In nature, species evolve thanks to those lucky organisms who cheat death. An environmental pressure may come in and kill of a high percentage of critters, but those critters who survive the bloodbath live on to spread their genes. When this bottle-necking occurs in disease-causing bacteria, we call it drug resistance: an antibiotic may knock off 99 percent of a species, but the 1 percent immune to the treatment will live on to reproduce and create an entire population immune to the drug.

As the drugs developed to fight cancers become more and more sophisticated, a similar principle is in play for tumor cells. New “targeted” chemotherapy drugs, such as sorafenib or imatinib, which attack tumor cells by one specific mechanism, have typically shown initial success followed by recurrence and resistance. The reason, suggests Wei Du, associate professor in the Ben May Department for Cancer Research at the University of Chicago, is evolutionary.

“If you really think about it, it’s sort of like evolution on the scale of your body,” Du said. “Cancers are heterogeneous and often display genomic instability. When the selective pressure of a drug is applied, a small number of cancer cells will likely be able to survive and grow. This will eventually lead to the development of resistance, just like antibiotics for the bacteria.”

In bacterial infections, doctors get around the resistance threat by ganging up on the bacteria, hitting a patient with multiple antibiotics that each employ unique killing strategies. That “Magnificent Seven” approach would be ideal for treating cancers, but physicians are limited by the limited number of mechanistically unique chemotherapy drugs available.

In a recent paper published in Cancer Cell, Du’s laboratory set out to remedy that problem by laying the groundwork for a new cancer-killing strategy. When a cell becomes cancerous, its genetic factory goes haywire, with some gene products being over-produced and others under-produced. Many drugs are developed to try to rein in the former, known as oncogenes, but few attempt to target the inactivated “tumor-suppressor” genes normally tasked with policing excessive cell growth.

One of those lost policeman is a gene called retinoblastoma protein, or Rb. The Rb gene is mutated in roughly 10 percent of tumors and functionally inactivated in many more, making the protein a factor in a majority of cancers. Rb-inactivated cells lose the brakes for proliferation, producing the uncontrolled cell growth characteristic of tumors. Du’s group launched a hunt for a “synthetic lethal” gene, a second, coincident mutation that would cause Rb-negative cells to self-destruct while sparing the innocent, non-cancerous cells standing by.

“The idea will be that the mutation by itself does not cause cell death, but in conjunction with loss of tumor suppressors you actually have a synergistic effect for cell death induction,” Du said. “That type of drug would be really nice in that it will have very low toxicity, but have specificity for the cancer cells.”

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Illustration by Clint May

Most people who have spent any length of time in a laboratory know the pain and frustration of Western blots. There’s probably a little bit of PTSD in every cell biologist related to gels falling apart, leaky electrophoresis chambers, or bands that should be there but aren’t, causing you to wonder which of the preceding 40 steps went wrong.

But don’t hate the method, hate the human error - Western blots, for all the agony they’ve caused, have been one of the most widely-used and productive lab methods of the past 30-some years. Used to detect the amount of protein in a given cell or tissue sample, Western blots have furthered our understanding of the intricate machinery of the cell, from the assembly line that builds it to the defects that can lead to cancer and other diseases. More specific than another protein assay, mass spectrometry, Western blots are the weapon of choice for laboratories that want to characterize the amount and status of a specific protein.

Nevertheless, Western blots have their limits, and the key word is “protein,” singular. Due to the limited size of a Western blot gel and the expense of the antibodies needed to “visualize” the proteins within, blots can only assay, at most, a handful of proteins in each run. Given that the protein networks of cells can contain hundreds or even thousands of proteins, that’s like trying to figure out the image on a puzzle by looking at only one piece at a time. The search was on for a better method, one that could take a snapshot of hundreds of proteins from a cell sample simultaneously.

Such a breakthrough was announced over the weekend in the journal Nature Methods, where a team of scientists led by Richard Jones, assistant professor at the University of Chicago’s Ben May Department for Cancer Research and the Institute for Genomics and Systems Biology described a promising new technique: micro-western arrays.

“When you walk into a dark room and don’t have much information, it’s difficult to predict where everything is going to be,” Jones said. “If someone can simply turn on the light, you don’t have to progress one step at a time by bumping into things. With this new technology, you can potentially see everything at the same time.”

