Skip to main content

telomeres

Each time your cells divide, telomeres—complexes of specialized DNA sequences, RNA, and protein that protect the tips of your chromosomes—shorten just a bit.  And, as the video shows, that shortening renders the genomic information on your chromosomes more vulnerable to changes that can drive cancer and other diseases of aging.

Consequently, over the last few decades, much research has focused on efforts to understand telomerase, a naturally occurring enzyme that helps to replace the bits of telomere lost during cell division. But there’s been a major hitch: until recently, scientists hadn’t been able to determine telomerase’s molecular structure in detail—a key step in figuring out exactly how the enzyme works. Now, thanks to better purification methods and an exciting technology called cryo-electron microscopy (cryo-EM), NIH-funded researchers and their colleagues have risen to the challenge to produce the most detailed view yet of human telomerase in its active form [1].

This structural biology advance is a critical step toward learning more about the role of telomerase in cancers, as well as genetic conditions linked to telomerase deficiencies. It’s also an important milestone in the quest for drugs targeting telomerase in different ways, perhaps to slow the growth of cancerous cells or to boost the proliferative capacity of life-giving adult stem cells.

One reason telomerase has been so difficult to study in humans is that the enzyme isn’t produced at detectable levels in the vast majority of our cells. To get around this problem, the team led by Eva Nogales and Kathleen Collins at the University of California, Berkeley, first coaxed human cells in the lab to produce larger quantities of active telomerase. They then used fluorescent microscopy, along with extensive knowledge of the enzyme’s biochemistry, to develop a multi-step purification process that yielded relatively homogenous samples of active telomerase.

The new study is also yet another remarkable example of how cryo-EM microscopy has opened up new realms of scientific possibility. That’s because, in comparison to other methods, cryo-EM enables researchers to solve complex macromolecular structures even when only tiny amounts of material are available. It can also produce detailed images of molecules, like telomerase, that are extremely flexible and hard to keep still while taking a picture of their structure.

As described in Nature, the researchers used cryo-EM to capture the structure of human telomerase in unprecedented detail. Their images reveal two lobes, held together by a flexible RNA tether. One of those lobes contains the highly specialized core enzyme. It uses an internal RNA template as a guide to make the repetitive, telomeric DNA that’s added at the tips of chromosomes. The second lobe, consisting of a complex of RNA and RNA-binding proteins, plays important roles in keeping the complex stable and properly in place.

This new, more-detailed view helps to explain how mutations in particular genes may lead to telomerase-related health conditions, including bone marrow failure, as well as certain forms of anemia and pulmonary fibrosis. For example, it reveals that a genetic defect known to cause bone marrow failure affects an essential protein in a spot that’s especially critical for telomerase’s proper conformation and function.

This advance will also be a big help for designing therapies that encourage telomerase activity. For example, it could help to boost the success of bone marrow transplants by rejuvenating adult stem cells. It might also be possible to reinforce the immune systems of people with HIV infections. While telomerase-targeted treatments surely won’t stop people from growing old, new insights into this important enzyme will help to understand aging better, including why some people appear to age faster than others.

As remarkable as these new images are, the researchers aren’t yet satisfied. They’ll continue to refine them down to the minutest structural details. They say they’d also like to use cryo-EM to understand better how the complex attaches to chromosomes to extend telomeres. Each new advance in the level of atomic detail will not only make for amazing new videos, it will help to advance understanding of human biology in health, aging, and disease.

References:

[1] Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nguyen THD, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, Collins K. Nature. 2018 April 25. [Epub ahead of publication]

Links:

High Resolution Electron Microscopy (National Cancer Institute/NIH)

Nogales Lab (University of California, Berkeley)

Collins Lab (University of California, Berkeley)

NIH Support: National Institute of General Medical Sciences   

Posted In: Cool Videos, News

Tags: , , , , , , , , , , , , , , , , ,

2 Comments

MinION sequencing device

Caption: MinION sequencing device plugged into a laptop/Oxford Nanopore Technologies

It’s hard to believe, but it’s been almost 15 years since we successfully completed the Human Genome Project, ahead of schedule and under budget. I was proud to stand with my international colleagues in a celebration at the Library of Congress on April 14, 2003 (which happens to be my birthday), to announce that we had stitched together the very first reference sequence of the human genome at a total cost of about $400 million. As remarkable as that achievement was, it was just the beginning of our ongoing effort to understand the human genome, and to use that understanding to improve human health.

That first reference human genome was sequenced using automated machines that were the size of small phone booths. Since then, breathtaking progress has been made in developing innovative technologies that have made DNA sequencing far easier, faster, and more affordable. Now, a report in Nature Biotechnology highlights the latest advance: the sequencing and assembly of a human genome using a pocket-sized device [1]. It was generated using several “nanopore” devices that can be purchased online with a “starter kit” for just $1,000. In fact, this new genome sequence—completed in a matter of weeks—includes some notoriously hard-to-sequence stretches of DNA, filling several key gaps in our original reference genome.

(more…)

Posted In: Health, Science, technology

Tags: , , , , , , , , , , , , , , , ,

Hennie with her family

Caption: Hendrikje van Andel-Schipper (2nd from the left) in her youth. She was born June 29, 1890, premature and so tiny that no one thought she would survive. However, she lived to be 115.
Credit: Ramon Schipper

Not too long before 115-year-old Hendrikje “Hennie” van Andel-Schipper died in 2005, this Dutch “supercentenarian” attributed her remarkable longevity to eating raw salted herring, to drinking orange juice, and—with a twinkle in her eye—“to breathing.”

Because very few humans have survived as long Hennie, it’s only logical to ask whether some of the secrets to her impressive lifespan might lie in her genes. And we find ourselves in a great position to explore such questions, thanks to the convergence of two things: recent advances in DNA sequencing technology, and Hennie’s generous decision, made when she was a mere 82 years old, to donate her body to science upon her death.

(more…)

Posted In: Science

Tags: , , , , , , , , , , ,

Faces of the NIH grantees receiving the Breakthrough Prize in the Life Sciences (as listed below)

NIH grantees receiving the Breakthrough Prize in the Life Sciences
(in order as listed below)

The brand new $3 million Breakthrough Prize in the Life Sciences [1] delivered a very nice reward and well deserved recognition to eleven exceptionally creative scientists who have devoted their careers to biology and medicine. And, with five awards to be given each year, I hope this inspires other life scientists to embark on innovative and high-risk endeavors.

For this inaugural round, I’m proud to say that nine of the eleven winners were NIH grant recipients—some for more than three decades. Now, you may not have heard of most of these scientists. Quite frankly, that’s a shame. These folks have discovered fundamental principles of biology—everything from cancer causing genes to techniques for creating stem cells. These discoveries have boosted our understanding of health and disease, and led to the development of many drugs and therapies.

So these individuals really should be household names—and more of that kind of recognition would be a good thing to inspire youth to explore careers in science. In the United States, virtually everyone can list names of multiple movie stars and athletes, but two-thirds of Americans can’t name a single living scientist [2].

(more…)

Posted In: Health, Science

Tags: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,