Fruit flies like banana? Yes, but they might like alcohol more

Specific behaviors have been evolved to protect us from pathogens. An interesting study shows that flies drink for medication benefit.

        Sometimes when stimulated, our bodies give rise to mysterious unconscious response the occurance of which we don’t understand at all. For example, when watching horror movies we may show gooseflesh that push us to avoid those disgusting scenes. As a result, we feel relaxed and comfortable. These natural responses like gooseflesh are protective measures our bodies acquired during evolution. Similar behaviors include our unconscious fear of snakes, spiders, and other animals. These protective behaviors are reminiscent of our immune system that is evolved to use cells and molecules in our bodies to prevent invading parasites. For such a resemblance, behavioral immune system was coined to describe our behavioral response against outside hazards.

        In general, any biological behaviors protecting an organism from infection can be called behavioral immune. Medication, the use of substance or procedures by humans to fight infection, belongs to behavioral immune response.

        Behavioral immune system can explain some of our unconscious behaviors. For example, we sometimes dislike strangers for no reason. It is not for no reason. It is only a reason you don’t realize. Your behavioral system automatically discriminate different persons according to their faces, their poses, their age, their figure or their smell. Thus, behavioral immune may lead to prejudices against obese, elderly, short or disabled individuals. Moreover, behavioral immune system even contributes to xenophobia and ethnocentrism.   

        Flies are much smarter than we thought. They can use behavioral changes to adapt to environments. Flies often face the threat from wasps under natural environments. Alcohol is useful for flies to prevent infection from wasps. Although flies are not alcoholic, they do use alcohol to combat infection from wasps. A paper in this volume of Science¹ unveiled an interesting discovery about how flies tackle this threat from wasps by utilizing alcohol, showing us an example of self-medication of flies.

        Researchers placed 300 flies in cages containing two food dishes one of which was added with 6% alcohol by volume. In addition, flies were also housed with or without female wasps as a threat. Fly eggs were collected for counting from different dishes in each situation (with or without wasps). Interestingly, researchers found in the cages no wasps were provided, flies preferred laying eggs in dishes without alcohol. On the contrary, in dishes with wasps, flies laid more eggs in dishes with alcohol.

        This is not the whole astonishing story. Flies can even tell the gender of wasps. Female wasps are more dangerous. When flies were housed with male wasps, flies would just ignore them and did not show preference on alcohol containing dishes.

        Under the situation when wasps don’t exist, flies have some tendency toward alcohol. They prefer laying eggs in 3% alcohol. This means flies like a little bit alcohol. However, when realizing deadly wasps are nearby, they would like to try even 12—15% alcohol, the highest level of alcohol found in nature.

        How can flies tell wasps, especially more deadly female wasps are nearby? They may do this by olfactory or visual cues. To answer this question, flies harboring mutations that result in defects in olfactory or visual system were used to observe their alcohol preference. Researchers found flies with mutations in response to olfactory stimuli can still display alcohol preference whereas vision mutants of flies failed to show their fancy on alcohol. Thus, flies must use sight to sense the existence of wasps. A small protein called neuropeptide F has been shown to increase of alcohol tolerance of flies. In this study, researchers also found neuropeptide F played a role in transmitting visual signal from wasps to guide the alcohol preference behavior of flies.

        Flies can have a short time memory of the existence of wasps. When flies were first housed with female wasps and then wasps were removed, flies still displayed an alcohol preference at most 4 days after wasps were devoid.

        Flies’s behavioral immune system showed an vivid example how organisms have obtained ability to adapt to nature.

[1] Fruit Flies Medicate Offspring After Seeing Parasites. SCIENCE VOL 339 22 FEBRUARY 2013 947-950.

Note: the attached picture is from website: http://en.paperblog.com/mental-health-fruit-flies-turn-to-alcohol-when-sexually-frustrated-163917/

A big lotto for biologists

The biggest life sciences prize ever

        Nobel prizes have long been regarded as the most influential prizes in history not only because of its high selection standards but also because of its huge amount of reward which is about 1 million dollars allocated to at most 3 laureates. Nobel physiological prize will still take the lead in boosting life science in the near future. However, the number of the reward has been eclipsed by a new announced Breakthrough Prize which is worth 3 million dollars, the most lucrative annual prize in the history of science.

        The Breakthrough Prize was launched by Mark Zuckerburg, the founder of Facebook, Yuri Milner, the co-founder of Google, and Sergey Brin, a venture capitalist with an intention to combat cancer, diabetes, and other maladies. The establishment of this prize was ignited by the dramatic progression in some state-of-the-art technologies like genome sequencing. This year, the prize goes to 11 scientists from United States, Japan, Italy, and Netherlands. Among these recipients, some really famous names in life sciences are hit including Yamanaka, the 2012 Noble Laureate for his contribution in induced stem cell, and Robert A Weinberg, who discovered the first human oncogene Ras and first tumor suppressor Rb.

        It is still premature to evaluate any influence of this prize on life sciences. One point is clear, smart and energetic scientists will be encouraged to make great breakthrough for human health.

List of recipients of 2013 Breakthrough Prize.   

