The Power of Flower

 

We know we don’t ‘understand cancer’ — for if we did we would at least be well on the way to preventing the ten million annual deaths from these diseases and perhaps even stymieing their appearance in the first place. But at least, after many years of toil by thousands of curious souls, we might feel brave enough to describe the key steps by which it comes about.

Here goes!

Our genetic material, DNA, carries a code of four different units (bases) that enables cells to make twenty-thousand or so different types of proteins. Collectively these make cells — and hence us — ‘work’. An indicator of protein power is that we grow from single, fertilized cells to adults with 50 trillion cells. That phenomenal expansion involves, of course, cells growing and dividing to make more of themselves — and, along the way, a bit of cell death too. The fact that there are nearly eight billion people on planet earth testifies to the staggering precision with which these proteins act.

Nobody’s perfect

As sports fans will know, the most successful captain in the history of Australian rugby, John Eales, was nicknamed ‘Nobody’ because ‘Nobody’s perfect’. Well, you might care to debate the infallibility of your sporting heroes but when it comes to their molecular machinery, wondrous though it is, perfect it is not.

Evidence: from the teeming eight billion there emerges every year 18 million new cancer cases (that’s about one in every 444). And cancers are, of course, abnormal cell growth: cells growing faster than they should or growing at the wrong time or in the wrong place — any of which means that some of the masterful proteins have suffered a bit of a malfunction, as the computer geeks might say.

How can that happen?

Abnormal protein activity arises from changes in DNA (mutations) that corrupt the normal code to produce proteins of greater or lesser activity or even completely novel proteins.

These mutations may be great or small: changes in just one base or seismic fragmentation of entire chromosomes. But the key upshot is that the cell grows abnormally because regulatory proteins within the cell have altered activity. Mutations can also affect how the cell ‘talks’ to the outside world, that is, the chemical signals it releases to, for example, block immune system killing of cancer cells.

Clear so far?

Mutations can change how cells proliferate, setting them free of normal controls and launching their career as tumour cells and, in addition, they can influence the cell’s environment in favour of unrestricted growth.

The latter tells us that cancer cells cooperate with other types of cell to advance their cause but now comes a remarkable discovery of a hitherto unsuspected type of cellular collaboration. It’s from Esha Madan, Eduardo Moreno and colleagues from Lisbon, Arkansas, St. Louis, Indianapolis, Omaha, Dartmouth College, Zurich and Sapporo who followed up a long-known effect in fruit flies (Drosophila) whereby the cells can self-select for fitness to survive.

Notwithstanding the fact that flies do it, the idea of a kind of ‘cell fitness test’ is novel as far as human cells go — but it shouldn’t really surprise us, not least because our immune system (the adaptive immune system) features much cooperation between different types of cell to bring about the detection and removal of foreign or damaged cells.

Blooming science

So it’s been known for over forty years that Drosophila carries out cell selection based on a ‘fitness fingerprint’ that enables it to prevent developmental errors and to replace old tissues with new. However, it took until 2009 before the critical protein was discovered and, because mutant forms of this protein gave rise to abnormally shaped nerve cells that looked like bunches of flowers, Chi-Kuang Yao and colleagues called the gene flower‘.

Cells can make different versions of flower proteins (by alternative splicing of the gene) the critical ones being termed ‘winner’ and ‘loser’ because when cells carrying winner come into contact with cells bearing loser the latter die and the winners, well, they win by dividing and filling up the space created by the death of losers.

The effect is so dramatic that Madan and colleagues were able to make some stunning movies of the switch in cell populations that occured when they grew human breast cancer cells engineered to express different version of flower tagged with red or green fluorescent labels.

Shift in cell populations caused by two types of flower proteins. 

Above are images at time zero and 24 h later of co-cultures of cells expressing  green and red proteins (losers and winners). From Madan et al. 2019.

Click here to see the movie on the Nature website.

Winner takes almost all

The video shows high-resolution live cell imaging over a 24 hour period compressed into a few seconds. Cells expressing the green protein (hFwe1 (GFP)) were co-cultured with red cells (hFwe2 (RFP)). Greens are losers, reds winners. As the movie progresses you can see the cell population shifting from mainly green to almost entirely red, as the first and last frames (above) show.

How does flower power work?

Flower proteins form channels across the outer membrane of the cell that permit calcium flow, and it was abnormal calcium signalling that caused flowers to bloom in Drosophila nerves. It would be reasonable to assume that changes in calcium levels are behind the effects of flower on cancer cells. Reasonable but wrong, for Madan & Co were able to rule out this explanation. At the moment we’re left with the rather vague idea that flower proteins mediate competitive interactions between cells and these determine whether cells thrive and proliferate or wither and die.

Does this really happen in human cancers?

Madan and colleagues looked at malignant and benign human tumours and found that there was more ‘winner’ flower protein in the former than the latter and that ‘loser’ levels were higher in normal cells next to a tumour than further away. Both consistent with the notion that tumour cells express winner and this induces loser in nearby normal cells leading to their death. What’s more they reproduced this effect in mice by transplanting human breast cancer cells expressing winner.

So there we are! After all this time a variant on how cancer cells can manipulate their surroundings to promote the development of tumours. Remarkable though this finding is, in a way that is familiar it’s just the beginning of this story. We don’t know how flower proteins work in giving cancers a helping hand and we don’t know how effective they are. Until we answer those questions it would be premature to try to come up with therapies to block their effect.

But it is a moment to sit back and reflect on the astonishing complexity of living organisms and their continuing capacity to surprise.

Reference

Madan, E. et al. (2019). Flower isoforms promote competitive growth in cancer. Nature 572, 260-264.

Yao, C-K., et al., (2009). A synaptic vesicle-associated Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis. Cell 138, 947–960.

Shifting the Genetic Furniture

 

Readers of these pages will know very well that cells are packets of magic. Of course, we often describe them in the simplest terms: ‘Sacs of gooey stuff with lots of molecules floating around.’ And it’s true that we know a lot about the protein pathways that capture energy from the food we eat and about the machinery that duplicates genetic material, makes new proteins and sustains life. Even so, although we’ve worked out much molecular detail, we have scarcely a clue about how ‘stuff’ in cells is organised. How do the tens of thousands of different types of proteins find their places in the seemingly chaotic jumble of a cell so that they can do their job? If that remains a mystery there’s an even more perplexing one in the form of the nucleus. That’s a smaller sac (i.e. a compartment surrounded by a membrane) that is home to most of our genetic material — i.e. DNA.

