understand the biology behind ageing. In this chapter we briefly examine some of these future directions and how they might evolve.

Systems biology

We now know the complete DNA sequence of just a few humans. We also have a rapidly increasing understanding of the biochemical mechanisms involved in the day-to-day existence of the cell and how it divides and differentiates. In the past ten years, advances in molecular technology have allowed us to induce and monitor changes in thousands of genes, their accompanying RNA signals, and protein production. These changes can now be measured more or less at the same time and even within a single cell. The knowledge coming out of this collection of technologies has developed into its own subject, known as systems biology. It has allowed us to see millions of more subtle interactions between the different components of the cell. Early experiments monitored the changes that occur within a cell when it is subjected to a known pharmaceutical drug. For example, in the simplest case, a drug interacts with its target enzyme protein and stops it working. What is apparent now through our ability to analyse thousands of individual genes and their products simultaneously is that a drug also triggers changes in the levels of many other proteins, often seemingly unconnected to the original target enzyme, which may be increased or reduced, often at differing rates. This may account for some drug side effects but also allows the development of ‘cleaner’ more specific pharmaceuticals. By further applying this methodology to various biological systems, we are starting to discover the alterations in gene expression and protein levels that take place during various biological processes such as cell division and differentiation. While these experiments themselves take p. 124relatively little time to perform, understanding what they mean will take longer as the vast amount of data generated needs to interpreted. Fortunately, analysis of this information has been made possible by powerful computing. Increasingly, cell and molecular biology relies on this in silico biology, which is known as bioinformatics, to solve the difficult questions of biological behaviour in terms of DNA and protein sequence.

Leroy Hood, a pioneer of this field, suggested a beautiful example of how systems biology might work in medicine. A patient attends their doctor's surgery, giving a pin prick of blood. What follows is the full biochemical, gene, and protein analysis of the body's function and health state. This information will be instantly computed for all possible diseases, matched with the symptoms, and therapies or further tests suggested all in a matter of minutes. This is personalized medicine, a dream a few years ago, and now only a matter of (uncertain) time. Cancer researchers are already using advanced protein and DNA technology to monitor the extremely small number of cancer cells that can be found in the blood of a patient suffering from a solid tumour (a small number of tumour cells are continuously shed into the blood, passing through the capillaries supplying nutrients to the growing tumour). Pharmaceutical researchers are using these methods to investigate the general efficacy of new anticancer drugs.

Given the dynamic nature of the living cell, to follow the fate of individual proteins during biological processes (for instance during stem cell differentiation) requires the ability to tag one or more proteins and observe them in real time. Previously, molecules such as green fluorescent protein (GFP) would be used as labels but this tag could be many times larger than the molecule of interest, and possibly interfere with its normal activity. Tagging is now possible with minute inorganic spheres (quantum dots) which are so small (see Figure 1) that they pass straight through the cell membrane. Nanotechnology is the science of controlling matter on an atomic or molecular scale, and involves the p. 125interaction of materials between 1 and 100 nanometres (DNA strands have a diameter of two nanometres). The massive advantage of working at this scale is the ultra fast speed of the reactions, which are reminiscent of those found in the cell. This growing area of research is being applied to living cells in the molecular analysis of disease. Future applications will include the micro-manipulation of faulty genes, building cellular bio-sensors, and creating DNA computers. Imagine a time when an oral medicine is not just a chalky pill, but will consist of a capsule full of nanorobots programmed to find and reconstruct the DNA of cancer cells or dismantle a life-threatening virus. Cells from patients with an inherited disease could be corrected and affected organs could be restructured by surgical nanorobots.

Synthetic life

All living cells are related to each other by their use of the same genetic code and a small number of highly conserved protein sequences. This suggests that all modern life evolved from a single ancestral living entity. The components of the cell—DNA bases, amino acids, and even small polymers of these—have been created in the laboratory using recreations of the extreme chemical and physical conditions that existed as the new Earth cooled down. We are now in the era of creating entirely synthetic cells from elemental precursors.

