In 2012, deep inside Siberia’s Denisova Cave, Russian archaeologists uncovered a fossil that would forever change what we thought we knew about human evolution. The bone belonged to a girl, later nicknamed “Denny,” who lived around 90,000 years ago. But Denny wasn’t just an ancient human she was something entirely unprecedented.
DNA analysis revealed a stunning truth: Denny was the daughter of two different ancient human species. Her mother was a Neanderthal. Her father? A Denisovan. She’s the first known hybrid of her kind ever discovered a living link between two distinct branches of the human family tree once thought to be separate.
This wasn’t just a rare fossil it was a revelation. Until Denny, Neanderthals and Denisovans were considered distant cousins, each with their own separate story in our evolutionary past. But this find proved they didn’t just coexist they interacted, interbred, and raised families together. That means human evolution wasn’t a straight line it was a tangled web of connections, migrations, and shared moments.
What’s even more incredible? Modern humans today still carry bits of both Neanderthal and Denisovan DNA. That means Denny’s story isn’t just ancient history it’s part of ours.
So next time you hear the term “early human,” remember Denny. She’s not just a fossil—she’s a testament to how fluid, diverse, and interconnected our species truly is. A child of two worlds, and a reminder that even 90,000 years ago, boundaries were meant to be crossed.
Cancer-fighting gene called LIF6 died and rose again during elephants’ evolutionary history
Because animal cells keep dividing over an organism's life, and each division carries the risk of producing a cancerous mutation, it should follow that larger animals with longer life spans are at higher risk of developing cancer. Not for elephants, whose 5500-kilogram bodies have startlingly low rates of cancer, a fact that has puzzled scientists for decades. According to a study published yesterday in Cell Reports, researchers discovered that elephants have extra copies of two cancer-fighting genes: P53, which hunts for cells with miscopied DNA, and LIF6, which obliterates the mutated cells before they can form a tumor. When researchers checked the evolutionary record, they found that LIF6 became inactive in elephant DNA millions of years ago, and then mysteriously came back to life, The New York Times reports. The researchers hope to use the results to find new ways to treat cancer in humans.
What if it was possible to finally understand the inner workings of the human mind? Just think of the potential this new knowledge would have for reducing health care costs, overcoming addiction, improving our happiness and so much more. Get ready, because this site will open your eyes to the incredible technology we all have wired inside of us. As the supervisor of computer aided design for a large defense contractor and one of the designers of the space shuttle guidance and navigation system;
Imagine my surprise when I discovered that the vestibule of our inner ear was actually the same (x-y-z) 3 axis gyro and accelerometer sensor we used to guide the space shuttle.
Overwhelmed and humbled with this knowledge, I started researching the vestibular system from neuroscience research papers I found online. I was blown away with the complexity and design of this incredible sensor. The vestibule was connected to so many different regions of the brain, I needed to create a schematic just to map it. I became frightened when I realized that this technology was more advanced than anything I had worked on in the defense industry. This is 100% advanced engineering we are looking at, not some kind of random design. I could easily understand the engineering design of the vestibule, once I mapped all the connections on paper. Because the vestibule provides the same output as the sensors we designed in the defense industry, we can now better understand the circuitry that is processing this data. Trust me, this level of technology could never create itself, not even in a billion years. Researchers have even pinpointed the exact location in the brain where the vestibule is sending this data to calculate our movement in 3D space.
Researchers have discovered a sophisticated neural computer, buried deep in the cerebellum, that performs inertial navigation calculations to figure out a person's movement through space. "These calculations are no mean feat, emphasized the researchers.. -Brain's Inertial Navigation System Pinpointed: The Cell Press
Little did I know at the time that there was even greater technology I would find. Here are some of the key functions of the vestibule.
Functions of the Vestibule
Controls our balance through the cerebellum and its own spinal tract
Tracks movement through space using grid and place cells to give us our sense of direction
It stabilizes our vision as we move by firing the eye muscles to keep the eye from shaking
Keeps our eyes on a target as our head turns back and forth when we run
Tracks a target moving across our visual field by processing the visual data and firing our eye muscles
Senses all six degrees of freedom, xyz translational and xyz rotational. (see 6 degrees of freedom)
I believe it also can change our visual refresh rate depending on how fast we are moving
This video from a neuroscience site shows how the Vestibular Sensor works, but does not talk about the incredible systems that process the vestibular output. Unlike biologists, I have worked on these systems, so I understand them.
