The uptake of fluorescein-labeled peptides into cells via endocytosis at 5 microM peptide (top) and independent of endocytosis at 20 microM peptide (bottom)   Courtesy of Roland Brock

The-Scientist.com, February 15, 2010, by Bob Grant  —  Describing how peptides and proteins traverse cell membranes is huge in the field of cell biology. Peptides, short chains of amino acids, could one day be used as molecular ferries transporting therapeutic genes or proteins across lipid bilayers and directly into the cytosol, where many crucial biochemical pathways start. But the journey from outside a cell to the cytoplasm is no small feat for bulky peptides—researchers have been trying to map the various routes for decades.

Since the early 1990s, researchers studying how cell-penetrating peptides, which include some transcription factors and parts of viruses, gain access to the inside of cells have focused on different modes of endocytosis—where cells encapsulate extracellular material in membrane-bound vesicles and import them. Several flavors of endocytosis exist, from macropinocytosis, where cells gulp in large amounts of extracellular fluid containing macromolecules in solution, to uptake mediated by membrane proteins or lipids.

In 2007, a paper published by European researchers seemed to quell the debate over which mode of uptake was most important for peptides entering cells. Roland Brock, a cell biologist at the Nijmegen Centre of Molecular Life Sciences in the Netherlands and senior author on the paper, showed three different peptides entering human cells by simultaneously using three separate pathways: macropinocytosis and two modes that depend on membrane proteins and/or lipids.

“[The paper] in a way released the field” from arguing about which mode of endocytic uptake was most important, says Brock. “Everyone was very happy because everyone felt represented in this paper.”

“It’s obviously one of the most comprehensive studies in this field,” says Stockholm University biochemist Ülo Langel, who was not involved with the study. “The data are very trustable.”

But Brock and his colleagues noted something even more interesting: at higher extracellular peptide concentrations, the macromolecules made their way into cells via an endocytic-independent pathway. It appeared that the peptides were permeating directly into the cell’s cytoplasm. “For us, this was actually the most exciting finding,” Brock recalls. And one with potential clinical significance, since it would make it easier to deliver drug molecules directly to cytoplasm if they didn’t have to escape from vesicles that are formed during endocytosis.

This finding has not been as universally well received, and continues to stoke debate 2 years after it was published. To this day, some scientists claim that peptides didn’t enter cells independent of endocytosis and any finding that suggests otherwise was an artifact, while others are accepting the finding and trying to pinpoint the molecular mechanism behind it.

Not so fast

Some researchers maintain that Brock’s finding of endocytosis-independent entry represents an artifact of extremely high peptide concentrations outside the cell, rather than some novel mechanism of cellular uptake. Steve Dowdy, a cell biologist at the University of California, San Diego, says Brock and his colleagues were likely seeing peptides fill the cytoplasm of cells because at high concentrations—20 micromolar—molecules were in essence “blowing out a hole” in the membrane and allowing the peptides to rush in. This, Dowdy notes, makes this mode of peptide entry unacceptable for potential therapeutic use. “It’s literally destroying the membrane,” he says. “You can’t punch holes in membranes and not have some consequences for the cell.”

“We were certainly confronted with this concern during the submission process,” Brock admits. “We never claimed that this direct membrane permeation may be therapeutically relevant. We just said it was interesting.”

Other labs, working independently of Brock’s, observed similar phenomena around the same time. Arwyn Jones, cell biologist at Cardiff University’s Welsh School of Pharmacy, and his colleagues exposed the cells to peptide concentrations up to 12.5 micromolar, and observed endocytosis-independent uptake without any apparent damage to the cells (Biochem J, 403:335–42, 2007). “The cells look very healthy, and they live, and they divide, and there is no sign that there is a problem with them,” says Jones.

M. Cristina Cardoso, a cell biologist at the Max Delbrück Center for Molecular Medicine in Berlin, agrees that Brock’s observation of the nonendocytic uptake was valid. Cardoso’s lab published a recent paper corroborating the nonendocytic uptake pathway in mouse cells where modes of endocytic uptake were blocked by chemical inhibitors (J Biol Chem, 284:3370–78, 2009). “I truly believe that the data on nonendocytic uptake is absolutely correct,” she says.

Towards therapy

Even if the endocytosis-independent uptake noted by Brock and others is a valid biological phenomenon, using cell-penetrating peptides in a therapeutic context is far from becoming a reality. Brock’s study, like many others that support his findings, use peptides carrying fluorescent tags, which lets them track movement. But in a clinical setting, peptides would have to carry drugs or genetic molecules, which are much bigger. “If you want to deliver things with these cell-penetrating peptides, then the cargo has to be significantly larger,” Jones says.

A bevy of labs is trying to pinpoint the molecular mechanism that is at play in endocytosis-independent entry. Jones suggests that a membrane potential gradient might be “pulling” peptides into cells at high concentrations. Others suggest the existence of transient pores that are opened in specific extracellular conditions. Brock claims that his group has created a knockout mouse that does not show the nonendocytic uptake, suggesting a single enzyme mediates this peptide transduction, but declines to provide more information before publishing.

Jones says that researchers should continue studying all peptide uptake pathways for their potential use in delivering therapies. “What we need to do,” Jones says, “is learn more from these systems.”

Read more: The Path Less Traveled – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/2010/2/1/45/1/#ixzz0fjdzWdfR

By Mehmet Oz MD and Michael Roizen MD  —  “Wow, that’s really low.” We hear that a lot when we tell people what their blood pressure should be. National medical groups recommend keeping blood pressure at or below 120/80, but there’s plenty of evidence that scooching down to 115/76 is even better, and that’s where we YOU Docs want to see yours. In one landmark study, people with a blood pressure of 120/80 or below had half as many cardiovascular events (meaning heart attacks, strokes, and heart failure) as those whose blood pressure was just a little bit higher. And heart risk falls to that of someone much younger as blood pressure falls to . . . you guessed it . . . 115/76.

High blood pressure is the single biggest cause of arterial aging — and, trust us, you want young arteries. The most effective ways to stop that aging process and hit your blood pressure numbers are weight loss, healthful eating (enjoy colorful veggies, shun saturated and trans fats; avoid added simple sugars and syrups, eat only grains that are 100% whole), and daily physical activity. In fact, just 30 minutes of walking three times a week can drop blood pressure 5 points in 12 weeks. Get even more benefit: Add 30 minutes of resistance exercises and 60 minutes of stamina training (swimming or cycling) a week, and call a buddy regularly to destress.

What about medications? In our own practices, we start you on drugs until you reach 125/82 or lower, and then we back off as long as you stay under those numbers. It’s not that hard: About 60% of people who do not want to be on blood pressure drugs can get off of them — and attain that ideal 115/76 — with lifestyle changes. 

………………………………………………………………………………………..

Read more by Mehmet Oz MD and Michael Roizen…………….

A little fresh-fruit snack may put you on the fast track to better blood flow.

People in a study experienced better blood flow in their brachial arteries just 3 hours after eating the equivalent of one and a quarter cups of grapes. At 60 calories a delicious cup, that’s a pretty juicy deal.

Boundless Benefits
The blood flow benefits were even better after 3 weeks of consistent eating. Researchers think it may be the antioxidants in grapes that help keep blood vessels relaxed and blood flowing freely. In fact, grapes may even help protect your blood vessels from fatty meals — something that normally does immediate, transient damage. And early animal research suggests that something in grapes may help protect your blood pressure from salty foods, too..

Reality Check
Of course, no single food will make your heart and arteries impervious to the perils of a bad diet. So in addition to fresh fruit like antioxidant-rich grapes, feed your heart what it really wants, including:

  • Garlic, olive oil, and dark chocolate.
  • Oatmeal with strawberries and (advice from Target Health Global…….or blueberries or red grapes.)
  • A couple of shakes of cinnamon each day.. Cinnamon, researchers have discovered, has potent antioxidant properties, most likely due to the heart-healthy phenols in the spice. To help protect yourself against heart disease, occasionally indulge in a cup of hot cocoa, latte, or mulled cider with ground cinnamon sprinkled on top.  And, (advice from Target Health Global) sprinkle cinnamon on your oatmeal, each morning.

………………………………………………………………………………………………………………………………

More advice from Mehmet Oz MD and Michael Roizen MD……………….

