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Oxygen map: This image shows a mouse’s legs, with a tumor in the left leg.
Hypoxic regions are indicated in light blue. Credit: Murali Churukali/NCI
A startup is developing oxygen-carrying compounds that it says could make radiation therapy more effective in half of all cancer patients.
MIT Technology Review, December 8, 2010, by Katherine Bourzac – About 50 percent of cancer patients have tumors that are resistant to radiation because of low levels of oxygen—a state known as hypoxia. A startup in San Francisco is developing proteins that could carry oxygen to tumors more effectively, increasing the odds that radiation therapy will help these patients.
Last month, the National Cancer Institute (NCI) gave that startup, Omniox, $3 million in funding. Omniox is collaborating with researchers at the NCI to test whether its oxygen-carrying compounds improve radiation therapy in animals with cancer.
Most tumors have hypoxic regions, and researchers believe they have a significant impact on treatment outcomes in about half of patients. Tumor cells proliferate with such abandon that they outstrip their blood supply, creating regions with very low levels of oxygen. This lack of oxygen drives tumor cells to generate more blood vessels, which metastatic cells use to travel elsewhere in the body and spread the cancer.
Radiation therapy depends on oxygen to work. When ionizing radiation strikes a tumor, it generates reactive chemicals called free radicals that damage tumor cells. Without oxygen, the free radicals are short-lived, and radiation therapy isn’t effective. “Radiation treatment is given today on the assumption that tumors are oxygenated” and will be damaged by it, says Murali Cherukuri, chief of biophysics in the Center for Cancer Research at the NCI in Bethesda, Maryland. “Hypoxic regions survive treatment and repopulate the tumor.”
Since the 1950s, researchers have tried many ways to get more oxygen into tumors, without success. Having patients breathe high levels of oxygen prior to radiation doesn’t work, and developing an agent to carry oxygen through the blood to a tumor has proved very difficult. Artificial proteins that mimic the body’s natural oxygen carrier, hemoglobin, can be dangerously reactive—destroying other important chemicals in the blood. And other oxygen carriers tend to either cling to oxygen too tightly or release it too soon, before it gets to the least oxygenated regions of the tumor.
“We’re hoping that since most tumors are hypoxic, we could improve the effectiveness of radiation therapy in a large number of people,” says Stephen Cary, cofounder and CEO of Omniox. The company has developed a range of proteins that are tailored to hold onto oxygen until they’re inside hypoxic tissue. These proteins are not based on hemoglobin, so they don’t have the same toxic effects.
The company’s technology comes from the lab of Michael Marletta, a professor of chemistry at the University of California, Berkeley. “Most blood substitutes have failed,” says Marletta, because they were based on globin proteins, which includes hemoglobin. Hemoglobin is able to work in the body because it’s encased in red blood cells. Unprotected, oxygenated globin proteins react with nitric oxide in the blood, destroying the oxygen, the nitric oxide, and the protein itself.
Marletta began looking for protein fragments that bound to oxygen, but not to nitric oxide. He started with the genetic sequence for the section of the globin proteins that binds to oxygen. He then used a computer program to scan through genome databases for similar sequences. This turned up a group of similar sequences in single-celled organisms. Marletta studied these protein sequences and found a group of them that bind to oxygen but not to nitric oxide. By altering the sequences slightly, Marletta found he was able to tailor how tightly the protein binds to oxygen. This level of control means Omniox can design a protein that releases oxygen only when the surrounding levels of the oxygen are very low—meaning the protein must travel all the way to the hypoxic part of the tumor before it releases the oxygen.
Cary, who was formerly a postdoctoral researcher in Marletta’s lab, cofounded Omniox in 2006 to develop a therapeutic oxygen-carrying agent. The company has raised a total of about $4 million from the NCI and the University of California’s Institute for Quantitative Biosciences. The company is currently housed in the university’s biotech startup incubator, the QB3 Garage.
Omniox has so far demonstrated that its proteins accumulate in tumors in living animals, and that the proteins increase the oxygen concentration there.
Studies of the proteins are now underway at the NCI. Cherukuri, who is not affiliated with Omniox, has developed a tracer for use with magnetic resonance imaging that allows him to make a high-resolution, 3-D map of tumor oxygen concentrations.
