How to Live Long and Prosper – a Vulcan's Dream

 

By Jesica Levingston Mac leod, PhD

 

A new Harvard study found that we are living longer and better, too. In fact, the life expectancy for a 65 year old in USA grew a lot in the last 20 years: the life expectancy for females is now 81.2 years and for males it’s 76.4 years. The 3 pillars of this improvement are the less smoking, healthier diet and the medical advances. Going straight into the deep science latest developments, two start ups (BioViva and Elysium Health) were in the news recently for their cutting-edge “anti-aging” approaches. The first group to research  telomeres gene therapy is Maria Blasco’s group. A study by Bernardes de Jesus et al. demonstrated how telomerese gene therapy in adult and old mice could delay aging and increase longevity, without the collateral effect of increasing the propensity of developing cancer.

In the study, the scientists showed how the treatment of 1- and 2-year old mice with an adeno associated virus expressing mouse telomerase reverse transcriptase (TERT) had beneficial effects on health and fitness, with an increase in median lifespan of 24% and 13%, respectively. Some other benefits included better insulin sensitivity, reduced osteoporosis, improved neuromuscular coordination and improvements in several molecular biomarkers of aging. In cancer cells, the expression of the telomerase is enhanced, giving this protein a bad reputation as having a “tumorigenic activity”. Elizabeth Parrish, the CEO of BioViva, went all the way to Colombia, to receive two gene therapies that her company had developed: one to lengthen the telomeres and the other to increase muscle mass. The results of the treatment were very positive: the telomeres in leukocytes grew from 6.71 kb to 7.33 kb in seven months. As a side note, petite leukocyte telomere length may be associated with several psychiatric disorders (including major depressive disorder) and with poor response to psychiatric medications in bipolar disorder and schizophrenia.

In a nutshell, human telomeres are composed of double-stranded repeat arrays of “TTAGGG” terminating in a single-stranded G-rich overhang. The fidelity of that sequence is maintained by the enzyme telomerase, which uses an intrinsic RNA molecule containing the CAAUCCCAAUC template region and the reverse transcriptase component (TERT), to synthesize telomeric DNA de novo onto the chromosome terminus. The telomeres were named after the greek words télos (end, extremity) and méros (part). Take home message: Telomerase adds DNA to the ends of telomeres and by lengthening telomeres, it extends cellular life-span and/or induces immortalization. The telomerase is not active in normal somatic cells while active only in germ-line, stem and other highly proliferative cells.

 

Last year, Dr. Fagan and collaborators, published in PLoS One that the transcendental meditation and lifestyle variations stimulate two genes that produce telomerase (hTERT and hTR). Even cheerier news were reported in Nature for thanksgiving: the edible dormouse (super cute, small, long tail mouse – Glis glis) telomere length significantly increases from an age of 6 to an age of 9 years. As they state in the paper “the findings clearly reject the notion that there is a universal and inevitable progressive shortening of telomeres that limits the number of remaining cell cycles and predicts longevity”.  These species of mouse skip reproduction in years with low food availability, this “sit tight” strategy in the timing of reproduction might pushed “older” dormouse to reproduce, and this could facilitate telomere attrition, this strategy may have led to the evolution of increased somatic maintenance and telomere elongation with increasing age.

The other company, Elysium, co-founded by MIT professor Lenny Guarente, is focus in the mitochondria and the NAD (nicotinamide adenine dinucleotide). Mitochondria are our energy generators and they get crumbly as we age. Dr. Guarente demonstrated in mice how it may be possible to reverse mitochondrial decay with dietary supplements that increase cellular levels of NAD, like nicotinamide riboside (NR, a precursor to NAD that is found in trace amounts in milk), resveratol (a red wine ingredient) or pterostilbene (present in berries and grapes). Elysium has just realized the results of the clinical trial that was placebo-controlled, randomized, and double-blinded, where they evaluated the safety and efficacy of BASIS (the diateary supplement with nicotinamide riboside (NR) and pterostilbene) in 120 healthy participants ages 60-80 over an eight-week period. Participants received either the recommended dose (250 mg NR and 50 mg pterostilbene) or double the dose. In both cases, the intake of Basis resulted in the increase of NAD+ levels in the blood safely and sustainably, 40% and 90% respectively.

 

A former Guarante’s postdoc –  Dr. Sinclair – has just published in Science the discovery of a NAD binding area in a protein that regulate NAD’s interactions with other proteins related to aging. The Sinclair’s lab reported that the binding of NAD+ to DBC1 (Deleted in Breast Cancer 1 protein) prevents it for inhibiting another protein –  PARP1, an important DNA repairing protein. Furthermore, they have shown that as the mice aged, the concentration of NAD+ decreased, and more DBC1 was available to bind to PARP1, culminating in the accumulation of DNA damage. On a brighter note, this process was reversed by restoring higher levels of NAD+. The good news are that NAD+modulation might protect against cancer, radiation and aging.