It’d be nice if there were such a thing as mental Viagra — just swallow a pill and get a little brain boost when you need it. But the verdict’s still out on many pills, supplements, and vitamins that purport to make your memory stronger. Here’s our take on the ones that get most of the attention:

Pill Recommended by the YOU Docs? The Fine Print
Aspirin Yes Research shows a 40% decrease in arterial aging — a major cause of memory loss — for people who take 162 milligrams (mg) of aspirin a day. Science isn’t sure how it protects against memory loss, but it may be because aspirin helps reduce gunky beta-amyloid proteins from clogging up your brain, and it improves circulation.
Vitamin E Yes — in your diet, ideally People who consume high amounts of vitamin E are 43% less likely to develop Alzheimer’s. You can get the vitamin E you need by eating just 3 ounces (15 mg) of nuts or seeds a day, which is the method we prefer. Alternatively, you can take a supplement of 400 international units (IU) daily if you take it with vitamin C and are not taking a statin drug, such as Lipitor.
Vitamins B6, B12, and folic acid Yes Without B vitamins, your neurotransmitters don’t work efficiently. To compound the problem, without B vitamins, your homocysteine levels rise, and that doubles the risk of developing Alzheimer’s. Although there’s no scientific evidence that shows B supplements benefit the thinking process, the products are generally safe, and anecdotal evidence is enticing. We recommend a daily supplement with 400 micrograms (mcg) of folic acid, 800 mcg of B12, and 40 mg of B6.
Acetyl L-carnitine/alpha-lipoic acid Not yet There are lots of strong theoretical reasons why this should enhance brain health — specifically, by improving mitochondrial activity and reducing decay, resulting in higher neurotransmitter function — but there’s not enough evidence showing effectiveness in humans.
Rosemary, roses, and mint Yes Not to ingest, but to smell. Research suggests that inhaling any of these three aromas at the time of learning a new task can enhance recall when you’re exposed to the scent at a later time.
Ginkgo biloba If you want to Though there are no large studies to support its use, there’s some promise that this very commonly used supplement may be effective in helping to improve cognition. It can also thin the blood, which can be beneficial to folks with blood vessel disease but dangerous for those who are anticipating surgery or who have a clotting disorder. Because it’s considered a safe antioxidant supplement, we’re comfortable with you trying 120 mg daily to see if it has any positive effects.
Huperzine A Maybe This ancient Chinese herb was used for memory loss even before we learned that it increases levels of acetylcholine, a chemical that transmits information between nerve cells. If you have mild cognitive impairment, we recommend 200 mcg twice daily and suggest that your doctor help adjust the dose if other pharmaceuticals with similar effects are being used.
Vinpocetine No There’s not enough evidence that this supplement — from a periwinkle plant — helps memory, and it can reduce your blood pressure too much, so we would rather wait for more clinical trials.
Phosphatidylserine If you want to About 70% of our cell membranes are made from phosphatidylserine, and as we age, the level drops, and the membranes become brittle. This supplement seems to strengthen cell membranes and the sheathing around the nerves, protecting the information-transferring cables from shorting out. Since risks are few, taking 200 mg daily is reasonable.
Coenzyme Q10 Yes, but for other reasons This supplement has a beneficial effect in protecting against Parkinson’s disease (a neural disease that can be caused by trauma, as in the case of boxers, or through viruses and genetics). A potent antioxidant, coenzyme Q10 may help prevent inflammatory damage to the brain, but this remains unproven. The ideal dose is 100 mg twice a day (some research says that 300 mg four times a day is even better). But be warned: This is one supplement where more than 90% of what’s sold doesn’t contain the real thing, so look for products that have been shown repeatedly to contain what’s on the label. Check this Web site: www.consumerlab.com

…………………………………………………………………………………………………………………………………

More advice from Mehmet Oz MD and Michael Roizen MD…………………………

Your first line of sleep therapy should be our Deep Sleep Plan, but some people may need medications or herbal supplements. Despite the fact that 35 million prescriptions for sleep medicine were written in the United States in 2005 (twice as many as in 2000), many docs don’t prescribe medications that are intended to get at the source of the problem. This guide will help you and your doctor make the decision that’s right for you.

Is This You? Try Why
You’re just beginning to experience some mild sleep problems Benadryl This nonaddictive over-the-counter (OTC) option contains an ingredient that makes you groggy (it’s also the ingredient in many sleep medications). If you don’t have pain or other symptoms, stick to straight Benadryl. Otherwise, you can add an OTC painkiller. Downside: You may feel groggy in the morning and suffer memory problems. If so, stop using the medication.
You’re jet-lagged, or your work schedule varies frequently. Melatonin Available in health-food stores, this supplement helps reset your body clock and is a first-line therapy for travel-related sleep issues. The dose varies between 0.5 and 5 milligrams, so you’ll have to experiment with dosing to see what works best for you.
You’ve had sleep issues over an extended period of time. Ambien, Ambien CR, Lunesta, or Rozerem This long-acting prescription will give you less of a hangover than other drugs, but some docs believe it is addictive. The controlled-release (CR) version will give you a boost after 4 hours in order to avoid middle-of-the-night awakening. Lunesta works like Ambien but is thought to be nonaddictive. Rozerem works like melatonin, in our opinion, and it is nonaddictive.
You wake up in the middle of the night. Sonata This fast-acting hypnotic drug, available by prescription, is good if you wake up in the middle of the night, because it’s quickly effective and won’t last all night. It works to get you back to sleep, but it will not keep you asleep.
You can’t fall asleep because you’re worried or depressed. Desyrel (trazodone) This antidepressant is less expensive than some of the popular sleep drugs, and it’s actually one of the most frequently prescribed sleep medications because it’s effective and nonaddictive. One side effect for men: priapism (maintaining an erection for a lot longer than you want). Amitriptyline, an older antidepressant, may also be effective, but it has caused constipation in our patients.
You kick so much that you’re considering trying out for the Chicago Bears. Requip This drug helps with restless legs syndrome (RLS). But another option is just drinking a little diet tonic water at dinner. It contains quinine — an ingredient that helps quiet muscle cramps.

(Getty Images)

New Diagnostic and Statistical Manual of Mental Disorders Makes Changes to Eating and Gambling Disorders But Leaves Sex Alone
 

ABCNews.go.com/Health, February 15, 2010, by John Gever  —  Substantial changes are in the offing for the “psychiatrist’s bible,” the Diagnostic and Statistical Manual of Mental Disorders, according to a draft of the forthcoming fifth edition.

The American Psychiatric Association (APA) posted the draft of DSM-V on a special Web site, www.dsm5.org, to obtain comment from its members, other members of the mental health community, and the public.

At a telephone press briefing prior to the draft’s release, members of the APA team leading the DSM revision highlighted several substantial innovations they are proposing:

Re-categorizing learning disorders, including creation of a single diagnostic category for autism and other socialization disorders, and replacing the controversial term “mental retardation” with “intellectual disability”

Eliminating “substance abuse” and “substance dependence” as disorders, to be replaced with a single “addiction and related disorders” category

Creating a “behavioral addictions” category that will include addictions to gambling but not to the Internet or sex

Offering a new assessment tool for suicide risk

Including a category of “risk syndromes” for psychosis and cognitive impairment that are intended to capture mild versions of these conditions that do not always progress to full-blown psychotic disorders or dementia, but often do

Adding a new disorder in children, “temper dysregulation with dysphoria,” for persistent negative mood with bursts of rage

Revising criteria for some eating disorders, including creation of a separate “binge eating disorder” distinct from bulimia

Using “dimensional assessments” to account for severity of symptoms, especially those that appear in multiple diagnostic categories

The APA will accept comments through April 20. The work groups managing the revision will consider them and make further changes as needed to the draft, said Dr. David Kupfer, of the University of Pittsburgh and chairman of the DSM-V task force.

The draft diagnostic criteria will then undergo two years of field testing. The final DSM-V is scheduled for release in May 2013, a year later than originally planned.

In the area of neurodevelopmental disorders, DSM-V will put dyslexia and dyscalculia — reflecting disabilities of reading and mathematics, respectively — into a new category of learning disabilities.

Autism, Asperger’s syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified will make up the new “autism and related disorders” category.

The head of the APA’s work group on substance-related disorders, Dr. Charles O’Brien, of the University of Pennsylvania, told reporters on the press call that substance dependence and abuse had no basis in the research on addictions.

“We unanimously agreed that& there really isn’t evidence for an intermediate stage [short of addiction] that is now known as abuse,” he said. Instead, there will be substance use disorders for each of the major types of drugs that cause problems, such as alcohol.