“What I cannot create, I do not understand.” -Physicist Richard P. Feynman
Mapping the vestibule system was just the beginning of the project. Overwhelmed with this new knowledge, I spent the next six years mapping the rest of the brain. Each line on the maps below represents hundreds to millions of parallel connections that can all be backed up by neuroscience research. Each box in the maps represents millions to billions of data processing interneurons in the cortex, processing live data from our senses like a graphics card. Most scientists would have no idea what's really happening in the brain, because it's all electrical engineering. This work provides a window to unlock the hidden mysteries of the brain.
Isaiah 29:14 Therefore once more I will astound these people with wonder upon wonder; the wisdom of the wise will perish, the intelligence of the intelligent will vanish.”
How the Maps Were Created
In order to map the brain so precisely, neuroscientists use various techniques which I will briefly explain here. Using tracers, they inject dye in one region of the brain and the motor proteins of the neurons in that region will carry that chemical down their axons to all the regions that the neuron connects with. Another method would be to use brain scans to monitor what brain regions fire when a subject performs a certain task or views a certain type of image or other sensory input. Researchers typically specialize in just one area of the brain and even spend their entire career on just that one region. So as a design engineer, I was able to use thousands of research papers to construct the maps. From an engineering perspective, we are hi-tech, biological robots with the ability to form our own spirit using the inputs and experiences we receive throughout our life. Words and experiences can change the wiring and affect "who we are". Be sure to check out the End of Evolution page for even greater discoveries that will really blow your mind. Did you know that the brain has a region that recognizes and processes nude body parts and a processing region just for facial recognition? See The Brain section to find out more.
How the Vestibule Proves Man Could Not Evolve
Without the vestibule and all its related processing circuits, we couldn't even stand upright; we couldn't walk; we couldn't hunt for food; we couldn't see straight or even find our way back home. In fact, the vestibule is so important to our survival that mankind could not exist without it. In order for the vestibule to work, the three loops require 90 degree x-y-z construction and the three linear accelerometers also require 90 degree construction to be mathematically functional. So it is impossible for the vestibule to have evolved over time. The vestibule had to be built correctly from the beginning. It also had to be wired with all the electronics required to process the output of the signals, otherwise the sensor would provide no benefit of any kind. I traced all these axon wires through the brainstem, into the cerebellum, then out the spine. There's so much engineering, it's screaming intelligent design. Even Darwin himself said that discoveries like this would prove his theory to be false. So how did this ultra high-tech sensor get into the brains of all humans, animals, birds and reptiles? Frightened that this level of intelligence existed in the universe, I gave up my trust in science and spent the next 6 years wiring up the brain.
The human brain is a highly complex electronics system of over 80 billion neurons making over 60 trillion highly organized connections. Since each connection (or synapse) works like a transistor, we can now estimate the brain's processing power to be more than 34,000 iPhone processors.
It's In Our DNA
Most people might not realize this, but all engineers would know, that building anything this complex takes highly detailed drawings or electronic data and lots of assembly instructions. So where could all this data be stored? It must be in our DNA. Our DNA contains about 16GB of data per strand. All living things begin as one cell with one copy of DNA. The laws of engineering prove that all the instructions to wire up and assemble a human must be contained in that one strand of DNA. We are not talking just "genes" here but point to point wiring instructions for all neurons, bone shape assembly, muscle attachment locations, blood vessel plumbing diagrams and more. The human body is an engineering masterpiece and whoever designed it deserves our highest level of praise. Click here to learn more about DNA and how even Microsoft is using DNA for data storage. Even Ben Franklin did not believe in evolution because he was intelligent enough to observe Wisdom in what was created.
"It is that particular wise and good God, who is the Author and Owner of our (solar) System, that I propose for the Object of my Praise and Adoration.; For I conceive that he has in himself some of those Passions he has planted in us, and that, since he has given us Reason whereby we are capable of observing his Wisdom in the Creation." -Ben Franklin Articles of Belief and Acts of Religion Nov 20, 1728
We now have 100% engineering proof that all this incredible technology is stored in our DNA because, as Ben Franklin said, we can see it in the Creation. Just look at those brain maps and you can now see how our brain works and how organized it really is. Remember that each box on the map contains millions of interneurons that work like integrated circuits to process the information it receives from other regions. The lines you see on the map are just the interconnection between processing regions. There is no way we would be here today if our DNA did not contain all this assembly and wiring data. Can humans really be that gullible to have believed in evolution? Can we really be that blind? Apparently so. Isn't it about time that scientists accept the science? If you still have doubts that mankind is too complex to evolve, you owe it to yourself and your family to study the research on this site. See all the amazing electronic systems I have wired up on the End of Evolution page. Now that we finally have engineering proof that evolution is not possible, what other lies might we be blindly believing? (see the Truth). It seems that the evolution theory was conceived long before Darwin.