Cherukuri is using this method to study the effects of Omniox’s agents in mice with hypoxic tumors. “When you have a very hypoxic tumor, and you inject the animal with [the Omniox agent], the oxygenation increases,” he says. He is working with General Electric to develop a human-scale prototype of this imaging system.
The Omniox and NCI studies are aimed at figuring out which of the company’s proteins works best, when the proteins should be administered, and whether the treatment truly improves the effectiveness of radiation therapy. The studies will also look out for any dangerous immune responses to the foreign proteins. If the results are promising, the company hopes to begin tests in human patients in 2013.
The Known Universe
GoogleNews.com, FORBES.com, December 8, 2010, by Seth Borenstein, WASHINGTON — Lately, a handful of new discoveries make it seem more likely that we are not alone – that there is life somewhere else in the universe.
In the past several days, scientists have reported there are three times as many stars as they previously thought. Another group of researchers discovered a microbe can live on arsenic, expanding our understanding of how life can thrive under the harshest environments. And earlier this year, astronomers for the first time said they’d found a potentially habitable planet.
“The evidence is just getting stronger and stronger,” said Carl Pilcher, director of NASA’s Astrobiology Institute, which studies the origins, evolution and possibilities of life in the universe. “I think anybody looking at this evidence is going to say, ‘There’s got to be life out there.’”
A caveat: Since much of this research is new, scientists are still debating how solid the conclusions are.
Another reason to not get too excited is that the search for life starts small – microscopically small – and then looks to evolution for more. The first signs of life elsewhere are more likely to be closer to slime mold than to ET. It can evolve from there.
Scientists have an equation that calculates the odds of civilized life on another planet. But much of it includes factors that are pure guesswork on less-than-astronomical factors, such as the likelihood of the evolution of intelligence and how long civilizations last. Stripped to its simplistic core – with the requirement for intelligence and civilization removed – the calculations hinge on two basic factors: How many places out there can support life? And how hard is it for life to take root?
What last week’s findings did was both increase the number of potential homes for life and broaden the definition of what life is. That means the probability for alien life is higher than ever before, agree 10 scientists interviewed by The Associated Press.
Seth Shostak, senior astronomer at the SETI Institute in California, ticks off the astronomical findings about planet abundance and Earthbound discoveries about life’s hardiness. “All of these have gone in the direction of encouraging life out there and they didn’t have to.”
Scientists who looked for life were once dismissed as working on the fringes of science. Now, Shostak said, it’s the other way around. He said that given the mounting evidence, to believe now that Earth is the only place harboring life is essentially like believing in miracles. “And astronomers tend not to believe in miracles.”
Astronomers, however, do believe in proof. They don’t have proof of life yet. There’s no green alien or even a bacterium that scientists can point to and say it’s alive and alien. Even that arsenic-munching microbe discovered in Mono Lake in California isn’t truly alien. It was manipulated in the lab.
But, says NASA astrobiologist Chris McKay, who has worked on searches for life on Mars and extreme places on Earth, “There are real things we can point to and show that being optimistic about life elsewhere is not silly.”
First, there’s the basic question of where such life might exist. Until a few years ago, astronomers thought life was only likely to be found on or around planets circling stars like our sun. So that’s where the search of life focused – on stars like ours.
That left out the universe’s most common stars: red dwarfs, which are smaller than our sun and dimmer. Up to 90 percent of the stars in the universe are red dwarf stars. And astronomers assumed planets circling them would be devoid of life.
But three years ago, NASA got the top experts in the field together. They crunched numbers and realized that life could exist on planets orbiting red dwarfs. The planets would have to be closer to their star and wouldn’t rotate as quickly as Earth. The scientists considered habitability and found conditions near these small stars wouldn’t be similar to Earth but would still be acceptable for life.
That didn’t just open up billions of new worlds, but many, many times that.
Last week, a Yale University astronomer said he estimates there are 300 sextillion stars – triple the previous number. Lisa Kaltenegger of Harvard University says scientists now believe that as many as half the stars in our galaxy have planets that are two to 10 times the size of Earth – “super Earths” which might sustain life.
Then the question is how many of those are in the so-called Goldilocks zone – not too hot, not too cold. The discovery of such a planet was announced in April, although some scientists are challenging that.
The other half of the equation is: How likely is life? Over the past decade and a half, scientists have found Earth life growing in acid, in Antarctica and other extreme environments. But nothing topped last week’s news of a lake bacterium that scientists could train to thrive on arsenic instead of phosphorous. Six major elements have long been considered essential for life – carbon, hydrogen, nitrogen, oxygen, phosphorus and sulfur. This changed that definition of life.