He added that the term “dependence” was problematic as a psychiatric diagnosis because some types of physical dependence are “completely normal” for some medications, such as opioid painkillers.

In fact, under the draft the DSM-V will include “discontinuation syndromes” to allow physicians to properly assess symptoms of withdrawal from psychoactive substances which include caffeine, O’Brien said.

He also said his work group had considered including sex and Internet addictions as disorders, but decided there was insufficient evidence to develop reliable diagnostic criteria for them. Consequently, gambling addiction is slated to be the only disorder formally listed in the behavioral addictions category.

But O’Brien added that under current plans, sex and Internet addiction would be included in an appendix to DSM-V, intended to encourage additional research that could lead to their inclusion in future editions.

APA leaders also emphasized the two new suicide risk assessment scales planned for DSM-V, one for adolescents and one for adults.

Dr. David Shaffer, of Columbia University, told reporters on the press call that suicide nearly always occurs in the context of some psychiatric disorder, but not always depression.

The new risk assessment tools focus on risk factors such as impulsive behavior, heavy drinking, and chronic severe pain and illness.

In DSM-IV, suicidal ideation is treated as a symptom of major depression and certain other disorders.

Shaffer also explained the genesis of the proposed new childhood disorder, temper dysregulation with dysphoria (TDD).

“About 40 percent to 60 percent of the cases [seen by child psychiatrists] will be children who are doing things that other people don’t want them to do,” he said. Many of these are children who are “stubborn and resistant and disobedient and moody.”

There is currently a recognized syndrome known as oppositional defiant disorder, but some children also display severe aggression and negative moods that go beyond mere stubbornness, according to Shaffer.

Such children are often tagged as having juvenile bipolar disorder, but research has shown that the label is often inappropriate, since they usually do not qualify for a bipolar disorder diagnosis when they reach adulthood, though they remain dysfunctional. More often, these children are diagnosed as depressed when they become adults.

He said the addition of TDD would better describe the severity and frequency of irritable behavior while also recognizing the mood disorder that goes with it.

Another innovation in DSM-V will be the extensive use of so-called dimensional assessments. Whereas DSM-IV relied heavily on present-absent symptom checklists, the new edition will include severity scales for symptoms such as anxiety or insomnia that may appear to larger or smaller degrees in many different mental illnesses.

Dr. Darrel Regier, the APA’s research director, said such checklists “don’t always fit the reality that someone with a mental disorder experiences.” Often, a symptom like insomnia isn’t on the checklist for a particular disorder, he said, “but they can still affect patients’ lives and affect the treatment planning.”

Incorporating quantitative dimensional assessments should allow clinicians to develop treatment and response-monitoring plans better tailored to individual patients’ needs, Regier said.

A closely watched issue in the DSM-V revision has been whether to change or do away with gender identity disorder, now listed in DSM-IV. At this point, the draft retains the designation but with some changes, officials said.

People who consider themselves “transgendered” have long criticized DSM-IV and previous editions for labeling them with a mental disease when their problems, they believe, are purely somatic — that is, they have the wrong genitalia and hormonal balance.

At the APA’s annual meeting last May, members of the transgender community made a case for dropping gender identity disorder from DSM-V, but keeping some kind of “gender variance” diagnosis as a medical condition. Such an approach would eliminate the stigma of a psychiatric diagnosis while leaving a pathway for third-party (insurance) payment for gender transition treatments, they said.

Dr. William Narrow, the APA’s research director for DSM-V, told reporters that the draft does remove the term “disorder” from the condition when applied to children, renaming it as “gender incongruence.”

For adults, gender identity disorder will remain in DSM-V but with substantially altered diagnostic criteria, Narrow said.

But APA officials said the organization planned more discussions with members of the transgender community.

Kupfer, the DSM-V task force chairman, stressed that further changes in many diagnostic categories are likely following the comment period and field trials. Final revisions will be submitted in 2012 for approval by the APA’s two governing bodies, the Assembly and the board of trustees.

Artist’s impression of a Neanderthal hunter. New evidence suggests the Neanderthals and modern humans interbred.

Credit: American Museum of Natural History 

 

GoogleNews.com, February 16, 2010  —  As scientists come closer to completing a draft sequence of the Neanderthal genome, creating a living person from an ancient DNA sequence is becoming a real possibility, claims Archaeology Magazine.

As scientists come closer to completing a draft sequence of the Neanderthal genome, creating a living person from an ancient DNA sequence is becoming a real possibility, according to Archaeology Magazine.

In 2005, 454 Life Sciences began a project with the Max Planck Institute to sequence the genetic code of a 30,000 year old Neanderthal woman. Now nearly complete, the sequence will let scientists look at the genetic blueprint of humankind’s nearest relative, understand its biology and maybe even create a living person.

The work is possible today thanks to vast increases in computing power over the past few years. 454’s Thomas Jarvie told the magazine, “Six years ago if you wanted to sequence E. coli… it would have taken one or maybe two million dollars, and it would have taken a year and 150 people. Nowadays, one person can do it in two days.”

The restoration of DNA tens of thousands of years old has been challenged by chemical changes, breakdown of the biological matter and contaminants. And once the DNA sequencing is complete, creating a clone from it is still an inexact science. 

Some scientists believe that by making changes to the DNA inside a human cell — thousands or even millions of changes, that is — the human genome can be altered to match the recreated Neanderthal one. One cell is just a step towards  a living creature, but it’s a key one. 

Advances in stem cell science have led to proposals to alter a stem cell’s DNA to match the Neanderthal genome. That stem cell would be left to reproduce, creating a colony of cells that could be programmed to become any type of cell that existed in the Neanderthal’s body — even an entire person. Archaeology cites Robert Lanza, biotech firm Advanced Cell Technology‘s chief science officer, who notes that species such as cows and goats are now routinely cloned with few problems. 

There are many technical obstacles, but it’s reasonable to suppose that scientists could soon use that long-extinct genome to safely create a healthy, living Neanderthal clone. But should it be done? 

That’s the question that inspired author Zach Zorich to dig into the issue. He points out that legal precedents are on the side of Neanderthal human rights, noting that such a creature would deserve human rights. 

“I’ve been following Neanderthal gene research for years, and it started to dawn on me that all of these decades-old academic questions about how Neanderthals were related to modern humans might suddenly have human rights implications,” he told FoxNews.com.

“My hope is that the article will get people to think about what it is that makes us human beings so that there is a larger and better informed debate about how our society should proceed with cloning genetics research.”

Read more about this fascinating story, below………..

The scientific, legal, and ethical obstacles…………. 

The 50,000-year-old skull of a Neanderthal from the site of Shanidar in Iran (top) has a prominent browridge and more projecting face than the 40,000-year-old Homo sapiens skull found at Pestera cu Oase in Romania. (Erik Trinkaus)

 

Should We Clone Neanderthals?

Archaeology.org, March/April 2010, by Zach Zorich — If Neanderthals ever walk the earth again, the primordial ooze from which they will rise is an emulsion of oil, water, and DNA capture beads engineered in the laboratory of 454 Life Sciences in Branford, Connecticut. Over the past 4 years those beads have been gathering tiny fragments of DNA from samples of dissolved organic materials, including pieces of Neanderthal bone. Genetic sequences have given paleoanthropologists a new line of evidence for testing ideas about the biology of our closest extinct relative.

The first studies of Neanderthal DNA focused on the genetic sequences of mitochondria, the microscopic organelles that convert food to energy within cells. In 2005, however, 454 began a collaborative project with the Max Planck Institute in Leipzig, Germany, to sequence the full genetic code of a Neanderthal woman who died in Croatia’s Vindija cave 30,000 years ago. As the Neanderthal genome is painstakingly sequenced, the archaeologists and biologists who study it will be faced with an opportunity that seemed like science fiction just 10 years ago. They will be able to look at the genetic blueprint of humankind’s nearest relative and understand its biology as intimately as our own.

In addition to giving scientists the ability to answer questions about Neanderthals’ relationship to our own species–did we interbreed, are we separate species, who was smarter–the Neanderthal genome may be useful in researching medical treatments. Newly developed techniques could make cloning Neanderthal cells or body parts a reality within a few years. The ability to use the genes of extinct hominins is going to force the field of paleoanthropology into some unfamiliar ethical territory. There are still technical obstacles, but soon it could be possible to use that long-extinct genome to safely create a healthy, living Neanderthal clone. Should it be done?

