Apr 29th 2018

End of ageing and cancer? Scientists unveil structure of the ‘immortality’ enzyme telomerase

 

Making a drug is like trying to pick a lock at the molecular level. There are two ways in which you can proceed. You can try thousands of different keys at random, hopefully finding one that fits. The pharmaceutical industry does this all the time – sometimes screening hundreds of thousands of compounds to see if they interact with a certain enzyme or protein. But unfortunately it’s not always efficient – there are more drug molecule shapes than seconds have passed since the beginning of the universe.

Alternatively, like a safe cracker, you can x-ray the lock you want to open and work out the probable shape of the key from the pictures you get. This is much more effective for discovering drugs, as you can use computer models to identify promising compounds before researchers go into the lab to find the best one. Now a study, published in Nature, presents detailed images of a crucial anti-ageing enzyme known as telomerase – raising hopes that we can soon slow ageing and cure cancer.

Telomeres on a chromosome
Telomeres on a chromosome.

Every organism packages its DNA into chromosomes. In simple bacteria like E. coli this is a single small circle. More complex organisms have far more DNA and multiple linear chromosomes (22 pairs plus sex chromosomes). These probably appeared because they provided an evolutionary advantage, but they also come with a downside.

At the end of each chromosome is a protective cap called a telomere . However, most human cells can’t copy them – meaning that every time they divide, their telomeres become shorter. When telomeres become too short, the cell enters a toxic state called “senescence”. If these senescent cells are not cleared by the immune system, they begin to compromise the function of the tissues in which they reside. For millennia, humans have perceived this gradual compromise in tissue function over time without understanding what caused it. We simply called it ageing.

Enter telomerase, a specialised telomere repair enzyme in two parts – able to add DNA to the chromosome tips. The first part is a protein called TERT that does the copying. The second component is called TR, a small piece of RNA which acts as a template. Together, these form telomerase, which trundles up and down on the ends of chromosomes, copying the template. At the bottom, a human telomere is roughly 3,000 copies of the DNA sequence “TTAGGG” – laid down and maintained by telomerase. But sadly, production of TERT is repressed in human tissues with the exception of sperm, eggs and some immune cells.

Ageing versus cancer

Organisms regulate their telomere maintenance in this way because they are walking a biological tightrope. On the one hand, they need to replace the cells they lose in the course of their ordinary daily lives by cell division. However, any cell with an unlimited capacity to divide is the seed of a tumour. And it turns out that the majority of human cancers have active telomerase and shorter telomeres than the cells surrounding them.

This indicates that the cell from which they came divided as normal but then picked up a mutation which turned TERT back on. Cancer and ageing are flip sides of the same coin and telomerase, by and large, is doing the flipping. Inhibit telomerase, and you have a treatment for cancer, activate it and you prevent senescence. That, at least, is the theory.

The researchers behind the new study were not just able to obtain the structure of a proportion of the enzyme, but of the entire molecule as it was working. This was a tour de force involving the use of cryo-electron microscopy – a technique using a beam of electrons (rather than light) to take thousands of detailed images of individual molecules from different angles and combine them computationally.

Prior to the development of this method, for which scientists won the Nobel Prize last year, it was necessary to crystallise proteins to image them. This typically requires thousands of attempts and many years of trying, if it works at all.

Elixir of youth?

TERT itself is a large molecule and although it has shown to lengthen lifespan when introduced into normal mice using gene therapy this is technically challenging and fraught with difficulties. Drugs that can turn on the enzyme that produces it are far better, easier to deliver and cheaper to make.

We already know of a few compounds to inhibit and activate telomerase – discovered through the cumbersome process of randomly screening for drugs. Sadly, they are not very efficient.

Some of the most provocative studies involve the compound TA-65 (Cycloastragenol) – a natural product which lengthens telomeres experimentally and has been claimed to show benefit in early stage macular degeneration (vision loss). As a result, TA65 has been sold over the internet and has prompted at least one (subsequently dismissed) lawsuit over claims that it caused cancer in a user. This sad story illustrates an important public health message best summarised simply as “don’t try this at home, folks”.

The telomerase inhibitors we know of so far, however, have genuine clinical benefit in various cancers, particularly in combination with other drugs. However, the doses required are relatively high.

The new study is extremely promising because, by knowing the structure of telomerase, we can use computer models to identify the most promising activators and inhibitors and then test them to find which ones are most effective. This is a much quicker process than randomly trying different molecules to see if they work.

So how far could could we go? In terms of cancer, it is hard to tell. The body can easily become resistant to cancer drugs, including telomerase inhibitors. Prospects for slowing ageing where there is not cancer are somewhat easier to estimate. In mice, deleting senescent cells or dosing with telomerase (gene therapy) both give increases in lifespan of the order of 20% – despite being inefficient techniques. It may be that at some point other ageing mechanisms, such as the accumulation of damaged proteins, start to come into play.

But if we did manage to stop the kind of ageing caused by senescent cells using telomerase activation, we could start devoting all our efforts into tackling these additional ageing processes. There’s every reason to be optimistic that we may soon live much longer, healthier lives than we do today.