1 Cornelia I Bargmann
Torsten N Wiesel professor and head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behaviour at the Rockefeller University. Howard Hughes Medical Institute investigator.
For the genetics of neural circuits and behavior, and synaptic guidepost molecules.
2 David Botstein
Director and Anthony B Evnin professor of genomics. Lewis-Sigler Institute for Integrative Genomics at Princeton University.
For linkage mapping of Mendelian disease in humans using DNA polymorphisms.
3 Lewis C Cantley
Margaret and Herman Sokol professor and director of the cancer centre at Weill Cornell Medical College and New York-Presbyterian hospital.
For the discovery of PI 3-Kinase and its role in cancer metabolism.
4 Hans Clevers
Professor of molecular genetics at Hubrecht Institute.
For describing the role of Wnt signaling in tissue stem cells and cancer.
5 Titia de Lange
Leon Hess professor, head of the Laboratory of Cell Biology and Genetics, and director of the Anderson Centeer for Cancer Research at Rockefeller University.
For research on telomeres, illuminating how they protect chromosome ends and their role in genome instability in cancer.
6 Napoleone Ferrara
Distinguished professor of pathology and senior deputy director for basic sciences at Moores Cancer Centre at the University of California, San Diego.
For discoveries in the mechanisms of angiogenesis that led to therapies for cancer and eye diseases.
7 Eric S Lander
President and founding director of the Eli and Edythe L Broad Institute of Harvard and MIT. Professor of biology at MIT. Professor of systems biology at Harvard Medical School.
For the discovery of general principles for identifying human disease genes, and enabling their application to medicine through the creation and analysis of genetic, physical and sequence maps of the human genome
8 Charles L Sawyers
Chair, human oncology and pathogenesis programme at Memorial Sloan-Kettering Cancer Centre. Howard Hughes Medical Institute investigator.
For cancer genes and targeted therapy.
9 Bert Vogelstein
Director of the Ludwig Center and Clayton Professor of Oncology and Pathology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Howard Hughes Medical Institute Investigator.
For cancer genomics and tumor suppressor genes.
10 Robert A Weinberg
Daniel K Ludwig professor for cancer research at MIT and director of the MIT/Ludwig Centre for Molecular Oncology. Member, Whitehead Institute for Biomedical Research
For characterisation of human cancer genes.
11 Shinya Yamanaka
Director of the Centre for iPS Cell Research and Application, Kyoto University. Senior investigator and the LK Whittier Foundation investigator in stem cell biology at the Gladstone Institutes. Professor of anatomy at the University of California, San Francisco

Stay colder, live longer

        My mentor’s grandma passed away without any diseases at the age of 101. He told me his grandma is very nice and optimistic. She is also humorous. Her children kept calling her to say hello and she said each of her children wanted to be the first one to know she is dead by calling her. By the way, the grandma lived herself. The grandma likes drinking black coffee. Moreover, although my mentor is tall and strong, his grandma is pretty short. Optimism, humor, drinking coffee and being short have all been linked to longevity. But we cannot ignore another reason: my mentor is from Minnesota, a north state of United States where is very cold in winter. Cold temperature may have an important influence on longevity.

        Cold temperatures have been found to be related to extended lifespan of both poikilotherms and homeotherms. Like refrigerator storage of food can slower the decay, cold temperatures are believed to slowing aging in a similar way: reduce the rate of chemical reactions since life itself, in essential, is a kind of complicated chemical reactions. This hypothesis implicates that cold caused lifespan increase is a passive process. However, the truth is, life is not like food in the refrigerator and it makes active efforts to resistance cold temperature and to live longer.

         Researchers from University of Michigan tried to understand how cold temperatures are associated with lifespan by adopting C. elegans, a kind of worm which is a model animal frequently used for studying aging and senescence by scientists. They discovered that instead of slowing reactions, C. elegans struggle in cold temperatures to live longer. There exist some channels in cell surface of C. elegans which are sensitive to temperature drop. Once perceiving the change of temperature, these channels will activate some signaling pathways in cells and eventually a protein called DAF-16, which is a known lifespan extending factor, will be activated. Activated DAF-16 contributes to lifespan extension.

        Interestingly, cold-sensitive channels function mainly in intestine but not in other tissues. Neural system is evolved to respond environmental signals and is supposed to be a appropriate platform for cold temperature response. However, researchers in University of Michigan reported that it is intestine but not neural system in C. elegans to respond to temperature changes. In C. elegans, intestine is also the fat tissue. Thus, both intestine and fat tissues contribute to lifespan extension.

        What lesson can we learn from this cold associated lifespan extension? Considering the benefits of cold are only tested in C. elegans, it is premature to draw any similar conclusions in humans. At least in mice, lowering the whole body temperature of animals is known to extend lifespan. Anyway, people have performed ice bath for multiply purposes. Maybe we should add another one: you will live longer if you keep the habit of ice bath as along as you can.

[1] A Genetic Program Promotes C. elegans Longevity at Cold Temperatures via a Thermosensitive TRP Channel. Cell 152, 806–817, February 14, 2013.  

A new tool for genome editing

Bacteria defense system takes its place in human genome editing

        An RNA based nuclear acids degradation system found in bacteria and archaea was tamed for human genome editing.

        Genomes store information of life and human genome editing holds promise to improve human’ health and overcome diseases. Some available genome editing tools attract wide interests. Zinc finger nuclease (ZFN) technology and Transcription activator-like effector nucleases (TALENs), both of which were invented recently for genome editing, won the Method of the Year 2011, awarded by the journal Nature Methods. Lately, a new genome editing tool was released in Science¹.

        This new technology is based on an exogenous nuclear acid degradation system in bacteria and archaea. During evolution, bacteria and archaea face frequent and tremendous threats from environment. Exogenous nuclear acid constitute a main jeopardy because genomes of bacteria and archaea are not protected as well as that of advanced life. Bacteria and archaea thus develop a mechanism to combat exogenous nuclear acid. This system adopts RNA, which is characteristic of short repeats, and proteins to degrade invading nuclear acid. Shorted and repeated RNA is mainly responsible for the recognition of threatening exogenous nuclear acids whereas the RNA associated protein takes care of the degradation step. Although this nuclear acid degradation aims at invading DNA or RNA, they may be modified to target the human genome.

