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The Amazing Reality of Genes and The History of Scientific Inquiry

Posted on March 4, 2017  Comments (4)

cover of The Gene

The Gene by Siddhartha Mukherjee is a wonderful book. He does a great job of explaining the history of scientists learning about genes as well as providing understandable explanations for the current scientific understanding of genes and how they impact our lives.

As I have mentioned before, I find biology fascinating even though I found biology classes utterly boring and painful. I wish everyone could learn about biology with the insight people like Siddhartha Mukherjee provide. I realize not everyone is going to find the history and understanding of genes to be fascinating but for those who might this book is a great read. And don’t rule the idea out just because you found biology classes painful.

Life may be chemistry, but it’s a special circumstance of chemistry. Organisms exist not because of reactions that are possible, but because of reactions that are barely possible. Too much reactivity and we would spontaneously combust. Too little, and we would turn cold and die. Proteins enable these barely possible reactions, allowing us to live on the edges of chemical entropy – skating perilously, but never falling in.
– page 134

Whether it is the physics of our solar system or our biology there is a precarious band that allowed beings such as ourselves to evolve.

most genes, as Richard Dawkins describes them, are not “blueprints” but “recipes.” They do not specify parts, but processes; they are formulas, not forms. If you change a blueprint, the final product is change in a perfectly predictable manner: eliminate a widget specified in the plan, and you get a machine with a missing widget. But alteration of a recipe or formula doesn’t not change the product in a predictable manner: if you quadruple the amount of butter in a cake, the eventual effect is more complicated than just a quadruply buttered cake (try it; the whole thing collapses in an oily mess).
– page 454

The is a powerful idea. And when combined with turning genes on and off it is understandable how complex determining genetic impacts on biology and disease are. A few diseases or results (e.g. blue eyes) are nearly as simple as 1 or a few genes being altered in a specific way but most are not nearly so easy. And it isn’t like even that is so easy but with the amazing efforts scientists have made and the advanced tools those scientists created it can now seem simple to identify some such diseases.

The genetic code is universal. A gene from a blue whale can be inserted into a microscopic bacterium and it will be deciphered accurately and with near perfect fidelity. A corollary: there is nothing particularly special about human genes.
– page 480

This is something I have known and understood but it is still amazing. Genes and proteins and how they act to create the incredible diversity of life is something that is awe inspiring.

This book is a wonderful adventure for those interested in life and scientific inquiry.

Related: Epigenetics, Scientific Inquiry and Uncertainty – Human Gene Origins: 37% Bacterial, 35% Animal, 28% Eukaryotic – Unexpected Risks Found In Editing Genes To Prevent Inherited Disorders – Epigenetic Effects on DNA from Living Conditions in Childhood Persist Well Into Middle Age – Why Don’t All Ant Species Replace Queens in the Colony, Since Some Do

Defying Textbook Science, Study Finds Proteins Built Without DNA Instructions

Posted on January 3, 2015  Comments (2)

Open any introductory biology textbook and one of the first things you’ll learn is that our DNA spells out the instructions for making proteins, tiny machines that do much of the work in our body’s cells. Results from a recent study show for the first time that the building blocks of a protein, called amino acids, can be assembled without blueprints – DNA and an intermediate template called messenger RNA (mRNA). A team of researchers has observed a case in which another protein specifies which amino acids are added.

“This surprising discovery reflects how incomplete our understanding of biology is,” says first author Peter Shen, Ph.D., a postdoctoral fellow in biochemistry at the University of Utah. “Nature is capable of more than we realize.”

To put the new finding into perspective, it might help to think of the cell as a well-run factory. Ribosomes are machines on a protein assembly line, linking together amino acids in an order specified by the genetic code. When something goes wrong, the ribosome can stall, and a quality control crew is summoned to the site. To clean up the mess, the ribosome is disassembled, the blueprint is discarded, and the partly made protein is recycled.

Yet this study reveals a surprising role for one member of the quality control team, a protein conserved from yeast to man named Rqc2. Before the incomplete protein is recycled, Rqc2 prompts the ribosomes to add just two amino acids (of a total of 20) – alanine and threonine – over and over, and in any order. Think of an auto assembly line that keeps going despite having lost its instructions. It picks up what it can and slaps it on.

