Tiny machines

It's been a while since I posted, so I thought it was about time I wrote something. And what better to write about, than what I spend every day working on!

If you studied biology in school may remember this: DNA to RNA to Protein.

Proteins do almost everything in the cell. Anything you can think of, a protein does it.

Generate energy? Protein.

Shuttle things around? Protein.

Repair damage? Protein.

At any one time, a cell has tens of millions of proteins, all working to keep the cell healthy and functioning as it should. It's a mind-boggling operation, and it is happening in every one of your cells right now. When you consider that you have trillions of cells (there are more cells in your hand than there are people on earth!), the staggering complexity is difficult to grasp.

The cell needs to make all those proteins, and it needs instructions so it can make the right ones at the right time. These instructions are encoded in your DNA. Each "instructional" section of the DNA is called a gene, and every protein is encoded by a different gene. Every cell in your body has its own copy of the DNA (with some exceptions), and it is very precious. If the DNA gets damaged you lose the instructions for the proteins, and the cell will probably die as a result. Because of this it is stored in the nucleus, away from most of the things that could damage it. The problem is, proteins can not be made in the nucleus, so the cell needs a way to get the instructions for the proteins out of the nucleus, and into the body of the cell, the cytoplasm.

Life has come up with an ingenious solution to this problem: the cell can make a "photocopy" of the instructions of the protein it needs, and it can take that out of the nucleus. This "photocopy" is called mRNA, and it is then used to make as many copies of the protein that a cell needs. That way the DNA is kept safely locked away, but the cell can still make the protein. The process of "photocopying" the DNA to make mRNA is called "transcription".

I like to think of the DNA as an enormous book, that is kept behind lock and key in a special room in a library. There is only one copy of the book, so it is kept safe, away from all the people that work and visit the library. The problem is, people need the information that is in the book. In fact the book describes how everything works in the library, so without that information, the library would completely fall apart.

To get around this, a small number of trusted people can photocopy pages from the book, and they can then be passed to the workers in the library so they can carry out the instructions. If the photocopy gets damaged it isn't a problem; another photocopy can just be made.

In this analogy the photocopy is mRNA, and in reality, when it gets taken out into the cytoplasm, that is only the start of making a protein. The mRNA has to be transported to little machines called ribosomes, and the ribosome reads the mRNA, and produces the protein. This process is called "translation" because the cell is translating the instructions contained in the mRNA into a functional protein.

All of the tens of millions of protein in every cell are made like this, and the tiny machines (ribosomes) are at the centre of it all. They are amazing things; every single cell that has ever existed had ribosomes in it. Every animal, plant, fungus, and bacteria has ribosomes, all busily making protein from mRNA, sustaining all life in the process. And these ribosomes are what I spend my time studying.

Like everything in life, how they work is extremely simple and complex at the same time. The ribosome is shaped vaguely like a burger bun, with two parts, and it attaches mRNA with one part above and the other below. The mRNA then feeds through the ribosome until it has all been read. At the same time it is reading the mRNA, the ribosome is also making the protein (which is coming out the top of the ribosome in the gif above), so when it is finished reading, it is also finished making the protein.

For a long time it was thought that this process of reading an mRNA and producing a protein (translating the mRNA) was a pretty passive one. If the cell needed a lot of a protein, it would make lots of mRNA, and as a result, the ribosomes would make lots of protein. While that is true, we now know that it is not the only way a cell can make more protein, and that ribosomes have an important role in making sure that the correct amount of protein is being produced. If one ribosome is reading an mRNA, it will produce one protein. But if 10 ribosomes are reading the same mRNA, they they will produce 10 proteins. If a ribosome takes 20 seconds to read the mRNA, it will only produce half of the protein compared to one that takes 10 seconds. These (and many other subtleties) give ribosomes extraordinary control of the fate of the cell, and we are only beginning to understand this.

It's not an exaggeration to say that understanding ribosomes is key to understand all life. They carry out one of the most key processes in life, but there is still so much we do not understand about them. We also know that many diseases hijack ribosomes, including cancer, so increasing our knowledge is obviously important, and that is what we focus on in my lab. Tiny, beautiful, complex machines, that are so important that life wouldn't exist without them. And people wonder why I love my job so much!