Isaiah 29:15-18 Woe to those who go to great depths to hide their plans from the Lord, who do their work in darkness and think, “Who sees us? Who will know?” You turn things upside down, as if the potter were thought to be like the clay! Shall what is formed say to the one who formed it, “You did not make me”? Can the pot say to the potter, “You know nothing”? In that day the deaf will hear the words of the scroll, and out of gloom and darkness the eyes of the blind will see.
And that is the state of the world today; people living in gloom and darkness.
NATIVE RELATIVE This year, scientists analyzed the genetics of Kennewick Man, nearly two decades after the skeleton's discovery. The skull is similar to that of Polynesians, but DNA suggests a link to Native Americans.
DNA analysis shows close ties to present-day groups
Kennewick Man, whose 8,500-year-old skeleton sparked a controversy when it was found in Washington state, was a relative of present-day Native Americans, researchers reported this year. Since the discovery of the skeleton in 1996, Native American tribes have claimed Kennewick Man as their own and requested the bones be handed over for a ceremonial burial. Some scientists argued, though, based on the shape of his skull, that he was more closely related to native Polynesians or a native Japanese group called the Ainu.
Morten Rasmussen of the University of Copenhagen and colleagues wrested DNA from Kennewick Man’s skeleton and analyzed it for the first time. They found that Kennewick Man is more closely related to Native Americans in the northern United States than to any other living population (SN: 7/25/15, p. 6). Two donors who provided modern DNA for comparison came from a tribe that, with four other tribes, lost a 2004 lawsuit to bury Kennewick Man as one of their ancestors.
More work is needed to determine which of today’s Native American tribes, if any, has the closest genetic ties to the ancient American.
DOGS' EARLY DAYS This year, scientists analyzed the DNA from this 35,000-year-old piece of rib bone from an ancient wolf. The results suggest that dogs could have been domesticated as early as 40,000 years ago.
Man’s best friend might be much older than anyone thought.
In May, a genetic analysis of an ancient wolf’s rib bone suggested that wolves and dogs probably split sometime between 27,000 and 40,000 years ago (SN: 6/13/15, p. 10). The new evidence raises the possibility that dog domestication is quite ancient, corresponding roughly in time to the Neandertal extinction. But it’s also possible that these early members of the dog lineage weren’t yet tame or living with humans, says Pontus Skoglund, a geneticist at Harvard Medical School who led the study.
The earliest dog domestication probably occurred near present-day Nepal and Mongolia, Laura Shannon of Cornell University and colleagues wrote in a study published in October (SN: 11/28/15, p. 8). An analysis of 185,805 genetic markers showed that modern dogs from Central Asia are more diverse than dogs elsewhere. Previously proposed regions for early domestication include the Middle East, Europe, North Africa and Siberia.
EPIGENOME DEBUT Chemical modifications to DNA and histones can influence how genes are turned on and off during development and in health and disease. In 2015, scientists cataloged where these marks and other
In a landmark event more than a decade ago, geneticists unveiled the human genetic instruction book. This year, the book was turned into a movie adaptation in 3-D: Researchers cataloged how chemical modifications fold, compress and unwind the static DNA over time and how those modifications control when genes are on or off.
The crew of researchers involved in the Roadmap Epigenomics Project premiered their findings in more than 20 scientific papers published in February (SN: 3/21/15, p. 6).
It was a blockbuster effort that would never make it in Hollywood. For one thing, it largely ignores the stars of the genome, the genes, and instead focuses on a dizzying cast of background characters known as epigenetic marks. The researchers cataloged these marks — chemical modifications either of DNA itself or proteins called histones — in more than 100 types of human cells. The epic effort revealed that gene variants associated with Alzheimer’s disease are more active in immune cells in the brain than in nerve cells as researchers had assumed. Another plot twist: Tightly packed areas of the genome are more vulnerable to cancer-causing mutations.
Like a classic movie in which viewers notice something new with each showing, researchers using data from this project and other efforts to view the genome in 3-D have made startling discoveries (SN: 9/5/15, p. 18). For instance, researchers found that a gene called FTO, thought to be a major genetic contributor to obesity, isn’t involved in fat production. Instead, a genetic variant hiding in the gene’s vicinity actually determines what type of fat the body builds (SN: 9/19/15, p. 6). Disorganized DNA may be a cause of aging, researchers also discovered (see "Not all bodies act their age").
