Denisovan DNA in Focus

Using new techniques to study ancient DNA, scientists have unraveled the genetic details of a young girl who lived in central Asia around 50,000 years ago. She is the only individual of her kind, a unique branch of the human family called the Denisovans, named for the cave where her remains were found in 2008.

What makes the research all the more startling is that only two teeth and one pea-size bone fragment has been found. But from those tiny fragments of humanity, the story of the Denisovans is being pieced together.

The new techniques were developed by Matthias Meyer, working at the Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology in Leipzig, a research program led by Svante Pääbo. DNA extracted from the bone fragment was separated into two strands that were amplified and analyzed separately, many times over, until a highly reliable sequence was determined.

Laboratory for the extraction of ancient DNA. [Image courtesy of Max Planck Institute for Evolutionary Anthropology].

Researchers claim that the result is as complete and accurate as the sequence of living human beings. Already, the new technique is being used to study other ancient remains, including samples of Neandertal DNA. Denisovans and Neandertals, distinct but closely related forms of humanity, overlapped with anatomically modern humans (AMH) and interbred with them.

New methods in genetics, including the technical breakthrough described in this paper, are opening new windows on the human family tree, which resembles an inter-grown vine more than a straight line of branches.

So accurate is the genetic analysis that researchers can reach some conclusions about other Denisovans, even though no samples exist for them. For one thing, despite their wide geographic spread, they apparently never reached high numbers. Their DNA lives on today in the faint echo of ancient interbreeding found in the uniquely-Denisovan sequences carried by those who live in the islands of southeast Asia.

No one knows what Denisovans looked like, but they probably resembled us in many ways. The Denisovan girl whose DNA was studied carried genes that are associated today with brown hair, brown eyes, and dark skin. Like us they had 23 pairs of chromosomes (compared to chimps with 24), making interbreeding more readily possible.

Denisova molar, distal. [Image courtesy of Max Planck Institute for Evolutionary Anthropology].

One of the more tantalizing aspects of the report is the light it sheds not on the Denisovans or the Neandertals but on us anatomically modern human beings who live today. Why did we survive and flourish culturally when they did not?

One explanation may lie in the genetic differences between us and them, which can be studied for the first time in detail. In this paper, researchers identify specific changes in genes that are associated with brain complexity, synaptic connections, and speech development. According to the paper, “it is thus tempting to speculate that crucial aspects of synaptic transmission may have changed in modern humans.” In other words, tiny differences in DNA led to still relatively small differences in brain function that led to huge differences in culture.

Future technical advances will continue to shed new light on the complex story of recent human ancestry. By gaining ever-higher clarity on the genetic differences between Neandertals, Denisovans, and modern humans, we will come to know the story of our humanity in greater detail.

The paper ends with this reflection: “This [work] should ultimately aid in determining how it was that modern humans came to expand dramatically in population size as well as culturally complexity which archaic humans eventually dwindled in numbers and became physically extinct.” The paper, “A High-Coverage Genome Sequence from an Archaic Denisovan Individual,” is published in the 30 August 2012 issue of Science, published by the American Association for the Advancement of Science.

How Old Is Art?

Confirmed dates for the world’s oldest art just got older, according to the report of an international research team published in the May 14 issue of the Proceedings of the National Academy of Sciences.

Dating back about 37,000 years, the art consists of engravings made in stone that has since fallen from the ceiling of a cave at Abri Castanet in southwestern France. While not as visually arresting as the more famous cave art found at Chauvet, the Castanet engravings are both older and represent what is very likely an earlier stage in the history of the Aurignacian culture, which spanned 40,000 to about 28,000 years ago. Some of the Chauvet paintings are now confirmed at between 30,000 and 32,000 years ago.

Credit: HTO. A replica of a painting, now in the public domain.

The Castanet engravings are both simpler artistically and were located in the general living area of the cave. The Aurignacian culture that created both the paintings and the engravings is known for is many forms of art. According to New York University anthropology professor Randall White, one of the study's co-authors, the Aurignacians "had relatively complex social identities communicated through personal ornamentation, and they practiced sculpture and graphic arts."

"But unlike the Chauvet paintings and engravings, which are deep underground and away from living areas, the engravings and paintings at Castanet are directly associated with everyday life, given their proximity to tools, fireplaces, bone and antler tool production, and ornament workshops," White said in press release issued by NYU.

With more refined archeological techniques, the story of the rise of human symbolic culture is likely to become more complex and more ancient. While there may well have been bursts of cultural creativity in which symbolic advance occurred rapidly, additional findings may also suggest a more steady rise in the story of human art. The study, entitled “Context and dating of Aurignacian vulvar representations from Abri Castanet, France,” appears in the May 14, 2012 edition of PNAS.

Single-Atom Transistor: Why Small Is a Big Deal

A tiny achievement with huge significance was reported today by physicists at the University of New South Wales (UNSW). They have created a transistor that uses a single atom. Their work is described in a paper and an editorial published in the February 19 issue of Nature Nanotechnology.