 

Although all these advances are great, they won’t make you live longer in the next 10 years, so what can you do to live longer/healthier? Science comes again to answer this question! Harvard studies have shown that living “meaningful lives” helping others, having aims/motivations (and been conscious about the fact that we are taking our own decisions), been grateful, enjoying the present and significant relationships with other humans are key aspects to have a happy live. Obviously, exercising and having natural environments around us, as well as healthy eating are crucial points in a healthy life.

It might be an oversimplification, but 70% of your risk of disease is related to diet: soda and processed food are related with shortening the telomeres. Good news: you can slow down aging with a healthier life style: “Switch to a whole-food, plant-based diet, which has been repeatedly shown not just to help prevent the disease, but arrest and even reverse it” claims Dr. Greger’s, author of the Daily Dozen—a checklist of the foods we should try to consume every day. The super food list includes: Cruciferous vegetables (such as broccoli, Brussels sprouts, cabbage, cauliflower, kale, spring greens, radishes, turnip tops, watercress), Greens (including spring greens, kale, young salad greens, sorrel, spinach, swiss chard), other vegetables (Asparagus, beetroot, peppers, carrots, corn, courgettes, garlic, mushrooms, okra, onions, pumpkin, sugar snap peas, squash, sweet potatoes, tomatoes), beans (Black beans, cannellini beans, black-eyed peas, butter beans, soyabeans, baked beans, chickpeas, edamame, peas, kidney beans, lentils, miso, pinto beans, split peas, tofu, hummus),  Berries: (including grapes, raisins, blackberries, cherries, raspberries and strawberries),  other fruit (such as apples, apricots, avocados, bananas, cantaloupe melon, clementines, dates, figs, grapefruit, honeydew melon, kiwi, lemons, limes, lychees, mangos, nectarines, oranges, papaya, passion fruit, peaches, pears, pineapple, plums, pomegranates, prunes, tangerines, watermelon),  Flax seeds, nuts, spices (like turmeric), whole grains (Buckwheat, rice, quinoa, cereal, pasta, bread) and the almighty: water.

As you can expect, a lot of research is needed to get a magic pill that might boost your life expectancy but you can start investing in your future having a positive attitude, healthy diet, exercising and all the other things that you already know you should be doing to feel better, without forgetting that life is too short, so eat dessert first.

 

Science Holidays to Celebrate in 2017

 

By Deirdre Sackett

The holiday season is upon us! Whether you’re celebrating with family, friends, or your experiments, there’s no denying the festive spirit in the air. But, after celebrating the winter holidays, we scientists can continue the celebrations and look ahead to all the wonderful and weird science holidays of 2017. Mark your calendars!

Mathematical Holidays

Math is one of the most vital and oldest aspects of science, so it makes sense that there are holidays to celebrate its importance!

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  • Probably the most famous science holiday, Pi Day falls on March 14, 2017, which represents the first three numbers of Pi (3.14). Pi is a value that represents the ratio of a circle’s circumference to its diameter. People celebrate Pi Day by baking — you guessed it — pies.
  • Pi Days’ status as the most famous science holiday also brings with it some drama. Two other days contend with Pi Day’s fame: Pi Approximation Day and Tau Day. Pi Approximation Day falls on July 22, 2017, and represents the fraction that would equal Pi (7/22). Tau Day falls on June 28, 2017, and celebrates tau, the symbol that represents 6.28 (double pi’s value).
  • Want to celebrate a sensible measurement system? National Metric Week falls on the week of October 10th (the tenth day of the tenth month).
  • Mole Day celebrates Avogadro’s Number (the mole, 10^23 atoms of a substance) on October 23.
  • Pythagorean Theorem Day celebrates the famous equation we were all taught in middle school algebra. Just as a refresher, this theorem states that the square of the hypoteneuse of a right triangle is equal to the sum of the square of its two sides. In 2017, it falls on August 15, because 8*8 + 15*15 = 17*17. [/unordered_list]

 

Space Holidays

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  • Yuri’s Night falls on April 12 and celebrates Yuri Gagarin, the first man to go to space. Yuri’s Night is celebrated across the globe as a recognition of our achievements in space travel and looking toward humanity’s future as a space-faring species.
  • Probably the most unusual on this list, National Create A Vacuum Day falls on February 4. It’s a day to celebrate and understand the science behind vacuums — spaces where the pressure is lower than atmospheric pressure. Celebrators are encouraged to use their household vacuums to “create a vacuum”…and also clean their houses. [/unordered_list]

Nature Holidays

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  • Hagfish Day is October 18, and celebrates one of the ugliest creatures on the planet: the hagfish. The holiday is designed to help everyone appreciate the evolution of the hagfish, and to look past its unpleasant exterior – a valuable life lesson.
  • Coral Reef Awareness week is the third week in July, and celebrates the preservation of the world’s precious coral reefs.
  • Earth Day and Arbor Day are the most famous nature holidays. Earth Day is on April 22, and Arbor Day follows a week later on the 29th. You can celebrate these holidays by doing something nice for the planet, like planting a tree or cleaning up trash.[/unordered_list]

Science Education Holidays

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  • DNA Day is April 20, and is celebrated by scientists and educators worldwide. It falls on the anniversary of the human genome’s completion in 2003, and the discovery of the double helix structure in 1953. The day is dedicated to the knowledge and appreciation of DNA and genomics. The month of April is “Human Genome Month.”
  • Darwin Day is February 12, and celebrates Charles Darwin’s birthday as well as his theory of evolution.[/unordered_list]

Geeky Holidays

While not entirely scientific, these holidays can be celebrated by people who love science and nerdy things.