At the 454 Life Sciences offices, Gerald Irzyk, Jason Affourtit, and Thomas Jarvie explain the process they use to read the chemicals that made up Neanderthal DNA and the genes that determined a large part of their biology. DNA has a shape, called a double helix, that makes it look like a twisted ladder. Each rung on the ladder is called a base-pair. The rungs are made up of a pair of chemicals called nucleotides–adenine, thymine, cytosine, and guanine, which are usually referred to by their first initials. The sequence of the nucleotides in the DNA determines what genes an organism has and how they function.

Although most of the Neanderthal genome sequencing is now being done by the San Diego-based company Illumina, the Max Planck Institute initially chose 454 because it had come up with a way to read hundreds of thousands of DNA sequences at a time. Genome-sequencing technology is advancing at a rate comparable to computer processing power. “Six years ago if you wanted to sequence E. coli [a species of bacteria], which is about 4 million base-pairs in length, it would have taken one or maybe two million dollars, and it would have taken a year and 150 people,” says Jarvie. “Nowadays, one person can do it in two days and it would cost a few hundred dollars.”

Putting the fragments themselves in order can be a little tricky. “At first glance, it’s just this completely random assemblage of As, Ts, Cs, and Gs,” says Irzyk. “But it turns out there are patterns and motifs, and sometimes these are very specific to a group of organisms.” For the Neanderthal sample, the human and chimpanzee genomes were used as references for checking the sequence.

Working with ancient DNA can be much more problematic than sequencing genetic material from living species. Within hours of death, cells begin to break down in a process called apoptosis. The dying cells release enzymes that chop up DNA into tiny pieces. In a human cell, this means that the entire three-billion-base-pair genome is reduced to fragments a few hundred base-pairs long or shorter. The DNA also goes through chemical changes that alter the nucleotides as it ages–C changes into T, and G turns into A–which can cause the gene sequence to be interpreted incorrectly. In the case of the Neanderthal sample, somewhere between 90 and 99 percent of the DNA came from bacteria and other contaminants that had found their way into the bone as it sat in the ground and in storage. The contaminant DNA has to be identified and eliminated. Given the similarity between Neanderthal and modern human DNA, this can be especially difficult when the contamination comes from the people who excavated or analyzed the bone.

Neanderthals and Homo sapiens were in contact for 5,000 to 7,000 years. Both lived in the same type of environments, but our species had a competitive advantage that gradually forced Neanderthals to the edges of Europe. These maps show the range of Neanderthals (left) and Homo sapiens (right) between 38,600 and 36,500 years ago. By this time, Neanderthals had been crowded out of Europe except the Iberian peninsula. The orange and gray areas were suitable for habitation. The white circles are archaeological sites. (Courtesy William Banks)

According to Stephan Schuster, a geneticist at the Pennsylvania State University, the first draft of the Neanderthal genome is likely to contain many errors. He estimates that getting a completely accurate DNA sequence will require taking five separate samples from the same individual, and sequencing that genome 30 times.

Schuster sequenced the mammoth genome in 2007, and that approach might work for large animals, but taking five samples from a single Neanderthal would require the destruction of a large amount of valuable bone. Carles Lalueza-Fox, a paleogeneticist at Spain’s University of Barcelona, believes the accuracy of the DNA could be checked by resequencing dozens or hundreds of times the areas of the Neanderthal genome that seem likely to have errors.

Cloning a Neanderthal will take a lot more than just an accurately reconstructed genome. Artificially assembling an exact copy of the Neanderthal DNA sequence could be done easily and cheaply with current technology, but a free-floating strand of DNA isn’t much good to a cell. “The bigger challenge is–how do you assemble a genome without a cell?” asks James Noonan, a geneticist at Yale University. “How do you package DNA into chromosomes, and get that into a nucleus? We don’t know how to do that.” The shape of the DNA within the chromosomes affects the way that genes interact with chemicals inside the cell. Those interactions control when, how much, and what types of proteins a cell’s DNA produces. Those proteins are the building blocks of an organism, so the way a genome expresses itself is as important as the DNA. According to Schuster and Lalueza-Fox, the cellular damage that occurs after death makes it impossible to understand Neanderthal gene expression. This could mean that making a clone identical to someone who lived 30,000 years ago is impossible.

“If your experiment succeeds and you generate a Neanderthal who talks, you have violated every ethical rule we have, and if your experiment fails…well. It’s a lose-lose.”—James Noonan

One way to get around the problems of working with an artificial genome would be to alter the DNA inside a living cell. This kind of genetic engineering can already be done, but very few changes can be made at one time. To clone a Neanderthal, thousands or possibly millions of changes would have to be made to a human cell’s DNA. George Church, a professor of genetics at Harvard Medical School, is part of a research team that is developing a technique to make hundreds of alterations to a genome at the same time. The technique, multiplex automated genome engineering (MAGE), uses short strands of DNA called oligonucleotides to insert pieces of artificial genetic material into a cell’s genome at specifically targeted sites. MAGE has been used successfully to make 24 alterations to the genomes of bacteria, mice, and, more recently, human cells. Church estimates that it would take about 10 million changes to make a modern human genome match the Neanderthal genome. Accomplishing this would be a matter of drastically scaling up the technique.

Church believes the place to start with Neanderthal cloning is on the cellular level, creating liver, pancreas, or brain cells. “You can’t really tell anything from just looking at the gene sequence,” he says. “It’s hard to predict physical traits; you have to test them in living cells.” Neanderthal cells could be important for discovering treatments to diseases that are largely human-specific, such as HIV, polio, and smallpox, he says. If Neanderthals are sufficiently different from modern humans, they may have a genetic immunity to these diseases. There may also be differences in their biology that lead to new drugs or gene therapy treatments.

So far, efforts to revive extinct species using cloning have a dismal track record. On January 6, 2000, a violent storm in northern Spain caused a tree branch to fall on Celia, the last Pyrenean Ibex, crushing her skull. That would seem like a clear indication that the ibex’s evolutionary luck had run out, but a tissue sample taken from Celia’s ear provided DNA that a team of Spanish scientists used to reconstruct 439 eggs. Only 57 developed into embryos, 52 did not survive the full term of the pregnancy, four were stillborn, and the one clone that survived birth died of lung failure within hours of delivery.

The ibex clones were created using techniques pioneered by Advanced Cell Technology, a biotechnology company in Worcester, Massachusetts. The technique, called nuclear transfer, involves removing the nucleus, the part containing the cell’s genetic material, of a donor egg cell and replacing it with a nucleus containing clone DNA. In the ibex’s case, goat eggs were used because the species are closely related and goats have been successfully cloned many times, explains Robert Lanza, ACT’s chief scientific officer. According to Lanza, species such as cows and goats are now routinely cloned with few problems.

Excavators in Spain’s El Sidrön cave wear “clean-room” suits to keep their DNA from contaminating Neanderthal bones. (Courtesy Carles Lalueza-Fox)

Species that have not been repeatedly cloned still face risks. The nuclear transfer process disrupts the cell and often causes it to die. The number of sick and dead individuals produced by nuclear transfer cloning is the reason nearly all scientists are opposed to human reproductive cloning. But even if nuclear transfer cloning could be perfected in humans or Neanderthals, it would likely require a horrifying period of trial and error. There is, however, another option.

The best way to clone Neanderthals may be to create stem cells that have their DNA. In recent years, geneticists have learned how to take skin cells and return them to a state called pluripotency, where they can become almost any type of cell in the human body. Church proposes to use the MAGE technique to alter a stem cell’s DNA to match the Neanderthal genome. That stem cell would be left to reproduce, creating a colony of cells that could be programmed to become any type of cell that existed in the Neanderthal’s body. Colonies of heart, brain, and liver cells, or possibly entire organs, could be grown for research purposes.

This technique could also be used to create a person. A stem cell with Neanderthal DNA could be implanted in a human blastocyst–a cluster of cells in the process of developing into an embryo. Then, all of the non-Neanderthal cells could be kept from growing. The individual who developed from that blastocyst would be entirely the result of Neanderthal genes. In effect, it would be a cloned Neanderthal. Church believes that after the earliest stages of development, the genes would express themselves as they did in the original individual, eliminating any influences from the modern human or chimpanzee cell.

The technique is new, and has only been tested in mice so far, but Church thinks it might work in humans. However, he points out that anyone cloned by this process would still be lacking the environmental and cultural factors that would have influenced how the original Neanderthals grew up. “They would be something new,” Church says, “neo-Neanderthals.”