“In this case, we have a protein playing a role similar to that filled by mRNA,” says Adam Frost, M.D., Ph.D., assistant professor at University of California, San Francisco (UCSF) and adjunct professor of biochemistry at the University of Utah. He shares senior authorship with Jonathan Weissman, Ph.D., a Howard Hughes Medical Institute investigator at UCSF, and Onn Brandman, Ph.D., at Stanford University. “I love this story because it blurs the lines of what we thought proteins could do.”

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Cell Aging and Limits Due to Telomeres

Posted on March 17, 2013  Comments (2)

When cells divide the process fails to copy DNA all the way to the end. Telomeres are are the end of DNA strands, as essentially a buffer of material that won’t cause information to be lost when part of the telomere isn’t copied. As DNA is copied, as new cells are created, the length of telomeres at the end is reduced. Once the telomeres are gone the cell will no longer divide.

The 2009 Nobel Prize in Physiology or Medicine went to 3 scientists for discovering how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. The Nobel Laureates have shown that the solution is to be found in the ends of the chromosomes – the telomeres – and in an enzyme that forms them – telomerase.

There is some debate over the benefit of the mechanism of cells not dividing do to lack of telomere. This can prevent cancerous cells from replicating (once they replicate to the extent that the necessary telomere buffer is gone). It is also seen that as telomeres get shorter the cells become more likely to become cancerous.

Cancer also can stimulate the production of telomerase which can stop telomeres from getting shorter as cells divide and thus allow the cancer cells to keep dividing (thus producing more cancer cell and increasing the amount of cancerous cells). Using telomerase to allow health cells to avoid the limits of division is being researched.

Are Telomeres the Key to Aging and Cancer? (University of Utah)

An enzyme named telomerase adds bases to the ends of telomeres. In young cells, telomerase keeps telomeres from wearing down too much. But as cells divide repeatedly, there is not enough telomerase, so the telomeres grow shorter and the cells age.
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Cells normally can divide only about 50 to 70 times, with telomeres getting progressively shorter until the cells become senescent, die or sustain genetic damage that can cause cancer.
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shorter telomeres are associated with shorter lives. Among people older than 60, those with shorter telomeres were three times more likely to die from heart disease and eight times more likely to die from infectious disease.

While telomere shortening has been linked to the aging process, it is not yet known whether shorter telomeres are just a sign of aging – like gray hair – or actually contribute to aging.

Related: The Naked Mole Rat is the Only Known Cancerless Animal – Webcast of a T-cell Killing a Cancerous Cell – RNA interference webcast

Synthetic Biologists Design a Gene that Forces Cancer Cells to Commit Suicide

Posted on September 4, 2011  Comments (2)

Killing a cancer cell from the inside out

To create their tumor-killing program, the researchers designed a logic circuit — a system that makes a decision based on multiple inputs. In this case, the circuit is made of genes that detect molecules specific to a type of cervical cancer cell. If the right molecules are present, the genes initiate production of a protein that stimulates apoptosis, or programmed cell death. If not, nothing happens.

Because the genes used to create the circuits can be easily swapped in and out, this approach could also yield new treatments or diagnostics for many other diseases, according to Ron Weiss, an MIT associate professor of biological engineering and one of the leaders of the research team. “This is a general technology for disease-state detection,” he says.
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the researchers created a synthetic gene for a protein, called hBax, that promotes cell death. They designed the gene with two separate safeguards against the killing of healthy, non-HeLa cells: It can be turned off by high levels of microRNAs that are ordinarily low in HeLa, and can also be deactivated by low levels of microRNAs that are normally plentiful in HeLa. A single discrepancy from the target microRNA profile is enough to shut off production of the cell-death protein.

If all microRNA levels match up with the HeLa profile, the protein is produced and the cell dies. In any other cell, the protein never gets made, and the synthetic genes eventually break down.