        Scientists in Havard Medical School engineer this nuclear acids degradation system in order to obtain targeted degradation of DNA sequence in human genome. The designed DNA sequence targeting interested DNA in human genome was linked to a DNA scaffold that facilitates the access of the protein responsible for degradation. The protein for degradation was also engineered to ensure location and high expression in human cells. The artificial DNA and protein are sent to human cells together. The designed DNA will recognize its corresponding DNA in the genome. Then the protein will function to cut the DNA in the genome. All mentioned above is what this bacteria originated system does. Other steps were finished by DNA repair system in human cells. Realizing a DNA damage (here it is broken DNA), the DNA repair system will try to repair it based on a similar DNA sequence, which is the special designed DNA in the artificial DNA donor in this case. The desired mutations, insertions, deletions will be thus possible.

        What are the advantages of this new genome editing tool compared to other tools? This system is easier and more efficient compared to ZFNs and TALENs. Both ZFNs and TALENs adopt specific proteins to recognize interested DNA sequence. It is tricky to design appropriate protein scaffold to match DNA in genome. The bacteria originated gene editing system uses DNA to recognize DNA in genome so it is easier to design DNA sequence. Actually, the authors have designed DNA sequences that able to cover about 40.5% exons in human genome. This bacteria originated DNA editing tool is also effective. In the Science paper, this new gene editing system achieved at most about 8% gene editing rate whereas TALENs resulted in not more than 1% gene editing rate.  

        A key standard to evaluate a gene editing tool is its specificity. That means it will favor interested genome regions but not other regions. Theoretically, this bacterial originated DNA editing system is specific because it usually uses 20 nucleotides, the length of which guarantees the required specificity in human genome, to recognize genome DNA. However, off-target effect of genome editing is still necessary. The Science paper did not resolve this concern.

        An exciting thing about this bacteria originated gene editing tool is there is more space to develop this technology. Both DNA scaffold and degradation proteins can be engineered to improve their efficacy and specificity.

Luck control

        People fail to realize how lucky they are except when some tragedies hit someone else. Every day, by watching TVs, surfing internets all of which report so many accidents, we got the idea that the world is full of risks. China is occupied by hazardous air; United States is discussing gun control; North Korean is testing nuke weapons; Solomon islands are experiencing earthquakes. Thus, fortune is not the arrival of good luck in the future, but the escape of bad luck in the past. Chinese cherish this kind of fortune by coining a word “houpa” that means the fear after the event. Western culture has also a similar expression: no news is good news.

        It makes more sense that we did not realize how lucky we are when it is about cancer. Everyone will develop cancer very early if their bodies fail to repair a great deal of DNA mutations caused by environments. Majority of people have no idea how many mechanisms in our body work together to protect us from cancer. For example, when DNA in a cell was hurt by UV, radiation or other stress, a protein called p53 will be activated to induce a cascade of events that lead to the death of the cell. So many similar proteins exist that DNA mutations will be eliminated under different circumstances. Every day, our bodies have fixed a great volume of mistakes in DNA without our realization.

        Among all hiding safeguard mechanisms preventing us from cancer, immune system is fundamental and vital. Immune reactions are tamed to help to reject cancer. Research of how to tame immune system for cancer treatment is called cancer immunotherapy. Historically, cancer is controlled by surgery, radiation therapy, chemotherapy, and latest targeted therapy. All these methods kill cancer cells using foreign materials without considering if these materials will also do harm to our body. Different from these methods, cancer immunotherapy focuses on provoking our immune system to work better to kill cancer cells. As a result, the side effects of cancer immunotherapy are less and the efficacy of it is better.

        Everyone has immune system so we are all lucky. But under some circumstances like cancer, luck is not enough. We need to control luck. Luckily, we are on the way.

Cancer: task impossible? Depending on what measurements we use

It is better to admit failing to win the war against cancer than fail to admit it.

        The Wall Street Journal published an article by Bill Gates a couple of days ago. The heading is so striking that I cannot help reading the contents. The title is “my plan to fix the world’s biggest problems”. However, after I went through the paper, I was a little bit disappointed because what Mr. Gates had declared as great plan for resolving biggest problems is actually very basic. Mr. Gates described the process of solving problems as simple 4 stages “setting clear goals, choosing an approach, measuring results, and then using those measurements to continually refine our approach” and emphasized that measurements are extremely important and the key to fix the biggest problems in today’s world: poverty, disease, lack of education and so on. Although it sounds simple, what Mr. Gates had said is indeed instructive. Setting goals is easy. People who tend to make New Year’s resolution will be able to know how easy to set goals. Selecting an appropriate approach is harder and requires smart thinking. But they are not in the same street with measuring and subsequent refining in term of the measuring. Measuring enables us to know how close we are from the goal.

        Where are we on the road map of cancer research in the light of current measurements we adopted?

       The answer, according to today's starndard, is probably we stay where we were decades ago in cancer research. About forty years ago, the president Richard Nixon set the goal to eradicate cancer by signing the National Cancer Act in 1971. The war on cancer campaign also fosters mounting cancer research. However, cancer incidence and death rates, which are two main standards to measure cancer research, keep unchanged during the past 40 years. The measurements have told us that cancer remains a big burden for Unites States. Moreover, some cancers show increasing incidence and death rates in United States and other countries. 
        It may be smart for us to accept the fact that we failed to win the war on cancer based on today's measurements. Only by accepting this fact, we can make some adjustment to better control cancer.