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  • May 4, 2017 is Star Wars Day. May the Fourth be with you!
  • Geek Pride Day falls on May 25, 2017. Get your geek on and celebrate all things nerdy![/unordered_list]

A Spooky Story – How Science Became Science Fiction?

 

By JoEllen McBride, PhD

 

Which came first, science or science fiction? Today it is difficult to tell which has a greater influence on the other. But before the invention of the battery, scientists relied on uncontrollable static discharges to produce electricity and used only the facts in front of them to come up with new scientific ideas. The events surrounding the creation of a chemically produced source of electricity not only transformed the fields of chemistry, physics and biology; they ushered in a new genre of literature known as science fiction– providing a new way to motivate scientists and scientific advances.

 

The tale begins as any good sci-fi story does. In 1780, the effects of static electricity on living creatures intrigued the Italian scientist, Luigi Galvani. In order to create a static charge he had to rub frog skin together. Once a charge built up, he would apply it to the skinless frogs and record the results. One day while skinning frogs, he inadvertently charged a metal scalpel lying close to where he worked. When he touched the now electrically charged scalpel to the sciatic nerve of a dead frog, the frog’s leg kicked! This reanimation led Galvani to postulate that motion in living things is controlled by electricity that flows from the nerves to the muscles.

 

Galvani’s frenemy, the physicist Alessandro Volta, had a different hypothesis. Volta knew that Galvani would hang his frogs up by different types of metal wires. He speculated that the different metallic properties of the wires combined with the moist environment of the frog’s muscles transmitted the electricity from the scalpel into the muscles, causing the leg to move. He verified his hypothesis by replacing a frog leg with cloth soaked in brine and recorded an electric current through the attached wires. Volta believed he had disproved ‘galvanism’ and spent much of his life debating its merits with Galvani. Today we have an entire field of physiology known as electrophysiology. So while Galvani may not have discovered ‘animal electricity’ when he reanimated his frog leg, his hypothesis was not far from the truth.

 

When Volta wasn’t bashing galvanism, he spent his time tweaking his frog leg circuit to produce electricity without friction. For as long as they could remember, scientists had to spend time and energy generating static electricity and storing it in Leyden jars— glass jars with metal foil lining their inner and outer surfaces. The size of the jar limited the amount of electricity stored and the electrical output could not be controlled. Around 1800, Volta discovered that if he interleaved enough zinc, copper and brine soaked cloth he could produce a steady and usable amount of electricity without the need of friction or jars. Volta’s invention provided an independent and controllable electric source and many scientists rushed to replicate his results.

 

In 1808, two British scientists, William Nicholson and Anthony Carlisle, were constructing their own voltaic pile and needed a way to measure the electricity produced. They tried to connect their electroscope to the battery but did not have a reliable connection. They decided to use water as an intermediary between the electroscope contacts and the battery. But when they hooked up the circuit, the water would instantly vanish!

 

Being scientists, they knew this wasn’t witchcraft. After a few tests they confirmed that the water was not disappearing but being decomposed into oxygen and hydrogen. They had discovered electrolysis. Many scientists, most notably Sir Humphrey Davy, would go on to decompose other molecules and discover new elements such as potassium, sodium, calcium and magnesium. Davy would eventually hire Michael Faraday as his apprentice. Faraday would soon transform the fields of electrostatics and magnetism from his studies of electricity.

 

People in intellectual circles were aware of the fascinating scientific findings of Galvani, Volta, Nicholson, Carlisle and Davy. Born around the time that Volta made his first battery, Mary Shelley spent her entire life in the company of intellectuals. She hungered for knowledge at a young age and eventually became a prolific writer. She very likely read Davy’s book Elements of Chemical Philosophy, published in 1812, as her husband owned a copy and they enjoyed studying together.

 

While on holiday with her husband during the summer of 1816, their friend Lord Byron proposed that they all write their own ghost stories. Shelley grew anxious as nights passed and she still could not come up with a story. A few nights later, the group discussion turned to what gives beings life. Shelley suggested that electricity could be used to reanimate a corpse since ‘galvanism’ had been shown to give dead creatures motion. That very night, unable to sleep, her mind focused on reanimation and subconsciously fueled by her own scientific knowledge, it’s no wonder her ‘waking dream’ included visions of a monster brought to life by science.