More very cool research. It is exciting to see how much can be done when we invest in science and engineering research. Of course the path from initial research to implemented solutions is long and complex and often fails to deliver on the initial hopes. But some remarkable breakthroughs achieve spectacular results that we benefit from every day.

Related: Cancer Vaccines – Researchers Find Switch That Allows Cancer Cells to Spread – Global Cancer Deaths to Double by 2030 – Cloned Immune Cells Clear Patient’s Cancer

MIT Scientists Find New Drug That Could Cure Nearly Any Viral Infection

Posted on August 17, 2011  Comments (1)

New drug could cure nearly any viral infection

The drug works by targeting a type of RNA produced only in cells that have been infected by viruses. “In theory, it should work against all viruses,” says Todd Rider, a senior staff scientist in Lincoln Laboratory‘s Chemical, Biological, and Nanoscale Technologies Group who invented the new technology.
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There are a handful of drugs that combat specific viruses, such as the protease inhibitors used to control HIV infection, but these are relatively few in number and susceptible to viral resistance.

Rider drew inspiration for his therapeutic agents, dubbed DRACOs (Double-stranded RNA Activated Caspase Oligomerizers), from living cells’ own defense systems. When viruses infect a cell, they take over its cellular machinery for their own purpose — that is, creating more copies of the virus. During this process, the viruses create long strings of double-stranded RNA (dsRNA), which is not found in human or other animal cells.

As part of their natural defenses against viral infection, human cells have proteins that latch onto dsRNA, setting off a cascade of reactions that prevents the virus from replicating itself. However, many viruses can outsmart that system by blocking one of the steps further down the cascade.

Rider had the idea to combine a dsRNA-binding protein with another protein that induces cells to undergo apoptosis (programmed cell suicide) — launched, for example, when a cell determines it is en route to becoming cancerous. Therefore, when one end of the DRACO binds to dsRNA, it signals the other end of the DRACO to initiate cell suicide.

Combining those two elements is a “great idea” and a very novel approach, says Karla Kirkegaard, professor of microbiology and immunology at Stanford University. “Viruses are pretty good at developing resistance to things we try against them, but in this case, it’s hard to think of a simple path pathway to drug resistance,” she says.

Each DRACO also includes a “delivery tag,” taken from naturally occurring proteins, that allows it to cross cell membranes and enter any human or animal cell. However, if no dsRNA is present, DRACO leaves the cell unharmed.

Very cool stuff and potentially hugely beneficial. Just a reminder: this works against viruses – not bacteria (just as antibiotics do not work against viruses).

image showing the results of cultures treated with DRACO v. those not treated

Related: Science Explained: RNA Interference – 8 Percent of the Human Genome is Old Virus Genes – Virus Engineered To Kill Deadly Brain Tumors
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Changing Life as We Know It

Posted on December 2, 2010  Comments (1)

Update: Independent researchers find no evidence for arsenic life in Mono Lake

NASA has made a discovery that changes our understanding of the very makeup of life itself on earth. I think my favorite scientific discipline name is astrobiology. NASA pursues a great deal of this research not just out in space but also looking at earth based life. Their astrobiology research has changed the fundamental knowledge about what comprises all known life on Earth.

photo of Felisa Wolfe-Simon

Felisa Wolfe-Simon processing mud from Mono Lake to inoculate media to grow microbes on arsenic.

Carbon, hydrogen, nitrogen, oxygen, phosphorus and sulfur are the six basic building blocks of all known forms of life on Earth. Phosphorus is part of the chemical backbone of DNA and RNA, the structures that carry genetic instructions for life, and is considered an essential element for all living cells.

Phosphorus is a central component of the energy-carrying molecule in all cells (adenosine triphosphate) and also the phospholipids that form all cell membranes. Arsenic, which is chemically similar to phosphorus, is poisonous for most life on Earth. Arsenic disrupts metabolic pathways because chemically it behaves similarly to phosphate.

Researchers conducting tests in the harsh, but beautiful (see photo), environment of Mono Lake in California have discovered the first known microorganism on Earth able to thrive and reproduce using the toxic chemical arsenic. The microorganism substitutes arsenic for phosphorus in its cell components.

