Another Piece to a Century-Old Evolutionary Puzzle

After mating about 55,000 pairs of fruit flies and sifting through 333,000 daughter flies, a research team found six sons that each had mutations in the same gene that helped make two fruit fly species unique from each other. Credit: Jim Woolace, Fred Hutch News Service.

Nitin Phadnis and Harmit Malik Exit icon set out to conduct an experiment that could solve a century-old evolutionary puzzle: How did two related fruit fly species arise from one? Years after they began their quest, they finally have an answer.

The existence of a gene that helps make each of these fruit fly species unique and separate from each other had been guessed at since 1940, following experiments decades earlier in which geneticists first noticed that the two types of flies, when mated, had only daughters—no sons.

Scientists had previously discovered two other genes involved in driving the fruit fly species apart, but they knew those two genes weren’t the full story. Continue reading

New Views on What the Cell’s Parts Can Do

Studying some of the most well-tread territory in science can turn up surprising new findings. Take, for example, the cell. You may have read in textbooks how the cell’s parts look and function during important biological processes like cellular movement and division. You may have even built models of the cell out of gelatin or clay. But scientists continue to learn new facts that require those textbooks to be updated, and those models to be reshaped. Here are a few examples.

Nuclear Envelope: More Than a Protective Barrier

Damaged heterochromatin represented by nucleotides GCAT
Damaged heterochromatin, a tightly packed form of DNA, travels to the inner wall of the nuclear envelope for repair. Credit: Irene Chiolo and Taehyun Ryu, University of Southern California.

Like a security guard checking IDs at the door, the nuclear envelope forms a protective barrier around the cell’s nucleus, only letting specific proteins and chemical signals pass through. Scientists recently found that this envelope may also act as a repair center for broken strands of heterochromatin, a tightly packed form of DNA.

Irene Chiolo of the University of Southern California and Gary Karpen of the University of California, Berkeley, and the Lawrence Berkeley National Laboratory were part of a team that learned that healthy fruit fly cells mend breaks in heterochromatin by moving the damaged DNA strands to the inner wall of the nuclear envelope. There, proteins embedded in the envelope make the necessary repairs in a safe place where the broken DNA can’t accidentally get fused to the wrong chromosome. Continue reading

Four Ways Inheritance Is More Complex Than Mendel Knew

Original edition of Gregor Mendel’s 1866 publication, Experiments in Plant Hybridization
An original edition of Gregor Mendel’s 1866 publication, “Experiments in Plant Hybridization,” housed in NIH’s National Library of Medicine. Credit: Alisa Machalek.

This year marks the 150th anniversary of Gregor Mendel’s publication that—after sitting ignored for a few decades—helped launch the field of modern genetics. Mendel didn’t know about DNA. But after painstakingly cross-fertilizing tens of thousands of pea plants over the course of 8 years, this Austrian monk came very close to describing genes.

By picking a species with a handful of visible characteristics that occur in two easily identifiable forms, Mendel was able to pinpoint what he called “factors.” These factors determine traits like a pea’s shape or color, for instance, and are passed down from parents to offspring. He also observed that factors can be dominant or recessive.

Today, we know that inheritance is far more complex than what Mendel saw in his pea plants. Here are some of the things scientists have learned about how traits are passed from one generation to the next. Continue reading

Bacterial Biofilms: A Charged Environment

Bacillus subtilis biofilm
A Bacillus subtilis biofilm grown in a Petri dish. Credit: Süel Lab, UCSD.

Last summer, we shared findings from Gürol Süel Exit icon and colleagues at the University of California, San Diego, that bacterial cells in tight-knit microbial communities called biofilms expand in a stop-and-go pattern. The researchers concluded that this pattern helps make food at the nutrient-rich margin available to the cells in the starved center, but they didn’t know how. They’ve now shown that the cells use electrochemical signaling to communicate and cooperate with each other.

Because nutrients and other signals cells use to sense each other and their environment move rather slowly, the researchers looked for a faster, more active communication system in biofilms of the bacterium B. subtilis. They focused on electrical signaling via potassium, a positively charged ion that, for example, our nerve and muscle cells use to send or receive signals. Continue reading

Seeing Telomerase’s ‘Whiskers’ and ‘Toes’

Telomerase and its components.

The image here is the “front view” of telomerase, with the enzyme’s components shown in greater detail than ever before. Credit: UCLA Department of Chemistry and Biochemistry.

Like the features of a cat in a dark alley, those of an important enzyme called telomerase have been elusive. Using a combination of imaging techniques, a research team led by Juli Feigon Exit icon of the University of California, Los Angeles, has now captured the clearest view ever of the enzyme.

