GENETICS
Gene Therapy of Multiple Myeloma in Mice Shows Signs of Success
T-cells (right) were genetically modified to incorporate the protein chNKG2D
Researchers from the Dartmouth Medical School recently conducted an investigation into the effects of using genetically modified T-cells to combat multiple myeloma. Amorette Barber, Kenneth Meehan and Charles Sentman found that this gene therapy was successful in treating myeloma in mice. Multiple myeloma is a form of cancer that affects specific white blood cells present in the bone. This study, conducted last year, was recently published in Nature.
As part of the treatment, T-cells, a type of white blood cell, were genetically modified to incorporate the protein chNKG2D. This protein is the binding site for a ligand expressed by human myeloma tumor cells. This means the T-cells can target the myeloma cells specifically. In addition, upon contact, the T-cells containing chNKG2D can produce particular cytokines that kill human myeloma cells.
It was found that this model worked in mice; the injected T-cells found and targeted the tumors present in the rodents, to great effect. Compared to a single dose of the regular or wild type T-cell, a single dose of the modified version ensured longer survival for half the sample tested, and a double dose led to tumor-free survival in all mice. In addition, the mice developed a protective memory response to the antigens produced by these specific myeloma cells, meaning their immune systems recognize this particular type of myeloma and a relapse is therefore unlikely.
It was also found that the introduction of these modified T-cells into the bodies of the mice did not require lymphodepletion, a process in which the number of T-cells and lymphocytes present in the body are reduced. This process normally accompanies T-cell infusions because it prolongs the life of the new T-cells. However, the chNKG2D T-cells do not live very long, potentially reducing the need for lymphodepletion. This short lifespan also suggests that the T-cells induce anti-tumor immune responses in the host system, essentially “teaching” the body how to respond to this specific form of myeloma.
TECHNOLOGY
Lippman Offers Prime Explanation of Spam
Richard P. Lippman, a researcher at MIT’s Lincoln Laboratory, recently spoke at the Thayer School of Engineering. He addressed the issues surrounding the use of intellectually evolving machines to protect computers from spam, a significant online threat. Lippman noted that there is great potential for using such machines in a security capacity, as they can “automate decisions” and “adapt to frequent changes” in spammers’ attacks. However, such machines, according to Lippman, are all too easily spooked.
Lippman detailed the general manner by which such machines can be fooled. Spammers, or internet adversaries, can either directly manipulate the features of such machines to produce a desired outcome, or, they can more insidiously reconfigure a defending machine’s “training data” and open the floodgates to a torrent of attacks. Because both methods can have deleterious consequences for a computer, an “arms race” between attackers and defenders creating and maintaining machines has naturally ensued. He described a cyclical relationship between the nature of attacks and the framework of defense.
According to Lippman, spam has undergone a significant transformation since its early beginnings. Starting out as text only, spam then became pictures, then pictures and text, and finally, a synthesis of complicated designs, pictures and nonsensical words difficult for a computer to recognize. Each successive class of spam worked to fool protecting machines into believing that it was actually harmless when it obviously was not. Taking advantage of “social engineering,” a process by which the user mistakenly trusts the spam and clicks on it, the spam then proceeds to compromise and infect the user’s computer and possibly other systems connected to it.
NEUROSCIENCE
Ingestion of Common Chemicals Leads to Delayed Neurological Effects
Ingestion of substances such as antifreeze and brake fluid has long been known to cause immediate symptoms such as seizures and vomiting, but it has been recently shown that patients who survive poisoning often develop neurological problems as well later on. In a research paper by Nandi J. Reddy, Madhuri Sudini, and Lionel D. Lewis at the Dartmouth-Hitchcock Medical Center, ethylene glycol, diethylene glycol, and methanol were investigated for their capacity to cause delayed nervous system damage.
Ethylene glycol is an ingredient in antifreeze, which often leads to death when consumed due to its high toxicity. It acts as a central nervous system depressant, and has typically been associated with three distinct phases of poisoning. In the first stage, during the hours immediately after ingestion, patients often develop seizures and are at a high risk for death. In the second stage, after about twelve hours, respiratory symptoms begin. In the third stage, two to three days later, kidney failure develops.
