Heart Disease: Fishing for a cure

Girisaran Gangnatharan, Institut de Génomique Fonctionnelle, Montpellier, France.

It is not just a little fish

“Why?” You ask me.

Because the tiny zebrafish may be the answer to the problem of heart disease in our society. Or, to be specific, this fish might be able to teach us how to repair your heart if you have a heart attack.

Before I explain how that is possible, we need to understand what happens during a heart attack.

Let’s take as our example Mr. Sam.

Mr. Sam is in his late 40s. He works in a bank and exercises twice a week to keep himself healthy. One fine day, Mr. Sam is working in his office and feels a small pain in his chest. He clutches his chest and falls to the floor.

Mr. Sam is having a massive heart attack.

As he lies on the floor, let’s jump into our hypothetical nano-submarine and zoom into his heart.

You witness first-hand the destruction as it unfolds: thousands upon thousands of his heart-muscle cells are dying almost instantly. These heart-muscle cells are required for the pumping action of his heart. Unfortunately, these heart-muscle cells cannot be replaced, and his heart is unable to pump blood efficiently to the rest of his body. Eventually, his heart will fail, and unless Mr. Sam has a heart transplant, he will die prematurely.

Would it surprise you if I told you that you could be the next Mr. Sam?

In fact, heart disease is so rampant, one out of every three people reading this article will most likely die of a heart attack.

Unless a creative solution to the problem of heart disease is found.

So what is the nature of the problem?

The problem is that Mr. Sam, you, and I cannot replace our heart-muscle cells if they are damaged. One promising solution, then, would be to find a way to stimulate our hearts to replace damaged cells.

This is where the zebrafish comes in.

“What on earth is a fish going to tell me about my own abilities to heal my heart?” You might ask.

If you cut off a small portion of this fish’s heart it will heal spontaneously. It will fully regenerate and replace the lost heart muscle.

Now some of you must be thinking, “well, this is great!” It is –  if you are a zebrafish.

So the obvious question is: why can’t we heal our damaged hearts using the same mechanism that a zebrafish uses to heal its injured heart?

Why not?

Now I admit: you and I, we look nothing like fish. But did you know that zebrafish and humans share 70% of our genes? And, most importantly, did you know that the mechanism the zebrafish employs to heal its damaged heart also exists in mammals?

For example, if you were to remove a portion of the heart of a baby mouse, it would regenerate its heart in the same fashion as the zebrafish. However, as mice get older, they lose this ability to regenerate.

What this means is that the process by which a creature heals a damaged and injured heart is not specific to zebrafish; it is not specific to baby mice. It is not a genetic program specific to only a few animals. It is actually written in our own DNA.

But these genes were switched off in humans at some time during our evolution.

Our goal as scientists is to switch this genetic program back on. The zebrafish can tell us which human genes need to be turned on to repair the human heart.

Thanks to the zebrafish, cardiovascular disease could become a thing of the past in the coming decades: we would look at it the way we look at small pox today. Imagine a world where you would not have to go through the pain of losing a loved one to heart disease.

Who knows, this fish might actually save your life in the future.

It’s not just a fish…. It is hope!

About the Author:  

Girisaran is a Final Year Graduate Student in Chris Jopling’s Lab at the Institut de Génomique Fonctionnelle, Montpellier, France. For his thesis, he has been studying the zebrafish. Unlike ours, if a zebrafish’s heart is damaged it will repair itself.  If we could understand this process in the zebrafish, we could reverse engineer that into human therapies.

Outside the lab, you can find Girisaran singing with his acoustic guitar or swimming laps in Montpellier’s Olympic sized swimming pool.

A Prescription for Antibiotic Resistance: A Rare Vantage Point in the Fight Against Bacteria

Ross Harper, University College London.

We are at war. We have always been. Unfortunately, in this particular conflict we are outnumbered… seven hundred quintillion to one.

From the Black Death in the Middle Ages to the Victorian scourge of cholera, bacterial epidemics travel the globe, leaving devastation in their wake. Times were bleak in the nineteenth century; many battles were lost. And then, in 1928, humanity crafted a weapon. We stepped out of the darkness and into a new era: one of antibiotics. In a monumental stroke of luck, Alexander Fleming fell upon a fungus that produced a curious bacteria-killing substance. We now call it penicillin.

It’s easy to dramatize the history of antibiotics. While we can’t know exactly how many lives have been saved since their discovery, the figure is estimated to be in excess of 200 million. The world would certainly be a gloomier place without them, which begs the question: what will we do if they run out?