 

In her telling, Dr. Frankenstein did not use electricity to animate his monster. That interpretation would first appear in the 1931 film and every telling after. But the influences of galvanism are clear. Unfortunately for all the Dr. Frankensteins and Frankenweenies out there, electrophysiology tells us that electrical signals are detected in cells, muscles and organs throughout a living body. This means it would be impossible to reanimate a dead creature with a jolt of electricity.

 

Mary Shelley’s Frankenstein created a new genre of storytelling. Science fiction authors are motivated by recent scientific findings to explore further applications and possibilities. Science fiction stories, in turn, have influenced many young people to pursue careers in scientific fields. So this Halloween when you’re watching Frankenstein or playing Captain Kirk as you ask your phone what the weather will be like for trick or treating; remember it’s all possible because an Italian scientist accidentally electrocuted some frog legs.

 

 

Can we reprogram adult cells into eggs?

 

By Sophie Balmer, PhD

 

Oogenesis is the female process necessary to create eggs ready for fertilization. Reproducing these keys steps in culture constitutes a major advance in developmental biology. Last week, a scientific group from Japan amazingly succeeded and published their results in the journal Nature. They replicated the entire cycle of oogenesis in vitro starting from adult skin cells. Upon fertilization of these in vitro eggs and transfer in adult females, they even obtained pups that grew normally to adulthood providing new platforms for the study of developmental biology.

 

Gamete precursor cells first appear early during embryonic development and are called primordial germ cells. These precursors then migrate to the gonads where they will remodel their genome via two rounds of meiosis to produce either mature oocytes or sperm depending on the sex of the embryo. For oocyte maturation, these two cycles occur at different times: the first one before or shortly after birth and the second one at puberty. The second round of meiosis is incomplete and the oocytes remain blocked in metaphase until fertilization by male gametes. This final event initiates the process of embryonic development, therefore closing the cycle of life.

 

Up until last week, parts of this life cycle were reproducible in culture. For years, scientists have known how to collect and culture embryos, fertilize them and transfer them to adult females to initiate gestation. This process called in vitro fertilization (IVF) has successfully been applied to humans and has revolutionized the life of millions of individuals suffering specific infertility issues and allowing them to have babies. However only a subset of infertility problems can be solved by IVF.

Additionally, in 2012, the same Japanese group recreated another part of the female gamete development: Dr. Hayashi and colleagues generated mouse primordial germ cells in vitro that once transplanted in female embryos recapitulated oogenesis. Both embryonic stem (ES) cells or induced pluripotent stem (iPS) cells were used for such procedure. ES cells can be derived from embryos before their implantation in the uterus and iPS cells are derived by reprogramming of adult cells. Finally, a couple of months ago, another group also reported being able to transform primordial germ cells collected from mouse embryos into mature oocytes.

 

However, replicating the full cycle of oogenesis from pluripotent cell lines in a single procedure constitutes an unprecedented discovery. To achieve this, they proceeded in different steps: first, they produced primordial germ cells in vitro from either skin cells (following their de-differentiation into iPS cells) or directly from ES cells. Second, they produced primary oocytes in a specific in vitro environment called “reconstituted ovaries”. Third, they induced maturation of oocyte up until their arrest in meiosis II. This process took approximately the same time as it would take in the female mouse and it is impressive to see how the in vivo and in vitro oocytes are indistinguishable. Of course, this culture system also produced a lot of non-viable eggs and only few make it through the whole process. For example, during the first step of directed differentiation, over half of the oocytes contain chromosome mispairing during meiosis I, which is about 10 times more than in vivo. Additionally, only 30% complete meiosis I as shown by the exclusion of the 1st polar body. However, analysis of other parameters such as the methylation pattern of several genes showed that maternal imprinting was almost complete and that most of the mature oocytes had normal number of chromosomes. Transcription profiling also showed very high similarities between in vitro and in vivo oocytes.

The in vitro oocytes were then used for IVF and transplanted into mouse. Amazingly, some of them developed into pups that were viable, grew up to be fertile and had normal life expectancy without apparent abnormalities. However, the efficiency of such technique is very low as only 3.5% of embryos transplanted were born (compare to over 60% in the case of routine IVF procedures). Embryos that did not go through the end of the pregnancy showed delayed development at various stages, highlighting that there are probably conditions that could be improved for the oocytes to lead to more viable embryos.

Looking at the entire process, the rate of success to obtain eggs ready for transplant is around 7-14% depending on the starting cell line population. Considering how much time these cells spend in culture, this rate seems reasonably good. However, as mentioned above only few develop to birth. Nonetheless, this work constitutes major advancement in the field of developmental biology and will allow researchers to look in greater detail at the entire process of oogenesis and fertilization without worrying about the number of animals needed. We can also expect that, as with every protocol, it will be fine-tuned in the near future. It is already very impressive that the protocol led to viable pups from 6 different cell line populations.

