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Playing God with Monsters
Howard writes "Horrified by "There Be Monsters Here" tales, some members of Congress called for a ban on DNA research in the mid '70s. Because those calls were rejected, millions of people around the world can now hope for DNA-based vaccines against AIDS, malaria and other deadly diseases that have destroyed lives, communities and nations. Here's an illustration: The name of Joseph DeRisi keeps coming up in connection with deadly diseases. No, he's not a modern-day Typhoid Mary. Just the opposite. The University of California, San Francisco researcher is using his own custom-built DNA microarrays to look inside the "minds" of some serious serial killers. The "minds" are genes, and his home-brewed gene chips helped solve the SARS mystery earlier this year. Now, DeRisi has chosen malaria as his next victim. For the complete commentary, please go to Howard Lovy's NanoBot."
I think you might be thinking of the baboon-to-baby heart transplant (mid-80s?). In any case, that operation was a failure (as predicted), and never really led anywhere as far as I know.
Roving Web-Teleoperated Robot
Researchers racing to develop new treatments for malaria, a disease now resurgent in Africa, have found a peculiarity in the parasite's molecular machinery that may make it vulnerable to the biological equivalent of a computer crash.
The parasite, a single-cell organism known as a protozoan, goes through different phases in both its mosquito and nigger hosts. Yet it has developed a very simple control system for governing at least part of this complex cycle. If this system could be disrupted, the sand coon's thousands of genes would lose their tightly choreographed coordination.
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Last year biologists determined the full sequence of DNA units in the microbe's genetic playbook. It has a genome of 22.8 million units, coding for more than 5,400 genes.
Two teams of researchers, led by Dr. Joseph DeRisi at the University of California at San Francisco, and Dr. Elizabeth Winzeler of the Scripps Research Institution in San Diego, have now made significant advances toward the next goal, that of finding out what all these genes do. The teams have used rival forms of expression chips, devices that track what genes are active at a given time in the parasite's life cycle.
The parasite spends the proliferative phase of its life cycle in the red cells of human blood, feasting on hemoglobin and breaking out to infect further cells. The successive rounds of infection cause the 48-hour cyclical fever of malaria.
Dr. DeRisi's team cultured the Plasmodium falciparum, the most deadly of the four forms of malaria, in a vat containing some five quarts of his own and others' blood. In an article being published online later this month in the Public Library of Science, a new open access journal, he reports the surprising finding that the microbe, at least in its blood-living stage, follows a just-in-time inventory system.
Each gene is switched on just before its product is needed, Dr. DeRisi said. The genes turn on and off throughout the blood infection cycle in a smooth cascade as regular as clockwork.
Most microbes have elaborate control systems that engineer a response to every change in the environment. The malaria parasite has been able to dispense with these complex controls, Dr. DeRisi said, probably because it lives in the highly controlled environment of a human blood cell. Less than 10 of the master regulatory genes known as transcription factors have been detected in the malaria parasite's genome, compared with the 141 reported in yeast and the thousand or so that control the operations of a human cell.
The simplicity of the parasite's control system, Dr. DeRisi said, may open it to sabotage. "If you disrupt just one of the regulatory program genes, you may disrupt hundreds of genes downstream and cause the whole system to crash," he said.
The usual targets of antimalaria drugs until now have been the metabolic enzymes the parasite uses to digest hemoglobin or synthesize building blocks of DNA. But the microbe can develop resistance by waiting for a mutation to arise that helps it sidestep these one-target drugs. A drug that damaged its control system, however, might present a quite different problem.
Dr. DeRisi's team tracked the expression of the genes in the malaria parasite with a device of their own design, a glass slide spotted with an array of short DNA segments that can recognize and bind to every gene in the organism's genome. The technique for building these DNA microarrays, developed by Dr. DeRisi and Dr. Pat Brown of Stanford University, has been made available to researchers. Dr. Winzeler's group used a commercial chip system, developed by Affymetrix, that has a very different design but performed the same task, that of signaling when a given gene is active in the parasite.
Dr. Winzeler, whose results were published in last week's Science, said she had observed the same broad pattern of gene control as Dr. DeRisi. She had also examined two other stages of the life cycle besides those that occur inside the red blood
The stem cell research ban is because the cells come from aborted fetuses. There isn't a fear of the research itsself. They just don't want any good to come out of abortions.
This guy shouldn't have to waste his time on curing malaria. It could have been dealt with years ago. We had a prevention for it: DDT. At least, we did until environmentalists used bad science and hype to stop the use of DDT, an action which has killed millions of people.
For a biologist you don't seem to know much about stem cells. Last time I looked in a tissue culture flask you couldn't differentiate HEK293's into anything other than cancerous kidney cells which is what they are... The point of a stem cell is that it can differentiate into other cell types.
I don't read your sig, why do you read mine?
Okay, I work with Microarrays. Here's how they work. Somebody prepares tissue and puts on the actual array somehow. He cooks this and scans it. The information gets dumped into a big binary file that gets parsed into small file. This is the "CEL" file, in Affy terminology. This is a text file with some quality control information. It can be easily processed into a two dimensional array of doubles. That's the easiest way to think of it.
We're limited to about 20,000 genes; 16 probes per gene. The chip itself is subject to scratches and other anomalies so the 16 probes within a probeset get dispersed to different random locations throughout the chip. That way a scratch won't take out a whole gene (as detected by a probe set).