          Once we admit the fact that we failed the war on cancer, we will be able to figure out what we should do next. The direction for cancer control should be averted to cancer diagnostics and cancer prevention both of which entail broad and deep understanding of cancer genetic factors and environmental factors.      

        We might also need to adjust the standard we used to measure cancer control. Incidence rate and death rate of cancer have been used as golden standard for measuring cancer situation but may mask what we have achieved in cancer research. New measurements should be adopted in evaluating cancer control. Early detection rate, for example, may be used as a standard to measure cancer control and incorporated in cancer statistics.    

        Due to the aging population and deteriorating environment, the world will suffer tougher cancer burden. However, if we follow the direction of cancer diagnostic and prevention and adopt new measurements for cancer control, we might witness a tremendous progression in cancer control.

Discovery of Richard III's skeleton: DNA meets archaeology

Analysis of DNA in ancient remains enables us to reevaluate history.

        A 500-year-old remains found beneath parking lot in Greyfriars, Leicester was confirmed to belong to King Richard III, the last Plantagenet king of England, who is the subject of many works of literature including Shakespeare’s play Richard III.

        How was the skeleton regarded to be that of Richard III? On the one hand, ancient maps and records support that the parking lot which used to be a friary is actually the place where Richard III resided in. On the other hand, DNA test provided the decisive proof. DNA test was performed by comparing DNA from the remains discovered in Greyfriars and that from Canadian-born Michael Ibsen who is a direct descendent of Anne of York, Richard’s elder sister. Researchers responsible for this project have alleged: “It is the academic conclusion of the University of Leicester that beyond reasonable doubt, the individual exhumed at Greyfriars in September 2012 is indeed Richard III, the last Plantagenet king of England.”

        How can they be so sure that skeleton belongs to Richard III? Researchers did not disclose many details. But what they have announced is not convincing.

        The DNA test University of Leicester researchers have done must be like paternity testing which can tell if two individuals have a biological parent-child relationship by analyzing specific DNA information between two individuals that will be inherited from parent to child. In a standard DNA paternity test, usually a child, alleged father, and the mother are involved. The mother’s participation in the paternity test helps to exclude half of the child’s DNA, leaving the other half for comparison with the alleged father’s DNA. The DNA test about the identity of Richard III must be based on a method similar to paternity testing: comparing DNA information between the skeleton and Michael Ibsen. But at least two controls (controls with known information are used in biological experimental designs for ruling out or ruling in a candidate) should be set: first, an irrelevant random DNA should be incorporated as a negative control, and second, DNA sample from another descendent of Richard III should be incorporated as a positive control. These two controls are useful to rule out systematic errors.      

        DNA has played a role in identifying one of great names in history. In the future, DNA may be useful to disclose the health conditions of those great names in history that may shape the characters of those people or influence key events in history. In this way, the involvement of DNA in archaeology will change the landscape of archaeology.

The future of cancer genome sequencing

Three trends in cancer genome sequencing

        No doubt that genome sequencing will dominate future cancer research and clinic. A great number of papers published in high impact journals have adopted genome sequencing to resolve questions in cancer research that were once unrealistic to answer. Many oncologists hope to acquire the genome information of patients to guide their clinical administration. A few growing biotechnology companies have launched genome sequencing based products for cancer diagnostics. Media also pay much attention to genome sequencing. The essential reason of this trend is the genomic origin of cancers. Like what famous cancer geneticist Robert A. Weinberg has proposed in one of his most broadly cited papers, cancer actually originates from genome instability and relevant mutations. Another important reason for the blossom of genome sequencing is tumor heterogeneity which means there are no two tumors alike. Only by genome sequencing can we know exactly how special a tumor is and what therapy is best for it. Thus, the capacity of detecting genome information using sequencing tool has been favored by both Ph.Ds and M.Ds.

        The genome sequencing is in adolescence for basic research and in babyhood in clinic. How will it grow up? There might be three kinds of trends.

        Single cancer cell sequencing

        There are no two pieces of leaves alike. So are tumor cells. A tumor cell’s special identity can be recognized by expressed proteins, RNAs in the cell. But the fundamental way to distinguish a tumor cell is genome sequencing. Single cancer cell sequencing is thus important.

        Sequencing itself requires a certain amount of DNA that usually cannot be acquired from a single cell. Amplification of DNA extracted from a single cell is necessary to obtain enough DNA for sequencing. Latest state-of-the-art sequencing technology is viable for single cell sequencing.

        Single cell sequencing may not be suitable for clinic because analyzing a tumor instead of a single tumor cell is more appropriate for patient’s benefit. However, it is indispensible for studying fundamental questions in cancer research like cancer origin, cancer stem cell and so on.

        Dynamic sequencing

        No man ever steps in the same river twice. Tumors change their genome quickly, especially when they undergo anti-cancer drug exposure. Genome-changed tumors may not be sensitive any more to the drug that works formerly. Finding out the changed genome information is necessary before a new therapy will be applied. This implies that the genome sequencing should be performed periodically to monitor genome dynamic so that optimized therapy can be administrated. This dynamic genome sequencing will be especially important when tumors have improved drug resistance to a drug by producing new mutations. 

        Noninvasive sequencing

        Current genome sequencing requires pathology tissues. However, sometimes acquiring pathology tissues are painful and even dangerous for patients. Melanoma represents such an example. This situation calls for noninvasive test. At least under one condition noninvasive test becomes possible. It is when tumor cells shed from the primary tumor into bloodstream and circulate there. This phenomenon is christened as circulating tumor cells. By analyzing genomes obtained from circulating tumor cells, the cancer mutation signature can be captured and appropriate therapy options can be suggested. 