 

Besides its potential for increasing knowledge in the oogenesis process, the impact of such research might reach beyond the scope of developmental biology. Not surprisingly, these results came with their share of concerns that soon this protocol would be used for humans. How amazing would it be for women who cannot use IVF to use their skin cells and allow them to have babies? Years ago, when IVF was introduced to the world, most people thought that “test-tube” babies were a bad idea. Today, it is used as a routine treatment for infertility problems. However, there is a humongous difference between extracting male and female gametes and engineering them. I do not believe that this protocol will be used on humans any time soon because it requires too many manipulations that we still have no idea how to control. Nonetheless, in theory, this possibility could be attractive. Also, for the most sceptic ones, one of the major reason why this protocol is not adaptable to human right now is that we cannot generate human “reconstituted ovaries”. This step is key for mouse oocytes to grow in vitro and necessitate to collect the gonadal somatic cells in embryos which is impossible in humans. So, until another research group manages to produce somatic gonadal cells from iPS cells, no need to start freaking out 😉

 

 

Repair Gone Wrong: Targeting The DNA Damage Response To Treat Cancer

By Gesa Junge, PhD

 

Our cells are subject to damage every minute of every day, be it from endogenous factors such as reactive oxygen species generated as part of normal cell respiration, or exogenous factors such as UV radiation from the sun. Together, these factors can lead to as many as 60 000 damaged DNA bases per cell per day. Most of these are changes to the DNA bases or single strand breaks (SSBs), which only affect one strand of the double helix, and can usually be repaired before the DNA is replicated and the cell divides. However, about 1% of SSBs escape and become double stand breaks (DSBs) upon DNA replication. DSBs are highly toxic, and a single DSB can be lethal to a cell if not repaired.

Usually, cells are well-equipped to deal with DNA damage and have several pathways that can remove damaged DNA bases and restore the DNA sequence. Nucleotide excision repair (NER, e.g. for UV damage) and base excision repair (BER, for oxidative damage) are the main SSB repair pathways, and homologous recombination (HR) and non-homologous enjoining (NHEJ) repair most DSBs. HR is the more accurate pathways for DSB repair, as it relies on a homologous DNA sequence on the sister chromosome to restore the damaged bases, whereas NHEJ simply relegates the ends of the break, potentially losing genetic information. However, NHEJ can function at any time in the cell cycle whereas HR requires a template and is only active once the DNA is replicated (i.e. in G2 and S-phase).

Depending on the severity of the damage, cells can either stop the cell cycle to allow for repair to take place or, if the damage is too severe, undergo apoptosis and die, which in a multicellular organism is generally favourable to surviving with damaged DNA. If cells are allowed to replicate with unrepaired DNA damage, they pass this damage on to their daughter cells in mitosis, and mutations in the DNA accumulate. While mutations are essential to evolution, they can also be problematic. Genomic instability, and mutations in genes such as those that control the cell cycle and the DNA damage response can increase the risk of developing cancer. For example, germline mutations in ATM, a key protein in HR pathway of DSB repair, leads to Ataxia Telangiectasia (AT), a neurodegenerative disorder. AT sufferers are hypersensitive to DSB-inducing agents such as x-rays, and have a high risk of developing cancer. Deficiencies in NER proteins lead to conditions such as Xeroderma Pigmentosa or Cockayne Syndrome which are characterised by hypersensitivity to UV radiation and an increased risk of skin cancer, and mutations BRCA2, another key HR protein, increase a woman’s risk of developing breast cancer to 60-80% (compared to 13% on average).

Even though deficiencies in DNA repair can predispose to cancer, DNA repair is also emerging as a viable target for cancer therapy. For example, DNA repair inhibitors can be used to sensitise cancer cells to chemotherapy- or radiation-induced damage, making it possible to achieve more tumour cell kill with the same dose of radiation or chemotherapy. However, this approach is not yet used clinically and a major complication is that it often increases both the efficacy as well as the toxicity of treatment.

Another approach is the idea of “synthetic lethality”, which relies on a cancer cell being dependent on a specific DNA repair pathway because it is defective in another, such that deficiency of either one of two pathways is sustainable, but loss of both leads to cell death. This concept was first described by Calvin Bridges in 1922 in a study of fruit flies and is now used in the treatment of breast cancer in the form of an inhibitor of Poly-ADP ribose polymerase (PARP), a key enzyme in the repair of SSBs. Loss of PARP function leads to increased DSBs after cell division due to unrepaired SSBs, which in normal tissue are removed by the DSB repair system. However, BRCA2-deficient tumours are defective in HR and cannot repair the very toxic DSBs, leading to cell death. Therefore, BRCA2-deficient tumours are hypersensitive to PARP inhibitors, which are now an approved therapy for advanced BRCA2-deficient breast and ovarian cancer.

PARP inhibitors are a good example of a so-called “target therapy” for cancer, which is the concept of targeting the molecular characteristics that distinguish the tumour cell from healthy cells (in this case, BRCA2 deficiency), as opposed to most older, cytotoxic chemotherapies, which generally target rapidly dividing cells by inducing DNA damage, and can actually lead to second cancers. With an improved understanding of the molecular differences between normal and tumour cells, cancer therapy is slowly moving away from non-specific cytotoxic drugs towards more tolerable and effective treatments.