What happens when we don't publish clinical trials

The last blog I posted emphasised the importance of publishing all clinical trials. The story of Lorcainide is a stark warning of what happens when we don’t.In 1980 a cardiologist in Nottingham named Alan Cowley carried out a small clinical trial of a drug called Lorcainide. It was known at the time that heart attacks could cause irregular heartbeats in patients (known as arrhythmia), and these arrhythmias often lead to early death. Lorcainide had been shown to suppress arrhythmia, so it made sense that patients who came to hospital with a heart attack should be treated with the drug. Cowley and his colleagues carried out a small trial with 95 patients, and tested them to see whether they were getting more or fewer arrhythmias. The drug worked, lowering the frequency of serious arrhythmia.The doctors noticed something else however. Of the 48 patients on the drug, 9 had died, compared to only 1 patient on the placebo. This was a very small trial, so the doctors weren’t overly alarmed. It’s not surprising that 10 patients died in the study; these are patients who are presenting with heart attacks after all. It was just worrying that there was such an imbalance between the groups. The doctors chalked it up to bad luck, and viewed their trial as a success.At the time, this was a perfectly valid opinion. The study had been designed to analyse arrhythmias, not look at mortality. Furthermore, it was a tiny study, so they were justified in assuming the increased death was down to chance. Unfortunately however, what happened next ensured that the importance of this study would not be recognized.The doctors wrote an article describing their findings and tried to get it published. They submitted it to three different journals, but without success.  At the same time, the company that made Lorcainide decided to discontinue it (for unrelated commercial reasons), so the doctors lost interest and decided not to publish their results.To be clear, they were trying to publish the study as a success. Lorcainide was able to decrease serious arrhythmias after a heart attack. But within the paper was the information about increased mortality, and this would have been noticed. If it had been published, the study may not have prevented prescription, but it would certainly have suggested the need for further study.Although Lorcainide was never brought to market, other similar anti-arrhythmia treatments were prescribed to heart attack patients throughout the 80s. However, in 1983 there was a review of the available literature that proposed that there was no benefit in using these drugs. The authors of that study actually suggested that there might even be increased death following treatment, but this harmful effect was too small to be sure it was real.In hindsight it is clear that this small effect on mortality was in fact bigger than was realised. That study looked at published data to come to their conclusion. However, they were missing an important clinical trial, one that was in fact sitting unpublished on a hospital desk. If they had access to this data, they may have come to a different conclusion, flagging up the danger years earlier than it was.Towards the end of the decade, after more trials were published, two studies were carried out, both of which suggested that these drugs were doing more harm than good. At this point the danger was realised, and prescriptions dropped. However, it is estimated that 20,000 to 75,000 people died every year because of the use of anti-arrhythmia medication.In 1993, 13 years after it was originally carried out, the clinical trial on Lorcainide was published. The authors pointed out that it was perfectly reasonable to assume the increased death was a matter of chance, and they are probably correct in that. Unfortunately, when they decided not to publish and leave their study to gather dust, they contributed to an unfolding tragedy. At the time, the need to publish all trials regardless of their results wasn’t appreciated, so whether they can be blamed for what happened is a difficult question. What is certain however is that as a result of not publishing hundreds of thousands of people died.Well carried out clinical trials are the bedrock of modern medicine, and unbelievably, we are still in a ridiculous situation where reporting and publishing of trials is patchy at best. Until this situation is corrected we are at risk of another catastrophe like Lorcainide. Sign the AllTrials petition here to register your support for reform.

Problems with clinical trials

Clinical trials are at the heart of our progress in medicine. If we have a new therapy, clinical trials tell us whether it is better than the current one. They measure outcomes, but also look out for side effects and unexpected consequences of taking the therapy. They are absolutely essential to our progress, and it is vital that they are carried out properly and transparently.In recent years there has been an increasing awareness that our current mechanism to ensure this happens has been failing miserably. This has led to the formation of the All Trials initiative, which is campaigning for reform of the system. A paper this week in F1000Research emphasises the extent of the problems with clinical trials at the moment.The authors took a look at trials in the clinicaltrials.gov database. This is a database run by the National Institutes of Health in the US, and the FDA require that all clinical trials report a summary of their results there within 12 months of completion. What the authors of this study did was pretty simple: they mined the data for trials that were finished and also for those that had published their results. By comparing the two, they could figure out who was failing to share their trial results, and who was publishing.The study looked as far back as 2006, when it became a legal requirement for trial results to be published, so had a list of nearly 26,000 trials to analyse. The results were pretty stark. Over 45% of trials had not reported their results. This is a shocking but not unexpected finding. Previous studies had suggested such a high level of non-reporting, but this was the most thorough analysis to date.So why is it so important that results be published? Simply put, we need all the evidence about a treatment to understand its risks and benefits. The AllTrials campaign put it like this:

“If you tossed a coin 50 times, but only shared the outcome when it came up heads and you didn’t tell people how many times you had tossed it, you could make it look as if your coin always came up heads. This is very similar to the absurd situation that we permit in medicine, a situation that distorts the evidence and exposes patients to unnecessary risk that the wrong treatment may be prescribed.”