Sizing up the problem

It’s easy to see why evolution came up with the idea of a separate enclosure for DNA which only has to do two things: reproduce itself and enable regions of its four base code to be transcribed into molecules that can cross the nuclear membrane to be translated into proteins in the body of the cell. But here’s the puzzle. The nucleus is very small and there’s an awful lot of DNA — over 3,000 million bases in each of the two strands of human DNA (and, of course, two complete sets of chromosomes go to make up the human genome) — so 2 metres of it in every cell. A rather pointless exercise, unless you go in for pub quizzes, is to work out the length of all your DNA if you put it together in a single string. 1013 cells (i.e. 1 followed by 13 zeros) in your body: 2 metres per cell. Answer: your DNA would stretch to the sun and back 67 times.

Mmm. More relevantly, the nucleus of a cell is typically about 6 micrometres (µm) in diameter — that’s six millionths of a metre (6/1,000,000 metre), into which our 2 metres must squeeze.

Time for some serious packing to be done but it’s not just a matter of stuffing it in any old how and sitting on the lid. As we’ve just noted, every time cells divide all the DNA has to be replicated and regions (i.e. genes) are continually being “read” to make proteins. So the machinery in the nucleus has to be able to get at specific regions of DNA and disentangle them sufficiently for code reading. Part of evolution’s solution to these problems has been to add proteins called histones to DNA (the term chromosome refers to DNA together with histone packaging proteins and other proteins). To understand how this leads to “more being less”, consider DNA as a length of cotton. If you just scrunch the cotton up into a ball you get a tangled mess. But if you use cotton reels (aka histones — two or three hundred million per cell), you can reduce the great length to smaller, more organized blocks — which is just as well because they’re all that stands between life and a tangled mess.

Thinking of histones as cotton reels helps a bit in thinking about how the nucleus achieves the seemingly impossible but the fact of the matter is that we have no real idea about how DNA is unravelling is controlled so that the two strands can be unzipped and replicated, yet alone the way in which starting points for reading genes are found by proteins.

Undeterred by our profound ignorance Haifeng Wang and colleagues at Stanford University have just done something really amazing. They came up with a way of moving regions of DNA from the jumble of the nuclear interior to the membrane and they showed that this can change the activity of genes. They used CRISPR (that we described in Re-writing the Manual of Life) to insert a short piece of DNA next to a chosen gene. The insert was tagged with a protein designed to attach to a hormone that also binds to a protein (called emerin) that sits in the nuclear membrane. So the idea was that when the hormone is added to cells it can hook on to the DNA tag and, by attaching to emerin, can drag the chosen gene to the membrane. The coupling agent is a plant hormone (abscisic acid) although it also occurs in other species, including humans. Wang & Co christened their method CRISPR-GO for CRISPR-Genome Organizer.

Tagging a DNA insert with a protein so that a coupling molecule can pull a region of DNA to a protein in the membrane of the nucleus. From Wang et al., 2018.

Repositioning regions of DNA in the nucleus. DNA is labeled blue which defines the shape of the nucleus. Red dots are specific genes before (left) and after (right) adding the coupling agent. From Pennisi 2018.

How did CRISPR-GO go?

Astonishingly well. Not only could it shift tagged DNA from the interior to the membrane of the nucleus but the rearrangements could change the way cells behaved. Depending on which regions were moved and where to, cells grew more slowly or more rapidly.

So this is a really remarkable technical feat — but it’s not just molecular pyrotechnics for fun. It looks as though this approach may offer at long last a way of dissecting how cells go about getting a controlled response out of the mind-boggling complexity that is their genetic material.

References

Wang, H. et al. (2018). CRISPR-Mediated Programmable 3D Genome Positioning and Nuclear Organization. Cell 175, 1405-1417.

Pennisi, E. (2018). Moving DNA to a different part of the nucleus can change how it works. Science Oct. 11th.

Now wash your hands!

 

You must have spent the last 20 years on a distant planet if you’re unaware that we’re heading for Antibiotic Armaggedon — the rise of “Superbugs”, i.e., bacteria resistant to once-successful medication. Microbes resistant to multiple antimicrobials are called multidrug resistant. It’s a desperate matter because it means trivial infections may become fatal and currently safe surgical procedures may become dangerous.

Time-line of the discovery of different antibiotic classes in clinical use. The key point is that the last antibiotic class to become a successful treatment was discovered in 1987.

What’s the problem?
It’s 30 years since we came up a new class of antibiotics. The golden age launched by Fleming’s celebrated discovery of penicillin is long gone and while the discovery curve has drifted ever downwards since 1960 the bugs have been busy.

Just how busy a bug can be was shown by a large-scale experiment carried out by Roy Kishony and friends. They built a “Mega-Plate” — a Petri Dish 2 ft by 4 ft filled with a jelly for the bacteria to grow in. The bugs were seeded into channels at either end so they would grow towards the middle. The only thing stopping them was four channels dosed with antibiotic at increasing concentrations — 10 times more in each successive channel.

The bugs grow until they hit a wall of antibiotic. There they pause for a think — and, after a bit, an intrepid little group start to make their way into the higher dose of drug. Gradually the number of groups expand until a tidal wave sweeps over that barrier. This is repeated at each new ‘wall’ — four times until the whole tray is a bug fest.

When they pause at each new ‘wall’ they’re not ‘thinking’ of course. They’re just picking up random mutations in their DNA until they are able to advance into the high drug environment. So this experiment is a fantastic visual display of bugs becoming drug-resistant. And it’s terrifying because it takes about 11 days for them to overcome four levels of drug. It’s even more scary in the speeded-up movie as that lasts less than two minutes.

Sound familiar?
It should do as this is a cancer column and readers will know that cancers arise by picking up mutations. To highlight the similarities the picture below is the left-hand half of the bug tray with new colonies shown as linked dots. You could perfectly well think of these as early stage cancer cells acquiring mutations in ‘driver’ genes that push them towards tumour formation.

So that’s pretty scary too and the only good news is that animal cells reproduce much more slowly than bacteria. The fastest they can manage is about 48 hours to grow and divide into two new cells and for many it’s much slower than that. Bugs, on the other hand, can do it in 20 minutes if you feed them enough of the right stuff.

Which is why we don’t all get zonked by cancer at an early age.

The evolution of bacteria on a “Mega-Plate” Petri Dish. The vertical red lines mark the boundaries of increasing antibiotic concentrations. You could equally think of each dot that represents a new bacterial colony being early stage cancer cells acquiring mutations in ‘driver’ genes (white arrows) that push them towards tumour formation. From Roy Kishony’s Laboratory at Harvard Medical School.

