Friday, December 19, 2014

What ever happened to Brontosaurus?

I have only recently realized that Brontosaurus is no longer a dinosaur. All of my son's books about dinosaurs had the longed-necked sauropod labeled as Apatosaurus, suggesting that something is very different from when I was a kid. Luckily, Brian Switek's book My Beloved Brontosaurus: on the road with old bones, new science, and our favorite dinosaurs explains what happened. Briefly: in 1877, Yale paleontologist O.C. Marsh discovered a partial skeleton of a young dinosaur that he named Apatosaurus; two years later when he found a similar skeleton, he called it Brontosaurus. In 1903, another paleontologist (Elmer Riggs) argued that the differences between the two skeletons were not great enough to warrant two different species. Because Apatosaurus was named first, it had priority for the scientific name. For some unknown reason, this development did not filter down to popular culture or even museums. According to Switek, the changes weren't made until the late eighties. Even after that, it was hard for people to adapt to the change. Switek compares the sadness we experienced at the loss of Brontosaurus with the news that Pluto was no longer a planet.

Brontosaurus stamp from 1989
Switek, a lifelong dinosaur freak, uses what he learned about dinosaurs as a child to illustrate how much our understanding of dinosaurs has changed. In the case of dinosaurs like Apatosaurus, everything we were taught was incorrect: they are no longer considered to be slow creatures, dragging their tails through a semi-aquatic environment. Another major change in our picture of dinosaurs is that they were not scaly like alligators; scientists now think that most, if not all, dinosaurs had feathers. As the connection between dinosaurs and birds is strengthened, scientists have started to consider that the prehistoric creatures may have even been brightly colored like birds. This is another case where the general public is likely to have a tough time adapting its image of Tyrannosaurus rex as a furry rather than a scaly lizard.

Young adult (left) and adult Triceratops skull
Switek also highlights some of the major unanswered questions about dinosaurs, including what sort of developmental changes dinosaurs went through. Interestingly, the well-known Triceratops shows how much dinosaurs may change in their lifetime. The skull on the left is consistent with what we think of as a Triceratops. The skull on the right is also a Triceratops (although for a while it was called a Torosaurus); the difference may simply be age. (Switek digs further into this story for Smithsonian.) Of course, the big question still is: what caused the extinction of the dinosaurs? The author treats this question fairly, discussing where scientists are landing on this issue (most agree that a very large meteor was to blame). Along the way, he also discusses how dinosaurs were not immune to the "slings and arrows of life". Many fossilized dinosaur remains have been diagnosed with pathogens of varying sorts, as well as cancer (as I learned in reading The Cancer Chronicles).

It is a great time to be a dinosaur lover. There have been some really amazing dinosaur finds in the past few years. For instance, for more than fifty years, the 8-foot-long set of arms shown on the right spurred the curiosity of many dinosaur fanatics; in October, researchers published their discovery of a full Deinocheirus skeleton, which was almost as weird as you might have imagined looking at those crazy arms (coverage by Ed Yong). The gigantic sauropod (and not so close relative of the Brontosaurus) called Dreadnaughtus was found in southern Argentina also made headlines due to its great size. Amazingly, this is not the end of the size spectrum for sauropods; size was clearly a huge advantage for these beasts.

The stories of these amazing creatures that dominated the Earth for millions of years are fascinating. Switek's book has inspired me to visit some of the great museums and dig sites in the states.

Sunday, November 23, 2014

LabLit: books about scientists and the realities of life in the lab

While exploring the Internet, I recently found the LabLit List, a frequently updated list of books that have scientists as central characters. In contrast to science fiction, these books occur in realistic settings. Lab lit books include some science to contribute to the plot. Because most lab lit is written by non-scientists, the science is not always very detailed. However, there are a few novelists who trained as scientists, including Carl Djerassi, Ann Lingard, and Jennifer Rohn (Rohn's book The Honest Look is next on my reading list). The lab lit books that I have read really capture the intensity of life in the lab, showing both the camaraderie and the competitiveness. So if you left the lab, but still fondly remember your days as a lab rat, this is likely a good genre for you. Below, I have written short reviews of three representative lab lit books that I have enjoyed.

Antisense by Richard Marshall

Principal investigator Daniel Hayden is a neuroscientist studying the molecular basis of aggressive behavior in mice. The beginning of Antisense is firmly planted in the lab, but quickly veers into the personal life of Hayden. I enjoyed some of the science bon mots; for example, when explaining blotting techniques Marshall writes, "we ran out of things to blot before we could head east." By the middle of the book, I worried that the plot would be the common male midlife meltdown, but the story generally redeemed itself. The science was interesting, but not very detailed. I was frustrated when Hayden started making grand conclusions based on a single experiment, but soon realized that this was likely the author's way of showing the PI's changing mental state. Likewise, the title was a clever choice, which was appropriate for the science as well as the character's journey.