The epigenome movie is sure to spark a series of sequels, each one revealing deeper secrets about human biology and suggesting new ways to improve human health.
GAME OF TAGS By mapping epigenetic marks in 111 types of tissues and cells (some shown here), researchers gained new insights into how the body is built and maintained. Some of these details aren’t captured in studies of DNA alone.
A revolutionary gene-editing technology made headlines this year as much for the ethical and societal issues it raised as for the scientific accomplishments it enabled.
CRISPR (pronounced crisper) burst on the scientific scene in 2012, when researchers transformed what had originally been identified as a rudimentary immune system in bacteria into one of the most powerful tools in molecular biology. Composed of RNA and an enzyme that slices up invading viruses, CRISPR allows researchers to edit nearly any gene in any organism much more precisely and efficiently than older methods.
Many people hope doctors will soon find a way to use the gene editor to fix mutations that cause genetic diseases, a boon for gene therapy. But that potential also comes with big concerns about the possibility of human germline editing — altering eggs, sperm, embryos or other tissue in such a way that the change could be inherited (SN: 5/30/15, p. 16). Those concerns came to the forefront in April when researchers in China announced that they had attempted to use the system to edit nonviable human embryos (SN Online: 4/23/15). The experiment was partially successful, but the team concluded that there are still hurdles to overcome before CRISPR is safe for clinical use. Publication of the paper horrified many in the field who were already calling for a moratorium on human germline editing. The wider public started thinking again about designer babies and a real-world Gattaca.
In early December, an international summit of experts convened by the U.S. National Academies of Sciences and Medicine, the Chinese Academy of Sciences and the United Kingdom’s Royal Society hashed through scientific, ethical and governance issues associated with human gene editing. “We’re on the verge of a technological breakthrough that could change the future of mankind, and we should not blindly charge ahead,” said U.S. Rep. Bill Foster, a member of the House Committee on Science, Space and Technology.
CRISPR is a major improvement over previous gene-editing systems because it doesn’t require researchers to customize proteins for every DNA cut. Instead, researchers design an RNA that binds to the gene to be edited. The RNA guides an enzyme called Cas9 to the gene, where the enzyme snips the DNA. Depending on the goal, the editing system, officially known as CRISPR/Cas9, can disable or repair a gene or paste a new gene in the specified location. Researchers can create a usable CRISPR system in days, compared with weeks or months for other systems, says Mark Osborn, a molecular geneticist at the University of Minnesota Medical School in Minneapolis.
The technology was first described by Jennifer Doudna of the University of California, Berkeley, Emmanuelle Charpentier of the Max Planck Institute for Infection Biology in Berlin and colleagues. But Feng Zhang of the Broad Institute of MIT and Harvard (SN: 10/3/15, p. 20) won the patent rights after submitting evidence that he was the first to devise gene editors based on CRISPR. The researchers’ universities are now embroiled in a lawsuit over who invented the technology first.
Almost immediately after the technology debuted, scientists turned to CRISPR to genetically engineer organisms in the lab, including rhesus macaques, mice, zebrafish, fruit flies, yeast and some plants. In October, researchers reported setting a record for the most genes edited at once (SN: 11/14/15, p. 6). That record — 62 genes — removed viruses embedded in pig DNA to make pig organs safer for human transplants. Chinese researchers announced the same month that they had successfully edited dogs with CRISPR, producing a female beagle with a mutation that resulted in more muscular thighs than her unedited littermates (SN: 11/28/15, p. 16).
CRISPR has also been on the lips of scientists, environmentalists and regulators because of an application of the technology called gene drives — engineered genes designed to break typical inheritance rules and get passed to nearly all of a carrier’s offspring (SN: 12/12/15, p. 16). For more than a decade, scientists have been attempting to construct effective gene drives with the hopes of eradicating mosquito-borne diseases such as malaria and eliminating populations of invasive species. That process becomes much easier with the development of CRISPR.
In March, researchers reported creating a CRISPR gene drive in fruit flies, and in late November and early December, two teams reported the creation of gene drives that could help eradicate malaria. One of the gene drives essentially turns mosquitoes into vaccine distributors for each other; the second sterilizes female mosquitoes (SN Online: 12/7/15). Great promise comes with these developments, but there are also fears that gene drive–altered organisms could escape the lab and infect wild animals or could run amok in other ways. The debates aren’t anywhere near settled. They have barely begun.