Enough of that!
But for once I don’t want to talk about cancer but about a really fascinating piece of work that caught my eye in the journal Cell Reports. It’s by Gianni Panagiotou, Kang Kang and colleagues from The University of Hong Kong and The Hans Knöll Institute, Jena, Germany and it’s all about their travels on the Hong Kong MTR (Mass Transit Railway). This is the network of over 200 km of railway lines with 159 stations that serves the urbanised areas of Hong Kong IslandKowloon, and the New Territories and has a cross- border connection to the neighboring city of Shenzhen in mainland China.

An MTR train on the Tung Chung line that links Lantau Island with Hong Kong Island.

Being scientists of course they weren’t just having a day out. They wanted to know the contents of the microbiome that they and their fellow travellers picked up on the palms of their hands when riding the rails. ‘Microbiome’ means all of the collection of microorganisms — though in practice this is almost entirely bacteria. So they swabbed the palms of volunteers and then threw the full power of modern DNA sequencing and genetic analysis at what they’d scraped off. Or, as they put it: “We conducted a metagenomic study of the Hong Kong MTR system.”

And if you’re thinking it might be possible to take a trip on the Hong Kong Metro without grabbing a handrail or otherwise engaging in what on the London Underground used to be called ‘strap-hanging’ you clearly haven’t tried it!

Hong Kong MTR.

 

The MTR System and Sampling Procedure. Left: The eight urban lines studied: the Airport Express line and Disneyland Resort branch were excluded. The Central-Hong Kong station and the cross-border rail stations connecting with the MTR and the Shenzhen metro system are labeled. Right: The sampling procedure included handwashing, handrail touching for 30 min and swabbing. From Kang et al. 2018.

Hold very tight please! 

It’s going to become a seriously bumpy ride. The major findings were:

  1. Four groups (phyla) of bacteria dominated: Actinobacteria [51%], Proteobacteria [27%], Firmicutes [11%] and Bacteroidetes [2%]. Followers of this blog will be delighted to spot the last two (B & F) as we’ve met them several times before (in Hitchhiker Or Driver?, Fast Food Fix Focuses on Fibre, Our Inner Self, The Best Laid Plans In Mice and Men, and, of course, in it’s a small world) — that’s how important they are in the context of cancer.
  2. The dominant organism (29% of the community) was P. acnes (one of the Actinobacteria — it’s the bug linked to the skin condition of acne).
  3. Some non-human-associated species (e.g., soil organisms) also popped up that varied enormously in amount from day to day — perhaps because of weather conditions (e.g., humidity).
  4. Variation in the make-up of the microbial communities picked up depended, more than anything else, on the time of day. There was a marked decrease in diversity in afternoon samples compared with those taken in the morning.
  5. Specific species of bacteria associated with individual metro lines. That is, sets of bug types are relatively abundant on a given line compared with all other lines, giving a kind of line-specific signature — though the distinction declines from morning to afternoon. The most physically isolated line, MOS (Ma On Shan), had a greater number of signature species. The MOS runs entirely above ground alongside the Shing Mun Channel, a polluted brackish river, and its ‘signature’ includes bacteria found in sewage.
  6. All of which brings us to bugs with antibiotic resistance genes (ARGs). Across the network 136 ARG families were detected including 24 that are clinically important. Strikingly, lines closer to Shenzhen (ER (East Rail) and MOS) tend to have higher ARG input during the day. Critically, the ER line a.m. signatures become p.m.-enriched in all MTR lines far from Shenzhen — that is, these ARG families spread over the network during the day.

Simplified map of the Hong Kong MTR indicating how antibiotic resistance genes spread during the day from the ER and MOS lines to the entire network. Tetracycline resistance genes: tetA, tetO, tetRRPP and tetMWOS; vancomycin resistance genes: vanC, vanX. From Kang et al. 2018.

These results clearly suggest that the ER line, the only cross-border line linked to mainland China, may be a source of clinically important ARGs, especially against tetracycline, a commonly used antibiotic in China’s swine feedlots. Antibiotics, including tetracycline, can be detected in the soil in the Pearl River Delta area where the cities of Hong Kong and Shenzhen are located.

It should be said that this is by no means the first survey of bugs on rails. Notable ones have looked at the New York and Boston metro systems and they too revealed the potential health risks of the bug communities found on trains and in the stations, including the presence of pathogens and antibiotic resistance. The Boston survey highlighted that different types of materials have surfaces that are preferred by different microbes with high variation in functional capacity and pathogenic potential.

One obvious suggestion from these studies is that world-wide we could do a lot to improve sanitation, e.g., by having hand sanitizer dispensers in all sensible places (at the exits of metro, railway and bike-sharing stations and airports and of course in hospitals). The Hong Kong data are seriously frightening and most people seem blissfully unaware that the invisible world they reveal carries the potential for the destruction of us all.

But, as ever, there’s two sides to the matter. We’ve evolved over millions of years to live with bugs and they with us. However you wash your hands you won’t get rid of every bug and anyway, as what’s-his-name almost says, “They’ll be back!” We all carry around micro-organisms that can be fatal if they get to the wrong place. But, if you’re reasonably fit, there’s a lot to be said for simply following sensible, basic hygiene rules with a philosophy of ‘live and let live.’

Have a nice day commuters, wherever you are!

References

Kang K., et al. (2018). The Environmental Exposures and Inner- and Intercity Traffic Flows of the Metro System May Contribute to the Skin Microbiome and Resistome. Cell Reports 24, 1190–1202.

Wu, N., Qiao, M., Zhang, B., Cheng, W.D., and Zhu, Y.G. (2010). Abundance and diversity of tetracycline resistance genes in soils adjacent to representative swine feedlots in China. Environ. Sci. Technol. 44, 6933–6939.

Li, Y.W., Wu, X.L., Mo, C.H., Tai, Y.P., Huang, X.P., and Xiang, L. (2011). Investigation of sulfonamide, tetracycline, and quinolone antibiotics in vegetable farmland soil in the Pearl River Delta area, southern China. J. Agric. Food Chem. 59, 7268–7276.

Leung, M.H., Wilkins, D., Li, E.K., Kong, F.K., and Lee, P.K. (2014). Indoor-air microbiome in an urban subway network: diversity and dynamics. Appl. Environ. Microbiol. 80, 6760–6770.

Robertson, C.E., Baumgartner, L.K., Harris, J.K., Peterson, K.L., Stevens, M.J., Frank, D.N., and Pace, N.R. (2013). Culture-independent analysis of aerosol microbiology in a metropolitan subway system. Appl. Environ. Microbiol. 79, 3485–3493.