This is not an unfounded fear. In 1980, nine men died during a trial for a drug called Lorcainide, compared to only one in the placebo arm of the study. The manufacturer stopped the drug’s development (for commercial reasons rather than safety reasons), but crucially the researchers never managed to published the study. Over time other companies developed similar drugs, and they were prescribed throughout the 1980s. In 1993, the original researchers published their results, and the drug was removed from the market. Tragically, an estimated 20,000 to 75,000 people died every year from Lorcainide. It is essential that all the information is available when people’s health is on the line.A deeper look at the data published in this paper shows that some companies and institutions are a lot worse than others. This tool developed by the authors allows you to visualise this. The pharmaceutical company Sanofi, for example, has only published 150 of their 435 completed trials (35%). The Mayo Clinic, a prestigious Minnesota hospital and research centre, has not published 157 of their 312 trials (50%).Unfortunately, this issue has not been getting better with time. The most recent year that was analysed in this study was 2014, and in that year only 50% of trials were reported (see graph below), which is obviously unacceptable.This is a major issue in medicine at the moment, and one it is vital to be aware of. I would urge you all to sign this petition on the AllTrials website. The sooner this situation is rectified, the better.

Correlation vs Causation

The following headline caught my eye recently:

“Migraines could be caused by gut bacteria, study suggests”The Guardian – 18/10/16

To anybody who suffers from migraines, this is very interesting; at the moment, we really don’t understand what causes them. If a study has figured this out, then we may be able to help the estimated 15% of the population who are sufferers.This report is based on a paper published this week, titled:

“Migraines Are Correlated with Higher Levels of Nitrate-, Nitrite-, and Nitric Oxide-Reducing Oral Microbes in the American Gut Project Cohort”mSystems – 2016

The eagle eyed among you may have spotted the problem with this already. The Guardian has switched the word “correlated” for the word “caused”, so immediately you can see why the headline is wrong. Unfortunately the research did not show that gut bacteria cause migraines. What it did show was that people who suffer from migraines are more likely to have slightly different bacteria in their mouths than people who don’t. While this might lead you to think that there is a link, you cannot conclude this from the data. The difference between the two is easiest to explain in an example.The sales of ice-cream (A) correlates with the number of shark attacks (B). This could mean one of a number of things:

1. That A causes B.

Sharks are attacking more because people are buying more ice-cream.

2. That B causes A.

People are buying more ice-cream because of all the stark attacks.

3. That something else causes both A and B.

In good weather people go swimming more, and also buy more ice-cream.