Earlier this year, researchers led by Kim Lewis at Northeastern University in Boston, Massachusetts, announced the discovery of teixobactin, a promising new antibiotic and the first of its kind for over thirty years. In studies in mice, teixobactin was shown to kill the infamous MRSA (methicillin-resistant Staphylococcus aureus) bacterium, as well as a host of other microbial nasties. Lewis and colleagues extracted bacterial cells from soil and sorted them into individual chambers in a new device they call the ‘iChip’. The iChip was then submerged back in the ground where essential nutrients could enter each of the chambers, allowing the bacteria to thrive. In this way, the researchers were able to culture strains that would normally be unwilling to adapt to life on a petri dish. Thus, like many of its predecessors, teixobactin is actually produced by one bacterial species in order to kill others. The enemy of my enemy is my friend – and in this case, our new friend is Eleftheria terrae.

Modern medicine can breathe a sigh of relief. The looming threat of a return to pre-antibiotic times has been pushed back into the shadows. However, now is not the time for complacency. The problem persists and is even on the rise.

“Antimicrobial resistance poses a catastrophic threat”, says UK Chief Medical Officer, Dame Sally Davies, in her 2013 annual report. The issue remains integral to science policy, and it also highlights a key area of cell biology. Humanity is engaged in an ancient competition: big vs. small, eukaryote vs. prokaryote, us vs. them.

So from where does antibiotic resistance originate? Just as Fleming discovered, rather than invented penicillin, so too must we acknowledge that resistance is a naturally occurring phenomenon. Where there are chemicals that kill bacteria, evolution responds with immunity to them. Indeed, Darwinian natural selection is rarely illustrated so neatly. Once in a while, a random mutation in the bacterial genome will spontaneously generate a degree of resistance – for example, a change of just a few amino acids in the protein, beta-lactamase, can protect against penicillin. When penicillin is present, the mutant cell enjoys a competitive advantage over its peers, reproducing to a greater extent and spreading the mutated beta-lactamase gene throughout subsequent generations.

It’s a profoundly troubling thought. Though we may take some comfort in our ability to understand the threat. After all, this process is consistent with everything we already know about evolution and gene transmission in a population, right? Well perhaps not. We typically only consider DNA to move in a vertical direction – parent to child, or in the case of a single cell, when it divides. However, many microbes are also able to move DNA and share useful genes horizontally between individuals. This horizontal gene transfer (HGT) helps bacteria acquire resistance far quicker than they would through conventional methods alone.

Mechanisms of HGT can be categorised into three main groups: transformation, transduction, and conjugation. Transformation is when a bacterium takes in DNA from its surrounding environment (perhaps left behind by a fallen comrade). Transduction, however, involves a viral middleman to transfer genetic information during infection. Conjugation embodies a more cooperative approach, where DNA is shared directly between two cells via the construction of a small bridge, or ‘pillus’. While these are the tactics of our enemy, it is worth noting that research into HGT has been crucial to biotechnology. We can trick bacteria into taking up DNA fragments of our own design. In a satisfying twist of fate, the biosynthetic machinery of E. coli is commonly hijacked to produce proteins, such as insulin for the treatment of diabetes. This form of microbial slave labour has become a cornerstone of the pharmaceuticals industry.

Antibiotic resistance may not itself be a human creation, but we are certainly quite adept at accelerating its development. The sheer scale of antibiotic use in medicine, agriculture and waste disposal has seen the emergence of ‘superbugs’, such as MRSA, Clostridium difficile, and the unnervingly named, TDR-TB (totally drug-resistant tuberculosis). It’s a textbook dilemma: antibiotics are the cause of, and solution to our problem. Prescription-only policies go some way to reducing widespread public health usage (particularly in the futile attempt to treat many viral infections), and there has been much discussion of ‘cycling’ front-line antibiotics to reduce environmental exposure to any one type. From a research perspective, current strategies explore ways to block the efflux systems that bacteria commonly use for resistance. Whereas a more conceptual approach might be to target only microbe pathogenicity, leaving the cell inert but otherwise able to reproduce, thus mitigating the selection pressure for resistance.

There are many ways in which we might seek to reduce the problem of antibiotic resistance; these are deserving of their own separate discussion. For now, the discovery of teixobactin serves as a welcome boost – a few more steps in the footrace against bacteria. Pursuit of iChip-like technologies, coupled with effective science policy, will keep us ahead of our competitor for a while longer. But, the race is relentless. The finish line, if it exists, remains out of sight.

 About the Author:  

Holding an MA in natural sciences from the University of Cambridge, and an MRes in modelling biological complexity from University College London, Ross is now two years along a PhD in the chronobiology department at University College London. His research seeks to combine experimental and computational techniques in order to understand the differential processing of sensory modalities in circadian clocks.

Outside of the lab, Ross edits ‘science lifestyle’ magazine, Guru, and has experience running his own technology start-ups.