Telomerase maintains the DNA at the ends of our chromosomes, known as telomeres, which act like the plastic tips on the ends of shoelaces. In the absence of telomerase activity, telomeres get shorter each time our cells divide. Eventually, the telomeres become so short that the cells stop dividing or die. On the other hand, cells with abnormally high levels of telomerase activity can constantly rebuild their protective chromosomal caps. Telomerase is particularly active within cancer cells. Continue reading

Sharing ‘Behind the Scene’ Stories About Scientific Discoveries

If a picture is worth a thousand words, what’s a video worth? For cell biologist Ron Vale, it’s priceless.

Screen shot from the video
In this iBiology Exit icon “discovery talk,” Ron Vale describes the twists and turns that led him to unexpected findings, including a motor protein involved in important cellular processes.

In 2006, Vale started a video-based science outreach project called iBiology Exit icon to give people around the world broader access to research seminars. The free online videos, which cover a range of biomedical fields and career-related topics, take viewers behind the scenes of scientific findings and convey the excitement of the discovery process.

While geared mostly for undergraduate students, graduate students and postdoctoral researchers, the videos are also a rich resource for anyone who wants a better understanding of many biomedical areas, including those we cover on this blog. Continue reading

From Basic Research to Bioelectronic Medicine

Kevin Tracey
Kevin J. Tracey of the Feinstein Institute for Medical Research, the research branch of the North Shore-LIJ Health System, helped launch a new discipline called bioelectronic medicine. Credit: North Shore-LIJ Studios.

By showing that our immune and nervous systems are connected, Kevin J. Tracey Exit icon of the North Shore-LIJ Health System’s Feinstein Institute for Medical Research helped launch a new discipline called bioelectronic medicine. In this field, scientists explore how to use electricity to stimulate the body to produce its own disease-fighting molecules.

I spoke with Tracey about his research, the scientific process and where bioelectronic medicine is headed next.

How did you uncover the connection between our immune and nervous systems?

My lab was testing whether a chemical we developed called CNI-1493 could stop immune cells from producing inflammation-inducing molecules called TNFs in the brain of rats during a stroke. It does. But we were surprised to find that this chemical also affects neurons, or brain cells. The neurons sense the chemical and respond by sending an electrical signal along the vagus nerve, which runs from the brain to the internal organs. The vagus nerve then releases molecules that tell immune cells throughout the body to make less TNF. I’ve named this neural circuit the inflammatory reflex. Today, scientists in bioelectronic medicine are exploring ways to use tiny electrical devices to stimulate this reflex to treat diseases ranging from rheumatoid arthritis to cancer. Continue reading

5 Reasons Biologists Love Math

Biologists use math in a variety of ways, from designing experiments to mapping complex biological systems. Credit: Stock image.

On Saturday (at 9:26:53 to be exact), math lovers and others around the world will celebrate Pi—that really long number that represents the ratio of the circumference of a circle to its diameter. I asked our scientific experts why math is important to biomedical research. Here are a few reasons.

  1. Math allows biologists to describe how molecules move in and out of cells, how bacteria shuttle through blood vessels, how drugs get broken down in the body and many other physiological processes.
  2. Studying the geometry, topology and other physical characteristics of DNA, proteins and cellular structures has shed light on their functions and on approaches for enhancing or disrupting those functions.
  3. Math helps scientists design their experiments, including clinical trials, so they result in meaningful data, a.k.a statistical significance.
  4. Scientists use math to piece together all the different parts of a cell, an organ or an entire organism to better understand how the parts interact and how perturbations in these complex systems may contribute to disease.
  5. Sometimes it’s impossible or too difficult to answer a research question through traditional lab experiments, so biologists rely on math to develop models that represent the system they’re studying, whether it’s a metastasizing cancer cell or an emerging infectious disease. These approaches allow scientists to indicate the likelihood of certain outcomes as well as refine the research questions.

Want more? Here’s a video with 10 reasons biologists should know some math.

The “Virtuous Cycle” of Technology and Science

A scientist looking through a  microscope. Credit: Stock image.
Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Credit: Stock image.

Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Its central role is particularly clear from this month’s posts.

Some show how different tools led to basic discoveries with important health applications. For instance, a supercomputer unlocked the secrets of a drug-making enzyme, a software tool identified disease-causing variations among family members and high-powered microscopy revealed a mechanism allowing microtubules—and a cancer drug that targets them—to work.