“The definition of life has just expanded,” said Ed Weiler, NASA’s associate administrator for the Science Mission Directorate. “As we pursue our efforts to seek signs of life in the solar system, we have to think more broadly, more diversely and consider life as we do not know it.” This finding of an alternative biochemistry makeup will alter biology textbooks and expand the scope of the search for life beyond Earth.

In science such huge breakthroughs are not just excepted without debate, however, which is wise.

Thriving on Arsenic:

In other words, every experiment Wolfe-Simon performed pointed to the same conclusion: GFAJ-1 can substitute arsenic for phosphorus in its DNA. “I really have no idea what another explanation would be,” Wolfe-Simon says.

But Steven Benner, a distinguished fellow at the Foundation for Applied Molecular Evolution in Gainesville, FL, remains skeptical. If you “replace all the phosphates by arsenates,” in the backbone of DNA, he says, “every bond in that chain is going to hydrolyze [react with water and fall apart] with a half-life on the order of minutes, say 10 minutes.” So “if there is an arsenate equivalent of DNA in that bug, it has to be seriously stabilized” by some as-yet-unknown mechanism.

It is sure a great story if it is true though. Other scientists will examine more data and confirm or disprove the claims.

“We know that some microbes can breathe arsenic, but what we’ve found is a microbe doing something new — building parts of itself out of arsenic,” said Felisa Wolfe-Simon, a NASA Astrobiology Research Fellow in residence at the U.S. Geological Survey in Menlo Park, Calif., and the research team’s lead scientist. “If something here on Earth can do something so unexpected, what else can life do that we haven’t seen yet?”
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A Breakthrough Cure for Ebola

Posted on May 31, 2010  Comments (0)

A breakthrough cure for Ebola By Steven Salzberg

Last week, in what may be the biggest medical breakthrough of its kind in years, a group of scientists published results in The Lancet describing a completely new type of anti-viral treatment that appears to cure Ebola. They report a 100% success rate, although admittedly the test group was very small, just 4 rhesus monkeys.

This is a breakthrough not only because it may give us a cure for an uncurable, incredibly nasty virus, but also because the same method might work for other viruses, and because we have woefully few effective antiviral treatments. We can treat bacterial infections with antibiotics, but for most viruses, we have either a vaccine or nothing. And a vaccine, wonderful as it is, doesn’t help you after you’re already infected.

The scientists, led by Thomas Geisbert at Boston University, used a relatively new genomics technique called RNA interference to defeat the virus. Here’s how it works.
First, a little background: the Ebola virus is made of RNA, just like the influenza virus. And just like influenza, Ebola has very few genes – only 8. One of its genes, called L protein, is responsible for copying the virus itself. Two others, called VP24 and VP35, interfere with the human immune response, making it difficult for our immune system to defeat the virus.

Geisbert and his colleagues (including scientists from Tekmira Pharmaceuticals and USAMRIID) designed and synthesized RNA sequences that would stick to these 3 genes like glue. How did they do that? We know the Ebola genome’s sequence – it was sequenced way back in 1993. And we know that RNA sticks to itself using the same rules that DNA uses. This knowledge allowed Geisbert and colleagues to design a total of 10 pieces of RNA (called “small interfering RNA” or siRNA) that they knew would stick to the 3 Ebola genes. They also took care to make sure that their sticky RNA would not stick to any human genes, which might be harmful. They packaged these RNAs for delivery by inserting them into nanoparticles that were only 81-85 nanometers across.
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Related: Science Explained: RNA Interference – Amazing Science: Retroviruses – Ebola Outbreak in Uganda (Dec 2007)

Protein Synthesis: 1971 Video

Posted on December 2, 2009  Comments (2)

The above webcast shows protein synthesis, from a 1971 Stanford University video with Paul Berg (Nobel Laureate – 1980 Nobel Prize for Chemistry and National Medal of Science in 1983). The film does not exactly present the traditional scientist stereotype. It does pretty much present the typical California 1970’s hippie stereotype though.