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Picture a boxing match, Tao Pan said. A cell, facing viral or bacterial invasion, starts building new proteins, while the infection generates dangerous reactive oxygen species that rampage through the cell causing serious damage. When the new proteins meet the reactive oxygen species (ROS), they face off like welterweights circling each other in the ring - ROS dart in, trying to do damage to the protein’s most important sites, while the protein deflects attacks with an amino acid, called methionine, capable of absorbing those blows.

Cells can place protective methionines into proteins the old-fashioned way, by encoding for the amino acid in the DNA recipe. But in a paper published this week in the journal Nature, researchers from the University of Chicago and the National Institute of Allergy and Infectious Diseases describe a new, post-genetic way for cells to add methionine bodyguards to proteins when they are threatened: making purposeful mistakes.

To discover this useful fallibility, Pan - a professor of biochemistry and molecular biophysics at the University of Chicago - and graduate student Jeffrey Goodenbour developed a novel assay for measuring particular errors called misacylations. If you recall the central dogma of molecular biology, DNA is used to make protein via intermediaries called RNA. First, an RNA copy of the DNA gene for a particular protein is created, called messenger or mRNA. Then that mRNA moves to a cellular machine called a ribosome. Specific transfer RNAS - tRNAs - are then recruited to the ribosome, bringing along amino acids that are placed in order according to the mRNA recipe. After hundreds or downloadable software thousands of amino acids are arranged into a chain, you have a completed protein.

One would think it was a bad thing for mistakes to happen along this manufacturing process, and scientists have long believed that quality-control measures are in place to ensure that the proteins come out the way DNA says they should. One step that prevents mistakes is tRNA specificity - each of the 20 tRNA varieties can only bind to one type of amino acid. Occasionally, a tRNA grabs the wrong amino acid, an error called misacylation, but laboratory studies in artificial systems estimated that this mistake only happens about once every 10,000 times.

The keyword there is “artificial systems” - because when Goodenbour and Pan looked at the misacylation rate in live cells, it was much higher: 1 out of every 100 methionines was placed incorrectly, they found. And when the cell was stressed by a virus, bacteria, or a caustic chemical such as hydrogen peroxide, that methionine error rate went up even higher, with as many as 1 out of 10 off-recipe placements. That emergency measure would make new proteins more resistant to ROS damage when the cell needs them the most, Pan said.

“This mechanism allows every protein to get some protection,” Pan said. “The genetic code is considered untouchable, but this is a non-genetic strategy used in cells to create a bodyguard for proteins.”

The scientific question raised by this discovery is: why? Cells could more directly protect their proteins by loading them up with methionines through the DNA code, removing the need to rely on random “errors” imposed later in the translation process. But Pan proposes that very randomness as the secret weapon cells employ to make their proteins difficult targets for ROS attacks. By placing the protective methionines in different places in each protein, cells generate a diverse population of proteins each with their own unique set of armor - a strategy that would be impossible if translation of DNA into protein was perfect. Just like on the species level, diversity is one of the  best defense against attack.

“This sounds chaotic and doesn’t make a lot of sense according to the textbook,” Pan said. “But this way the cells can always ensure that a subset of these proteins is somewhat less sensitive to the extra hits. I think that’s the most important part of this - to make every protein molecule different - and you cannot do this genetically.”

The Nobel Prize Medal (from nobelprize.org)

The University hasn’t directly won any of the first two Nobel Prizes awarded this week, but one of today’s winners has a UChicago connection: George E. Smith, one of three scientists who will share the $1.4 million prize in physics, received his doctorate at the University of Chicago 50 years ago in 1959. And Monday’s prize has a much more tenuous connection to the proprietor of this very blog, which I’ll explain below.

First, today’s prize rewarded innovations that power technology integral to our daily lives: digital cameras and the Internet. Smith and Willard S. Boyle received the award for the invention of charge-coupled devices, CCDs, the technology put to work in the millions of digital cameras now in use. Charles K. Kao, the third recipient of today’s award, was responsible for improving the use of fiber optic cables, changing the material used in those cables to dramatically extend the distance that light can travel within. Thanks to Dr. Kao, I can quickly research this blog post and you can quickly read it, downloading the information through fiber optic cables that he helped create.