4. That it is just coincidence that A and B are happening together.

Unlikely in this case, but actually extremely common, as I describe below.It is very, very easy to find correlations between random things. Take this fact, for example: the divorce rate in Maine is correlated with the consumption of margarine (see image below). This obviously does not mean that margarine causes divorces.Or the fact that the number of people who drown by falling in pools each year is correlated with the number of films that Nicholas Cage has been in that year. While it is tempting to suggest that Nicholas Cage films are so bad they are causing people to fall into pools, it seems a bit of an extreme reaction to his awful acting.These kinds of spurious correlations are everywhere if you look for them. There is a very good website (here) that mines data to find new ones, including the two examples I have used above. While these correlations are usually obviously nonsense, sometimes a correlation makes instinctive sense, and it is easy to believe that one thing is causing another, without actually having any evidence that it is true. This unfortunately can cause serious damage.As the rate of vaccination has increased over the last few decades, we have seen an explosion in the number of diagnoses of autism, which has led some people to claim that vaccines cause autism. It is an understandable assumption. The symptoms of autism appear at around the same stage as vaccination, so you can see why some parents jump to that conclusion. However, it has been clearly shown that there is no link between the two. In fact, the increase in the rate of autism is largely down to increased awareness and reporting, and not actually a result of more kids being autistic. Unfortunately however, the belief that these correlated events (autism onset and vaccination) are linked has led to a decrease in vaccination rates, and many preventable illnesses and deaths*.This problem of mixing up correlation and causation is common in the media, and an easy trap to fall into. Certainly correlation sometimes does mean causation, but without additional evidence we simply cannot say that it does. Correlation studies are common in science, and are an important research tool, particularly for informing future studies. Unfortunately, these are sometimes over-interpreted, and lead to things being linked without cause.The migraine study that I started this blog post with shows a correlation, but not causation. However, other studies have shown that chemicals that these bacteria produce can indeed cause headaches. While neither study is conclusive, it suggests that it may be worth following up these findings in further studies, which is exactly what the researchers recommend. Unfortunately, that wouldn’t make such a good headline. *It is worth pointing out that a certain percentage of people will get these illnesses, regardless of vaccinations. The numbers on the linked website above include these cases, so it is very difficult to know how many are directly due to decreased vaccination. It is clear though that the numbers have been increasing with decreasing vaccination rates, but if this blog post has taught you anything, it is that we cannot say that one has definitely caused the other. However, when combined with other available evidence, we can be very sure of that assertion. 

Trust in science

As with every other week, the last 10 days has brought a slew of tabloid stories, linking various things with causing or curing cancer:GOOD: antacids, Chinese herbal remedy, berries and tea, anthrax, frying foodBAD: being tall, tonsils, artificial football pitches, The RAF, oral sexAs always, these stories are largely nonsense, suitable only for the bin. Unfortunately, they are reported credulously and are widely read, and this saturation of health-related articles has several negative consequences.The constant bombardment of people with often-contradictory health information can drown out real health advice, making people think that eating some nuts can offset the effects of a terrible lifestyle for example. There is an enormous industry based on the peddling of cancer-preventing foods and supplements, often with a thin veneer of scientific respectability, and thanks to tabloid reporting, a much wider reach than should be allowed. It’s infuriating.However, the most insidious problem with poor media portrayal of science is the gradual erosion of trust in science. This may not seem like a significant issue, but it may be the most important. The rejection of vaccines, denial of climate change and resistance to genetic modification of foods, for example, are all rooted in science denial.This is an issue with many causes. Both political and religious beliefs play a major role in our view of the evidence, as does self-interest, meaning that arguments are often politicised or financially motivated. When Andrew Wakefield, for example, “found” a link between vaccines and autism, he personally profited from people not using the MMR.The driving force behind denialist movements are often organisations that stand to gain from the confusion (climate change denial has largely been funded by groups that will suffer most from restrictions on fossil fuels). There has been a deliberate drive to manufacture controversy in many areas, most famously by the tobacco industry, whose tactic was not to win the debate, but to “foster and perpetuate the illusion of controversy in order to muddy the waters around scientific findings that threaten the industry”. A leaked memo to George W Bush on climate change tactics from 2002 suggested that although the scientific debate was closing, it was important “to continue to make the lack of scientific certainty a primary issue in the debate”. Media organisations are often complicit in this, and there are many examples of the deliberate undermining of the scientific process, most notably by Fox News in the US.That being said however, the large majority of people who subscribe to denialist views are people who have no such motivation. These people appear to have a basic mistrust of science, and are swayed by the anti-science rhetoric. It is easy to understand why parents hesitated to vaccinate after the initial reports of a link to autism, but despite this link being definitively shown to be false, vaccination rates in large parts of the world are still suffering. Be it the left-wing embracing of alternative medicine, the right-wing support of climate change denial or religious creationism, the anti-science movement is a pervasive one, largely based on the mistrust of science.There are several roots of this mistrust. An obvious one is that science can undermine deeply held beliefs. When this happens, people are likely to reject the evidence, rather than give up their belief. In fact, when challenged on such a belief, people are more likely to strengthen their belief rather than the other way around (known as the “backfire effect”). This needn’t be a religious belief, and is something that has been observed in many areas of life, such as the belief in superstition or alternative medicine. If science continuously challenges these beliefs, then people stop believing in the science.It is also the case that a misunderstanding of what science actually is also contributes to this issue. Many people see science as an “institution”, something that is telling us what to do. The reality is that it is a process. This misunderstanding of science makes it much easier for people to rationalise the rejection of valid conclusions, regardless of the strength of the evidence. The power of anecdotal evidence is a classic example of this: “my father smoked 20 a day, and he lived ‘til he was 90”. This view of science as an “institution” also feeds into an anti-establishment mentality that can also result in science denial. This is the same mentality that is behind the belief in grand conspiracies.And this brings me back to the tabloids. If you are told every day that random things are making you sick, or are essential to health, it is likely that you will become desensitised to them. It is easy for people to reject science-based advice, because tabloid reporting makes science appear far more confused than it actually is. The reporting of preliminary findings, or of badly carried out science, leads to a confused picture of our current understanding. Scientists are constantly studying and learning, working towards the truth. Bad science and incorrect results are inevitable in science, but it is a self-correcting process that gradually works to show what is real and what is not.Our entire civilisation is based on scientific innovation and progress. While that progress cannot be halted, it can be slowed by the mistrust of the public in the scientific process. That can only be a bad thing.