Intuition by Allegra Goodman

Allegra Goodman's 2006 novel Intuition is set in a high-stakes, ultra-competitive lab at a fictional cancer research institute in Boston's Longwood Medical Area. (Coincidentally, I was working at a similar institute when I read the book in 2007.) Intuition explores why the stakes are so high and what can happen when scientists succumb to the pressure. Goodman spent time in several labs to understand the lab environment. As a result, the book successfully captures many of the typical lab characters and accurately paints the daily life of a researcher. However, the science is not very detailed. Rather, the story focuses more on interpersonal dynamics in the lab and the possibly fraudulent data of one researcher. In light of some of the recent, high profile retractions (e.g., STAP stem cells) and the growing concerns about reproducibility in science, Intuition is increasingly relevant.

Life by Gwyneth Jones

Life tells the story of Anna Senoz, a mid-career scientist who makes an amazing discovery about the X and Y chromosomes: her sequencing data suggest that the Y chromosome is slowly being transferred to the X chromosome. Senoz studies the transferred Y story in secret, as she fears the implications and consequences of her results. The author chose the topic of sex chromosome balance as a way to discuss gender discrimination. (Here is a fascinating essay from Gwyneth Jones on her intentions for this novel.) Senoz suffers both major events (e.g., sexual assault) and minor slights (e.g., senior scientists referring to Senoz as a "good girl"), which affect Senoz's career and personality. The science in the book was well detailed, but did not feel realistic. Perhaps the book could have focused on an authentic scientific phenomenon, like intragenomic conflict in sex chromosomes (some discussion of the topic here). For me, this was the most successful of the many lab lit books I have read. However, it feels a bit more like science fiction than the other titles. Indeed, Life won the Philip K. Dick award in 2005. 

Saturday, October 25, 2014

The Cancer Chronicles - George Johnson's personal exploration of cancer, its origins, and treatments

I have recently reviewed books about the discovery and treatment (The Philadelphia Chromosome) and the causes of cancer (Toms River). So the subject matter in George Johnson's The Cancer Chronicles is quite familiar to me. Johnson does have a unique angle – his wife was diagnosed with uterine cancer, which led him to use his expertise as a science writer to learn more about the disease. This perspective helps create a personal element to the book, but does not distract from the science.

Several of the stories were previously covered in other books that I have reviewed: Boveri's prescient hypothesis linking chromosomal aberrations with cancer (The Philadelphia Chromosome), Thomas Hunt Morgan's mutant fruit flies (The Violinist's Thumb), scrotal cancer in chimney sweeps (Toms River), and the Radium girls (The Poisoner's Handbook). Johnson covers new ground in the chapter called "Jurassic Cancer", which examines the other animals in which cancers have been found. In fact, most animals get cancer; the one exception is naked mole rats. Surprisingly, various types of malignancies have even been identified in dinosaur fossils. Another chapter examines how far back in human populations cancers have been described. Johnson writes, "There were signs of cancer in an Iron Age man in Switzerland and a fifth century Visigoth from Spain" (p 49). In both animals and humans, it is difficult to know the exact frequency of the disease, but it is clear that cancer is not strictly linked to industrialization or environmental factors. 

Hanahan and Weinberg, 2000.
Rather, it seems that cancer is inevitable. The landmark review "The Hallmarks of Cancer" (and its update in 2011) states that cancer is basically caused by the accumulation of several mutations. The review's author Robert Weinberg estimates that every second four million cells are replicating in a human body. Each time a cell replicates, there is a chance for error. While there are many error correction mechanisms, mistakes do get through. This genetic variability is the fodder for evolution by natural selection. It is also the source for cancer. Thus, it makes sense that cancer is generally seen throughout the animal kingdom and throughout time. Johnson concludes that it is comforting to know that cancer has always been with us.

Johnson also discusses cancer cell evolution, which is a topic of intense interest in scientific research. Cancer cells are constantly changing to evade the body's defense mechanisms. During treatment, some cancer cells can develop resistance to chemotherapeutics. Understanding how chemoresistant cancers can be treated is a major unanswered question. In the case of Gleevec/imatinib-resistant cancer, a single mutation is responsible for Gleevec-resistance, which allowed the development of a second drug (nilotinib) to kill cells with the imatinib-resistant mutation. Unfortunately, and as is to be expected with a complex disease such as cancer, most chemo-resistant cancers are not as clear cut. 

Overall, the book is quite easy to read and covers many important topics, albeit not at the depth of other, more focused books on the topic of cancer. I will definitely be adding The Emperor of All Maladies to my reading list to give this topic another perspective.

** Post script: Johnson's book was short-listed for the 2014 Royal Society Winton Prize for Science books. 

Saturday, October 4, 2014

The Tale of the Dueling Neurosurgeons - more weird science from Sam Kean

I normally don't get very excited for a book release because I always seem to have lots of books on my reading list. Since I enjoyed the previous books from Sam Kean (The Disappearing Spoon and The Violinist's Thumb) so much, I actually set my calendar to remind me about the release of The Tale of the Dueling Neurosurgeons. I don't know much about neuroscience, so I knew that Kean would teach me something new. As usual, Kean finds the most fascinating stories to keep you in awe of how the brain works and highlight the numerous ways in which the brain can malfunction.