Structure of ethylene glycol
The paper reviewed past cases on ethylene glycol ingestion and discovered that there is a fourth stage of poisoning, which starts five days to a several weeks after ingestion. This delayed stage is characterized by damage to the seventh cranial nerve, which is responsible for facial sensation and movement as well as taste.
This damage causes impaired speech and difficulty swallowing, symptoms which are remarkably similar to those of Parkinson’s disease. However, whereas damage from ethylene glycol poisoning is mostly localized to the face, Parkinson’s disease causes damage to other areas of the body as well.
Diethlyene glycol and methanol poisonings share an initial stage of high mortality followed by damage to the seventh cranial nerve. Their pathologies are also similar: in the body, these compounds are broken down by enzymes, forming intermediates that cause the symptoms to develop. Regardless of their metabolism, each of the three compounds has a similar effect on the nervous system.
When asked for comments, author Lionel D. Lewis stressed that it is still unclear why the seventh cranial nerve is the most affected. The region of the brain usually responsible for delayed nervous system damage is the basal ganglia, clusters of cells that control voluntary motor function.
ENVIRONMENTAL SCIENCES
Going Green: Leadership, Climate Change, Innovation
“The earth is warming and mankind is most probably responsible for what is happening,” asserted Peter Darbee, the C.E.O. of Pacific Gas and Electric Corporation (PG&E Corp.), this past fall at a Jones Seminar in the Dartmouth Thayer School of Engineering. He discussed such topics as climate change, innovation, and leadership in relation to environment sustainability.
According to Darbee, excessive carbon emissions are the most detrimental of all the problems facing the environment. His goal is to have one third of California’s power supply be a product of renewable energy sources by 2020. These include nuclear and solar power, two fields that have seen significant technological advances.
Darbee, with regard to his company’s use of nuclear power, explained that while there may be controversy surrounding its safety, the newer generation of nuclear reactors is much safer. These devices feature the use of convection currents rather than pumps to circulate cooling, making power plants more secure.
Additionally, recent innovation with regard to solar energy could prove to be an “immense breakthrough,” according to Darbee. PG&E Corp. is currently under contract with Solaren Corp. in which the latter company agreed to establish a satellite that will collect solar energy in outer space, convert the energy into microwaves, and beam the waves to the Earth. No longer will the process of capturing solar energy be dependent on the time of day or be interrupted by atmospheric and weather conditions.
These recent innovations and their applications to increasing sustainability have earned PG&E the title of the seventh most innovative company in the United States. As a leader in the energy industry, Darbee has been “working everyday to try to reduce [his company’s] emissions” and encouraging other companies in the industry to follow suit with progressive ideas to improve environmental conservation.
BIOCHEMISTRY
Think Zinc
Recently, Amanda Bird, molecular genetics professor at Ohio State University, spoke at Dartmouth’s Biology Cramer Seminar about her research on zinc regulation and the role of non-coding RNAs in zinc binding protein production.
She detailed the biological importance of zinc. Zinc is an essential nutrient for the body, and 7% of the human genome encodes various zinc-binding proteins, including ribosomes, and RNA and DNA polymerases. In cases of zinc deficiency, humans show very serious symptoms including dermatitis, hair loss, diarrhea, growth retardation, and an impaired immune response. Too much zinc can be toxic to the body as well. Symptoms include respiratory and gastrointestinal disorders, as well as impaired copper and iron uptake. Zinc homeostasis is key to health.
Zinc is an essential nutrient for the body.
Bird’s lab uses eukaryotic yeast models such as Saccharomyces cerevisiae to look at zinc expression on the cellular level. A family of proteins of particular interest to Bird’s lab is the alcohol dehydrogenases, which bind one or more atoms of zinc to function. Bird specifically studies the cytoplasmic Adh1 and mitochondrial Adh4, which bind two zinc atoms and one zinc atom, respectively, as shown by x-ray crystallography. They function in oxidizing acetaldehyde during alcohol metabolism, and the reverse in glucose metabolism.
Bird found that Adh1 expression is decreased in zinc deficient conditions, and production of certain non-coding RNAs (ncRNAs) is increased. She concluded that ncRNAs can be regulated at a transcriptional level in response to nutrient limitation, specifically zinc. Bird’s research continues to shed more light on zinc, a metal so essential to health.