 

Richard Faragher, Professor of Biogerontology, University of Brighton

This article was originally published on The Conversation. Read the original article.

 

 

Please sing up to my Twitter account for What's New on Facts & Arts.

Olli Raade, Editor to Facts & Arts 

Browse articles by author

More Essays

Jan 10th 2019
Extracts from the article: "Last November, Michael Bloomberg made what may well be the largest private donation to higher education in modern times: $1.8 billion to enable his alma mater, Johns Hopkins University, to provide scholarships for eligible students unable to afford the school’s tuition. Bloomberg is grateful to Johns Hopkins, he explains, because the opportunity to study there, on a scholarship, “opened up doors that otherwise would have been closed, and allowed me to live the American dream.” In the year after he graduated, he donated $5 to the school, all he could afford. Thanks to the success of Bloomberg L.P., the international financial-information company he founded in 1981, he has now given a total of $3.3 billion......And yet I cannot applaud Bloomberg’s donation to a university that already had an endowment of $3.8 billion and charges undergraduate students $53,740 per year to attend. My preference is for Hank Rowan, who back in 1992 gave $100 million to Glassboro State College, a public university in New Jersey that at the time had an endowment of $787,000 and annual fees of about $9,000. Rowan himself was a graduate of MIT, one of the world’s finest universities, but gratitude was not his motivation for donating. He wanted to make the biggest difference he could, and believed that one makes a bigger difference by strengthening the weak links in the higher education system than by giving even more to those who already have a lot."
Jan 9th 2019
Marcel Proust was the master of artistic time travel, as he spent the final decades of his life exploring the nature of memory, in a quest to understand the relationship between past and present. In today’s troubled present of economic malaise and political agitation, the art world of Paris is currently engaged in a Proustian exercise of reexamining, and celebrating, a lost golden age of splendor and creativity.
Dec 10th 2018
The current exhibition of Eugène Delacroix (1798-1863) at New York’s Metropolitan Museum of Art – the first of its kind to be mounted in North America – is indeed an extraordinary revelation. Delacroix was one of the great creative minds of the nineteenth century: an artist who embodied the spirit of Romanticism, a dramatist and virtuoso of coloration who never ceased to experiment, to take inspiration from the old masters – from Veronese and Rubens, Rembrandt and Caravaggio – whose works he would often copy at the Louvre, “that book from which we learn to read,” as Cézanne put it.
Dec 6th 2018
Your body has two metabolically different states: fasted (without food) and post-fed. The absorptive post-fed state is a metabolically active time for your body. But is also a time of immune system activity. When we eat, we do not just take in nutrients – we also trigger our immune system to produce a transient inflammatory response. Inflammation is a normal response of the body to infection and injury, which provides protection against stressors. This means that just the act of eating each meal imparts a degree of physiological stress on the immune system. And so for people snacking around the clock, their bodies can often end up in a near constant inflammatory state.
Dec 5th 2018
Researchers have developed a test that could be used to diagnose all cancers. It is based on a unique DNA signature that appears to be common across cancer types. The test has yet to be conducted on humans, and clinical trials are needed before we know for sure if it can be used in the clinic.
Dec 4th 2018
The late great Russian-born novelist Vladimir Nabokov (pictured below by Michael Johnson) amassed a range of critical comments during his 78 years, more than enough to qualify him as a literary giant and keep his books in print. But most of the assessments have an edge – he was irascible, independent-minded, contradictory, arbitrary, arrogant, tongue-tied, obscene. For such a tumultuous life, he died in opposite conditions: quietly in Montreux, Switzerland, having spent his last 16 years with few friends and almost no family around him. Making sense of this unique talent has been a hobby of mine since the 1960s, enjoying his quirky prose style, his trilingual puns and his forays into forbidden territory, particularly with Bend Sinister, Lolita, Pnin, Pale Fire and Ada. Have I ever made sense of him?
Nov 26th 2018
There is now good evidence that the risks versus benefits of alcohol are strongly influenced by the type of alcohol and the way it is drunk.
Nov 14th 2018
Jean Gabin - pictured below by the author of this book review Michael Johnson - lives on vibrantly through international film festivals, art houses and television reruns although he died in Paris 42 years ago. Just last week in prime time I watched one of his classic films, “Pépé le Moko”, a story of considerable depth that pops up regularly on television. American author Joseph Harriss rightly calls it “Casablanca for grownups”. Other classics abound – “La Grande Illusion”, “Le Quai des Brumes” “Touchez pas au grisbi”, for example. 
Nov 13th 2018
Over the last ten years, research has demonstrated the importance of creative practice in the arts and humanities. They can help maintain health, provide ways of breaking down social barriers and expressing and understanding experiences and emotions, and assist in developing trust, identities, shared understanding and more compassionate communities. So, hopefully, this sidelining of the arts in health terms is changing.
Nov 13th 2018
I am here to sing Will Kemp’s [in the picture below] praises and review this new e-book because I have been studying with Will since January 2016, long distance but close in heart—Will lives in Britain and I live in the States.
Nov 13th 2018