The reproducibility problem

The scientific process is an amazing thing. Between the Palaeolithic era (the era between 2 million and 20,000 years ago) and the year 1900, the average life expectancy at birth hardly increased at all, remaining around 30 years. Since then, as a result of the application of the scientific process to health care, it has more than doubled, with the worldwide average now being 71 years. Consider that. In just 100 years we have given ourselves more life that we managed in the previous 2 million years! Through science (the process of making observations, developing a hypothesis, testing that hypothesis and then refining and building on it) we have transformed our lives.Science is based on the fact that observations are consistent. If, for example, a surgeon washes his hands before operating, his patients will consistently get fewer infections. Without this consistency, this ability to repeat an experiment and get similar results, the whole scientific endeavour stops. This is why a recent publication in the journal PLOS Biology is so worrying.The article suggests that 50% of life sciences research cannot be reproduced and is therefore useless. Furthermore, the authors estimate that $28 billion is wasted in the US every year on studies that are never repeated. It must be pointed out that the way the authors defined “reproducible” was extremely broad, and as a result, there is a large margin of error in their estimate. However, the study does shine an uncomfortable light on the current state of science. It has been acknowledged that there is a “reproducibility problem” in the life sciences at the moment. A previous study by scientists at Bayer Healthcare stated that their own staff could only reproduce 24 of 67 studies published in peer-reviewed journals.These reports suggests that most of the irreproducibility is as a result of poor study design, biological reagents that are not publically available, badly described protocols, and poor interpretation of results. Poor study design is mostly due to (inexcusable) bad lab practice, whereas the problems with reagents and protocols largely result from an extremely restrictive word count applied to the material and methods section of most journals. This word count means that the way experiments are carried out isn’t adequately described, and as a consequence others can’t repeat it. Finally poor interpretation of results is down to a lack of understanding of statistics and a selection bias that exists in science. This selection bias means that positive results are far more likely to be published than negative ones. In the extremely competitive scientific environment, this unfortunately forces authors toward sensationalising their findings in order to get them published, often to the detriment of the study itself.Theoretically, the process of peer review (wherein papers are critically analysed by their peers before publication) should ensure good quality science. This process however does not tackle the problem of the editorial policy, which does not reward studies whose results are unspectacular but reliable. Such studies are essential for scientific progress. For example, a paper was published in the journal Nature in 2013 demonstrating a method of generating stem cells. However, the same journal refused to publish a study the following year that showed that this method was entirely false.At present, a scientist is measured by the standard of his/her publications. To be awarded a grant you have to show that you can publish in a high impact journal. As a result, there is little incentive in science to reproduce other’s work, even if it is just part of a study. Furthermore, if a study does fail to reproduce another, it is usually filed away in a drawer and is not published. Unfortunately, the quality and reproducibility of someone’s work is not included when they are being judged as a scientist.A lot of money is spent every year in life sciences research. In the US, the budget is around £35 billion ($56 billion). Numbers are harder to come by in the UK, but the total spend on science and engineering is roughly £5.8 billion. While in the grand scheme of spending, this is a small amount (pensions alone cost the UK £1.5 trillion per year) it is still vital that the money is spent efficiently. The public, either through charity or governmental means, largely funds the life sciences. If there is a public perception that the results cannot be trusted, science risks losing the confidence of the public, and potentially the funding that is so essential for this work. The advances in public health that we have made in the last centaury prove how important this research is and how important it is that we remedy this reproducibility problem.