Phineas Gage and his tamping rod

The theme of the book is that neuroscience is unique in that most of the early lessons about the function of the brain came from observing the behavior of people with damage to a particular region of the brain. This is still the case; a recent story about a young woman without a cerebellum demonstrates the plasticity of the brain and its ability to compensate for problems in even the most seemingly critical parts. The book includes lots of case studies and stories of strange behavior. The final chapter presents the tale of Phineas Gage, who is a bit of a legend in the field of  neuroscience. Sam Kean wrote a piece for Slate about Phineas Gage; I recommend reading it if you want to get a quick idea of whether or not you will like the Dueling Neurosurgeons.

Perhaps the most fascinating tidbit concerned Teddy Roosevelt and his treatment by neurologist Silas Weir Mitchell, whose "West cure" for men included a variety of rugged outdoor pursuits. Before seeking the cure in the 1880s, Roosevelt had been compared to Oscar Wilde for his effeminate voice and foppish mannerisms. As you would expect for the time, Mitchell's cure for women was very different; women suffering from "hysteria" were prescribed long term, isolated bed rest with massages and fatty foods. Many women suffered through this treatment, including Virginia Woolf. (You can read more about the gender-biased treatments of Silas Mitchell here.) Silas Mitchell built his reputation on his work in the area of phantom limb, the phenomenon where an amputee may feel an itch or pain in the limb that has been removed. Radiolab had an excellent story on this topic, which covered the innovative but simple approaches used to treat this strange problem. 

When you hear about people who taste colors or see smells, they are typically exhibiting synesthesia. The most common forms of synesthesia are people who see sounds in certain colors or hear sounds in connection with particular letters or numbers. Physicist Richard Feynman and author Vladimir Nabokov both experienced these sensory combinations (the internet tells me that Lady Gaga was also born this way). The reason that these particular combinations are more common is likely due to brain geography: the regions that analyze sounds, colors, and letters are close together. Interestingly, sixty different types of synesthesia exist, but it is not completely clear what causes this jumbled wiring. It is becoming clear that this commingling of the senses could be a benefit. Some synesthetes have an excellent memory, which they attribute to their unusual perception of the five senses. This correlation suggests that training your brain to link colors and letters, for example, could improve cognitive function. Some synesthetes have links between their sense of smell or taste and the other senses. This causes them to experience sounds or colors associated with some flavors. As you could imagine, this might expand their palate, as described in this NPR story about the benefits of being a synesthete in the food and beverage industry.

Dueling Neurosurgeons was another excellent outing for Sam Kean, who continues to amaze me with stories of weird science. I also loved the rebus puzzles that Kean added at the start of each chapter. Like the DNA acrostic in The Violinist's Thumb, Kean has found a novel way to engage his readers.

Wednesday, September 10, 2014

Advice from a Scientific Editor

As a Scientific Editor for BBA for the past two years, I have read lots of manuscripts (you can learn more about my job here). This gives me a good sense of what helps a paper make a good first impression. Here are my tips that should help your paper be judged based on the science.**

Write a great abstract

Your abstract is the first thing that an editor or reviewer will see; it serves as your elevator pitch and it is the most important place to make a good first impression. The abstract should clearly say what your paper is about and why that matters. In the simplest terms, your abstract should succinctly state the following: what are the knowns, what are the unknowns, what novel information your paper brings to the topic, and what the significance of the work is. Be sure to get several opinions (e.g., from scientists both inside and outside your field) on your abstract; it doesn't take long to read an abstract, so your colleagues would likely be willing to help.

Learn the proper structure for a scientific paper

When I was a graduate student How to Write and Publish a Scientific Paper was a useful resource. It outlines exactly what each section of the paper should include and what the purpose of the section is.  This information is critical to guide the writing of a manuscript. Most journals include the guidelines for the structure of a manuscript in their guide for authors. The best way to learn the structure of a paper is to read published papers, especially those written by well-established investigators in your field. Organizational issues (e.g., the discussion is simply a re-iteration of the results; the figure legends are too similar to the materials and methods) are a common complaint of reviewers. While this alone might not be a reason to reject a paper, it is best to ensure that the writing and organization of a manuscript does not give editors or reviewers a bad impression.

Find the right journal and know what that journal is looking for

With so many options available, choosing the right journal can be a daunting task. There are two tools that I use to see where similar papers are published: JANE (Journal, Author, Name Estimator) and Journal Finder (this is for Elsevier journals). Both use the title and abstract of your paper to find similar articles and where they were published. Of course, the more standard approach is to check your references. A properly referenced paper should give a clear idea of where the related papers have been published. Alternatively, you can use the related papers feature on Scopus or PubMed; if you look at the results for papers related to your work, you can determine where the majority of papers on the topic have been published. Once you have a list of potential journals, investigate those journals carefully to determine if the scope fits your manuscript. You should also learn what the journal is looking for (e.g., mechanism, animal model). These facts can be found on the journal's website in their description of scope and/or the guide for authors. Please see the additional resources below for other useful links.