Afshinnekoo, E., Meydan, C., Chowdhury, S., Jaroudi, D., Boyer, C., Bernstein, N., Maritz, J.M., Reeves, D., Gandara, J., Chhangawala, S., et al. (2015). Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics. Cell Syst 1, 72–87.

Hsu, T., Joice, R., Vallarino, J., Abu-Ali, G., Hartmann, E.M., Shafquat, A., Du- Long, C., Baranowski, C., Gevers, D., Green, J.L., et al. (2016). Urban Transit System Microbial Communities Differ by Surface Type and Interaction with Humans and the Environment. mSystems 1, e00018–e00016.

No It Isn’t!

 

It’s great that newspapers carry the number of science items they do but, as regular readers will know, there’s nothing like the typical cancer headline to get me squawking ‘No it isn’t!” Step forward The Independent with the latest: “Major breakthrough in cancer care … groundbreaking international collaboration …”

Let’s be clear: the subject usually is interesting. In this case it certainly is and it deserves better headlines.

So what has happened?

A big flurry of research papers has just emerged from a joint project of the National Cancer Institute and the National Human Genome Research Institute to make something called The Cancer Genome Atlas (TCGA). This massive initiative is, of course, an offspring of the Human Genome Project, the first full sequencing of the 3,000 million base-pairs of human DNA, completed in 2003. The intervening 15 years have seen a technical revolution, perhaps unparalled in the history of science, such that now genomes can be sequenced in an hour or two for a few hundred dollars. TCGA began in 2006 with the aim of providing a genetic data-base for three cancer types: lung, ovarian, and glioblastoma. Such was its success that it soon expanded to a vast, comprehensive dataset of more than 11,000 cases across 33 tumor types, describing the variety of molecular changes that drive the cancers. The upshot is now being called the Pan-Cancer Atlas — PanCan Atlas, for short.

What do we need to know?

Fortunately not much of the humungous amounts of detail but the scheme below gives an inkling of the scale of this wonderful endeavour — it’s from a short, very readable summary by Carolyn Hutter and Jean Claude Zenklusen.

TCGA by numbers. The scale of the effort and output from The Cancer Genome Atlas. From Hutter and Zenklusen, 2018.

The first point is obvious: sequencing 11,000 paired tumour and normal tissue samples produced mind-boggling masses of data. 2.5 petabytes, in fact. If you have to think twice about your gigas and teras, 1 PB = 1,000,000,000,000,000 B, i.e. 1015 B or 1000 terabytes. A PB is sometimes called, apparently, a quadrillion — and, as the scheme helpfully notes, you’d need over 200,000 DVDs to store it.

The 33 different tumour types included all the common cancers (breast, bowel, lung, prostate, etc.) and 10 rare types.

The figure of seven data types refers to the variety of information accumulated in these studies (e.g., mutations that affect genes, epigenetic changes (DNA methylation), RNA and protein expression, duplication or deletion of stretches of DNA (copy number variation), etc.

After which it’s worth pausing for a moment to contemplate the effort and organization involved in collecting 11,000 paired samples, sequencing them and analyzing the output. It’s true that sequencing itself is now fairly routine, but that’s still an awful lot of experiments. But think for even longer about what’s gone into making some kind of sense of the monstrous amount of data generated.

And it’s important because?

The findings confirm a trend that has begun to emerge over the last few years, namely that the classification of cancers is being redefined. Traditionally they have been grouped on the basis of the tissue of origin (breast, bowel, etc.) but this will gradually be replaced by genetic grouping, reflecting the fact that seemingly unrelated cancers can be driven by common pathways.

The most encouraging thing to come out of the genetic changes driving these tumours is that for about half of them potential treatments are already available. That’s quite a surprise but it doesn’t mean that hitting those targets will actually work as anti-cancer strategies. Nevertheless, it’s a cheering point that the output of this phenomenal project may, as one of the papers noted, serve as a launching pad for real benefit in the not too distant future.

What should science journalists do to stop upsetting me?

Read the papers they comment on rather than simply relying on press releases, never use the words ‘breakthrough’ or ‘groundbreaking’ and grasp the point that science proceeds in very small steps, not always forward, governed by available methods. This work is quite staggering for it is on a scale that is close to unimaginable and, in the end, it will lead to treatments that will affect the lives of almost everyone — but it is just another example of science doing what science does.

References

Hutter, C. and Zenklusen, J.C. (2018). The Cancer Genome Atlas: Creating Lasting Value beyond Its Data. Cell 173, 283–285.

Hoadley, K.A. et al. (2018). Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell 173, 291–304.

Hoadley, K.A. et al. (2014). Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin. Cell 158, 929–944.

John Sulston: Biologist, Geneticist and Guardian of our Heritage

 

Sir John Sulston died on 6 March 2018, an event reported world-wide by the press, radio and television. Having studied in Cambridge and then worked at the Salk Institute in La Jolla, California, he joined the Laboratory of Molecular Biology in Cambridge to investigate how genes control development and behaviour, using as a ‘model organism’ the roundworm Caenorhabditis elegans. This tiny creature, 1 mm long, was appealing because it is transparent and most adult worms are made up of precisely 959 cells. Simple it may be but this worm has all the bits required for to live, feed and reproduce (i.e. a gut, a nervous system, gonads, intestine, etc.). For his incredibly painstaking efforts in mapping from fertilized egg to mature animal how one cell becomes two, two becomes four and so on to complete the first ‘cell-lineage tree’ of a multicellular organism, Sulston shared the 2002 Nobel Prize in Physiology or Medicine with Bob Horvitz and Sydney Brenner.

Sir John Sulston

It became clear to Sulston that the picture of how genes control development could not be complete without the corresponding sequence of DNA, the genetic material. The worm genome is made up of 100 million base-pairs and in 1983 Sulston set out to sequence the whole thing, in collaboration with Robert Waterston, then at the University of Washington in St. Louis. This was a huge task with the technology available but their success indicated that the much greater prize of sequencing of the human genome — ten times as much DNA as in the worm — might be attainable.

In 1992 Sulston became head of a new sequencing facility, the Sanger Centre (now the Sanger Institute), in Hinxton, Cambridgeshire that was the British component of the Human Genome Project, one of the largest international scientific operations ever undertaken. Astonishingly, the complete human genome sequence, finished to a standard of 99.99% accuracy, was published in Nature in October 2004.