        These three trends are not mutual exclusive and combining these methods will enable us to better understand cancer.

Cancer genome sequencing: a routine examination in the near future?

        Bill Gates is not necessarily right in every investment. However, as a shrewd businessman, he will not invest without a solid reason.  Recently, Foundation Medicine, a new biotechnology company launched in 2010, said they received an investment of 13.5 millions from Bill Gates. Its first product, FoundationOne, is an integrated service of cancer genomic test which will suggest the best therapy for a cancer patient based on his genome information. What made Gates send money to this company? The answer is simple: this company is promising. It was rated as one of the 15 fierce biotechnology companies in 2012. It has won investments not only from Gates but also from big capitals such as the Third Rock and Google Ventures.

        In fact, I would rather say that Bill Gates and other venture capitals invested in the future of cancer genome sequencing than the company. Cancer genome sequencing and relevant analysis hold the promise for cancer control in the future.

        Currently four types of cancer treatment are available in clinic: surgery, radiation therapy, chemotherapy, and targeted therapy. These four treatments have all been adopted as routine therapy in clinic practice. Targeted therapy, in which the drug is designed against specific cancer mutations, becomes increasingly popular for its specificity and low toxicity. It is likely to surpass radiation and chemical therapy to become the primary option for cancer patients in the future. Since cancerous mutations are tremendously diverse among individuals, cell types, and clinical stages, the success of targeted therapy is highly dependent on how accurately the mutations can be measured. FoundationOne, as the company has described, can probe the whole genome information of a patient using a piece of solid tumor tissue. Moreover, FoundationOne service can be updated regularly as more mutations are indentified and more targeted therapies become available. FoundationOne represents one of available clinical practices translated from the so-called personalized medicine, a concept favored by today’s oncologists.  

        How good is FoundationOne?

        It is not as good as it sounds to be. There are some reasons for the imperfection of personalized cancer treatment. First of all, targeted therapy itself is not perfect. The biggest problem of targeted therapy is drug resistance. All known anti-tumor drugs targeting mutations result in drug resistance in 6 to 18 months after usage. Secondly, targeted therapy is more expensive than the traditional therapies. For example, Erlotinib, a drug targeting mutations in lung cancer, extends life by an average of 3.3 month at a cost of $95000. Thirdly, not all cancerous mutations are suitable for drug targets. For example, there is currently no drug against Ras mutation, a frequently mutated gene in cancer. Fouthly, tumor genome, which is different from normal genome, changes rapidly, thus requires periodical examination.       

        Although FoundationOne is not perfect  at this point, it is  being improved, as stated on the company’s website. As the cost goes down, cancer genome sequencing will hopefully become a routine medical examination in the future, just like blood test and urine test. As new drugs are being designed and drug resistance mechanisms being unraveled, the power of cancer genome sequencing may truly come to play.    

DNA disk

        Animals use urine to mark territory. By using urine, they broadcast the news: I am the boss of this place! Other animals read the information that the place has been owned by someone else from urine. Then the newcomers may choose to leave or stay to fight for the territory. In this case, urine was used to store information. Urine is so cheap that it is practical for animals to claim territory. However, urine cannot hold too much information. For example, it is hard for newcomers to tell how strong the settlers are so that they can decide if they might stay to fight. Urine cannot last too long either so animals have to pee frequently to make a territory claim. To sum up, urine is practical to store simple information for a short while, that can be read by other animals. From this example, we can learn a lesson about how humans store information. When we store information, we usually consider four factors: practicality (how easy the information can be produced), capacity (how much information can be accommodated), maintenance (how long information can be kept), and readability (how easy information can be read).

        Books written in papers are first milestone of information storage. Books are practical because papers are cheap and easy to handle. Books can last many years. People with normal intellect can learn how to read and write without too much difficulty. With the emergency of silicon chips, humans achieved tremendous progression in information storage. Simple symbols, namely 0s and 1s, were used to represent everything. Silicon chips beat books in every aspects: higher capacity, easier to maintain, and easier to read. Smaller hard drives with higher capacity are created continuously.

         However, we still face unmet need for information storage. More and more information was produced especially in biology field. For example, genome sequencing has produced and is producing a vast volume of information. How to store these massive amounts of information poses a huge challenge to humans.

        What should be the next-generation carrier of information deluge after books and silicon chips? DNA may be the qualified candidate since it has been used to store information by nature for millions of years. Scientists figured out how to use DNA to store information.

        Nick Goldman designed a method to store information in DNA. They tried to store in DNA Shakespeare’s sonnets (ASCII text), Waston and Crick’s paper about the identification of DNA double helix (PDF), a colorful photo of European Bioinformatics Institutes (JPEG 2000), Martin Luther King’s “I have a dream” speech (MP3), and Huffman code. These documents were encoded into binary text, namely 0s and 1s. Subsequently, these binary texts were translated into base 3 encoded files (0s, 1s and 2s) that correspond to long DNA sequences. Long DNA sequence is supposed to store information but it is hard to read by sequencing. Thus, short DNA sequences with overlapping segments were designed to represent long DNA.  Moreover, indexing information were added to short DNA sequences so that it is possible to find which DNA corresponds to which document. Overall, the five files listed above were represented by a total of 153,335 strings of DNA, each comprising 117 nucleotides (nt). The DNA was synthesized and lyophilized for shipment in ambient temperature from USA to Germany via UK. In Germany, DNA was resuspended, amplified, purified and sequenced. Then full-length DNA sequence corresponding original files was reconstructed based on sequencing results. For these five files, it turned out to be a 100% accuracy of reconstruction.  Martin Luther King's speech is still clear and heart-stirring. 