Click to Open Overlay GallerySay hello to your little friend ... that lives on your face. USDA
WHEN YOU LOOK in the mirror, you’re not just looking at you—you’re looking at a whole mess of face mites. Yeah, you’ve got ‘em. Guaranteed. The little arachnids have a fondness for your skin, shoving their tubular bodies down your hair follicles, feeding on things like oil or skin cells or even bacteria. The good news is, they don’t do you any harm. The better news is, they’ve got fascinating secrets to tell about your ancestry.
New research out today in the Proceedings of the National Academy of Sciences reveals four distinct lineages of the face mite Demodex folliculorum that correspond to different regions of the world. African faces have genetically distinct African mites, Asian faces have Asian mites, and so too do Europeans and Latin Americans have their own varieties. Even if your family moved to a different continent long ago, your forebears passed down their brand of mites to their children, who themselves passed them on down the line.
Looking even farther back, the research also hints at how face mites hitchhiked on early humans out of Africa, evolving along with them into lineages specialized for certain groups of people around the planet. It seems we’ve had face mites for a long, long while, passing them back and forth between our family members and love-ahs with a kiss—and a little bit of face-to-face skin contact.
Leading the research was entomologist Michelle Trautweinof the California Academy of Sciences, who with her colleagues scraped people’s faces—hey, there are worse ways to make a living—then analyzed the DNA of all the mites they’d gathered. “We found four major lineages,” says Trautwein, “and the first three lineages were restricted to people of African, Asian, and Latin American ancestry.”Click to Open Overlay GalleryTrautwein taking samples at the California Academy of Sciences. CALIFORNIA ACADEMY OF SCIENCES
The fourth lineage, the European variety, is a bit different. It’s not restricted—it shows up in the three other groups of peoples. But Europeans tend to have only European mites, not picking up the mites of African, Asian, or Latin American folks. (It should be noted that the study didn’t delve into the face mites of all the world’s peoples. The researchers didn’t test populations like Aboriginal Australians, for instance, so there may be still more lineages beyond the four.)
So what’s going on here? Well, ever since Homo sapiensradiated out of Africa, those four groups of people have evolved in their isolation in obvious ways, like developing darker or lighter skin color. But more subtly, all manner of microorganisms have evolved right alongside humans. And with different skin types come different environments for tiny critters like mites.
“Some [skin types] do show different levels of hydration, and different levels of oil production, and different density of glands,” Trautwein says. “All kinds of differences.” So African mites may have evolved with uniquely African skin, while on the other side of the globe Latin American mites evolved with Latin American skin. As for those European mites, which show up on faces around the world, their spread is probably a side effect of imperialism and globalization. When Europeans occupied new countries, from Brazil to the Philippines, they brought along their face mites.
The populations of different lineages on our skin, though, are by no means static. Kiss your grandma on the cheek and you could exchange mites. “If you do have multiple people in your family that you spend a lot of time being physically close to, if you have multiple romantic partners across your life, there’s all these different opportunities to be colonized,” says Trautwein. Because families tend to be more kissy with each other than strangers, their blends of mites may persist for generations. But it’s always a give and take, mites coming and going, as cheeks hit cheeks. Out of Africa
Any self-respecting paleoanthropologist will tell you that Homo sapiens got their start in Africa, then exploded across the globe. Wherever humans settled, they evolved differently to fit their environment. So too did their face mites. And while scientists can’t go and sequence the DNA from a face mite attached to an early human, they’ve got a trick for figuring out how these organisms’ genes have changed over expanses of evolutionary time.
Click to Open Overlay GalleryThat tubular body fits nicely in your hair follicles. USDA
The raw fuel of evolution is the mutation, which bestows an organism with a characteristic that’s either positive, neutral, or negative in regards to surviving and passing down its genes (a slightly different coloration, for example, that helps it better blend in with its surroundings). And these mutations tend to crop up at a certain rate as a species reproduces. “Because we have some understanding about how frequently DNA changes over time, how many mutations occur over time,” says Trautwein, “we can add a molecular clock to that and put a date on how long it’s taken for these changes to emerge.”
Comparing the DNA of the four lineages of face mite, the researchers determined that the varieties started diverging from each other between 2.4 million and 3.8 million years ago, right around the same time that our genus Homo was coming up in the world. And among the lineages, the African and Asia brands appear to be the oldest, in keeping with the idea that humans first evolved in Africa, then moved into Asia and onwards.