Using a scanning tunneling microscope—the essential tool in nanotechnology that allows researchers to visualize and manipulate single atoms—the UNSW group positioned a phosphorous atom between nano-scale electrodes. A video explaining the feat is available.

CAPTION:This is a single-atom transistor: 3D perspective scanning tunnelling microscope image of a hydrogenated silicon surface. Phosphorus will incorporate in the red shaded regions selectively desorbed with a STM tip to form electrical leads for a single phosphorus atom patterned precisely in the center. Credit: ARC Centre for Quantum Computation and Communication, at UNSW.

What seems to be most important about this achievement is the accuracy of the placement of the phosphorous atom. This opens the possibility that precisely placed atoms may be used to create a whole new generation of computer chips that are both reliable and smaller than anything used today.

"Our group has proved that it is really possible to position one phosphorus atom in a silicon environment—exactly as we need it –with near-atomic precision, and at the same time register gates," said lead author Dr Martin Fuechsle in a press release from UNSW.

The leader of the research group, Professor Michelle Simmons, claims that "This is the first time anyone has shown control of a single atom in a substrate with this level of precise accuracy." Simmons is director of the ARC Centre for Quantum Computation and Communication at UNSW.

According to the famous “Moore’s Law,” which argues from past achievement in chip design and predicts future a doubling in chip power ever 18 months, single atom or quantum computing should be achieved by the year 2020. Fuechsle and Simmons are speculating that because of this breakthrough, technology is ahead of schedule.

If so, then arguments advanced by futurists such as Ray Kurzweil take on added significance. As chips grow in power and shrink is size, more and more powerful computing becomes possible. Smaller chips are more implantable, bringing us closer to they day when they are implanted not just for medical but for other purposes (see previous post).

Even more significant is that smaller and more powerful processing paves the way for more highly intelligent machines. Kurzweil predicts that within a few decades, machines with greater than human intelligence will be produced. What then? Will our inventions become the inventors of the future, and will they still need us? The report, "A Single-Atom Transistor," is published in the February 19 is of Nature Nanotechnology.

Humans Beings, DNA Nano-Robots, and Implantable Chips

Technological devices inside the human body are fast becoming more fact than fiction, and two reports released on February 16 are significant milestones along that path.

In one study, appearing in Science Translational Medicine, microchips were implanted in women suffering from osteoporosis. Researchers at Harvard Medical and Case Western worked with MicroCHIPS, the manufacturer of the device.

Patients with advanced osteoporosis, whose bones have weakened and lost density, are currently able to give themselves with a daily injection of a drug that requires refrigeration. By implanting a device, researchers want to make the process easier compliance more consistent.

The microchips implanted in the study contain tiny reservoirs of the drug. The device releases a daily dose when it receives a wireless signal. It also monitors the release of the drug and reports back to the physician, who is able to modify the prescription by sending new instructions to the device from another wireless device, such as a smart phone. This is believed to be the first wirelessly controlled implanted drug-delivery device.

"This trial demonstrates how drug can be delivered through an implantable device that can be monitored and controlled remotely, providing new opportunities to improve treatment for patients and to realize the potential of telemedicine," according to Robert Langer of MIT and the cofounder of MicroCHIPS, Inc. "The convergence of drug delivery and electronic technologies gives physicians a real-time connection to their patient's health, and patients are freed from the daily reminder, or burden, of disease by eliminating the need for regular injections," Langer said in a release issued by the MicroCHIPS.

The drug delivery device (on right) next to an everyday computer memory stick. Courtesy of MicroCHIPS, Inc., Massachusetts.

The company also reported that it is currently developing new designs of its microchip-based implant to include as many as 400 doses per device providing daily dosing for one year or multi-year therapy for less frequent dosing regimens.

In another study reported today, a team of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University report on their work in assembling tiny robots out of DNA.

Building on previous advances in what is popularly known as “DNA origami,” the Wyss team used a computer to fabricate a barrel-like structure capable of containing specific molecules for delivery to targeted cells in the body. For example, cancer cells could be targeted with molecules that cause them to self-destruct, much the way the body’s own immune system carries out its functions.

“DNA origami” allows researchers to use DNA as a construction material. They are able to fold it and weave its strands together. What’s more, since DNA is a chemical code, specific patterns or sequences in the DNA can be used to “read” a signal and “act” accordingly. In this study, researchers built a DNA “latch” or locking mechanism. Their DNA barrel kept its molecular payload safely under wraps until it arrived on the surface of the target cell. On the surface of the target cell is a protein that unlocks the DNA latch, releasing the molecule at just the right location.

Cell-targeting DNA nano-robots bearing antibody-fragment payloads. [Image created by Campbell Strong, Shawn Douglas, & Gaël McGill using Molecular Maya & cadnano]

"We can finally integrate sensing and logical computing functions via complex, yet predictable, nanostructures—some of the first hybrids of structural DNA, antibodies, aptamers and metal atomic clusters—aimed at useful, very specific targeting of human cancers and T-cells," said George Church, Ph.D., a Wyss core faculty member and Professor of Genetics at Harvard Medical School, who is Principal Investigator on the project.