As the Human Genome Project gained momentum it found itself in competition with a private venture aimed at securing the sequence of human DNA for commercial profit — i.e., the research community would be charged for access to the data. Sulston was adamant that our genome belonged to us all and with Francis Collins — then head of the US National Human Genome Research Institute — he played a key role in establishing the principle of open access to such data, preventing the patenting of genes and ensuring that the human genome was placed in the public domain.

One clear statement of this intent was that, on entering the Sanger Centre, you were met by a continuously scrolling read-out of human DNA sequence as it emerged from the sequencers.

In collaboration with Georgina Ferry, Sulston wrote The Common Thread, a compelling account of an extraordinary project that has, arguably, had a greater impact than any other scientific endeavour.

For me and my family John’s death was a heavy blow. My wife, Jane, had worked closely with him since inception of the Sanger Centre and not only had his scientific influence been immense but he had also become a staunch friend and source of wisdom. At the invitation of John’s wife Daphne, a group of friends and relatives gathered at their house after the funeral. As darkness fell we went into the garden and once again it rang to the sound of chatter and laughter from young and old as we enjoyed one of John’s favourite party pastimes — making hot-air lanterns and launching them to drift, flickering to oblivion, across the Cambridgeshire countryside. John would have loved it and it was a perfect way to remember him.

Then …

When John Sulston set out to ‘map the worm’ the tools he used could not have been more basic: a microscope — with pencil and paper to sketch what he saw as the animal developed. His hundreds of drawings tracked the choreography of the worm to its final 959 cells and showed that, along the way, 131 cells die in a precisely orchestrated programme of cell death. The photomontage and sketch below are from his 1977 paper with Bob Horvitz and give some idea of the effort involved.

Photomontage of a microscope image (top) and (lower) sketch of the worm Caenorhabditis elegans showing cell nuclei. From Sulston and Horvitz, 1977.

 … and forty years on

It so happened that within a few days of John’s death Achim Trubiroha and colleagues at the Université Libre de Bruxelles published a remarkable piece of work that is really a descendant of his pioneering studies. They mapped the development of cells from egg fertilization to maturity in a much bigger animal than John’s worms — the zebrafish. They focused on one group of cells in the early embryo (the endoderm) that develop into various organs including the thyroid. Specificially they tracked the formation of the thyroid gland that sits at the front of the neck wrapped around part of the larynx and the windpipe (trachea). The thyroid can be affected by several diseases, e.g., hyperthyroidism, and in about 5% of people the thyroid enlarges to form a goitre — usually caused by iodine deficiency. It’s essential to determine the genes and signalling pathways that control thyroid development if we are to control these conditions.

For this mapping Trubiroha’s group used the CRISPR method of gene editing to mutate or knock out specific targets and to tag cells with fluorescent labels — that we described in Re-writing the Manual of Life.

A flavor of their results is given by the two sets of fluorescent images below. These show in real time the formation of the thyroid after egg fertilization and the effect of a drug that causes thyroid enlargement.

Live imaging of transgenic zebrafish to follow thyroid development in real-time (left). Arrows mark chord-like cell clusters that form hormone-secreting follicles (arrowheads) during normal development. The right hand three images show normal development (-) and goiter formation (+) induced by a drug. From Trubiroha et al. 2018.

John would have been thrilled by this wonderful work and, with a chuckle, I suspect he’d have said something like “Gosh! If we’d had gene editing back in the 70s we’d have mapped the worm in a couple of weeks!”

References

International Human Genome Sequencing Consortium Nature 431, 931–945; 2004.

John Sulston and Georgina Ferry The Common Thread: A Story of Science, Politics, Ethics and the Human Genome (Bantam Press, 2002).

Sulston, J.E. and Horvitz, H.R. (1977). Post-embryonic Cell Lineages of the Nematode, Caenorhabitis elegans. Development Biology 56, 110-156.

Trubiroha, A. et al. (2018). A Rapid CRISPR/Cas-based Mutagenesis Assay in Zebrafish for Identification of Genes Involved in Thyroid Morphogenesis and Function. Scientific Reports 8, Article number: 5647.

And Now There Are Six!!

Scientists eh! What a drag they can be! Forever coming up with new things that the rest of us have to wrap our minds around (or at least feel we should try).

Readers of these pages will know I’m periodically apt to wax rhapsodic about ‘the secret of life’ – the fact that all living things arise from just four different chemical units, A, C, G and T. Well, from now on it seems I’ll need to watch my words – or at least my letters – though maybe for a while I can leave it on the back burner in the “things that have been but not yet” category, to use the melodic prose of Christopher Fry.

Who dunnit?

The problem is down to Floyd Romesberg and his team at the Scripps Research Institute in California.

Building on a lot of earlier work, they’ve made synthetic units that stick together to form pairs – just like A-T and C-G do in double-stranded DNA. But, as these novel chemicals (X & Y) are made in the lab, the bond they form is an unnatural base pair.

Left: Two intertwined strands of DNA are held together in part by hydrogen bonds. Right top: Two such bonds (dotted lines) link adenine (A) to thymine (T); three form between guanine (G) and cytosine (C). These bases attach to sugar units (ribose) and phosphate groups (P) to form DNA chains. Right bottom: Synthetic X and Y units can also stick together and, via ribose and phosphate, become part of DNA.

After much fiddling Romesberg’s group derived E. coli microbes that would take up X and Y when they were fed to the cells as part of their normal growth medium. The cells treat X and Y like the units they make themselves (A, C, G & T) and insert them in new DNA – so a stretch of genetic code may then read: A-C-G-T-X-T-A-C-Y-A-T-… And, once part of DNA, the novel units are passed on to the next generation.

Science fiction?
If this has you thinking creation and exploitation of entirely new life forms?!!’ you’re not alone. Seemingly Romesberg is frequently asked if he’s setting up Jurassic Park but, as he points out, the modified bugs he’s created survive only as long as they’re fed X and Y so if they ‘escape’ (being bugs this would probably be down the drain rather than over a fence), they die. Cunning eh?!!

Is this coming to a gene near you?
No. It is, however, clear that more synthetic bases will be made, expanding the power of the genetic code yet further. What isn’t yet known is what the cells will make of all this. In other words, the whole point of tinkering with DNA is to modify the code to make novel proteins. In the first instance the hope is that these might be useful in disease treatment. Rather longer-term is the notion that new organisms might emerge with specific functions – e.g., bugs that break down plastic waste materials.

At the moment all this is speculation. But what is now fact is amazing enough. After 4,000 million years since the first life-forms emerged, more than five billion different species have appeared (and mostly disappeared) on earth – all based on a genetic code of just four letters.