By making life more likely in extreme places, it increases the number of planets that are potential homes for life, said Kaltenegger, who also works at the Max Planck Institute in Germany.
Donald Brownlee, an astronomer at the University of Washington, is less optimistic because he believes what’s likely to be out there is not going to be easy to find – or that meaningful. If it’s out there, he said, it’s likely microbes that can’t be seen easily from great distances. Also, the different geologic and atmospheric forces on planets may keep life from evolving into something complex or intelligent, he said.
If life is going to be found, Mars is the most likely candidate. And any life is probably underground where there is water, astronomers say. Other possibilities include Jupiter’s moon Europa and Saturn’s moons Enceladus and Titan.
There’s also a chance that a telescope could spot a planet with an atmosphere that suggests photosynthesis is occurring, Kaltenegger said. And then there’s the possibility of finding alien life on Earth, perhaps in a meteorite, or something with an entirely different set of DNA.
And finally, advanced aliens could find us or we could hear their radio transmissions, McKay said. That’s what the SETI Institute is about, listening for intelligent life.
That’s where Shostak puts his money behind his optimism. At his public lectures, Shostak bets a cup of coffee for everyone in the audience that scientists will find proof of alien life by about 2026. The odds, he figures, have never been more in his favor.
Carl Sagan, Outer Space Guru
The New York Times, December 8, 2010, by Simon Johnson, a professor at the M.I.T. Sloan School of Management and a senior fellow at the Peterson Institute for International Economics, is the co-author of “13 Bankers: The Wall Street Takeover and The Next Financial Meltdown.”
Writing in the Washington Post, in November 2009, Jamie Dimon, chief executive of JP Morgan Chase, argued:
“Creating the structures to allow for the orderly failure of a large financial institution starts with giving regulators the authority to facilitate failures when they occur. Under such a system, a failed bank’s shareholders should lose their value; unsecured creditors should be at risk and, if necessary, wiped out. A regulator should be able to terminate management and boards and liquidate assets. Those who benefited from mismanaging risks or taking on inappropriate risk should feel the pain.”
There is not a single piece of evidence that society gains from having megabanks at today’s scale or leverage ratios.
But the Dodd-Frank financial reform legislation does not create a “resolution mechanism” that can deal with cross-border megabanks; this point is admitted by all involved. And there is nothing in the G20 process or underway with any other international forum that would make a difference in this regard.
So when very big banks are on the brink of failure, the Obama administration and Congress will have to face this choice: either let this big bank go through bankruptcy, like Lehman Brothers, or provide it with a bailout — meaning complete protection for all creditors (but hope you can at least remove some management this time around).
Unfortunately, the Irish experience shows that the “let’s do an unsavory bailout” will likely not end well next time. Our megabanks are getting bigger — as we demonstrated in 13 Bankers and as Thomas Hoenig argued in the Times last week — not because of any kind of legitimate market process, but because they benefit from an unfair and non-transparent government subsidy. And these big banks have recklessly dangerous levels of debt relative to equity, as Anat Admati and her colleagues have pointed out.
Put simply, by allowing our biggest banks to become even bigger — and more leveraged — the government is taking on a large contingent fiscal liability. Whatever you think of current fiscal policy — and whatever the outcome of the current debate over taxes and spending in the U.S. — remember this: by all standard balance sheet measures, Ireland was running responsible fiscal policy over the past decade. But the implicit liabilities of the Irish state were ballooning out of control, in direct proportion to the size of the biggest Irish banks. Three banks failed and this has taken down the entire Irish economy.
There are no economies of scale or scope in banking over about $100 billion in assets. Bankers, like Jamie Dimon, make claims to the contrary — including in an interview published in the New York Times on Sunday. But they do not have a single piece of evidence that society gains from having megabanks at today’s scale and with today’s leverage.
Our biggest banks are already subject to a partial size cap. According to the Riegle-Neal Act of 1994, no one bank can have more than 10 percent of total retail deposits in the United States. Unfortunately, the growth of wholesale financing and the global spread of these banks essentially made a mockery of this sensible macroprudential regulation.
We should update and apply the Riegle-Neal Act, exactly as proposed by Senators Sherrod Brown and Ted Kaufman in spring 2010.