Review papers

A great way to know what journals publish is to review papers. Once you go behind the curtain, it becomes clear what a journal is looking for. From my point of view, it's quite simple: something nicely executed that people will be interested in reading. For young investigators, it can be difficult to get experience reviewing, as many of the invitations go to more established scientists. You could consider asking established investigators that you know to mention your name if they decline to review. Once you establish yourself as a competent reviewer, you can also generate a name recognition with a journal. Thus, even if you don't "get credit" publicly for your reviewing, it can help you get to know the journal better and have the journal editors know you.

Talk to editors

If you attend large conferences in your field, it is likely that journal editors (both professional and academic) will also be in attendance. Some journals even list the meetings where you can meet their editors on the journals' web page. Alternatively, many journals and publishers host seminars about submitting your manuscript. These seminars can include the general (e.g., write a good abstract) and the specific (e.g., procedures for a particular journal). The more you can learn about the process, the easier the process will become.

Recommend useful reviewers

Most editors would probably not put this on their list, but this is a personal pet peeve. If you expect me to evaluate your work seriously, the reviewers that you suggest should have the credentials necessary to review your paper. In addition, the reviewers should not have recently co-authored papers with the authors on your paper (different journals have varying standards for this issue). If you know that the journal you will submit to relies on the Editorial Board for reviewing, then suggest useful members. This is another subtle way that you can convince journal editors that you know what you are doing.

Craft an artful response to reviewers

Cartoonist Nick Kim's take on peer review
In your response to reviewers, be sure to include the reviewers' original comments as well as your reply. It is also helpful to the reviewer to include a marked copy of your manuscript or to direct the reviewer to where your reply can be found (the specific requirements for these items vary from journal to journal). Such things will not necessarily ensure that your manuscript will be accepted, but it may engender some good will from reviewers, who are likely busy and will appreciate the ability to judge the revised manuscript quickly. You should also remember that you don't have to do everything the reviewers ask of you. If it is outside the scope of the paper or would not be necessary for the journal to which you are submitting, feel free to make that argument, just remember to keep a courteous tone.

While the peer review process can be daunting and tiring, it is important to remember that the point of peer review is to ensure that the paper is as good as it can be.

Additional Resources: 

Here the Senior Editor for Cell Reports offers advice on publishing your paper

Journal Finders: Journal Selector (in development); Journal finder tool

Tips from publishing pros on choosing the right journal

**Disclaimer: These suggestions are based on my experience and do not guarantee acceptance of your manuscript in any given journal. These opinions are my own and do not necessarily represent the opinions of my journal as a whole.

Tuesday, July 22, 2014

Toms River by Dan Fagin - New Jersey, Superfund, and cancer clusters

Toms River, once a quintessential Jersey shore town, is the focus of Dan Fagin's Pulitzer prize-winning book Toms Rivers: A Story of Science and Salvation. When Toms River welcomed the Swiss chemical company Ciba-Geigy (now known as Novartis) in 1952, they did not know that the company had left towns in both Switzerland and Ohio due to complaints about air and water pollution. The Swiss company owned and operated the Toms River Chemical Corporation for over 30 years without incident even though it was treating the local rivers and oceans as a dumping ground for its chemical waste. In the name of job creation and economic development, the people of Toms River turned a blind eye. (Of course, this is still the case. In places with a weak economy, job creation means absolution for any environmental sin.)

Toms River Chemical Corporation expanded rapidly, building a fortress-like factory isolated from the town by acres of forest. To the executives of Ciba-Geigy, the lesson from Basel and Cincinnati was that they should keep their waste practices hidden from residents to operate with impunity. Treating their toxic waste to even minimal standards would cut into the bottom line. The company had standing, unlined pools where untreated waste would be dumped year after year; the sandy soil of the Jersey shore readily absorbed the waste, giving the company the unforeseen benefit of disappearing waste. Unfortunately for the people of Toms River, those toxic chemicals didn't really disappear, especially from the water table. Complaints about the water supply tasting and smelling like chemicals precipitated the 1965 development of a pipeline to dump untreated wastes offshore. Even though this toxic waste pipeline ran through their backyards, the people of Toms River had seemingly no idea that it was present. At least not until a leak in the pipeline created a sinkhole on a city street in 1984. A company spokesman said that the effluent was simply salt and water, but the chemicals in the waste were likely the cause of the leak. Moreover, tests performed by independent agencies suggested that this "salt water" was highly mutagenic and not safe for sea life.

This toxic sink hole was a major turning point for the opposition to the chemical company in Toms River. The people of Toms River no longer felt safe with the waste practices of their neighbor, and they began to demand change. Around the same time, the story of Love Canal**, a town near Niagara Falls that was built on the site of a former chemical plant, had gained national attention. Love Canal residents were experiencing a variety of health problems, including asthma, miscarriages, and cancer. In 1980, the US government started CERCLA, more commonly known as Superfund. New Jersey had the most sites of any state in the US; two sites were in Toms River. One, Reich's Farm, was used as a dumping site by several local chemical companies, who paid a local entrepreneur $3.50 per drum to dispose of toxic waste. The companies included Ciba-Geigy and Union Carbide (whom you may remember from the Bhopal Disaster in India; UC is now part of Dow Chemical). The other site was the Toms River Chemical Corporation grounds.