Now, in a small lab in southern California, Mother Nature has been given an upgrade. It’s going to be fascinating to see what she does with it!

Reference

Zhang, Y. et al. (2017). Proceedings of the National Academy of Sciences 114, 1317-1322.

Re-writing the Manual of Life

A little while ago we talked about a fantastic triumph by a team at Great Ormond Street Hospital (Gosh! Wonderful GOSH) in using a form of immunotherapy to save a little girl. What they did was to take the T cells from a sample of her blood and use gene editing – molecular cutting and pasting – to remove some genes and add others before growing more of the cells and then putting them back into the patient.

Gene editing – genetic engineering that removes or inserts sections of DNA – uses engineered nucleases, enzymes that snip DNA but do so in a controlled way by homing in on a specific site (i.e. a defined sequence of As, Cs, Gs and Ts).

We mentioned that there are four main ways of doing this kind of engineering – the GOSH group used ‘transcription activator-like effectors’ (TALEs). However, the method that has made the biggest headlines is called CRISPR/Cas, and it has been very much in the news because a legal battle is underway to determine who did what in its development and who, therefore, will be first in line for a Nobel Prize.

Fortunately we can ignore such base pursuits and look instead at where this technology might be taking us.

What is CRISPR/Cas?

CRISPRs (pronounced crispers) are bits of DNA that contain short repetitions of base sequence, each next to a ‘spacer’ sequence. The spacers have accumulated in bacteria as a defence mechanism – they’re part of the bacterial immune system – and they’re identical to sequences found in viruses that infect microbes. In other words, the cunning bugs pick up bits of dangerous viruses to make a rogues gallery so they can recognize and attack those viruses next time they pop in.

Close to CRISPR sit genes encoding Cas proteins (enzymes that cut DNA, so they’re ‘nucleases’). When the CRISPR-spacer DNA is read by the machinery of the cell to make RNA, the spacer regions stick to Cas proteins and the whole complex, including the viral sequences, can roam the cell seeking a virus with genetic material that matches the CRISPR RNA. The CRISPR RNA sticks to the virus and Cas chops its DNA – end of virus. So Cas, by binding to CRISPR RNA, becomes an RNA-guided DNA cutter.

crispr-pic

CRISPR-CAS: Bug defence against invaders. Viruses can attack bacteria just as they can human cells. Over time bugs have evolved a cunning defence strategy: they insert short bits of viral DNA into their own genome (above). These contain repeated sequences of bases and each is followed by short segments of ‘spacer DNA’ (above). This happens next to DNA that encodes Cas proteins so that both are ‘read’ to make RNA (transcription). Cas proteins bind to spacer RNA, leaving the adjacent viral RNA free to attach to any complementary viral DNA it encounters. The Cas enzyme is thus guided to DNA that it can cleave. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats.

Why is CRISPR/Cas in the headlines?

We saw in Gosh! Wonderful GOSH how the Great Ormond Street Hospital team tinkered with DNA and in Self Help – Part 2 we summarized another way of doing this using viruses (notably a disabled form of the human immunodeficiency virus) to carry novel genes into cells.

A further arm of immunotherapy attempts to reverse an effect called checkpoint blockade whereby the immune system response to tumours is damped down – e.g. by using antibodies that target a protein called PD-1 (Self Help – Part 1).

Now comes news of a Chinese trial which will be the first time cells modified using CRISPR–Cas9 gene editing have been injected into people. The chap in charge is Lu You from Sichuan University’s West China Hospital in Chengdu and the plan is to take T cells from the blood patients with metastatic non-small cell lung cancer for whom chemotherapy, radiation therapy and other treatments have failed.

The target will be the PD-1 gene, the idea being that, if you want to stop PD-1 doing its stuff, far better than mucking about with antibodies is to just knock out its gene: no gene no protein! What could possibly go wrong?

Well, wonderful though CRISPR is, it doesn’t always hit the right target but in this trial the cells can be tested to make sure it’s the PD-1 gene that’s been zonked – so that shouldn’t be a problem. However, it’s a blockbuster in that all the multiplied T cells put back into the patient will be active – i.e. will have lost the PD-1 brake. Whilst that may be good for zonking tumours, goodness knows what it might do elsewhere.

The initial trial is on a small scale – just 10 people. If there are problems one possibility is to try to take the T cells from the site of the tumour, which might select those specifically targeting the tumour – not straightforward as lung cancers are difficult to get at.

Anyone for a DNA upgrade?

It’s hard to say where all this is leading. However, as Chinese scientists have already made the first CRISPR-edited human embryos and the first CRISPR-edited monkeys, the only safe bet is that China will be to the fore.

 

The Shocking Effect of Boiled Bugs

There’s never a dull moment in science – well, not many – and at the moment no field is fizzing more than immunotherapy. Just the other day in Outsourcing the Immune Response we talked about the astonishing finding that cells from healthy people could be used to boost the immune response – a variant on the idea of taking from patients cells that attack cancers, growing them in the lab and using genetic engineering to increase potency (generally called adoptive cell therapy).

A general prod

Just when you thought that was as smart as it could get, along comes Angus Dalgleish and chums from various centres in the UK and Spain with yet another way to give the immune system a shock. They used microorganisms (i.e. bugs) as a tweaker. The idea is that bacteria (that have been heat-killed) are injected, they interact with the host’s immune system and, by altering the proteins expressed on immune cells (macrophages, natural killer cells and T cells) can boost the immune response. That in turn can act to kill tumour cells. It’s a general ‘immunomodulatory’ effect. Dalgleish describes it as “rather like depth-charging the immune system which has been sent to sleep”. Well, giving it a prod at least.

bugs-pic

Inactivating bugs (bacteria) and waking up the immune system.

And a promising effect

The Anglo-Spanish effort used IMM-101 (a heat-killed suspension of a bacterium called Mycobacterium obuense) injected under the skin, which has no significant side-effects. The trial was carried out in patients with advanced pancreatic cancer, a disease with dismal prognosis, and IMM-101 immunotherapy was combined with the standard chemotherapy drug (gemcitabine). IMM-101increased survival from a median of 4.4 months to 7 months with some patients living for more than a year and one for nearly three years.

Although the trial numbers are small as yet, this is a very exciting advance because it looks as though immunotherapy may be able to control one of the most serious of cancers in which its incidence nearly matches its mortality.

References

Dalgleish, A. et al. (2016). Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. British Journal of Cancer doi: 10.1038/bjc.2016.271.