“It’s certainly not that we acquired these mites in the last 10,000 years, or that we got them from domesticated animals or anything like that,” Trautwein says. “It seems like these are really old splits, which means that these mites have been living with humans for all of our history, if not before.”
As humans evolved into the plethora of peoples we know today, the mites evolved along with us as our little facial companions. “The fact that they’re evolving on our face brings home this idea that evolution isn’t this distant thing that happened in the past, or that’s happening out there to something else,” Trautwein says. “But it’s happening right here under our noses.”
This year's Nobel Prize in chemistry was given to three scientists who each focused on one piece of the DNA repair puzzle. Now a new study, reported online Oct. 28 in the journal Nature, reports the discovery of a new class of DNA repair enzyme. When the structure of DNA was first discovered, scientists imagined it to be extremely chemically stable, which allowed it to act as a blueprint for passing the basic traits of parents along to their offspring. Although this view has remained prevalent among the public, biologists have since learned that the double helix is in fact a highly reactive molecule that is constantly being damaged and that cells must make unceasing repair efforts to protect the genetic information that it contains.
"It's a double-edged sword," said Brandt Eichman, associate professor of biological sciences and biochemistry at Vanderbilt University, who headed the research team that made the new discovery. "If DNA were too reactive then it wouldn't be capable of storing genetic information. But, if it were too stable, then it wouldn't allow organisms to evolve."
The DNA double-helix has a spiral staircase structure with the outer edges made from sugar and phosphate molecules joined by stair steps composed of pairs of four nucleotide bases (adenine, cytosine, guanine and thymine) that serve as the basic letters in the genetic code.
There are two basic sources of DNA damage or lesions: environmental sources including ultraviolet light, toxic chemicals and ionizing radiation and internal sources, including a number of the cell's own metabolites (the chemicals it produces during normal metabolism), reactive oxygen species and even water.
"More than 10,000 DNA damage events occur each day in every cell in the human body that must be repaired for DNA to function properly," said first author Elwood Mullins, a postdoctoral research associate in the Eichman lab.
The newly discovered DNA repair enzyme is a DNA glycosylase, a family of enzymes discovered by Tomas Lindahl, who received this year's Nobel prize for recognizing that these enzymes removed damaged DNA bases through a process called base-excision repair. It was the first of about 10 different DNA repair pathways that biologists have identified to date.
In base-excision repair, a specific glycosylase molecule binds to DNA at the location of a lesion and bends the double-helix in a way that causes the damaged base to flip from the inside of the helix to the outside. The enzyme fits around the flipped out base and holds it in a position that exposes its link to the DNA's sugar backbone, allowing the enzyme to detach it. After the damaged base has been removed, additional DNA-repair proteins move in to replace it with a pristine base.
Eichman and his collaborators discovered that a glycosylase called AlkD found in Bacillus cereus - a soil-dwelling bacterium responsible for a type of food poisoning called the "fried rice syndrome" - works in a totally different fashion. It does not require base flipping to recognize damaged DNA or repair it.
Seven years ago, Eichman's group discovered that AlkD had a structure unlike any of the other glycosylases. The researchers determined that the enzyme was able to locate damaged DNA that has a positive electrical charge. This is the signature of alkylation, attaching chains of carbon and hydrogen atoms of varying lengths (methyl, ethyl etc.), to specific positions on the damaged base. Positively charged alkylated bases are among the most abundant and detrimental forms of DNA damage. However, they are highly unstable, which has made them very difficult to study.
Now the researchers have captured crystallographic snapshots of AlkD in the act of excising alkylation damage and have shown that the enzyme doesn't use base flipping. Instead, they have determined that AlkD forms a series of interactions with the DNA backbone at and around the lesion while the lesion is still stacked in the double helix. Several of these interactions are contributed by three amino acids in the enzyme that catalyze excision of the damaged base.
According to the researchers, the AlkD mechanism has some remarkable properties:
It can recognize damaged bases indirectly. AlkD identifies lesions by interacting with the DNA backbone without contacting the damaged base itself.
It can repair many different types of lesions as long as they are positively charged. By contrast, the base-flipping mechanism used by other glycosylases relies on a relatively tight binding pocket in the enzyme, so each glycosylase is designed to work with a limited number of lesions. AlkD doesn't have the same type of pocket so it isn't restricted in the same way. Instead, the catalytic mechanism that AlkD uses is limited to removing positively charged lesions.