Related: Friday Fun – CERN Version – Roger Tsien Lecture On Green Florescent Protein

Image of Viral Coat

Posted on March 23, 2009  Comments (0)

image of exterior of virus - made up of 5 million atomsHigh-energy X-ray diffraction was used to pinpoint some 5 million atoms in the protective protein coat of the PsV-F virus. The coat’s symmetrical features are shared by hundreds of viruses. The red and yellow sections illustrate how building blocks of four proteins come together to form the spherical shell.

The image reveals the structure of a type of protein coat shared by hundreds of known viruses containing double-stranded RNA genomes. The image was painstakingly created from hundreds of high-energy X-ray diffraction images and paints the clearest picture yet of the viruses’ genome-encasing shell called a “capsid.”

Viruses can reproduce themselves only by invading a host cell and highjacking its biochemical machinery. But when they invade, viruses need to seal off their genetic payload to prevent it from being destroyed by the cell’s protective mechanisms. Though there are more than 5,000 known viruses, including whole families that are marked by wide variations in genetic payload and other characteristics, most of them use either a helical or a spherical capsid.

“Spherical viruses like this have symmetry like a soccer ball or geodesic dome,” Pan said. “The whole capsid contains exactly 120 copies of a single protein.” Previous studies had shown that spherical capsids contain dozens of copies of the capsid protein, or CP, in an interlocking arrangement. The new research identified the sphere’s basic building block, a four-piece arrangement of CP molecules called a tetramer, which could also be building blocks for other viruses’ protein coats.

Full press release

Related: Viruses and What is Life – Viruses Eating Bacteria – MRI That Can See Bacteria, Virus and Proteins – Finding the Host Genes Viruses Require

MicroRNAs Emerged Early in Evolution

Posted on October 2, 2008  Comments (1)

New Research Shows MicroRNAs Emerged Early in Evolution

“MicroRNAs have been available to regulate and shape gene expression as far back as we can go in animal evolution—they might even predate animals,” says Bartel, a leader in the discovery and functional study of microRNAs. “They might have helped to usher in the era of multi-cellular animal life.”

First discovered in 1993, microRNAs are strands of RNA that are 21-24 nucleotides in length. They dampen gene expression by intercepting messenger RNA before it can turn the cellular crank that translates a gene into a protein. Earlier, Bartel’s research team showed that each microRNA can regulate the expression of hundreds of genes.

The ability of microRNAs to silence gene expression likely evolved from a more ancient defense against viruses, bacteria, and other mobile genetic elements that can mutate host DNA.
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The scientists determined that the starlet sea anemone has both microRNAs and piRNAs. In addition, the anemone makes proteins resembling those that interact with these small RNAs in humans. Both types of small RNA were also found in the sponge. The third target of their search, Trichoplax, did not contain any microRNAs, though Bartel suspects they may have existed in ancestral forms and later disappeared.

Related: Scientists discover new class of RNA – RNA related posts – Nobel Prize in Chemistry – 2006

Learning How Viruses Evade the Immune System

Posted on July 24, 2008  Comments (2)

photo of Naama Elefant

MicroRNA genes are a class of very tiny genes found in a variety of organisms. First discovered in 1993 and at the time considered relatively unimportant, they are now recognized as major players in diverse biological processes.

MicroRNAs are important regulators of protein production. Proteins, the building blocks of the cell, must be produced precisely at the right time and place. MicroRNAs specifically latch on to other genes (their targets) and inhibit the production of the protein products of these genes. Hundreds of microRNAs have already been discovered, but the identity of their target genes remains mostly unknown and presents a great challenge in the field.

Elefant developed a computer algorithm that predicts the targets of microRNAs. Her algorithm, named RepTar, searches the thousands of genes in the human genome and through sequence, structural and physical considerations detects matches to hundreds of microRNAs.

For her work in this field, Naama Elefant, a student of Prof. Hanah Margalit of the Faculty of Medicine at the Hebrew University and an Azrieli fellow, was named one of this year’s winners of the Barenholz Prizes for Creativity and Originality in Applied Computer Science and Computational Biology. This discovery also was declared by the magazine Nature Medicine as ”one of the ten notable advances of the year 2007.”
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