Your Teleportation Dream Might Be a Reality Soon

Scotty, pleaaaase beam me up…

 

By Jesica Levingston Mac leod, PhD

Jokes aside… well, I can’t stop myself for writing “Scotty, beam me up”, teleportation has already been done with atoms, photons and ions, for example in Universities in China, Germany and Maryland. Are you surprise by all this examples? The process of quantum teleportation of multiple degrees of freedom of a single photon has been done at the University of Science and Technology of China last year. They performed a free-space, ground level link measuring approx. 100 km across the Qinghai Lake in China with high fidelity. The official name of the protocol is “long distance quantum teleportation with polarization qubits” (or quantum bit is the analogue of a “bit” of information). A second group from China has plans to create a quantum space communications system by sending to space a satellite that could facilitate quantum teleportation of photons between earth and space.

Other successful story in teleportation was performed using optical modes. Lee and collaborators generated an EPR state by using two degenerate optical parametric oscillators and a balanced beam splitter. The EPR paradox is a fundamental concept introduced by Einstein, Podolsky and Rosen (their last names initial gave the name to this theory) back in 1935. They claimed that the wave function, as the representation of a particular pure quantum state, does not provide a complete description of the physical reality. Also, quantum teleportation with matter has been performed by other group using atomic ensembles of caesium atoms at room temperature, showing light-to-matter teleportation of a coherent state of an optical mode into a collective atomic spin. More than 13 years ago, Gao and collaborators, performed the amazing quantum teleportation from a propagating photon to a solid-state spin qubit, by exiting a neutral quantum dot onto the electron spin of a charged second quantum dot. So they were the first ones who teleported a photonic frequency qubit.  These advances in quantum teleportation are the Holy Grail for the “real” teleportation that we are all crossing fingers to be bring to our everyday world soon…hopefully very soon.

Moreover, these advances in teleportation technology opened the talk to pass to the next frontier: the teleportation of a live organism. The good news on this topic were published in Science at the beginning of this year. Two physicist from China, Tongcang Li and Zhang-qi Yin, propose to put a microorganism with a mass much smaller than the mass of the electromechanical membrane ( for example a bacterium) on top of an electromechanical membrane oscillator integrated with a superconducting circuit to prepare the quantum superposition state of a microorganism and teleport its quantum state. This tiny microorganism will not significantly affect the quality factor of the membrane and can be cooled to the quantum ground state together with the membrane. With a strong magnetic field gradient, the internal states of a microorganism, such as the electron spin of a glycine radical, can be entangled with its center-of-mass motion and be teleported to a remote microorganism. Since internal states of an organism contain information, this proposal provides a scheme for teleporting information between two remote organisms. Basically, what they described was a method to put a microorganism in two places at the same time, and provide a scheme to teleport the quantum state of a microbe (read more about it here). Unfortunately, all this is a just a great theory so far…

Sadly, as an Aprils fool joke, a really good one, the US army reported that they had teleported 9 soldiers from Massachusetts to Germany (here is the funny full article). They remained me that the term “teleportation” has coined by and American author Charles Port in 1931, he was a researcher of anomaly phenomena, phenomena that fall outside of existing understanding.

Recently, German researches from the Institute of Applied Physics at the University of Jena reported the Implementation of quantum and classical discrete fractional Fourier transforms, which represented a huge advance toward teleportation. Back in 2014, they had already generated of a new class of optical beams that are radially self-accelerating and non-diffracting. These beams continuously evolve on spiraling trajectories while maintaining their amplitude and phase distribution in their rotating rest frame. Also check out the fun article in Nature title “photonics: random sudoku light”, were the same authors described how they have imprinted on the laser beam a phase pattern that corresponds to numerical solutions to overlapping sodukus.  Translated to “normal” humans it means that they teleported elementary particles (light particles and electrons) in a “spatially delocalized state,” which allows them to be in two separate places at the same time. Oh Germans, such a bunch of funny people… at least in science related fields.

Mr. Elon Musk, founder of Tesla, SpaceX and PayPal, wants to build a high-speed tube service Hyperloop which is capable of travelling around 700 mph. He is targeting to make the trip from Los Angeles to San Francisco as short as 30 min using this “as close as you can get to teleportation” system. Let me leave you with a geeky quote from the book Endure by Carrie Jones: “We teleported,” Issie finishes. “Like in Star Trek or Harry Potter, sort of. No! Like in Dr. Who in that episode with the Sontarans and the brilliant human boy, or really any Dr. Who ever if you think of the Tardis! Holy canola! That is just the coolest thing ever! Wowie, wow, wow!”

 

How Low Can You Go? Designing a Minimal Genome

By Elizabeth Ohneck, PhD

How many genes are necessary for life? We humans have 19,000 – 20,000 genes, while the water flea Daphnia pulex has over 30,000 and the microbe Mycoplasma genitalium has only 525. But how many of these genes are absolutely required for life? Is there a minimum number of genes needed for a cell to survive independently? What are the functions of these essential genes? Researchers from the J. Craig Venter Institute and Synthetic Genomics, Inc., set out to explore these questions by designing the smallest cellular genome that can maintain an independently replicating cell. Their findings were published in the March 25th version of Science.