Monday, the award was given to three scientists who made crucial advances in the study of chromosomes, cancer and aging. No, it wasn’t Janet Rowley, but her friend Elizabeth Blackburn was one of the awardees alongside Jack Szostak and Carol Greider. The trio were honored for the discovery of telomeres, repeated sequences at the ends of DNA that prevent genetic material from being damaged and degraded every time a cell is replicated. There really is no better metaphor to explain the function of telomeres than the one used by the Associated Press all day yesterday: “It’s been compared to the way plastic tips on the ends of shoelaces keep the laces from fraying.”

In honor of their award, Scientific American republished an excellent article by Greider and Blackburn that explains why telomeres (and their enzyme partner telomerase, which preserves telomere length) are significant to the study of aging and cancer. As people and their cells age, telomerase works less efficiently, and telomeres and chromosomes shrink, making the cell replication process less accurate. The inability to create new cells could lead to conditions associated with old age, such as artherosclerosis and a weakened immune system. In cancer cells, on the other hand, telomerase is a bad thing, allowing tumor cells to replicate rapidly, grow, and spread around the body. Researchers have thus turned to telomerase inhibitors as a potential cancer treatment.

It is with tongue firmly in cheek that I note my nanoscale contribution to the field of telomere research, from my time at the National Institute of Child Health and Human Development in 2002. I worked in the laboratory of Jeffrey Baron, who studied mechanisms of bone growth in children. As humans grow, a strip of cartilage in the bones of arms and legs called the growth plate produces new cells that lengthen those bones; some time after puberty, those growth plates disappear. With Ben Nwosu and Ola Nilsson, we studied whether the telomeres in those growth plates grow shorter with age - I mostly helped by doing dissections on our chosen animal model, the rabbit, as we bantered about World Cup results. Somewhat unfortunately, we found that the telomere length does not change as a rabbit grows older, suggesting that telomeres are not responsible for the closing of the growth plate after puberty. But disproving a hypothesis is just as important sometimes as proving one, and we were able to publish the results in the journal Hormone Research.

So on behalf of telomere researchers the world over, I’d like to thank the Nobel Committee for their award. But I’ll happily defer the prize money to Blackburn, Grieder and Szostak.

In each cell of the body is a busy factory, containing all of the elements needed for that cell to develop and perform its unique function. A neuron sprouts a long extension and develops the ability to conduct electrical impulses. A liver cell secretes bile and can absorb toxic substances to neutralize them. Muscle cells elongate, form multiple nuclei and build long fibers that contract powerfully when stimulated.

But as different as the end product may be, the machines that make up the inner workings of these cells are largely the same, built from the identical set of genetic instructions that all cells share. Indeed, all of the body’s hundreds of cell types originate from one ambitious type of cell with the potential to become almost anything – the pluripotent stem cell to which so much scientific attention has been recently paid. What destiny that neutral cell follows is largely determined by how it organizes its factory, placing its machines in various orders that can have dramatically different outcomes.

Charting those interactions in specialized cells is a frequent goal of scientific research, as understanding a cell’s inner workings will help doctors make repairs when something goes wrong. The laboratory of Dr. Marcus Clark, chief of the Section of Rheumatology at the University of Chicago Medical Center, has devoted itself to the machinery of the B cell, the immune system cells responsible for producing antibodies that fight off disease. In a paper published this week in the journal Nature Immunology, Clark’s group fills in much of the story of what signals are involved in a crucial step of early B cell development, and shows that one of those signals, called Ras and typically associated with cancer in other cells, is surprisingly a key component in the healthy formation of a B cell.

“Ras is one of the best described oncogenes out there, it contributes to cancer in a variety of different formats.” Clark said. “It’s always seen as this pro-proliferative thing: if you put Ras in, the cells start dividing autonomously, and that’s cancer. In our hands, Ras turned off proliferation, it was very unexpected.”

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Kenneth Miller gave a typically captivating talk at the AAAS meeting yesterday in which he showed an eye-popping video illustrating what goes on in our cells all the time.

Ken was kind enough to send us a link to the full library of videos, by the BioVisions group at Harvard University. Here’s a YouTube video with highlights - watch for the big vesicle being tugged along a microtubule by a motor protein with little protein “shoes.”