In northern Spain 49,000 years ago, 11 Neanderthals were murdered. Their tooth enamel shows that each of them had gone through several periods of severe starvation, a condition their assailants probably shared. Cut marks on the bones indicate the people were butchered with stone tools. About 700 feet inside El Sidrön cave, a research team including Lalueza-Fox excavated 1,700 bones from that cannibalistic feast. Much of what is known about Neanderthal genetics comes from those 11 individuals.

Lalueza-Fox does not plan to sequence the entire genome of the El Sidrön Neanderthals. He is interested in specific genes. “I choose genes that are somehow related to individuality,” he says. “I’d like to create a personal image of these guys.” So far, his work has shown that Neanderthals had a unique variant of the gene for pale skin and red hair, which may mean their skin and hair color differed from modern humans. Lalueza-Fox tested the blood types of two Neanderthals and found they were both type O. He also discovered that modern humans and Neanderthals share a version of a gene called FOXP2, which is associated with language ability and means that Neanderthals probably spoke their own languages.

The Neanderthals broke away from the lineage of modern humans around 450,000 years ago. They evolved larger brains and became shorter than their likely ancestor, Homo heidelbergensis. They also developed a wider variety of stone tools and more efficient techniques for making them. On average, Neanderthals had brains that were 100 cubic centimeters (about 3 ounces) larger than those of people living today. But those differences are likely due to their larger overall body size. Those large brains were housed inside skulls that were broader and flatter, with lower foreheads than modern humans. Their faces protruded forward and lacked chins. Their arms and the lower part of their legs were shorter than modern humans’, making them slower and less efficient runners, but they also had more muscle mass. Their bones were often thicker and stronger than ours, but they typically show a lot of healed breaks that are thought to result from hunting techniques requiring close contact with large game such as bison and mammoths. They had barrel-shaped chests and broad, projecting noses, traits some paleoanthropologists believe would have helped Neanderthals breathe more easily when chasing prey in cold environments.

At 454 Life Sciences, DNA samples are loaded into three-inch long plates containing 3.6 million wells. Each well can hold one of the large DNA extraction beads. Next, the plate is filled with enzymes (right) that release a flash of light whenever a chemical called a nucleotide bonds with the DNA in a well, revealing a genetic code. (Courtesy 454 Life Science)

Recent studies comparing Neanderthal and modern human anatomy have created some surprising insights. “Neanderthals are not just sort of funny Eskimos who lived 60,000 years ago,” says Jean-Jacques Hublin, a paleoanthropologist at Max Planck. “They have a different way to give birth to babies, differences in life history, shape of inner ear, genetics, the speed of development of individuals, weaning, age of puberty.” A study comparing Neanderthal and modern children showed Neanderthals had shorter childhoods. Some paleoanthropologists believe they reached physical maturity at age 15.

As different as Neanderthals were, they may not have been different enough to be considered a separate species. “There are humans today who are more different from each other in phenotype [physical characteristics],” says John Hawks, a paleoanthropologist at the University of Wisconsin. He has studied differences in the DNA of modern human populations to understand the rate of evolutionary change in Homo sapiens. Many of the differences between a Neanderthal clone and a modern human would be due to genetic changes our species has undergone since Neanderthals became extinct. “In the last 30,000 years we count about 2,500 to 3,000 events that resulted in positive functional changes [in the human genome],” says Hawks. Modern humans, he says, are as different from Homo sapiens who lived in the Neolithic period 10,000 years ago, as Neolithic people would have been from Neanderthals.

Clones created from a genome that is more than 30,000 years old will not have immunity to a wide variety of diseases, some of which would likely be fatal. They will be lactose intolerant, have difficulty metabolizing alcohol, be prone to developing Alzheimer’s disease, and maybe most importantly, will have brains different from modern people’s.

Bruce Lahn at the University of Chicago studies the evolutionary history of the genes that control human brain development. One gene that affects brain size particularly interests him, a variant of the microcephalin gene, which Lahn thinks may have entered the human gene pool through interbreeding with Neanderthals. If that turns out to be true, roughly 75 percent of the world’s population has a brain gene inherited from Neanderthals. Lahn is excited to see what the Neanderthal microcephalin gene sequence looks like. “Is the Neanderthal sequence more similar to the ancestral version or the newer, derived version of the gene?” Lahn asks. “Or is the Neanderthal yet a third version that is very different from either of the two human versions? No matter how you look at it, it makes that data very interesting.”

“This is a species-altering event, it changes the way we are creating a new generation.”—Lori Andrews

The Neanderthals’ brains made them capable of some impressive cultural innovations. They were burying their dead as early as 110,000 years ago, which means that they had a social system that required formal disposal of the deceased. Around 40,000 years ago, they adopted new stone-tool-making traditions, the Châttelperronian tradition in Western Europe and the Uluzzian in Italy, that included a greater variety of tools than they had used in hundreds of thousands of years. But even if they were as adaptable as Homo sapiens, the question remains–if they were so smart, why are they dead? Chris Stringer of London’s Natural History Museum believes our species hunted and gathered food so intensively that there simply was not enough room for the Neanderthals to make a living. In other words, they had the same problem as many species facing extinction today–they were crowded out of their ecological niche by Homo sapiens. Finding a place in the world for a Neanderthal clone would be only one dilemma that would have to be solved.

Bernard Rollin, a bioethicist and professor of philosophy at Colorado State University, doesn’t believe that creating a Neanderthal clone would be an ethical problem in and of itself. The problem lies in how that individual would be treated by others. “I don’t think it is fair to put people…into a circumstance where they are going to be mocked and possibly feared,” he says, “and this is equally important, it’s not going to have a peer group. Given that humans are at some level social beings, it would be grossly unfair.” The sentiment was echoed by Stringer, “You would be bringing this Neanderthal back into a world it did not belong to….It doesn’t have its home environment anymore.”

There were no cities when the Neanderthals went extinct, and at their population’s peak there may have only been 10,000 of them spread across Europe. A cloned Neanderthal might be missing the genetic adaptations we have evolved to cope with the world’s greater population density, whatever those adaptations might be. But, not everyone agrees that Neanderthals were so different from modern humans that they would automatically be shunned as outcasts.

“I’m convinced that if one were to raise a Neanderthal in a modern human family he would function just like everybody else,” says Trenton Holliday, a paleoanthropologist at Tulane University. “I have no reason to doubt he could speak and do all the things that modern humans do.”

“I think there would be no question that if you cloned a Neanderthal, that individual would be recognized as having human rights under the Constitution and international treaties,” says Lori Andrews, a professor at Chicago-Kent College of Law. The law does not define what a human being is, but legal scholars are debating questions of human rights in cases involving genetic engineering. “This is a species-altering event,” says Andrews, “it changes the way we are creating a new generation.” How much does a human genome need to be changed before the individual created from it is no longer considered human?

At 454 Life Sciences, DNA samples are loaded into three-inch long plates containing 3.6 million wells. Each well can hold one of the large DNA extraction beads. Next, the plate is filled with enzymes (right) that release a flash of light whenever a chemical called a nucleotide bonds with the DNA in a well, revealing a genetic code. (Courtesy 454 Life Science)

Recent studies comparing Neanderthal and modern human anatomy have created some surprising insights. “Neanderthals are not just sort of funny Eskimos who lived 60,000 years ago,” says Jean-Jacques Hublin, a paleoanthropologist at Max Planck. “They have a different way to give birth to babies, differences in life history, shape of inner ear, genetics, the speed of development of individuals, weaning, age of puberty.” A study comparing Neanderthal and modern children showed Neanderthals had shorter childhoods. Some paleoanthropologists believe they reached physical maturity at age 15.

As different as Neanderthals were, they may not have been different enough to be considered a separate species. “There are humans today who are more different from each other in phenotype [physical characteristics],” says John Hawks, a paleoanthropologist at the University of Wisconsin. He has studied differences in the DNA of modern human populations to understand the rate of evolutionary change in Homo sapiens. Many of the differences between a Neanderthal clone and a modern human would be due to genetic changes our species has undergone since Neanderthals became extinct. “In the last 30,000 years we count about 2,500 to 3,000 events that resulted in positive functional changes [in the human genome],” says Hawks. Modern humans, he says, are as different from Homo sapiens who lived in the Neolithic period 10,000 years ago, as Neolithic people would have been from Neanderthals.