The Superfund status meant that Ciba-Geigy would have to pay to clean up the hazardous waste on its factory grounds. In addition, the increasing pressure from residents helped ensure that the company would also have to treat their new chemical waste properly. These changes meant that doing business in Toms River was less profitable for Ciba. Predictably, the company started to decrease the size of the plant, eventually transferring their dye-making operations to Southeast Asia. (This move was purportedly to be closer to the textile industries there; the lower wages and relaxed environmental standards didn't hurt either.) However, even after the company left Toms River, the town's trouble wasn't over.

Fagin intercalates the history of Toms River with the scientific developments in environmental toxicology and cancer epidemiology. The author describes how the initial links between illness and chemical contaminants were made based on the observation that certain types of workers were more likely to have particular diseases. For example, chimney sweeps, who often cleaned chimneys naked, were more likely to get scrotal cancer, while dye workers, who were exposed to chemicals like those used in the plant in Toms River, were more likely to get bladder cancer. The first direct evidence that chemicals cause cancer came when rabbits whose ears were painted with coal tar (the starting ingredient in dye manufacturing) developed tumors (Yamagiwa and Itchikawa, 1915).

In Toms River, many chemical company workers developed cancer. It also seemed that the entire town experienced an increase incidence of cancer, particularly childhood blood and brain cancers. Such cancer clusters are difficult to study because the number of cases is not high enough to be statistically significant and because confounding factors (e.g., smoking, diet) were more likely to be the cause of the cancers. Perhaps most importantly, cancer is a complex disease, which could be considered a collection of diseases (blood cancers are different than solid tumors, which are different at each affected site). The causes of cancer are also complicated; for example, the Knudson hypothesis posits that multiple hits are necessary to cause cancer. A person might start with a genetic susceptibility (as I discussed in the case of BRCA mutations) or a viral infection (as was the situation for Henrietta Lacks) and then be exposed to pollution or some other mutagen, which would then lead to cancer. Thus, even if an entire town is exposed to the same chemical, they will experience the effects differently due to subtle genetic and environmental differences.

The later chapters detail how the cancer cluster was proven to be statistically significant (at least in some populations) and how the likely source of the cancer was identified. A case from a Superfund site in Massachusetts (which later became the basis for the book and movie A Civil Action) showed a definitive link between water pollution and a cancer cluster; this was a landmark outcome in epidemiology. In the case of Toms River, the connections were somehwat more tenuous. In 2001, the affected families received a combined $35 million settlement from Dow and Novartis (nee Ciba-Geigy). Interestingly, Novartis made headlines later that year for its development of the revolutionary drug Gleevec (discussed in my previous post about The Philadelphia Chromosome). The name change coincided with the company's move into pharmaceuticals, but was also a way to distance itself from its toxic past.

Throughout the book, Fagin's journalistic writing style is useful for the subject matter. The story can be deeply frustrating at times due to the mistakes made by Ciba-Geigy as well as at the lack of oversight and the absence of repercussions for the company. Fagin chooses to focus on the "good guys", the people who helped identify the cancer cluster and those who fought to fix the problem. Today, the people of Toms River are safer, and cancer incidence has decreased since the cleanup. However, people living close to where Dow and other chemical giants are currently operating are also experiencing cancer clusters. Despite this grim information, Fagin ends hopefully, discussing how the new developments in molecular epidemiology could improve the ability to link a disease with a pollutant. 


** For additional information see this excellent video of the history of Love Canal with updates

Wednesday, June 18, 2014

The Philadelphia Chromosome by Jessica Wapner: a story of scientific discovery from the bench to the clinic

The Philadelphia Chromosome by Jessica Wapner focuses on the development of the drug Gleevec for the treatment of leukemia. Wapner really hits the sweet spot of science writing: she explains complex processes completely such that an experienced scientist would be interested and yet simply enough that a layman would also understand. The book's primary source material consists of interviews with scientists. This gives the reader details not found in published articles and makes the book very readable, as the story of scientific discovery becomes about the scientists doing the research. The Philadelphia Chromosome highlights how understanding basic biology can lead to significant advances in the clinic.

Reciprocal translocation of chr. 22with chr. 9. Image by
Peter Lowell
The link between cancer and chromosomal rearrangements had been hypothesized since the work of Theodor Boveri in 1902. However, it was not until the mid-20th century that scientists had the right tools to investigate this connection. By arresting and staining cells during cell division, scientists were able to reliably count chromosomes. (As I learned in The Violinist's Thumb, this was one reason that it took so long to learn how many chromosomes humans actually had.) In the 1950s, Nowell and Hungerford used this staining technique to look for chromosomal rearrangements in patients with chronic myelogenous leukemia (CML). They noticed that chromosome 22 was shorter than it should be, suggesting that part of the chromosome was deleted. The shortened chromosome 22 was termed the Philadelphia chromosome for the city in which it was discovered.