        Needless to say that DNA can hold much more information and can be maintained more easily than magnetic tapes. But Is DNA storage practical? Currently the cost of DNA storage is about $12400/MB for information storage and $220/MB for information decoding. This cost is much higher than magnetic tapes. However, information stored in magnetic tapes needs to be copied frequently in case they will not be extracted because magnetic tapes cannot last very long. By contrast, synthesized DNA can last thousands of years under normal maintenance. DNA encoding will also be cheaper if the current trend of DNA manipulating continues. In less than 50 years, DNA storage will be practical. The information writing and reading into DNA is not competitive with current technology but can be accelerated. In summary, DNA storage holds a big promise for massive amounts of information storage.

        It is possible to connect a DNA synthesizing machine and a DNA sequencing machine to a computer. Then we will be able to manipulate information in a DNA based format.  

[1] Towards practical, high-capacity, low-maintenance information storage in synthesized DNA. Nature (2013) doi:10.1038/nature11875 Received 15 May 2012 Accepted 12 December 2012 Published online 23 January 2013

Body size vs. cancer: the bigger the better, or the smaller the better?

        The hypothesis that cancer arises from accumulated mutations can account for many findings. For example, the longer an organism lives, the more likely it is to have cancer, because theoretically it builds up more mutations over time. This has been supported by epidemiological studies that showed a vast increase in the number of cancer patients in many countries owing to an aging population.

        Aside from longevity, another interesting issue is body size. One may assume that the bigger  organisms are more likely to get cancer than smaller ones, because bigger bodies have more cells and thus more mutations. Although this idea sounds logical, it has been proven to be only partly true. Larger individuals do appear to have increased risk of cancer than smaller ones of the same species,. However, cross-species studies failed to support this hypothesis. No correlation was found between body size and the incidence of cancer between different species. For example, the incidence of cancer in humans is much higher than that in whales, which are about 100 times the size and about 1000 times the cell number of humans. In another example, humans and rodents have similar incidences of cancer despite the fact that they are enormously different in size.

        One explanation scientists have for this paradox is that bigger-sized species are usually more resistant to carcinogenesis.  They do so by developing many mechanisms, one of which is low metabolic rate. At lower metabolic rate the body produces fewer free radicals, which are an essential culprit that leads to cancer.

[1] Peto’s Paradox: evolution’s prescription for cancer prevention. Trends in Ecology and Evolution, April 2011, Vol. 26, No. 4.

The memory of mental trauma

     What we experienced mentally as a child may have unspoken impact on our characters as an adult. It is well-known that Hitler experienced a miserable adolescence when he was severely abused. This troubled upbringing was believed to have a dominant negative effect on Hitler’s moral psychological development. On the contrary, Beethoven grew into a great musician with the tough training from his abusive father. Both environmental stresses and our genetic factors shape us. But how does this happen? 

        Imagine an injury when we got cut by a knife. Suppose that a child got hurt on his finger when he was carelessly playing with a sharp knife. He was left with a scar that may be conspicuous even years later. Four things are important during this process: the finger, the knife, the injury represented by blood, and a hidden genetic profiling of the kid. This fourth hidden genetic factor can be easily overlooked, but it is very important. For example, when a kid with haemophilia is cut in the finger, he will experience excessive bleeding.

What resembles the finger, the knife, the injury and the genetics when we get mentally stressed? They are dopaminergic neurons, specific stress, glucocorticoids, and similar genetic factors. Dopaminergic neurons are located in the midbrain. Although fewer in numbers, they are involved in a lot of behavioral processes, including mood, reward, addiction, and in particular, stress. One specific example of mental stress is social isolation. Glucocorticoids are important hormones responsible for regulating a lot of physiological events. It is glucocorticoids that affect dopaminergic neurons. The hidden genetic factors can be complicated, and a great number of genes are related to mental stress response. One gene called DISC1 was found to predispose individuals to schizophrenia and clinical depression. When an adolescent boy gets socially isolated, the “knife” of stress leaves “cuts” in the dopaminergic neurons. He will experience changes in his dopaminergic neurons and in the secretion of glucocorticoids. These changes will reshape, to a degree, his personality.If the kid unfortunately has an altered DISC1, the changes will probably have more severe consequences. 

        Then how are the changes in dopaminergic neurons retained in the mind to allow a profound influence to present itself years later? It is unlikely that the genes in dopaminergic neurons have changed, because DNA sequences, except those in tumors, often remain the same during one's lifetime. However, DNA can undergo some modification, such as methylation. The modifications may last for a long time. In dopaminergic neurons, a gene named tyrosine hydroxylase can undergo DNA methylation, and such methylation can be burnt into memory that will affect behavior years later. Therefore, although the DNA sequence remains the same, the function has changed. The DNA modifications such as methylation, acetylation, and histone modification, constitute the so-called epigenetics, which is a hot research field in genetics.

        What a surprise to know that our genetics is susceptible to mental trauma, and that DNA modifications can stay with us for so long! Please rest assured because the other side of the coin is that these discoveries bring forward new solutions. First, with the aid of personal genome sequencing, which is becoming affordable nowadays, a clinician can tell if a person is predisposed to sustain certain mental diseases. This can lead to early prevention and better diagnosis of mental illness. Secondly, scientists can develop new medicine to re-modify the DNA modifications and to help patients recover from mental trauma. 

[1] Dopaminergic neurons. Int J Biochem Cell Biol. 2005 May;37(5):942-6.