Clones created from a genome that is more than 30,000 years old will not have immunity to a wide variety of diseases, some of which would likely be fatal. They will be lactose intolerant, have difficulty metabolizing alcohol, be prone to developing Alzheimer’s disease, and maybe most importantly, will have brains different from modern people’s.

Bruce Lahn at the University of Chicago studies the evolutionary history of the genes that control human brain development. One gene that affects brain size particularly interests him, a variant of the microcephalin gene, which Lahn thinks may have entered the human gene pool through interbreeding with Neanderthals. If that turns out to be true, roughly 75 percent of the world’s population has a brain gene inherited from Neanderthals. Lahn is excited to see what the Neanderthal microcephalin gene sequence looks like. “Is the Neanderthal sequence more similar to the ancestral version or the newer, derived version of the gene?” Lahn asks. “Or is the Neanderthal yet a third version that is very different from either of the two human versions? No matter how you look at it, it makes that data very interesting.”

“This is a species-altering event, it changes the way we are creating a new generation.”—Lori Andrews

The Neanderthals’ brains made them capable of some impressive cultural innovations. They were burying their dead as early as 110,000 years ago, which means that they had a social system that required formal disposal of the deceased. Around 40,000 years ago, they adopted new stone-tool-making traditions, the Châttelperronian tradition in Western Europe and the Uluzzian in Italy, that included a greater variety of tools than they had used in hundreds of thousands of years. But even if they were as adaptable as Homo sapiens, the question remains–if they were so smart, why are they dead? Chris Stringer of London’s Natural History Museum believes our species hunted and gathered food so intensively that there simply was not enough room for the Neanderthals to make a living. In other words, they had the same problem as many species facing extinction today–they were crowded out of their ecological niche by Homo sapiens. Finding a place in the world for a Neanderthal clone would be only one dilemma that would have to be solved.

Bernard Rollin, a bioethicist and professor of philosophy at Colorado State University, doesn’t believe that creating a Neanderthal clone would be an ethical problem in and of itself. The problem lies in how that individual would be treated by others. “I don’t think it is fair to put people…into a circumstance where they are going to be mocked and possibly feared,” he says, “and this is equally important, it’s not going to have a peer group. Given that humans are at some level social beings, it would be grossly unfair.” The sentiment was echoed by Stringer, “You would be bringing this Neanderthal back into a world it did not belong to….It doesn’t have its home environment anymore.”

There were no cities when the Neanderthals went extinct, and at their population’s peak there may have only been 10,000 of them spread across Europe. A cloned Neanderthal might be missing the genetic adaptations we have evolved to cope with the world’s greater population density, whatever those adaptations might be. But, not everyone agrees that Neanderthals were so different from modern humans that they would automatically be shunned as outcasts.

“I’m convinced that if one were to raise a Neanderthal in a modern human family he would function just like everybody else,” says Trenton Holliday, a paleoanthropologist at Tulane University. “I have no reason to doubt he could speak and do all the things that modern humans do.”

“I think there would be no question that if you cloned a Neanderthal, that individual would be recognized as having human rights under the Constitution and international treaties,” says Lori Andrews, a professor at Chicago-Kent College of Law. The law does not define what a human being is, but legal scholars are debating questions of human rights in cases involving genetic engineering. “This is a species-altering event,” says Andrews, “it changes the way we are creating a new generation.” How much does a human genome need to be changed before the individual created from it is no longer considered human?

Later this year a group of scientists at the Max Planck Institute in Leipzig, Germany, plans to release a first draft of the full Neanderthal DNA sequence. Most of the genome comes from a small fragment of 30,000-year-old bone (below, right) found in Vindija cave, Croatia. (Courtesy Max Planck Institute for Evolutionary Anthropology)

Legal precedent in the United States seems to be on the side of Neanderthal human rights. In 1997, Stuart Newman, a biology professor at New York Medical School attempted to patent the genome of a chimpanzee-human hybrid as a means of preventing anyone from creating such a creature. The patent office, however, turned down his application on the basis that it would violate the Constitution’s 13th amendment prohibition against slavery. Andrews believes the patent office’s ruling shows the law recognizes that an individual with a half-chimpanzee and half-human genome would deserve human rights. A Neanderthal would have a genome that is even more recognizably human than Newman’s hybrid. “If we are going to give the Neanderthals humans rights…what’s going to happen to that individual?” Andrews says. “Obviously, it won’t have traditional freedoms. It’s going to be studied and it’s going to be experimented on. And yet, if it is accorded legal protections, it will have the right to not be the subject of research, so the very reasons for which you would create it would be an abridgment of rights.”

Human rights laws vary widely around the world. “There is not a universal ban on cloning,” says Anderson. “Even in the United States there are some states that ban it, others that don’t.” On August 8, 2005, the United Nations voted to ban human cloning. It sent a clear message that most governments believe that human cloning is unethical. The ban, however, is non-binding.

The legal issues surrounding a cloned Neanderthal would not stop with its rights. Under current laws, genomes can be patented, meaning that someone or some company could potentially own the genetic code of a long-dead person. Svante Pääbo, who heads the Neanderthal genome sequencing project at Max Planck, refused to comment for this article, citing concerns about violating an embargo agreement with the journal that is going to publish the genome sequence. But he did send Archaeology this statement:”We have no plans to patent any of the genes in the Neanderthal.”

The ultimate goal of studying human evolution is to better understand the human race. The opportunity to meet a Neanderthal and see firsthand our common but separate humanity seems, on the surface, too good to pass up. But what if the thing we learned from cloning a Neanderthal is that our curiosity is greater than our compassion? Would there be enough scientific benefit to make it worth the risks? “I’d rather not be on record saying there would,” Holliday told me, laughing at the question. “I mean, come on, of course I’d like to see a cloned Neanderthal, but my desire to see a cloned Neanderthal and the little bit of information we would get out of it…I don’t think it would be worth the obvious problems.” Hublin takes a harder line. “We are not Frankenstein doctors who use human genes to create creatures just to see how they work.” Noonan agrees, “If your experiment succeeds and you generate a Neanderthal who talks, you have violated every ethical rule we have,” he says, “and if your experiment fails…well. It’s a lose-lose.” Other scientists think there may be circumstances that could justify Neanderthal cloning.

“If we could really do it and we know we are doing it right, I’m actually for it,” says Lahn. “Not to understate the problem of that person living in an environment where they might not fit in. So, if we could also create their habitat and create a bunch of them, that would be a different story.”

“We could learn a lot more from a living adult Neanderthal than we could from cell cultures,” says Church. Special arrangements would have to be made to create a place for a cloned Neanderthal to live and pursue the life he or she would want, he says. The clone would also have to have a peer group, which would mean creating several clones, if not a whole colony. According to Church, studying those Neanderthals, with their consent, would have the potential to cure diseases and save lives. The Neanderthals’ differently shaped brains might give them a different way of thinking that would be useful in problem-solving. They would also expand humanity’s genetic diversity, helping protect our genus from future extinction. “Just saying ‘no’ is not necessarily the safest or most moral path,” he says. “It is a very risky decision to do nothing.”

Hawks believes the barriers to Neanderthal cloning will come down. “We are going to bring back the mammoth…the impetus against doing Neanderthal because it is too weird is going to go away.” He doesn’t think creating a Neanderthal clone is ethical science, but points out that there are always people who are willing to overlook the ethics. “In the end,” Hawks says, “we are going to have a cloned Neanderthal, I’m just sure of it.”

http://www.archaeology.org/1003/etc/neanderthals.html

Read an older article about the research on Neanderthals………..

Redheads … a man and a replica of a Neanderthal

Image: Reuters

 

 

Michael Kahn in London
October 27, 2007

SydneyMorningHerald.com  —  THE image of Neanderthals may be in need of a makeover: scientists say at least some of these extinct hominids could have had fair skin and red hair.

Researchers studying the DNA of Neanderthals found a mutation in two individuals that can affect skin and hair pigmentation, they reported in Thursday’s online issue of Science.

The researchers homed in on the MC1R gene linked to hair and skin colour and used DNA analysis to find a variation that produced the same kind of pigmentation changes as in humans with red hair and pale skin.

The study comes a week after another set of researchers looking at a different gene said Neanderthals might have been capable of sophisticated speech.

“The papers make Neanderthals more like modern Europeans, with light skin and hair colour and language abilities, and yet there are no signs of interbreeding with modern humans,” said Dr Carles Lalueza-Fox, a molecular biologist at the University of Barcelona, in a commentary in Science.