Another theme featured in several posts is novel uses for established technologies. The scientists behind the cool image put a new spin on a long-standing imaging technology to gain surprising insights into how some brain cells dispose of old parts. Similarly, the finding related to sepsis demonstrates yet another application of a standard lab technique called polymerase chain reaction: assessing the immune state of people with this serious medical condition.

“We need tools to answer questions,” says NIGMS’ Doug Sheeley, who oversees biomedical technology research resource grants. “When we find the answers, we ask new questions that then require new or improved tools. It’s a virtuous cycle that keeps science moving forward.”

Meet Rhiju Das

Rhiju Das
Credit: Rhiju Das
Rhiju Das
Fields: Biophysics and biochemistry
Works at: Stanford University
Born and raised in: The greater Midwest (Texas, Indiana and Oklahoma)
Studied at: Harvard University, Stanford University
When he’s not in the lab he’s: Enjoying the California outdoors with his wife and 3-year-old daughter
If he could recommend one book about science to a lay reader, it would be: “The Eighth Day of Creation,” about the revolution in molecular biology in the 1940s and 50s.

At the turn of the 21st century, Rhiju Das saw a beautiful picture that changed his life. Then a student of particle physics with a focus on cosmology, he attended a lecture unveiling an image of the ribosome—the cellular machinery that assembles proteins in every living creature. Ribosomes are enormous, complicated machines made up of many proteins and nucleic acids similar to DNA. Deciphering the structure of a ribosome—the 3-D image Das saw—was such an impressive feat that the scientists who accomplished it won the 2009 Nobel Prize in chemistry.

Das, who had been looking for a way to apply his physics background to a research question he could study in a lab, had found his calling.

“It was an epiphany—it was just flabbergasting to me that a hundred thousand atoms could find their way into such a well-defined structure at atomic resolution. It was like miraculously a bunch of nuts and bolts had self-assembled into a Ferrari,” recounted Das. “That inspired me to drop everything and learn everything I could about nucleic acid structure.”

Das focuses on the nucleic acid known as RNA, which, in addition to forming part of the ribosome, plays many roles in the body. As is the case for most proteins, RNA folds into a 3-D shape that enables it to work properly.

Das is now the head of a lab at Stanford University that unravels how the structure and folding of RNA drives its function. He has taken a unique approach to uncovering the rules behind nucleic acid folding: harnessing the wisdom of the crowd.

Together with his collaborator, Adrien Treuille of Carnegie Mellon University, Das created an online, multiplayer video game called EteRNA Exit icon. More than a mere game, it does far more than entertain. With its tagline “Played by Humans, Scored by Nature,” it’s upending how scientists approach RNA structure discovery and design.

Das’ Findings

Treuille and Das launched EteRNA after working on another computer game called Foldit Exit icon, which lets participants play with complex protein folding questions. Like Foldit, EteRNA asks players to assemble, twist and revise structures—this time of RNA—onscreen.

But EteRNA takes things a step further. Unlike Foldit, where the rewards are only game points, the winners of each round of EteRNA actually get to have their RNA designs synthesized in a wet lab at Stanford. Das and his colleagues then post the results—which designs resulted in a successful, functional RNAs and which didn’t—back online for the players to learn from.

In a paper published in the Proceedings of the National Academy of Sciences Exit icon, Das and his colleagues showed how effective this approach could be. The collective effort of the EteRNA participants—which now number over 100,000—was better and faster than several established computer programs at solving RNA design problems, and even came up with successful new structural rules never before proposed by scientists or computers.

“What was surprising to me was their speed,” said Das. “I had just assumed that it would take a year or so before players were really able to analyze experimental data, make conclusions and come up with robust rules. But it was one of the really shocking moments of my life when, about 2 months in, we plotted the performance of players against computers and they were out-designing the computers.”

“As far as I can tell, none of the top players are academic scientists,” he added. “But if you talk to them, the first thing they’ll tell you is not how many points they have in the game but how many times they’ve had a design synthesized. They’re just excited about seeing whether or not their hypotheses were correct or falsified. So I think the top players truly are scientists—just not academic ones. They get a huge kick out of the scientific method, and they’re good at it.”

To capture lessons learned through the crowd-sourcing approach, Das and his colleagues incorporated successful rules and features into a new algorithm for RNA structure discovery, called EteRNABot, which has performed better than older computer algorithms.

“We thought that maybe the players would react badly [to EteRNABot], that they would think they were going to be automated out of existence,” said Das. “But, as it turned out, it was exciting for them to have their old ideas put into an algorithm so they could move on to the next problems.”

You can try EteRNA for yourself at http://eternagame.org Exit icon. Das and Treuille are always looking for new players and soliciting feedback.