[2] Adolescent Stress−Induced Epigenetic Control of Dopaminergic Neurons via Glucocorticoids. Science 339, 335 (2013)

Sequencing dominates latest biological research

        Having worked in biology field for 10 years, I witnessed the tremendous change in the focus researchers devote themselves to in order to solve the challenging puzzles in life sciences. Essentially, protein has given way to RNA and then RNA was surpassed by DNA. Protein dominated the stage decades ago. Western blotting, a way to detect protein, was once favored by researchers. Then RNA took the leading role. This owed to two key techniques: PCR (first developed in 1983 and awarded with Nobel prize) and microarray (nominated for Nobel prize a couple of times). Both methods use short oligos (primers in PCR and probes in microarray) to detect the amount of RNA. In this day and age, it becomes more about DNA.

        DNA has many advantages to be used to account for phenotypes. First, it is DNA that stores genetic information. Secondly, DNA encodes RNA and protein. Thirdly, DNA is more stable than RNA and protein. Protein and RNA were once heavily used to explain interesting phenotypes at a time when DNA sequencing was impractical. Nowadays, owing to the rapid progress in faster, more accurate, and more affordable DNA sequencing technology, DNA is becoming the primary choice of researchers.

       An adequate mass of tissue is favorable for DNA sequencing. However, not all cells in an organism have identical genomes. For example, tumor cells may harbor DNA mutations (the so-called tumor heterogeneity) which account for many clinical problems, such as drug resistance. Under this circumstance, single-cell sequencing would be ideal. In other occasions, single-cell sequencing is desirable because the available material is very limited. For example, in prenatal tests, only a few cells are collected from the fetus; in circulating tumor cell screening, only a few cells are shed into the bloodstream from the primary tumor; and in a forensic test, only a few cells are preserved.

        Since DNA content from a single cell is trace amount, an amplification of DNA is necessary to obtain enough DNA for sequencing. This is usually achieved by PCR amplification. However, PCR introduces extra bias, and it may not cover the whole genome. Primers (short DNA oligos used for PCR) and polymerase (the enzyme for DNA amplification in PCR) have been optimized to boost the PCR yield and the genome coverage, but the results are yet to be satisfying.  

        Recently Zong and colleagues (Science 2012: 338:6114, 1622-1626) developed a new method, MALBAC, to improve the coverage in DNA sequencing from a single cell. This method adopted multiple random primers, a DNA polymerase with strand-displacement activity, and semi-amplification process at various temperatures. By using this method, they successfully identified single-nucleotide polymorphism (SNPs) and copy-number variations (CNVs) from single human cells. This technology may prove to be a great contribution to life sciences at DNA age.

Rumor vs tumor: not only from R to T

           

        When 12-21-2012 was approaching, a girl in Shanghai, China, left Shanghai for a shelter in a small village far away, hoping to escape the catastrophe of the doomsday. We know that the world did not end on the so-called doomsday, and, with good wishes, we thought all those rumors would be soon gone. They did not. They still linger around us. One day, my friend asked me: do you know why it is so warm this winter? After getting an indifferent "I don’t know", he told me mystically about his theory: the volcanoes in Yellowstone will erupt this year! 
 

        People have so many weird ideas, and with the help of internet and especially social media like facebook, twitter, etc., these ideas can go viral. Then faulty ideas may become rumors. Interestingly, tumors are just like rumors. Both spread rapidly, both can boom out of control and both are dangerous. Now let’s make an in-depth comparison between rumors and tumors.

        Social phycologists have been studying rumors since long ago. Four concepts have been brought forward to help people understand rumors: motivation, situation, narrative context, and trust. We can find a counterpart for each of these four concepts in tumors.
        

        People are often motivated to find out if a rumor is true.  Sometimes it is hard to prove or disprove a rumor. So they rely on watching how other people respond to it. When they cannot disprove it, they pass it on. This is so-called motivation. Tumors, on the other hand, are initiated when they become wrong. Tumors harbor a variety of DNA mutations that frequently undergo scrutinizing by safeguard mechanisms of our body. When the body fails to fix mutated DNA, owing to genetic or environment factors, tumors may begin to develop. 


        Situation to a rumor is like drought weather to a wildfire. Situations that pose ambiguity or threats to assets (life, health, wealth, group honor, and cherished values) can foster rumors. Government policies which fails to avoid ambiguity to assets, For example, can stir up a lot of rumors in the stock market. Likewise, tumors can not exist without appropriate situations. The environment that surrounds tumors, the so-called niche or tumor microenvironment, plays a far more important role in tumor initiation and development than we originally recognized. Different from rumor situation that usually aids in rumor spreading, tumor niche contains both good and bad components. Several subsets of cells reside in tumor niche, including cancer stem cells, cancer associated fibroblast cells, immune inflammatory cells, endothelial cells, pericytes, and others. These cells can be good or bad, depending on various factors such as their numbers and ratios. 


       Narrative context is important, too. Chinese people may not get a joke told by an American. Rumors may sound more plausible in one group than another. Likewise, tumors don’t metastasize just anywhere. Certain tumors are predisposed to seed in particular organs. For example, prostate cancer tends to metastasize to the bones, colon cancer to the liver, and stomach cancer to the ovaries. This was first proposed as the “seed-soil” theory by Stephen Paget in 1889.      
    

         Trust may be the most important factor to the spread of rumors. Similarly, tumors can not exist without the trust of the immune system. Immune system, except its role in controlling pathogens, may also monitor proliferative cells that may develop into tumors and will kill them when they are threatening the health of the body. Immunosurveillance and succedent immunoediting were proposed to explain how tumors are monitored and even sculpted by immune system. Tumors have developed many ways to win the trust of the immune system and escape being killed. For example, tumors may enter dormancy and stop dividing so that the immune system will mark them as good cells.  