Taken together, the two studies are the first to extract nuclear DNA from Neanderthal remains and represent a new way to learn more about the extinct early humans, the researchers said. Nuclear DNA is the DNA in the nucleus of the cell that makes up nearly all the genetic information people carry.

Neanderthals were a dead-end offshoot of the human line who inhabited Europe and parts of west and central Asia. Research indicates they were expert tool-makers, used animal skins to keep warm and cared for each other.

Most researchers believe Neanderthals survived in Europe until the arrival of fully modern humans about 30,000 years ago, although controversial findings last year suggested they might have survived until as recently as 24,000 years ago.

The team produced a DNA sequence from the fragmented Neanderthal MC1R gene to make a modified copy they could study in a test tube, the researchers said.

This allowed the team to determine that the gene produced the same level of the chemical melanin as in people with red hair and light skin. The variation itself was different than in modern humans but the result was the same.

Light skin would have been an evolutionary advantage for Neanderthals by allowing them to soak up more vitamin D from the sun in cloudy Europe.

The findings also provide important clues about Neanderthal and human evolution, and represent the first of many such experiments likely to use the same DNA technique to learn far more than could be gleaned from fossils alone, researchers said.

“We have always had a bottleneck on the number of fossils we can work on,” Dr Michael Hofreiter, an evolutionary biologist at the Max Planck Institute in Leipzig, said in a telephone interview. “There will be more studies looking at specific genes that are interesting.”

An artist’s rendition of a Neanderthal family in Ice Age Europe.

Read more about Neanderthals………………..

Read an earlier article from the Smithsonian………………..

Research suggests the so-called brutes fashioned tools, buried their dead, maybe cared for the sick and even conversed. But why, if they were so smart, did they disappear?

  • By Joe Alper
  • Smithsonian magazine, June 2003

Bruno Maureille unlocks the gate in a chain-link fence, and we walk into the fossil bed past a pile of limestone rubble, the detritus of an earlier dig. We’re 280 miles southwest of Paris, in rolling farm country dotted with long-haired cattle and etched by meandering streams. Maureille, an anthropologist at the University of Bordeaux, oversees the excavation of this storied site called Les Pradelles, where for three decades researchers have been uncovering, fleck by fleck, the remains of humanity’s most notorious relatives, the Neanderthals.

We clamber 15 feet down a steep embankment into a swimming pool-size pit. Two hollows in the surrounding limestone indicate where shelters once stood. I’m just marveling at the idea that Neanderthals lived here about 50,000 years ago when Maureille, inspecting a long ledge that a student has been painstakingly chipping away, interrupts my reverie and calls me over. He points to a whitish object resembling a snapped pencil that’s embedded in the ledge. “Butchered reindeer bone,” he says. “And here’s a tool, probably used to cut meat from one of these bones.” The tool, or lithic, is shaped like a hand-size D.

All around the pit, I now see, are other lithics and fossilized bones. The place, Maureille says, was probably a butchery where Neanderthals in small numbers processed the results of what appear to have been very successful hunts. That finding alone is significant, because for a long time paleoanthropologists have viewed Neanderthals as too dull and too clumsy to use efficient tools, never mind organize a hunt and divvy up the game. Fact is, this site, along with others across Europe and in Asia, is helping overturn the familiar conception of Neanderthals as dumb brutes. Recent studies suggest they were imaginative enough to carve artful objects and perhaps clever enough to invent a language.

Neanderthals, traditionally designated Homo sapiens neanderthalensis, were not only “human” but also, it turns out, more “modern” than scientists previously allowed. “In the minds of the European anthropologists who first studied them, Neanderthals were the embodiment of primitive humans, subhumans if you will,” says Fred H. Smith, a physical anthropologist at LoyolaUniversity in Chicago who has been studying Neanderthal DNA. “They were believed to be scavengers who made primitive tools and were incapable of language or symbolic thought.”Now, he says, researchers believe that Neanderthals “were highly intelligent, able to adapt to a wide variety of ecologicalzones, and capable of developing highly functional tools to help them do so. They were quite accomplished.”

Contrary to the view that Neanderthals were evolutionary failures—they died out about 28,000 years ago—they actually had quite a run. “If you take success to mean the ability to survive in hostile, changing environments, then Neanderthals were a great success,” says archaeologist John Shea of the State University of New York at Stony Brook. “They lived 250,000 years or more in the harshest climates experienced by primates, not just humans.” In contrast, we modern humans have only been around for 100,000 years or so and moved into colder, temperate regions only in the past 40,000 years.

Though the fossil evidence is not definitive, Neanderthals appear to have descended from an earlier human species, Homo erectus, between 500,000 to 300,000 years ago. Neanderthals shared many features with their ancestors—a prominent brow, weak chin, sloping skull and large nose—but were as big-brained as the anatomically modern humans that later colonized Europe, Homo sapiens. At the same time, Neanderthals were stocky, a build that would have conserved heat efficiently. From musculature marks on Neanderthal fossils and the heft of arm and leg bones, researchers conclude they were also incredibly strong. Yet their hands were remarkably like those of modern humans; a study published this past March in Nature shows that Neanderthals, contrary to previous thinking, could touch index finger and thumb, which would have given them considerable dexterity.

Neanderthal fossils suggest that they must have endured a lot of pain. “When you look at adult Neanderthal fossils, particularly the bones of the arms and skull, you see [evidence of] fractures,” says Erik Trinkaus, an anthropologist at WashingtonUniversity in St. Louis. “I’ve yet to see an adult Neanderthal skeleton that doesn’t have at least one fracture, and in adults in their 30s, it’s common to see multiple healed fractures.” (That they suffered so many broken bones suggests they hunted large animals up close, probably stabbing prey with heavy spears—a risky tactic.) In addition, fossil evidence indicates that Neanderthals suffered from a wide range of ailments, including pneumonia and malnourishment. Still, they persevered, in some cases living to the ripe old age of 45 or so.

Perhaps surprisingly, Neanderthals must also have been caring: to survive disabling injury or illness requires the help of fellow clan members, paleoanthropologists say. A telling example came from an Iraqi cave known as Shanidar, 250 miles north of Baghdad, near the border with Turkey and Iran. There, archaeologist Ralph Solecki discovered nine nearly complete Neanderthal skeletons in the late 1950s. One belonged to a 40- to 45-year-old male with several major fractures. Ablow to the left side of his head had crushed an eye socket and almost certainly blinded him. The bones of his right shoulder and upper arm appeared shriveled, most likely the result of a trauma that led to the amputation of his right forearm. His right foot and lower right leg had also been broken while he was alive. Abnormal wear in his right knee, ankle and foot shows that he suffered from injury-induced arthritis that would have made walking painful, if not impossible. Researchers don’t know how he was injured but believe that he could not have survived long without a hand from his fellow man.

“This was really the first demonstration that Neanderthals behaved in what we think of as a fundamentally human way,” says Trinkaus, who in the 1970s helped reconstruct and catalog the Shanidar fossil collection in Baghdad. (One of the skeletons is held by the Smithsonian Institution’s National Museum of Natural History.) “The result was that those of us studying Neanderthals started thinking about these people in terms of their behavior and not just their anatomy.”

Neanderthals inhabited a vast area roughly from present-day England east to Uzbekistan and south nearly to the Red Sea. Their time spanned periods in which glaciers advanced and retreated again and again. But the Neanderthals adjusted. When the glaciers moved in and edible plants became scarcer, they relied more heavily on large, hoofed animals for food, hunting the reindeer and wild horses that grazed the steppes and tundra.

Paleoanthropologists have no idea how many Neanderthals existed (crude estimates are in the many thousands), but archaeologists have found more fossils from Neanderthals than from any extinct human species. The first Neanderthal fossil was uncovered in Belgium in 1830, though nobody accurately identified it for more than a century. In 1848, the Forbes Quarry in Gibraltar yielded one of the most complete Neanderthal skulls ever found, but it, too, went unidentified, for 15 years. The name Neanderthal arose after quarrymen in Germany’s NeanderValley found a cranium and several long bones in 1856; they gave the specimens to a local naturalist, Johann Karl Fuhlrott, who soon recognized them as the legacy of a previously unknown type of human. Over the years, France, the Iberian Peninsula, southern Italy and the Levant have yielded abundances of Neanderthal remains, and those finds are being supplemented by newly opened excavations in Ukraine and Georgia. “It seems that everywhere we look, we’re finding Neanderthal remains,” says Loyola’s Smith. “It’s an exciting time to be studying Neanderthals.”