Adapted from Montgomery et al., 2004.
In 1973, Janet Rowley, using an improved technique to stain chromosomes from CML patients, noticed that the missing part of chromosome 22 had migrated to the end of chromosome 9 and vice versa (see image above). Today, chromosomes are frequently imaged using spectral karyotyping (example on right), where each chromosome is fluorescently labeled with a unique color, making the identification of chromosomal abnormalities much simpler. Rowley's work showed that the Philadelphia chromosome was the result of a reciprocal translocation, referred to as t(9:22). In simple terms, if you imagine the genome is like a book with each chromosome being a chapter (yes, I am borrowing from Matt Ridley's book), then the Philadelphia chromosome would result from the switching of pages from the end of Chapter 22 with the later part of Chapter 9. A book with such an error would read very differently than the original version of the book.

The Philadelphia chromosome creates
a Bcr-Abl fusion protein.

The next question: how does the Philadelphia translocation change the DNA sequence on the two effected chromosomes? At the time, this proved to be a challenge because DNA cloning was still in its infancy. In 1978, Heisterkamp and Groffen started to investigate the location of the abl oncogene gene in the human genome. They developed an abl probe, which showed that the gene was on chromosome 9. This result raised the question: was the abl oncogene connected to CML and the Philadelphia chromosome? Amazingly, when the abl probe was used in cells from CML patients with the Philadelphia chromosome (Ph+ CML), the probe could be found both on the Philadelphia chromosome as well as the normal copy of chromosome 9. Next, they had to determine what gene was located next to the abl insertion. Looking at the sequence of chromosome 22 from Ph+ CML patients, they found the "breakpoint cluster region" or bcr next to abl. Thus, the Philadelphia chromosome results in a fusion of the bcr-abl genes (see figure above). Later research from the Baltimore lab demonstrated that introducing a bcr-abl fusion gene in mice could cause CML and CML-like symptoms.

Normally, abl encodes a protein tyrosine kinase. Kinases play an important role in cells: turning on target proteins. To ensure that proteins are activated only as needed, kinase activity must be carefully regulated. The Bcr/Abl fusion protein has unregulated kinase activity, which means that all of the target proteins are activated at higher than normal levels. In the case of CML, this leads to unfettered cell growth and proliferation, particularly in white blood cells. This result suggested that being able to turn off the kinase activity could stop the out of control growth of white blood cells in Ph+ CML patients.

The Bcr-Abl fusion protein (green)
is inhibited by STI-571/imatinib (red)
(from Wikipedia commons).
Around this time, increasing numbers of kinases were being linked to disease, especially cancers, which are typically due to unrestricted cell growth. This coincidence grabbed the attention of chemists at the Swiss pharmaceutical company Ciba-Geigy (now known as Novartis); they hypothesized that kinases could be excellent drug targets. This relatively new approach, called "rational drug design", would target the specific cause of a specific cancer, creating a drone strike as opposed to the "carpet bombing" tactic of most chemotherapeutics (p. 108). For the treatment of CML, scientists would need to design a compound to specifically inhibit the Abl kinase, which many doubted would be possible due to the large number of kinases in the cell. After six years of development, the Ciba-Geigy team identified a compound that selectively and specifically inhibited Abl kinase activity. Eventually, this compound landed in the hands of Brian Druker, who found that the Abl inhibitor (called STI-571 or imatinib) could specifically kill cells derived from Ph+ CML patients as well as from mice engineered to express the Bcr-Abl fusion protein.

Much of this section of the book focuses on the conflict between Druker and Ciba-Geigy, who were hesitant to devote resources to a drug for a relatively rare disease. However, the Orphan Drug Act helped tip the scales in Druker's favor. The approval of STI-571 as an orphan drug ensured that the company would have a fast track for FDA approval as well as a longer term for copyright protection. (Interesting side note: Botox was originally approved as an orphan drug to treat a rare muscle disease. Its later approval as a wrinkle smoother meant that the drug company benefited greatly from that status.) In 2001, after very successful phase I clinical trials, the FDA approved STI-571 under the trade name Gleevec. This caused a paradigm shift in cancer research; the new goal was to find driver mutations for each type of cancer. Today, more than 15 tyrosine kinase inhibitors are available for cancer treatment (e.g, erlotinib for lung cancer and lapatinib for breast cancer). Unfortunately, none of the drugs have been as successful as Gleevec; rather, these drugs give incremental improvements in survival rates. Another confounding factor is that diseases, particularly cancers, are rarely caused by single mutations. However, the advent of large scale genome sequencing projects (as covered in my review of Genome) is improving the chances of connecting diseases with specific mutations.

If I had one complaint about the book, it would be that the focus on Druker's career and personal life, while useful in terms of creating a narrative arc, sometimes distracted from other important elements of the story. The book highlights how basic scientific research is an important starting point for successful clinical outcomes. This lesson is critical to remember when funding for basic scientific research is decreasing and the focus on clinically and translationally relevant research is increasingly important for funding.