It can excise much bulkier lesions than other glycosylases. Base excision repair is generally limited to relatively small lesions. A different pathway, called nucleotide excision repair, handles larger lesions like those caused by UV radiation damage. However, Eichman's team discovered that AlkD could excise extremely bulky lesions, such as the one caused by the antibiotic yatakemycin, which is beyond the capability of other glycosylases.
"Our discovery shows that we still have a lot to learn about DNA repair, and that there may be alternative repair pathways yet to be discovered. It certainly shows us that a much broader range of DNA damage can be removed in ways that we didn't think were possible," said Eichman. "Bacteria are using this to their advantage to protect themselves against the antibacterial agents they produce. Humans may even have DNA-repair enzymes that operate in a similar fashion to remove complex types of DNA damage. This could have clinical relevance because these enzymes, if they exist, could be reducing the effectiveness of drugs designed to kill cancer cells by shutting down their ability to replicate."
Co-authors of the paper are graduate student Rongxin Shi and Postdoctoral Research Associate Zack Parsons from the Eichman Lab, Professor Sheila David and graduate student Philip Yuen from University of California, Davis and Professor Yasuhiro Igarashi from Toyama Prefectural University.
The research was supported by National Science Foundation grants MCB-1122098 and MCB-1517695 and National Institutes of Health grants R01ES01625 and R01CA067985.
Drug companies are exploiting rare mutations that make one person nearly immune to pain, another to broken bones byCaroline Chen
Steven Pete can put his hand on a hot stove or step on a piece of glass and not feel a thing, all because of a quirk in his genes. Only a few dozen people in the world share Pete’s congenital insensitivity to pain. Drug companies see riches in his rare mutation. They also have their eye on people like Timothy Dreyer, 25, who has bones so dense he could walk away from accidents that would leave others with broken limbs. About 100 people have sclerosteosis, Dreyer’s condition.
Both men’s apparent superpowers come from exceedingly uncommon deviations in their DNA. They are genetic outliers, coveted by drug companies Amgen, Genentech, and others in search of drugs for some of the industry’s biggest, most lucrative markets.
Illustration: Stephanie Davidson
Their genes also have caused the two men enormous suffering. Pete’s parents first realized something was wrong when, as a teething baby, their son almost chewed off his tongue. “That was a giant red flag,” says Pete, now 34 and living in Kelso, Wash. It took doctors months to figure out he had congenital insensitivity to pain, caused by two different mutations, one inherited from each parent. On their own, the single mutations were benign; combined, they were harmful.
Dreyer, who lives in Johannesburg, was 21 months old when his parents noticed a sudden facial paralysis. Doctors first diagnosed him with palsy. Then X-rays revealed excessive bone formation in his skull, which led to a diagnosis of sclerosteosis. Nobody in Dreyer’s family had the disorder; his parents both carried a single mutation, which Dreyer inherited.
Dreyer and Pete are “a gift from nature,” says Andreas Grauer, global development lead for the osteoporosis drug Amgen is creating. “It is our obligation to turn it into something useful.”
What’s good for patients is also good for business. The painkiller market alone is worth $18 billion a year. The industry is pressing ahead with research into genetic irregularities. The U.S. Food and Drug Administration is expected to approve a cholesterol-lowering treatment on July 24 from Sanofi and Regeneron Pharmaceuticals based on the rare gene mutation of an aerobics instructor with astoundingly low cholesterol levels. Amgen has a similar cholesterol drug, based on the same discovery, and expects U.S. approval in August. The drugs can lower cholesterol when statins alone don’t work. They are expected to cost up to $12,000 per patient per year and bring in more than $1 billion annually.
Drugmakers are also investing in acquisitions and partnerships to get their hands on genetic information that could lead to more drugs. Amgen bought an Icelandic biotechnology company, DeCode Genetics, for $415 million in 2012, to acquire its massive database on more than half of Iceland’s adult population. Genentech is collaborating with Silicon Valley startup 23andMe, which has sold its $99 DNA spit kits to 1 million consumers who want to find out more about their health and family history—more than 80 percent have agreed to have their data used for research. The Genentech partnership will study the genetic underpinnings of Parkinson’s disease. And Regeneron has signed a deal with Pennsylvania’s Geisinger Health System to sequence the genes of more than 100,000 volunteers.
Underlying this is the plummeting cost of gene sequencing. It took $3 billion and 13 years, from 1990 to 2003, to sequence the first human genome. The cost today is as low as $1,000 a patient, making it viable to sequence large numbers of people and discover relationships between genes and symptoms.