        Neither rumors nor tumors are like humor. They are not good, and they are not rare. The longer a rumor or tumor has existed, the more it will do harm to the world and our body. It is impossible to live in a world without rumors or tumors, but it is possible to tell a rumor from truth, tumor from normal cell earlier. In that way, we will be able to have more humor when facing both rumor and tumor.

[1] Rumour research can douse digital wildfires. Nature. 2013 493, 135-135, doi:10.1038/493135a

[2] Cancer immunoediting: from immunosurveillance to tumor escape.Nat Immunol. 2002 Nov;3(11):991-8.

Tumor sleeps

        All higher animals need sleep. Mammalian sleeps regularly. Some animals like bear even take prolonged winter sleep. Reptiles that are unable to keep constant body temperature go into various periods of dormancy depending on the latitude and the local environment. Adders in north Europe have a dormancy of 275 days, whereas adders in south Europe have a dormancy of 105 days. The dormancy period for adders In UK is only two weeks, owing to the warm climate provided by the Gulf Stream. Dormancy is a state of being relative less active and more resistant. It helps organisms to adapt to unfavorable environments.

        Tumors also enter dormancy to avoid certain extreme environments, such as the microenvironment in their early progression, during micrometastases, or after a successful anti-tumor treatment. During early progression, the immune system of the host attempts to nip tumors in the bud. In the process of micrometastases, tumors endure angiogenesis suppression. Right after anti-tumor treatment such as surgery, chemotherapy, or radiation, tumors face even tougher situations caused by invasive procedures or drugs. Some tumors get around these extreme environments by going dormant.

        The phenomenon of tumor dormancy poses many interesting questions: How do we detect sleeping tumors? Can they be killed more easily or will they go rampant if awakened? How is tumor dormancy initiated? If we can take advantage of tumor dormancy, we may be able to switch tumors to dormancy indefinitely so that patients will die with tumors but not of tumor.

        

      

       

How severe is PM2.5>900 in Beijing?

       

I am not surprised to see a picture which shows vividly how notorious Beijing’s air is. Last year I took a flight from Seattle to Beijing. Right before landing, I noticed that the sky was yellow and smoggy. When I went to the restroom, the worker there complained to me how he had to mop the floor and wipe the counter all day long to prevent the dust from smothering everything. 

        This time I am not surprised. What I saw in this picture is similar to that of last year. But this time, instead of giving it a casual glance, I stopped to think: how severely will this air pollution affect our health? 

       Some indexes by size have been used to classify particulates in the air. Unlike other parameters such as component and shape, size is a simple yet concrete standard, and is easy to measure. PM2.5 and PM10 (particulate matter with diameters of up to 2.5 micrometer and 10 micrometer, respectively) are two common categories. PM10 can enter the lung; PM2.5 can penetrate the air exchange membranes of the lung.

Some studies showed that PM2.5, once in the body, can induce oxidative stress and damage DNA. It has been associated with high risks of heart disease, cancer, and asthma. Even short-term exposure to high concentrations of PM2.5 can pose significant health risks. PM2.5 at 10 (10 microgram per cubic meter) or less is considered safe. PM2.5 at 75 or less is acceptable. Based on the news, some cities (not only Beijing) have detected PM2.5 at a concentration of over 900. That is more than 10 times of the acceptable level! 

        Needless to say, something must be done to curb this severe air pollution.

Drug resistance: maybe it is only because we have worked too much!

       

        People are no strangers to drug resistance of microbes: Bacteria and viruses cannot be killed by a certain amount of antibiotics which used to work miraculously. Unfortunately, drug resistance is not only limited to microbes but also occurs frequently in cancer cells exposed to drugs each of which targets a few dysfunctional genes in tumors. Such effective targeted anti-cancer drugs often lose its momentum after 6 or 12 month of usage. It seems that the tiny pathogen or tumor cells outsmart the human brain at almost every turn.

        Cancer cells with specific mutations that are targeted by drugs develop drug resistance by producing new mutations that cannot be targeted by drugs any more. Thus, designing new drugs that can target new mutations of cancer cells sounds to be the only way to overcome drug resistance. However, these new drugs will also encounter drug resistance due to the emergence of even more mutations. The scenario is the harder researchers work, the harder and smarter cancer cells work because they want to survive. Can we be smarter to figure out how to conquer drug resistance?  

       Here is the good news: a very simple method, discontinuous drug administration, may be a powerful weapon to help us defeat drug resistance. The so-called discontinuous drug application contains three steps: drug administration, pause of drug administration, and another round of drug administration. Depending on the specific situation of patients, this cycle of drug usage can be repeated or not. Although this strategy seems to be too simple to work, it is in fact working wonderfully.

        A latest paper published in Nature showed the effectiveness of discontinuous drug administration. Frequent mutations in a gene BRAF have been linked to melanoma, a notorious malignant skin tumor. A drug named Vemurafenib can target BRAF to inhibit melanoma. However, long term use of Vemurafenib can lead to drug resistance. Researchers showed that discontinuous dosing of Vemurafenib resulted in effective regression (healing) from drug-resistant tumors. The explanation is as follows: while the survived tumors develop drug resistance, they also become dependent on the drug exposure environment. By discontinuing the drug temporarily, tumors that have established drug resistance will regain the sensitivity to the drug.

        It is of great interest to see whether the discontinuous strategy works on other targeted therapies as well.  If this is proven true, patients will spend less money and suffer less pain in cancer therapy. Scientists will find their lives easier, too.

[1] Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature(2013) doi:10.1038/nature11814