Wednesday, May 7, 2014

Post collapse fiction versus reality - The World Without Us by Alan Weisman

I love post-collapse science fiction in any form, so it is no surprise that I have been binging on the genre of late. Most recently, I finished Children of Men, the basis for an excellent movie, and Margaret Atwood's MaddAddam, the final book in the eponymous trilogy that includes Oryx and Crake and Year of the Flood. MaddAddam struck me with some of the details and descriptions of the post-collapse environment. It reminded me of The World Without Us by Alan Weisman, which I decided to re-visit due to my recent obsession with apocalyptic fiction. The book is something of a thought experiment to address the question of how the world would look without humans; it is definitely on my great science reads list.

I am Legend's image of New York City without us
My original vision of a post-collapse world was a paradise where plants and animals take over the newly vacated cities. The traces of our civilization would be quickly covered in kudzu and dust, as seen in The Walking Dead or I am Legend. However, Weisman's book changed this view; his book suggests that while some vestiges of our existence would disappear rather quickly, other elements would persist long after we are gone.

A crumbling Brooklyn Bridge five years after us (K. Brown)
My favorite chapter is "The City Without Us". The author spoke with a variety of experts (e.g., engineers, chemists, geologists) to discover how New York City would change after humans disappear. During the development of Manhattan, various environmental engineering projects transformed the island from a tidal 
500 years after humans: New York City becomes a forest
marsh filled with rivers and streams to the metropolis we know today. All of this water, currently trickling unseen under the city, would be a major force for change after humans are gone. The subway tunnels would fill with water only a few days after the power turns off. As the water seeps through the subway system, it would cause weaknesses in the roads and sidewalks. In combination with seasonal changes in temperature, bridges and roads would collapse quite quickly. Without people around to maintain the infrastructure, roads and bridges would likely be crumbling after just five years. In about 500 years, Weisman predicts that the city would be a forest, with a unexpected array of animals, including deer, moose, bears, and coyotes. The images on the right are from the author's website, where you can find more amazing visions of New York City without humans.

Abandoned bumper cars in Pripyat, Ukraine, the site of Chernobyl
Within days of our disappearance, power plants would go offline, causing meltdowns at nuclear plants. Chemical and industrial plants would catch fire without maintenance, making the initial landscape rather hellish. While the fires would eventually extinguish, the chemical and nuclear wastes would persist. These pollutants would then become a force for adaptive change. The city of Pripyat, the site of the 1986 Chernobyl meltdown, can serve as an example of how the landscape changes without us. The fallout from the disaster is estimated to irradiate the environment nearby until at least 2135. The Exclusion Zone (a 30 km radius evacuated around the plant) has highlighted how adaptable nature can be. Weisman discusses how the biodiversity in the Exclusion Zone has improved; in fact, the zone has become home to an increasing number of animals (e.g., moose, voles, rabbits, birds). Surprisingly, it is unclear whether these animals are experiencing an increased mutation rate (primary article with coverage on ScienceBlogs). The inner reactor core has proven to be a unique niche for evolution: scientists discovered a  radiotrophic fungi as a black slime on the inner reactor core; this fungus converts gamma rays into energy for growth. Other published articles have described how plants have adapted in the highly radioactive environment.

One vestige of human existence that would persist without us: plastics. Weisman thoroughly discusses the issue of plastics pollution, including the North Pacific Subtropical Gyre, more commonly known as the Pacific garbage patch. Like the four other oceanic gyres, this area of the ocean has become a sink for plastics in varying states of decay; plastic debris is reduced to smaller and smaller sizes by the action of waves and the sun. The majority of the plastic wastes in these gyres is in the form of microplastics. Because plastics have only been in use for about 60 years, scientists are only starting to understand the ramifications and possible outcomes of the life cycle of plastics. Likewise, this relatively short time frame means that microbes have not yet evolved to degrade them. Despite the gloomy information in this chapter, the author keeps a positive tone, suggesting that while we do not know how long it will take for plastics to degrade, there is hope on the geological timescale: "Like trees buried in bogs a long time ago....were changed into oil and coal," maybe plastics will degrade when microbes evolve to degrade them or when something else changes them altogether (p. 128). This geological view from the book's website may also help keep things in perspective. 

The World Without Us informs the reader of the knowns and spurs the imagination of the unknowns. In this way, it captures the things about post-collapse fiction that I find appealing: that initial sadness at the loss of our humanity, the imaginings of what kind of place the world will become without us, and the hope that the world could be better.

More links: 

* The author also discusses the Mannahatta project, which has done extensive research to chronicle what Manhattan looked like before Henry Hudson landed. I am adding the book about the project to my ever-growing book list.

* To get some ideas for this post, I read a lot of opinions on why human are so obsessed with the apocalypse. I did not find a really satisfying answer, but this piece was the best of the relevant articles.

* If you enjoy the pictures here, be sure to check out the AbandonedPorn (SFW) Subreddit.

                                                  Talking Heads' (Nothing but) Flowers.

Thursday, March 13, 2014

My Favorite Science Reads - updated

Here is a running list of my favorite science reads (in no particular order), which I will attempt to keep updated. I have included links to the Amazon page as well as the related post from my blog.