Cells need to create copies of their molecules before they can divide, but they also need the software and all the complex protein synthesis machinery to get there. Therefore, the minimum requirements for a cell are: a containing structure; a DNA sequence laid out in the logical order of genes, each coding for a protein that can perform a simple chemical reaction; and, most importantly, the ability to bring these processes together with the information to consistently replicate itself. Fat molecules can self-assemble into primitive membranes, forming spherical structures to protect and concentrate their contents. Artificial p. 126ribosomes capable of assisting in protein synthesis, and functional synthesized genomes introduced into cells lacking a nucleus have been created successfully in the laboratory. Bioengineers have recently created a photosynthetic foam containing all the enzymes needed to convert 98% of sunlight into sugar. These biotechnology applications currently mimic natural life processes. Whether we will be able to recreate a complete independent life form is less certain but such work may help us to further define what life is.

Growing limbs and ears

In our own bodies, only the liver is capable of limited regeneration, but chop a limb off a starfish or a salamander, and it will grow a new one. We are starting to understand the molecular signals that are used by these species to regenerate limbs in adult life. Mammals seem to only use this signalling pathway during the growth of the early embryo but it is a pathway that may well have the potential to be reactivated. Following surgical removal, the wings can grow back in embryonic chickens when the production of a protein called wnt is switched on. Frog limb regeneration can also take place later in the life cycle when wnt protein is expressed. Tadpoles have this ability but it is normally lost when they metamorphose into frogs. The expression of wnt signalling protein around an injury is thought to cause a reprogramming or transdifferentiation of mature cells into stem cells capable of producing the cell types needed for the limb. Very young children have been known to re-grow severed fingertips, and so there are intriguing possibilities for human tissue regeneration.

An eternal existence

Can we live forever? Instead of growing old, the ‘immortal jellyfish’ (Turritopsis nutricula) reaches sexual maturity, then reverts back to its juvenile polyp stage (equivalent to embryonic cells). In mature jellyfish (medusa stage), cells from the bell p. 127surface and digestive canal organ become transdifferentiated into polyps which then develop into mature jellyfish and so on. This property of bypassing death by reversing its life cycle is, so far, unique in the animal kingdom, allowing a sole jellyfish to live and reproduce indefinitely. Fortunately, most of these jellyfish (they breed every 24 hours) are lost to the general hazards in the sea.

Recent studies have shown that an insulin-like receptor protein in the nematode worm C. elegans plays a vital role in controlling lifespan. This gene is important in regulating reproduction, heat tolerance, resistance to the lack of oxygen, and bacterial attack. Mutations in this gene allow the worm to live twice as long (albeit in laboratory conditions). Higher levels of a protein that controls the expression of this insulin receptor are also correlated with longevity. The worm leads the way to examining whether the equivalent genes in mammals are able to prolong life. As we understand more about how cells age, it may be possible to manipulate the genetics and mechanics of this process.

An alternative way of gaining immortality is to create a clone of yourself. The first mammal cloned was Dolly the sheep by way of somatic cell nuclear transfer (introducing the nucleus of an adult cell into an unfertilized egg followed by surrogate motherhood). This has led to the production of a range of ‘immortal’ cloned animals including beloved household pets. The problem with producing a new animal essentially from an adult nucleus is that it increases the risk of the early onset of age-related diseases including cancer. Human cloning and the growth of the early embryonic body has been suggested as a new and convenient cell source to provide therapeutic stem cells for transplantation. Ethical and political concerns have stopped further work in this area for the moment.

Life on this planet is based on the cell. Single-celled life forms like bacteria, yeasts, and algae have evolved over many millions of years into complex multicellular animals capable (in our own p. 128situation) of trying to understand how life itself works. Meticulous observation and profound thinking by 19th-century biologists helped us to understand what the cell is, how every new cell is related to its mother cell through its genes, and how one cell or collection of cells can evolve into new species by adapting to a changing environment under the influence of natural selection. The 20th century has seen the unravelling of the cell's components, the decoding of the vast amounts of information that lies in DNA and proteins, and an initial grasp of the complex communication between cells and the molecular components involved. The 21st century will probably yield ways of using cells, natural or synthetic, to cure disease, regenerate any part of the body, and extend lifespan. Perhaps we can even create cell-based supercomputers. Just as the evolving bacteria in Earth's early history changed the chemistry of the biosphere, similar approaches could be used to reverse the harm we have done in our continuing exploitation and pollution of the planet. Whatever happens in the future, living cells, in some form or other, are likely to survive and adapt to their environment. Whether humans will be around to see this is rather less certain.