 

Mutating into Gold

It’s probably just as well that few us are aware that the bodies we live in are a battlefield – the cells and molecules that make us are in constant strife to ensure our survival. The lid is lifted from time to time – when we get a cold or pick up some other infection and our immune response sorts it out but not without giving us a headache or a runny nose, just to let us know it’s on the job. By and large though, we plough our furrow in glorious ignorance.

Saving our cells

Perhaps the most important of all the running battles is to save our DNA – that is, to repair the damage continuously suffered by our genetic material so we can carry on. It’s an uphill struggle. The DNA in one of our cells can take up to a million hits every day – and the bombardment comes from every direction: from radiation, air pollution and carcinogens in some of the food we eat. And, of course, we don’t need to mention cigarette smoke.

Damaged chromosomes (blue arrows)

Damaged chromosomes    (blue arrows)

On top of all that cells have to make a new DNA copy every time they reproduce – and we do a lot of that: recall that you set sail on the journey of life as one single, fertilized egg cell and now look at you: a clump of ten trillion (1013) cells that, just to stay as you are, has to make one million new cells every second. What’s more some of your cells deliberately break their own DNA in a process called ‘gene shuffling’ that goes to make the finished product of your aforementioned immune system. The biochemical machinery that does these jobs is mighty efficient but nobody’s perfect – except, of course, for John Eales, Australia’s most successful rugby union captain, nicknamed “Nobody” because “Nobody’s perfect”. When the three thousand million base-pairs of DNA are stuck together for a new cell there’s a mistake about once in every million units added – but a kind of quality control check (mismatch repair) then fixes most of these, so that the overall error is about one in a thousand million. That’s one example of the nifty ways evolution has come up with to fix the damage suffered by our genetic material from all this replicating, assaulting and constructing.

Keeping the show on the road

The overall upshot of the repair machinery is that less than one mutation per day becomes fixed in our genomes – and thus passed on to succeeding generations of cells. The range of things that can damage DNA – and hence the different forms that damage can take – tells you that there must be several different repair systems and indeed we now know that about 200 genes and their protein products have a hand in some repair process or another. There’s so much to know that DNA damage and repair has its own data-base called, inevitably, REPAIRtoire. Much of what we know is, to a considerable extent, thanks to the labours of Tomas Lindahl, Paul Modrich and Aziz Sancar who have just been jointly awarded this year’s Nobel Prize in Chemistry. Because damage to DNA – aka mutations – drives the development of cancers you might suppose that in these pages we will have met these gentlemen before – and indeed we have, if not by name.

Tomas Lindahl Paul Modrich Aziz Sancar

Tomas Lindahl                      Paul Modrich                       Aziz Sancar

Winners of the 2015 Nobel Prize in Chemistry

Forty odd years ago much of the above would have bewildered cell biologists. Thirty years before then, in 1944, Oswald Avery, Colin MacLeod and Maclyn McCarty had shown for the first time that genes are composed of DNA, a finding confirmed in 1952 by Alfred Hershey and Martha Chase in a classic experiment using a virus that infects and replicates within a bacterium. But with the acceptance that, however improbable, our genetic material was indeed made of DNA there came the assumption that it must be very stable. After all, if it carried our most valuable possession then surely it had to be made of molecular granite, absolutely resistant to any kind of chemical change or degradation. Had the bewildered boffins been told that in the twenty-first century we would be sequencing woolly mammoth DNA from samples that are millions of years old they would have been confirmed in their view.

It was Tomas Lindahl in the early 1970s who demonstrated that, although DNA is indeed more stable than its close rello RNA (the intermediate in making proteins) it nevertheless decays quite rapidly under normal conditions – it’s only when sealed in permafrost or blobs of amber that it becomes frozen in time. Lindahl realized that for life based on DNA to have evolved there had to be repair systems that could sustain our genetic material in a functional state and he went on to resolve how one of these did it. Aziz Sancar has worked particularly on the circadian clock (discovering that CRY is a clock protein) and how cells repair ultraviolet radiation damage to DNA: people born with defects in this system develop skin cancer if they are exposed to sunlight. Paul Modrich has contributed mainly to our knowledge of mismatch repair.

Lindahl, Modrich, Sancar and their colleagues over many years haven’t come up with the philosopher’s stone – the chemists still can’t transmute base metals into gold without the aid of a particle accelerator. But what they have done is much more useful for mankind. Revealing the detail of how genome maintenance works has already lead to new cancer treatments and from this beginning will come greater benefits as time goes by. They should enjoy the proceeds of turning molecular knowledge if not to gold then into Swedish kronor (8 million of them) – for the rest of the world it’s a bargain.

References

Lindahl, T. (1993). Instability and decay of the primary structure of DNA. Nature 362, 709-715.

Yang YG, Lindahl T, Barnes DE. (2007). Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873-886.

Shao, H, Baitinger, C, Soderblom, EJ, Burdett, V, and Modrich, P. (2014). Hydrolytic function of Exo1 in mammalian mismatch repair. Nucleic Acids Research 42, 7104-7112.

Tan C, Liu Z, Li J, Guo X, Wang L, Sancar A, Zhong D. (2015). The molecular origin of high DNA-repair efficiency by photolyase. Nat Commun. 6, 7302.

Wonder of the World

Welcome back from our holidays on which, we trust, you had as much fun reading the four refresher pieces as I had writing them. Utter nonsense, of course. I’ve never found writing to be an orgasmic activity but, as they say about cod liver oil, it is good for you. However, whilst we were all improving ourselves on our deck-chairs and sun-loungers, the Tide of Science was waiting for no man: the waves of cancer biology have obliterated our sand castles and are fast approaching our toes. So let’s get on – albeit doing our best to make the segue from vacation to vocation as seamless as possible …..

So, on the subject of holidays, newspapers and magazines rather like the theme of ‘places to visit before you die’ – which is OK in that the world is wonderful and we should appreciate it. But there’s a problem in that one of the modern wonders is being able to see magnificent photos and movies of every far-flung nook, cranny and creature without leaving our sofa. So when we finally do get off our rear ends and chug past the Statue of Liberty on the Staten Island Ferry, zoom into Sydney or rock up to the Taj Mahal, the reaction is likely to be ‘That’s nice: looks just like on tv. Where next?’

Fortunately, being blasé has its limits. The only time I’ve made it to the Grand Canyon the mid-winter sun highlighted the colours of the rock striations so they were breathtaking in a way no photograph could quite capture. In the same vein, everyone should take the Trans-Siberian Railway we’re often told. And so you should but not because you will see houses and churches, rivers and trees that you can’t find on the Internet but because only borne by the train do you begin to sense the immensity of Mother Russia. The fact that the scenery is almost entirely birch trees minimizes distraction: all you can do is contemplate vastness – and the harshness that brings – an unvarying obbligato to Russian life.