The Immortal Life of Henriette Lacks - Rebecca Skloot (my post here)

The Violinist's Thumb - Sam Kean (my post here); The Disappearing Spoon was also excellent (my post)

The Philadelphia Chromosome - Jessica Wapner (my post

Lab Girl - Hope Jahren (my post at CrossTalk)

Inheritance: How Our Genes Change Our Lives and Our Lives Change Our Genes - Sharon Moalem (my post)

The Panda's Thumb - Stephen Jay Gould (all the books I have read by Gould have been excellent)

The Shadows of Forgotten Ancestors -  Carl Sagan and Ann Druyan

The Selfish Gene - Richard Dawkins (The Blind Watchmaker is also great)

Radioactive - Laura Redniss (my post

Blueprint for a Cell - Christian DeDuve 

The World Without Us - Alan Wiesman (my post here)

Stiff - Mary Roach (I review Packing for Mars here, but it wasn't as good)

Tuesday, March 4, 2014

Matt Ridley's Genome - 14 years later

Genome - The Autobiography of a Species in 23 Chapters  by Matt Ridley came highly recommended on Amazon. Despite the fact that the book was published in 2000, I decided to read it. The structure of the book is rather clever: each chapter focuses on one chromosome. This format allows Ridley to expand the metaphor that the human genome is a book: each chromosome is a chapter; the genes are the sentences; the codons (the three letter DNA sequences that the cellular machinery reads) are the words; and the DNA nucleotides are the letters. This kind of metaphor can help non-scientists visualize and remember the organization of the genome. Unfortunately, Ridley eschews the proper scientific terminology, calling codons "words" and nucleotides "letters". Science writing should teach people more about the subject matter; to eliminate the use of fundamental terminology seems a folly.

In each chapter, the author highlights one gene of interest on the chromosome. For example, the chapter on chromosome 13 introduces BRCA2. Like the Jeff Wheelwright book I reviewed previously, Ridley discusses the population genetics of BRCA2. In some chapters, he writes about genetic lessons from a particular chromosome. In some cases, the conceit works brilliantly (e.g., the chapter on the X and Y chromosomes examines sexually antagonistic genes), but other times, it was not as successful. Ridley uses Chapter 21 to discuss eugenics. While the history of the topic is interesting, the connection to chromosome 21 seems a bit tenuous. Parents are increasingly using prenatal screening to detect chromosomal abnormalities, the most common of which is Down syndrome, which is caused by an extra copy of chromosome 21. I found the book worked best when there was an obvious candidate gene to discuss on the chromosome.

It is amazing to consider how much the field of genomics has changed since the publication of Ridley's book (February 2000). In June of that year, the initial rough draft of the human genome was published. When the sequence was officially completed in April 2003, the final cost was estimated to be $2.7 billion; the project took more than a decade. Today, we are approaching the benchmark of the $1000 genome (discussed here and here). The next step is to improve the speed and portability of sequencing equipment as well as the ability to process and analyze the data.

The human genome project has been considered a success in terms of yields for basic research. However, there has been some disappointment that the completion of the project hasn't led to more clinical applications (for more specifics, see these editorials from Francis Collins and Craig Venter, the heads of the Human Genome Project). One problem is that very few diseases are caused by a single gene. Another confounding factor is that there is 1-3% difference between any two individuals' genome sequences. These variations can complicate genomic analyses. To perform a genomic study of a population with a genetic condition, knowing the differences that are normally present in the genome can help narrow down the possible regions that are linked to the condition of interest. Thus, having more complete sequences available will allow scientists to connect DNA sequences with genetic conditions. The 1000 Genomes Project plans to identify all the genetic variations present in the human population. The initial phase of this project was completed in just over four years with the publication of 1,092 complete human genome sequences from 14 populations across the globe. In the coming years, the project plans to complete a total of 2,500 genome sequences to improve the representation of various human populations across the globe. 

Another major change in the genomic landscape is the advent of personal genomics, such as 23andme. These companies offer DNA analysis service that supplies information on your possible ancestry as well as information about other genetic markers. These markers include both the innocuous ones, like whether you can detect a terrible smell in your urine after eating asparagus, and genes linked to possible health risks (e.g., BRCA, Huntington's disease). After intervention by the FDA, the service is now limited solely to ancestry. Scientific American had a fascinating piece about why we should really be concerned about companies like 23andme (TLDR: they are collecting and storing your most personal data
your DNA).

I would not recommend this book to a non-scientist. If you want to learn more about the human genome and DNA, look elsewhere. I highly recommend The Violinist's Thumb by Sam Kean; the recently updated Double Helix by James Watson and the newest book from Craig Venter are likely to be good reads. 


Want
* The Human Genome at 10 Special Issue in Nature covers the changes in the genomics landscape with editorials and articles by a number of major players in the field.
* There is also abundant information on other "big science" approaches to genomics, such as  the HapMap, the ENCODE project, and The Cancer Genome Atlas [TCGA]. I have not explored these for the sake of brevity.