The researchers started with a modified version of the Mycoplasma mycoides genome, which contains over 900 genes. Mycoplasmas are simplest cells capable of autonomous growth, and their small genome size provides a good starting point for building minimal cells. To identify genes unnecessary for cell growth, the team used Tn5 transposon mutagenesis, in which a piece of mobile DNA is introduced to the cells and randomly “jumps” into the bacterial chromosome, thereby disrupting gene function. If many cells were found to have the transposon inserted into the same gene at any position in the gene sequence, and these cells were able to grow normally, the gene was considered non-essential, since its function was not required for growth; such genes were candidates for deletion in a minimal genome. In some genes, the transposon was only found to insert at the ends of the genes, and cells with these insertions grew slowly; such genes were considered quasi-essential, since they were needed for robust growth but were not necessary for cell survival. Genes which were never found to contain the transposon in any cells were considered essential, since cells that had transposon insertions in these genes did not survive; these essential genes were required in the minimal genome.

The researchers then constructed genomes with various combinations of non-essential and quasi-essential gene deletions using in vitro DNA synthesis and yeast cells. The synthetic chromosomes were transplanted into Mycoplasma capricolum, replacing its normal chromosome with the minimized genome. If the M. capricolum survived and grew in culture, the genome was considered viable. Some viable genomes, however, caused the cells to grow too slowly to be practical for further experiments. The team therefore had to find a compromise between small genome size and workable growth rate.

The final bacterial strain containing the optimized minimal genome, JCVI-syn3.0, had 473 genes, a genome smaller than any autonomously replicating cell found in nature. Its doubling time was 3 hours, which, while slower than the 1 hour doubling time of the M. mycoides parent strain, was not prohibitive of further experiments.

What genes were indispensable for an independently replicating cell? The 473 genes in the minimal genome could be categorized into 5 functional groups: cytosolic metabolism (17%), cell membrane structure and function (18%), preservation of genomic information (7%), expression of genomic information (41%), and unassigned or unknown function (17%). Because the cells were grown in rich medium, with almost all necessary nutrients provided, many metabolic genes were dispensable, aside from those necessary to effectively use the provided nutrients (cytosolic metabolism) or transport nutrients into the cell (cell membrane function). In contrast, a large proportion of genes involved in reading, expressing, replicating, and repairing DNA were maintained (after all, the presence of genes is of little use if there is no way to accurately read and maintain them). As the cell membrane is critical for a defined, intact cell, it’s unsurprising that the minimal genome also required many genes for cell membrane structure.

Of the 79 genes that could not be assigned to a functional category, 19 were essential and 36 were quasi-essential (necessary for rapid growth). Thirteen of the essential genes had completely unknown functions. Some were similar to genes of unknown function in other bacteria or even eukaryotes, suggesting these genes may encode proteins of novel but universal function. Those essential genes that were not similar to genes in any other organisms might encode novel, unique proteins or unusual sequences of genes with known function. Studying and identifying these genes could provide important insight into the core molecular functions of life.

One of the major advancements resulting from this study was the optimization of a semi-automated method for rapidly generating large, error-free DNA constructs. The technique used to generate the genome of JCVI-syn3.0 allows any small genome to be designed and built in yeast and then tested for viability under standard laboratory conditions in a process that takes about 3 weeks. This technique could be used in research to study the function of single genes or gene sets in a well-defined background. Additionally, genomes could be built to include pathways for the production of drugs or chemicals, or to enable cells to carry out industrially or environmentally important processes. The small, well-defined genome of a minimal cell that can be easily grown in laboratory culture would allow accurate modeling of the consequences of adding genes to the genome and lead to greater efficiency in the development of bacteria useful for research and industry.

A Newly Discovered Bacterium Finds Plastic Fantastic

 

By Elizabeth Ohneck, PhD

We produce over 300 million tons of plastic each year. One of the most abundant forms of plastic is polyethylene terephthalate, or PET, a polyester frequently used in fabrics and the primary component of plastic beverage bottles and other types of food packaging. In 2013, approximately 56 million tons of PET were produced worldwide, but only about 2.2 million tons were recycled. The high demand for PET drives increased production of its monomers, terephthalic acid and ethylene glycol, both of which are industrially derived from petroleum, leading to high consumption of oil. The ubiquitous presence of PET and its resistance to biodegradation – it takes 5 to 10 years to naturally degrade – has led to a massive accumulation of PET in the environment, leaving us searching for ways to clean up the mess.

Nature may have just offered us a helping hand. Researchers from Japan have identified a bacterial species, which they’ve named Ideonella sakaiensis 201-F6, capable of breaking down PET to use as a food source. Their findings were published this month in Science.