A Provodnitsa looking after one of her passengers on The Trans-Siberian Railway

A Provodnitsa looking after one of her passengers on The Trans-Siberian Railway

The thrice-weekly freight at Grand Canyon Station, circa 1970

The thrice-weekly freight at Grand Canyon Station, circa 1970

 

 

 

 

 

 

Not Forgetting

All of which brings us to something else that is also truly a wonder of the world – cancer. If it seems a trifle weird to describe thus what’s usually classed as one of man’s greatest blights, consider this. The drive to control cancer has generated research on a scale unmatched in any other field of science. One upshot, not necessarily at the top of the list, is that we now have a breathtakingly detailed picture of the astonishing adaptability of life  – that is of our genetic material, DNA, and how its calisthenics can promote the most incredible behaviour on the part of individual cells. It’s true, you might point out, that we can see this by simply looking at the living world around us. The power of DNA to carry, in effect, limitless information produces the infinite cellular variety underpinning the staggering range of life that has evolved on earth. {Did you spot just the other day that a school field trip discovered 13 new species of spider in Queensland – yes, thirteen – inevitably headlined by The Sun as Creepy Hauly}

In the new world

But in focusing on cancers – what happens at the molecular level as they develop and how they evade our attempts to control them – the fine detail of this nigh-on incomprehensible power has been revealed as in no other way.

You’ll know what’s coming: the biggest single boost to this unveiling has been the arrival in the twenty-first century of methods for sequencing DNA and identifying which genes are expressed in cells at any given time. I know: in umpteen blogs I’ve gone on about its awe-inspiring power – but it is stunning and we’re at that stage when new developments leave one gasping almost on a monthly basis. The point here is that it’s not that the science keeps getting turned on its head. Far from it: the message remains that cells pick up changes to their DNA and, with time, these cumulative effects may drive them to make more of themselves than they should.

That’s cancer. But what is fantastic is the molecular detail that the ’omics revolution continues to lay bare. And that’s important because, as we have come to recognize that every cancer is unique, ideally we need to provide specifically tailored treatments, and we can only think of doing that when we know all the facts – even if taking them in demands a good deal of lying down in darkened rooms!

You could think of the fine molecular detail of cancers as corresponding to musical ornaments – flourishes that don’t change the overall tune but without which the piece would be unrecognizable. These include trills and turns – and all musicians will know their appoggiaturas from their acciaccaturas. They’re tiny embellishments – but just try removing them from almost any piece of music.

Lapping at your toes

So let’s look at three recent papers that have used these fabulous methods to unveil as never before the life history of cancers. The first is another masterful offering from The Sanger Institute on breast cancer: an in-depth analysis of 12 patients in which each tumor was sampled from 8 different locations. In the main the mutation patterns differed between regions of the same tumour. They extended this by looking at samples from four patients with multi-focal disease (‘foci’ being small clumps of tumour cells). As expected, individual foci turned out to be clearly genetically related to their neighbours but they also had many ‘private mutations’ – a term usually meaning a mutation found only in a single family or a small population. Here the ‘family’ are individual foci that must have arisen from a common ancestor, and you could think of them as a cellular diaspora – a localised spreading – which makes them a kind of metastasis. Quite often the mutations acquired in these focal sub-clones included major ‘driver’ genes (e.g., P53, PIK3CA and BRCA2). In general such potent mutations tend to be early events but in these foci they’ve appeared relatively late in tumour development. This doesn’t upend our basic picture: it’s just another example of ‘anything goes’ in cancer – but it does make the point that identifying therapeutic targets requires high-depth sequencing to track how individual cancers have evolved through continual acquisition of new mutations and the expansion of individual clones.

The authors used ‘coxcomb’ plots to portray these goings-on but they are quite tricky to make head or tail of. So, to avoid detail overload, I’ve converted some into genetic wallpaper, the non-repeating patterns illustrating the breathtaking variety that has evolved.

Wallpaper jpegDecorative DNA. The discs are ‘coxcomb’ plots – a variant of a pie chart. Here the colours and the wedge sizes represent mutations in different regions of four primary breast tumours. Every disc is different so that the message from this genetic wallpaper is of mutational variation not only between cancers but across the different samples taken from a single tumour. I trust that Lucy Yates, Peter Campbell and their colleagues will not be too upset at my turning their work into art (and greatly abbreviating the story): you can read the original in all its wondrous glory in Nature Medicine 21, 751–759.

The first person to come up with this very graphic way of conveying information was Florence Nightingale who, whilst working in Turkey during the Crimean War, realized that soldiers were dying in the hospitals not only from their wounds but, in much greater numbers, from preventable causes including infections, malnutrition and poor sanitation. Her meticulous recording and original presentation of hospital death tolls made her a pioneer in applied statistics and established the importance of sanitation in hospitals.

Something for the gentlemen

Two equally powerful onslaughts from Gunes Gundem, Peter Campbell and their colleagues at The Sanger Institute (again!) and Dan Robinson and pals from the University of Michigan Medical School have revealed the corresponding molecular detail of prostate cancer. Here too the picture is of each region of a tumour being unique in DNA terms. Moreover, they showed that metastasis-to-metastasis spread was common, either through the seeding of single clones or by the transfer of multiple tumour clones between metastatic sites.

Even that miserable old sod Lenin might have brightened at such fabulous science, before reverting to Eeyore mode with the inevitable “What’s to be done?” But it’s a good question. For example, as a general strategy should we try to kill the bulk of the tumour cells or aim for clones that, although small, carry very potent mutations.

Aside from the basic science, there is one quite bright ray of sunshine: about 90% of the mutations linked with the spread of prostate cancer are potentially treatable with existing drugs. And that really is encouraging, given that the disease kills 11,000 in the UK and over 30,000 in the USA every year.

prostate dogWe might also be heartened by the skills of German Shepherd dogs that can, apparently, be persuaded to apply one of their favourite pastimes – sniffing – to the detection of prostate cancer. Point them at a urine sample and 90% of the time they come up with the right answer. Given the well-known unreliability of the prostate-specific antigen blood test for prostate cancer, it’s nice to think that man’s best friend is on the job.

References

Yates, L.R., et al. (2015). Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nature Medicine 21, 751–759.

Robinson, D., et al. (2015). Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 161, 1215–1228.

Gundem, G., et al. (2015). The evolutionary history of lethal metastatic prostate cancer. ICGC Prostate UK Group (2015). Nature 520, 353–357.