One way in which the researchers tested their DNA nano-robots was by programming them to target and destroy cancer cells growing in culture, including leukemia and lymphoma cells. The results were promising. According to the study, ” These findings demonstrate that the robots can induce a variety of tunable changes in cell behavior. Furthermore, biologically active payloads may be bound indirectly via interactions with antibody fragments, enabling applications in which the robot carries out a scavenging task before targeted payload delivery.”

The work reported here is built on advances around the world in nanotechnology and synthetic biology. What is new is the way the Wyss team combined several of these advances for the first time. For example, the release mechanism used here responds to the presence of a protein, not just to the presence of DNA or RNA. That feature alone makes this work more immediately applicable for medical purposes.

Put together, these two reports are part of a far wider panorama of basic advances in biomedical research. They stand out in part because of what they promise in terms of future treatment strategies. But more than that, they catch our attention because advances like these continue to blur the lines between ourselves and our technology.

In the first case—a wireless implanted drug-delivering chip—we are not simply injecting a medication or implanting a device. The patients in this study are hosts to a high-tech subsystem implanted within them that interacts in sophisticated ways with another human being (their physician). What’s more, that other human being—even if half a world a way attending a medical conference—can send instructions that immediately cause an effect within the body (but perhaps without the knowledge) of the patient. Surely there’s a spy story here just waiting to be written. More than that, this seems to be another significant milestone on the way to the (post?-) human future.

In the second case (the DNA nanoscale robot), nothing is yet implanted, but that’s clearly a next step. What are we to make of this elegant piece of tiny engineering? It is so small that it can only be made using computers. It is built from the same sort of DNA that we have in every cell, but it's engineered to hold a desired shape and to respond to a specific signal. Then, if inserted in great numbers into the human body, it can emulate the human immune system but take it in directions far beyond evolution.

The report on the implantable chip is entitled "First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip" and appears in the February 16 issue of Science Translational Medicine. The report on DNA robots, "A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads," appears in the February 17 issue of the journal Science. Both journals are publications of the American Association for the Advancement of Science.

Regenerative Medicine: Repairing the Heart

A breakthrough in the use of stem cells for regenerative medicine has just been reported by researchers at Cedars-Sinai Heart Institute. Patients who suffered heart attacks were implanted with cells derived from their own hearts. Some of the scars left by the heart attacks dissolved and new heart muscle cells re-grew, according to a report in the February 14 issue of The Lancet.

Patients involved in the study had all experienced recent heart attacks that damage heart muscle. The first step in the procedure involved inserting a catheter through a vein in the neck under local anesthesia. Using the catheter, researchers withdrew a small sample of healthy heart tissue. The tissue contains some stem cells, but the key step in the procedure is to multiply and purify the small number of stem cells so that they number in the tens of millions.

These cardiac stem cells, multiplied but originally from the patient’s own heart, were then infused back into the site of the heart attack. The result seems to be a nearly 50% drop in the size of the scar and a re-growing of healthy heart muscle, at least as far as could be determined using imaging technology.

It is important to note that this study is a Phase I clinical trial. Its main purpose is to show that there is no unwarranted risk in the procedure. The outcome of this trial, however, shows a real likelihood of benefit. The evidence is strong that scaring is reduced and heart muscle regenerated. It is too soon, of course, to know the long-term benefits.

What is new in this study is the strong likelihood of actual regeneration of heart cells. Whether the implanted cells produced the new muscles or whether they acted indirectly, triggering neighboring cells to divide and regenerate tissues, is still not clear.

The lead researcher in the study, Eduardo Marbán, made this claim about the finding: "This has never been accomplished before, despite a decade of cell therapy trials for patients with heart attacks. Now we have done it. The effects are substantial, and surprisingly larger in humans than they were in animal tests." Marbán is the director of the Cedars-Sinai Heart Institute who invented the procedures and technology involved in the study, including the procedures for multiplying the stem cells.

"These results signal an approaching paradigm shift in the care of heart attack patients," said Shlomo Melmed, MD, dean of the Cedars-Sinai medical faculty and the Helene A. and Philip E. Hixon Chair in Investigative Medicine. "In the past, all we could do was to try to minimize heart damage by promptly opening up an occluded artery. Now, this study shows there is a regenerative therapy that may actually reverse the damage caused by a heart attack."

The study itself concludes with this claim: “Our study provides an initial indication that therapeutic regeneration might indeed be possible in cardiac tissue.”

The goal of regenerative medicine—the use of stem cells to help patients regrow cells and regenerate tissues or organs—has long been central to the dreams that surround stem cell research. Even though this in only a Phase I study and still must be replicated, it seems to be an important step in the development of regenerative medicine.

Many of course will be especially delighted that no embryonic stem cells were directly involved in this procedure. Those who object to the use of human embryos in research will regard these cells as “morally unproblematic.” It is also very significant to point out that because the cells come from the patients, there should be no issue of tissue rejection.

At the same time, it should be noted that the field of stem cell research advances as a whole field. Knowledge gained from one area (for example, using embryonic stem cells) opens the door for advances across the whole field.

The article, “Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial,” appears appropriately in the Valentine’s Day issue of the medical journal, The Lancet.