The researchers who study outliers are often the first to realize the potential power behind a mutation. In 2010, Socrates Papapoulos, a professor of medicine at the Leiden University Medical Center in the Netherlands, visited an isolated Dutch community where much of the population had overgrown skulls and abnormally large bones. At a town meeting, he asked if anyone had been in a major car accident. One man raised his hand. “He said, ‘I was crossing the street with my brother, and a Mercedes was coming, and I didn’t have time to move,’ ” Papapoulos says. “And I said, ‘What happened?’ and he said, ‘You should have seen the Mercedes.’ ”
Amgen realized that if researchers could mimic the effects of the genetic mutation, they could encourage bone growth strong enough to counter osteoporosis. People with sclerosteosis lack a protein that acts as a brake on bone growth. Without that protein, bones grow abnormally thick. It stood to reason, researchers thought, that a drug that could block the protein in patients with osteoporosis would encourage bone regrowth.
Amgen’s scientists created hundreds of antibodies that they tested to determine which might be able to get in the way of the protein. It took them three and a half years of research before they were able to identify the best antibody to inhibit the protein. Then NASA came calling.
In 2010 the space agency, preparing for its final space shuttle mission, was looking for promising research projects. It invited Amgen to test the drug’s ability to stop the loss of bone mass often seen during spaceflight. Amgen sent 30 mice on the Atlantis shuttle. Half got the drug, romosozumab. After 13 days, the injected mice had gained bone mineral density as the control group’s bones weakened.
Amgen has run two human trials since 2006. It is conducting two final-stage trials, with the first batch of results expected in early 2016. If the drug works as well as promised, it could bring Amgen $1 billion to $2 billion in sales per year, says Cowen Group analyst Eric Schmidt.
Illustrator: Stephanie Davidson
Unlike sclerosteosis patients, people such as Pete who don’t feel pain have no outward physical features that give them away. Instead, researchers have stumbled upon them more or less by chance. A research article on families in Pakistan came after the discovery of a 10-year-old boy who as a street performer stabbed himself with knives and walked on burning coals.
Xenon Pharmaceuticals, a small Canadian biotech, started studying more than a decade ago families who showed similar pain-free traits and tracked down the gene responsible, which regulates a pathway in the body called the Nav 1.7 sodium ion channel. With just a few dozen employees, Xenon turned for development help to Genentech, which is owned by Roche, and its 1,200 research and development scientists.
“The beauty of the phenotype is that you’re largely normal,” says Morgan Sheng, Genentech’s vice president for neuroscience, referring to how the genes are manifested in an individual. “You want to just prevent pain and not cause a bunch of other problems,” he says. The only other effect typically seen is a loss of the sense of smell.
The promise of the Nav 1.7 channel is to create an entirely new class of painkiller. Options on the market are all problematic. Opioids, such as morphine, are addictive, while nonsteroidal anti-inflammatory drugs, such as ibuprofen, are ineffective with severe pain and can cause gastrointestinal side effects including bleeding. Genentech is still in the earliest stage of clinical trials, and it could take more than five years before a drug is released.
While outliers may hold the secret to curing the ills of the rest of humanity, there is no profit motive to find treatments for their aberrant sufferings. The market is too small, even though their suffering is real. Pete’s left leg is permanently damaged from years of injuries he couldn’t feel, and he lives with the anxiety that he could overlook a severe illness, such as appendicitis, whose major symptom is pain. He regularly participates in research studies and says he wants to contribute to scientists’ knowledge to help them develop better painkillers. “Before a lot of us participated in these projects, very little about pain itself was known,” he says.
Excessive bone growth in Dreyer’s skull has led to multiple operations to relieve pressure on cranial nerves and the brain, though ultimately the surgeries were unable to prevent hearing loss.
Dreyer, a Ph.D. student in paraclinical science at the University of Pretoria, isn’t waiting for Big Pharma to come to his rescue. For his Ph.D. project, he’s researching treatments for his own disease and hopes to raise 2 million rand ($162,000) to fund his work. “There are thousands of people suffering from osteoporosis, so developing a treatment for them is great,” he says. “That being said, I do think it would be nice if they could help us out now that they understand our disease and are able to use it for their treatments.”
The bottom line: Genentech and Amgen are studying rare gene mutations to create blockbuster drugs for pain and osteoporosis.
Click to Open Overlay GallerySay hello to your little friend ... that lives on your face. USDA
Click to Open Overlay GalleryTrautwein taking samples at the California Academy of Sciences. CALIFORNIA ACADEMY OF SCIENCES
Click to Open Overlay GalleryThat tubular body fits nicely in your hair follicles. USDA