This address is in part about the musician who has studied as a concert pianist, but does not pursue the narrow and precise field for which he has been trained, yet does not quit; but does not often play solo recitals nor concerts, nor chamber music, nor strict lieder activities

Nov 2nd 2018
Writing is such hard work that those of us who dabble in prose often dread looking at the “white bull” – Hemingway’s term for a blank sheet of paper waiting to be filled up with our words. Will we defeat the bull today? It’s always a tossup. The stress and strain of writing perhaps explains why so many writers seek an outlet in the visual arts, particularly painting and sculpture. Visual output satisfies the hunger to create, and, as a bonus, the art form is more free and spontaneous. Great writers have produced great paintings. Look at Victor Hugo, Guillaume Apollinaire, Rudyard Kipling, Dante Gabriel Rossetti. Even more interesting to me is the somewhat lesser phenomenon of pianists who paint. They are seeking the same release, the same soulagement, the same need to liberate themselves. 
Nov 1st 2018
Modern life does have many benefits, but when it persuades us to use transport, sit in a chair at work, or watch TV for extended periods, we increasingly have to turn to medicine for solutions because these habits are killing hundreds of millions of us each year. With 70% of people in the US on prescription drugs (50% in the UK), it seems that as lifespan inches upwards, disease is skyrocketing. The irony is that many advances in modern medicine are firefighting those very problems that modern life itself has created.
Oct 30th 2018
It’s important to note that all studies, including our own, only show an association between the herpes virus and Alzheimer’s – they don’t prove that the virus is an actual cause. Probably the only way to prove that a microbe is a cause of a disease is to show that an occurrence of the disease is greatly reduced either by targeting the microbe with a specific anti-microbial agent or by specific vaccination against the microbe. Excitingly, successful prevention of Alzheimer’s disease by use of specific anti-herpes agents has now been demonstrated in a large-scale population study in Taiwan. Hopefully, information in other countries, if available, will yield similar results.
Oct 18th 2018
Leaving a major political body is nothing new for mainland Britain. In 409AD, more than 350 years after the Roman conquest of 43AD, the island slipped from the control of the Roman Empire. Much like the present Brexit, the process of this secession and its practical impacts on Britain’s population in the early years of the 5th century remain ill-defined. As with the UK and Brussels, Britain had always been a mixed blessing for Rome. In around 415AD, St Jerome called the island “fertile in tyrants” (meaning usurpers) and late Roman writers portrayed a succession of rebellions in Britain, usually instigated by the army – many of whom would have been born in the province.
Oct 16th 2018
One of the oldest Greek myths, the story of Pandora was first recorded more than 2,500 years ago, in the time of Homer. In the original telling, Pandora was not some innocent girl who succumbed to the temptation to open a forbidden jar......Pandora was deliberately devised to punish humankind for accepting the gift of fire from Prometheus. Essentially a seductive AI fembot, she had no parents, childhood memories, or emotions of any kind, nor would she ever age or die. She was programmed to carry out one malevolent mission: to insinuate herself in an earthly setting and then unseal the jar......With AI/machine learning quickly evolving into a “black box” technology, the symbol of Pandora’s sealed jar has taken on new meaning.
Oct 11th 2018
The Scottish National Gallery in Edinburgh is currently exhibiting a substantial selection of Rembrandt’s paintings, drawings, and prints – focusing on those works that reveal the story of “Britain’s Discovery of the Master.” Exploring the significance of Rembrandt to British collectors, artists, and writers provides us with the occasion to revisit some fifteen major oil paintings.....
Oct 10th 2018
On the fiftieth anniversary of Nicolas Garcia Uriburu’s first coloration, Buenos Aires’ National Museum of Fine Arts pays tribute to the landmark early accomplishment of its native son..........Uriburu’s role as an early environmentalist has never been appreciated outside of his native country. It is sad that this neglect was not remedied in his lifetime, but at least it should be done now; a full-scale retrospective of his pioneering work should be presented in the art world’s capitals, to inspire young artists.
Oct 2nd 2018
The 2018 Nobel Prize in Physiology or Medicine has been awarded to two immunologists for their revolutionary approaches to treat cancer. James Allison, based in the MD Anderson Cancer Center in Houston, Texas, and Tasuku Honjo, based at Kyoto University in Japan, led exciting and groundbreaking work on developing new types of immunotherapy that help our immune system fight cancer.
Sep 20th 2018
We all want other people to “get us” and appreciate us for who we really are. In striving to achieve such relationships, we typically assume that there is a “real me”. But how do we actually know who we are? It may seem simple – we are a product of our life experiences, which we can be easily accessed through our memories of the past. Indeed, substantial research has shown that memories shape a person’s identity......................But it turns out that identity is often not a truthful representation of who we are anyway – even if we have an intact memory. Research shows that we don’t actually access and use all available memories when creating personal narratives. It is becoming increasingly clear that, at any given moment, we unawarely tend to choose and pick what to remember.