There are furious but friendly debates about how to best normalize and compare probes and chips. The various methods do well at certain aspects. The are still figuring out how to compensate for concentation levels, binding efficiencies and non-specific hybridization.
Langmuir Isotherm Adsorption, Neighbor effects and quantile normalization are the latest publicly released buzzwords.
At the end of the day, you've got a pretty useful tool for detecting differential expression between two samples. A simple case is a diseased sample versus a normal sample. You could get burned by thinking that a gene is getting expressed but you are really getting expression from another gene which happens to have very similar sequences so you have to be careful. You also have a problem with alternate splicing. There could be differential expression but you're not detecting it because your probeset is not matching the part of the gene that's actually being expressed.
Rergadless, at this point you've go a pretty good hint as to what's going on. We don't know what half the genes do; but we do know what some of them do. If it's a gene that makes a protein that sits on the cell surface and detects whether there's tissue next to it and it's not being expressed, then you have a problem (cancer). If you have a gene expressing like crazy but the protein it's supposed to make then you have a problem. You might want to look for a mutation on the gene. The gene just can't make the right protein.
So, clearly you've got a powerful tool for looking into the pathways of the cell to see what's going wrong. Right now, the chips are great for research; but the costs will come down and process will be simple to operate. It will enter routine medicine for diagnosis. Probably within 5 years.
Hell, they could probably have take home kits for testing blood. I can't see people doing biopsies on themselves but it could be simple procedure done by a nurse or a PA in an assembly fashion for real cheap.
So, this stuff is quite likely to come up with some big benefits for all of us.
Are you the same kind of person that would use nuclear power everywhere, simply because we've only ever had 1 (recorded) nuclear meltdown in history, and "well, it seems safe now!" Nuclear power is about the analog of DDT: it's extremely powerful, and extremely dangerous. Actually, it's about the analog of nuclear power in the 1970s, when we DIDN'T know that much about how to control nuclear plants. Today, we still don't know how to deal with ecosystems well. Honestly, we suck - we're awful. The world is full of examples of how bad we are at managing ecosystems (Look at the outbreak of the aquarium decorative plant in the Mediterranean Sea for a recent example. Aw, it's just a pretty aquarium plant - that is rapidly turning the once-healthy Mediterranean into a single-species lawn, just ripe for a virus to come and wipe out a huge amount of oxygen producers).
There is a single, peer-reviewed, study showing adverse effects of use of DDT. Borneo, when the WHO decided to spray DDT to kill the mosquitos there. It made their lives MUCH worse than when the mosquitos - and malaria - were there. Careful - you didn't say "direct" effect, because ecology
Not using DDT now is like when people fought against using nuclear power everywhere when we weren't really that good at controlling it. It's intelligent. It's admitting "damn, this is powerful, and we really have no freaking clue how to make it not dangerous as hell."
Widespread use of DDT could cause a lot more damage than 300 million dead. A lot. Like, massive ecosystem destruction.
use stem cells on a regular basis (human embryonic kidney 293 cells (or HEK-293 for short)).
Uhhhh, check your facts....293s are most definately NOT stem cells. They are a cell line derived from embryonic kidney cells. They have been severely fucked with to make them grow in cell culture. They are immortalized (probably by introducing an oncoprotein which abrogates the limit on number of cell divisions) and are severely mutated. All these modifications may even cause them to have extra chromosomes. They are a fairly common laboratory cell line and have zero therapeutic benefit.
Stem cell lines are rare. Perhaps only a dozen exist and they are not immortalized. They were cultivated from human embryos and are pluripotent. That is, they are not already differentiated into kidney cells. In fact, they have the ability to differentiate into any other tissue type like neuronal, dental, or muscle. This could translate into disease treatments which benefit mankind significantly.
The Bush Administration has made it difficult to work with stem cells since they banned the culturing of new lines. Therefore, the few existing lines have to be doled out by a handful of laboratories. This is very difficult for just a few labs and requires a lot of paperwork. Furthermore, since the lines aren't immortal the supply is tightly regulated.
-DD
I beg to differ. The HEK293 cell line can hardly be considered a "stem cell". It is transformed by adenovirus DNA, i.e., it is a tumor cell, and is not diploid, hypotriploid according to the ATCC. You seem to be confusing embryonic and stem cell. Embryonal stem cells are diploid and are not cancerous.
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http://www.atcc.org/SearchCatalogs/longview.cfm
HEK293 was derived in 1977 or thereabouts from the kidney of a human embryo (I assume because of the name). To immortalize the cells, Graham et al made the cells incorporate (eat, transfected) DNA isolated from an adenovirus that they knew caused tumors. You almost never heard about scientists chopping up human embryos back then.
Embryos have become much more valuable and interesting due to stem cell technology. An explosive growth in the use and storage of stem cells poses novel legal issues in addition to ethical issues. Hence the current political interest in the use of embryos. The current limitations are quite restrictive and resemble limitations imposed when recombinant DNA technology became possible. The limitations on rDNA research lasted about five years, the dark ages (73 to 78 or 79). They were pretty much abolished by the mid 80s. I suspect that the enormous health benefits possible from stem cell research will lead to a swift (>5 years) relaxation of the restrictions.