Clues to some Neanderthal ways of life come from chemical analyses of fossilized bones, which confirm that Neanderthals were meat eaters. Microscopic studies hint at cannibalism; fossilized deer and Neanderthal bones found at the same site bear identical scrape marks, as though the same tool removed the muscle from both animals.

The arrangement of fossilized Neanderthal skeletons in the ground demonstrates to many archaeologists that Neanderthals buried their dead. “They might not have done so with elaborate ritual, since there has never been solid evidence that they included symbolic objects in graves, but it is clear that they did not just dump their dead with the rest of the trash to be picked over by hyenas and other scavengers,” says archaeologist Francesco d’Errico of the University of Bordeaux.

Paleoanthropologists generally agree that Neanderthals lived in groups of 10 to 15, counting children. That assessment is based on a few lines of evidence, including the limited remains at burial sites and the modest size of rock shelters. Also, Neanderthals were top predators, and some top predators, such as lions and wolves, live in small groups.

Steven Kuhn, an archaeologist at the University of Arizona, says experts “can infer quite a bit about who Neanderthal was by studying tools in conjunction with the other artifacts they left behind.” For instance, recovered stone tools are typically fashioned from nearby sources of flint or quartz, indicating to some researchers that a Neanderthal group did not necessarily range far.

The typical Neanderthal tool kit contained a variety of implements, including large spear points and knives that would have been hafted, or set in wooden handles. Other tools were suitable for cutting meat, cracking open bones (to get at fatrich marrow) or scraping hides (useful for clothing, blankets or shelter). Yet other stone tools were used for woodworking; among the very few wooden artifacts associated with Neanderthal sites are objects that resemble spears, plates and pegs.

I get a feel for Neanderthal handiwork in Maureille’s office, where plastic milk crates are stacked three high in front of his desk. They’re stuffed with plastic bags full of olive and tan flints from Les Pradelles. With his encouragement, I take a palm-size, D-shaped flint out of a bag. Its surface is scarred as though by chipping, and the flat side has a thin edge. I readily imagine I could scrape a hide with it or whittle a stick. The piece, Maureille says, is about 60,000 years old. “As you can see from the number of lithics we’ve found,” he adds, referring to the crates piling up in his office, “Neanderthals were prolific and accomplished toolmakers.”

Among the new approaches to Neanderthal study is what might be called paleo-mimicry, in which researchers themselves fashion tools to test their ideas. “What we do is make our own tools out of flint, use them as a Neanderthal might have, and then look at the fine detail of the cutting edges with a high-powered microscope,” explains Michael Bisson, chairman of anthropology at McGill University in Montreal. “Atool used to work wood will have one kind of wear pattern that differs from that seen when a tool is used to cut meat from a bone, and we can see those different patterns on the implements recovered from Neanderthal sites.” Similarly, tools used to scrape hide show few microscopic scars, their edges having been smoothed by repeated rubbing against skin, just as stropping a straight razor will hone its edge. As Kuhn, who has also tried to duplicate Neanderthal handicraft, says: “There is no evidence of really fine, precise work, but they were skilled in what they did.”

Based on the consistent form and quality of the tools found at sites across Europe and western Asia, it appears likely that Neanderthal was able to pass along his toolmaking techniques to others. “Each Neanderthal or Neanderthal group did not have to reinvent the wheel when it came to their technologies,” says Bisson.

The kinds of tools that Neanderthals began making about 200,000 years ago are known as Mousterian, after the site in France where thousands of artifacts were first found. Neanderthals struck off pieces from a rock “core” to make an implement, but the “flaking” process was not random; they evidently examined a core much as a diamond cutter analyzes a rough gemstone today, trying to strike just the spot that would yield “flakes,” for knives or spear points, requiring little sharpening or shaping.

Around 40,000 years ago, Neanderthals innovated again. In what passes for the blink of an eye in paleoanthropology, some Neanderthals were suddenly making long, thin stone blades and hafting more tools. Excavations in southwest France and northern Spain have uncovered Neanderthal tools betraying a more refined technique involving, Kuhn speculates, the use of soft hammers made of antler or bone.

What happened? According to the conventional wisdom, there was a culture clash. In the early 20th century, when researchers first discovered those “improved” lithics—called Châtelperronian and Uluzzian, depending on where they were found—they saw the relics as evidence that modern humans, Homo sapiens or Cro-Magnon, had arrived in Neanderthal territory. That’s because the tools resembled those unequivocally associated with anatomically modern humans, who began colonizing western Europe 38,000 years ago. And early efforts to assign a date to those Neanderthal lithics yielded time frames consistent with the arrival of modern humans.

But more recent discoveries and studies, including tests that showed the lithics to be older than previously believed, have prompted d’Errico and others to argue that Neanderthals advanced on their own. “They could respond to some change in their environment that required them to improve their technology,” he says. “They could behave like modern humans.”

Meanwhile, these “late” Neanderthals also discovered ornamentation, says d’Errico and his archaeologist colleague João Zilhão of the University of Lisbon. Their evidence includes items made of bone, ivory and animal teeth marked with grooves and perforations. The researchers and others have also found dozens of pieces of sharpened manganese dioxide—black crayons, essentially—that Neanderthals probably used to color animal skins or even their own. In his office at the University of Bordeaux, d’Errico hands me a chunk of manganese dioxide. It feels silky, like soapstone. “Toward the end of their time on earth,” he says, “Neanderthals were using technology as advanced as that of contemporary anatomically modern humans and were using symbolism in much the same way.”

Generally, anthropologists and archaeologists today proffer two scenarios for how Neanderthals became increasingly resourceful in the days before they vanished. On the one hand, it may be that Neanderthals picked up a few new technologies from invading humans in an effort to copy their cousins. On the other, Neanderthals learned to innovate in parallel with anatomically modern human beings, our ancestors.

Most researchers agree that Neanderthals were skilled hunters and craftsmen who made tools, used fire, buried their dead (at least on occasion), cared for their sick and injured and even had a few symbolic notions. Likewise, most researchers believe that Neanderthals probably had some facility for language, at least as we usually think of it. It’s not far-fetched to think that language skills developed when Neanderthal groups mingled and exchanged mates; such interactions may have been necessary for survival, some researchers speculate, because Neanderthal groups were too small to sustain the species. “You need to have a breeding population of at least 250 adults, so some kind of exchange had to take place,” says archaeologist Ofer Bar-Yosef of Harvard University. “We see this type of behavior in all hunter-gatherer cultures, which is essentially what Neanderthals had.”

But if Neanderthals were so smart, why did they go extinct? “That’s a question we’ll never really have an answer to,” says Clive Finlayson, who runs the Gibraltar Museum, “though it doesn’t stop any of us from putting forth some pretty elaborate scenarios.” Many researchers are loath even to speculate on the cause of Neanderthals’ demise, but Finlayson suggests that a combination of climate change and the cumulative effect of repeated population busts eventually did them in. “I think it’s the culmination of 100,000 years of climate hitting Neanderthals hard, their population diving during the cold years, rebounding some during warm years, then diving further when it got cold again,” Finlayson says.

As Neanderthals retreated into present-day southern Spain and parts of Croatia toward the end of their time, modern human beings were right on their heels. Some researchers, like Smith, believe that Neanderthals and Cro-Magnon humans probably mated, if only in limited numbers. The question of whether Neanderthals and modern humans bred might be resolved within a decade by scientists studying DNA samples from Neanderthal and Cro-Magnon fossils.

But others argue that any encounter was likely to be hostile. “Brotherly love is not the way I’d describe any interaction between different groups of humans,” Shea says. In fact, he speculates that modern humans were superior warriors and wiped out the Neanderthals. “Modern humans are very competitive and really good at using projectile weapons to kill from a distance,” he says, adding they also probably worked together better in large groups, providing a battlefield edge.

In the end, Neanderthals, though handy, big-brained, brawny and persistent, went the way of every human species but one. “There have been a great many experiments at being human preceding us and none of them made it, so we should not think poorly of Neanderthal just because they went extinct,” says Rick Potts, head of the Smithsonian’s Human Origins Program. “Given that Neanderthal possessed the very traits that we think guarantee our success should make us pause about our place here on earth.”

Find this article at:
http://www.smithsonianmag.com/science-nature/neanderthals.html

Artist’s rendition of female Neanderthal

Next Page →