The research team collected 250 environmental samples from soil, wastewater, sediment and sludge outside a PET bottle recycling plant and cultured the samples with PET films. One sample contained a bacterium that, when isolated, was able to grow with PET as the sole carbon source and to completely degrade the PET film in 6 weeks at 30°C (86°F). Genome sequencing of Ideonella sakaiensis 201-F6 identified two enzymes, subsequently called PETase and MHETase, with weak homology to enzymes from fungi previously shown to have PET-degradation activity. Purified PETase and MHETase were able to break down PET films to produce terephthalic acid and ethylene glycol. Interestingly, PET has only been produced since the 1940s, meaning the evolutionary window for such a drastic metabolic adaptation is relatively short, particularly since PETase and MHETase bear little resemblance to even the most closely related enzymes known in other species. When and how PETase and MHETase arose thus remain a mystery.

These findings have several important implications. Ideonella sakaiensis 201-F6 is not only able to degrade PET, but can subsequently metabolize the resulting terephthalic acid and ethylene glycol, which, while far more environmentally friendly than PET, are toxic at high levels. By using terephthalic acid and ethylene glycol as a food source, Ideonella sakaiensis 201-F6 is able to remove PET and its breakdown products from the environment. An exciting application would be isolation of the terephthalic acid and ethylene glycol to use in the production of new plastic. Recovering and reusing the PET monomers would drastically reduce the amount of oil needed to produce plastic, and allow true recycling of PET into fresh plastic suitable for packaging, rather than the current recycling tactic of melting and reforming PET plastic into other products.

Obviously, more research remains to be done before Ideonella sakaiensis 201-F6 or its PET-degrading enzymes are useful on a large scale. Reducing the time of PET degradation from decades to weeks could be beneficial in contaminated ecosystems, but adaptations to further speed the process are necessary for practical use at the industrial level. Additionally, the ability of Ideonella sakaiensis 201-F6 to survive in varying habitats and disruptions it might cause to specific ecosystems need to be carefully considered before releasing this bacterium or an adapted version into other environments for PET cleanup.

Nevertheless, the discovery of a bacterium that can degrade PET is promising for our efforts to combat the havoc our plastic-dependent lifestyle is creating in the environment. The PET-metabolizing power of Ideonella sakaiensis 201-F6 is a testament to the adaptability and resiliency of nature. Hopefully this discovery sparks new ideas and research into healthier and more efficient means of plastic production and recycling.

Epigenetic Inheritance, Trauma and the Holocaust

 

By Alison Bernstein, PhD

Since my research interests focus on environmental impacts on health and how epigenetic processes mediate those effects, my mother sent me this article, “Study of Holocaust survivors finds trauma passed on to children’s genes“, from The Guardian. This article reports the recent paper, “Holocaust exposure induced intergenerational effects on FKBP5 methylation“, in Biological Psychiatry. I get overly excited by teachable moments so I decided to take the opportunity to teach some more epigenetics (see my pages on Facebook or Google+ for my Intro to Epigenetics series).

Epigenetics literally means “over the genome”. It encompasses all meiotically and mitotically heritable changes in gene expression that are not coded in the DNA sequence itself. If we break that down, there are some key points to note:

  • “Not coded in the DNA”: There is no change in the DNA sequence. Thus, for these to be heritable, there must be mechanisms of inheritance besides DNA replication.
  • “Changes in gene expression”: The underlying assumption of all epigenetic studies should be that these changes alter gene expression (or change how inducible or repressible gene expression is, but that’s harder to measure).
  • “Meiotically and mitotically heritable”: This means heritable through cell division, but not necessarily heritable from parent to offspring.

Epigenetics generally refers to 4 mechanisms: DNA methylation (and other modifications to cytosine), histone modifications, non-coding RNAs, and long-range chromatin interactions (3D structure of chromosomes). In this paper, the authors focused on DNA methylation and identified changes in DNA methylation that occur in people who were in a Nazi concentration camp, witnessed or experienced torture, or hid from the Nazis during World War II. Similar changes were seen in their children. This transmission of a trait from parents to children is called intergenerational inheritance.

The effects of severe stress and other exposures has been shown to be inherited intergenerationally, multigenerationally (to grandchildren) and sometimes even transgenerationally (to great-grandchildren), both in animals and in people. The Dutch famine of 1944 and the polybrominated biphenyl exposure in Michigan in 1978 have provided evidence that exposures that occur prior to conception and in utero can have lasting effects on subsequent generations. However, it is difficult to separate out the different mechanisms that contribute to the inheritance of traits to subsequent generations. Thus, it is an important research question to ask how the effects of trauma, stress and other exposures are passed from generation to generation. This is the question the scientists wanted to address in this paper: is there an epigenetic component to the intergenerational inheritance of the effects of trauma?

This paper provides direct evidence in humans that the epigenetic effects of pre-conception stress can be seen in both parents and offspring. The authors looked at one specific gene only – FKBP5 – because it is known to be involved in the response to high glucocorticoid levels (a biological signal for stress) and is a possible novel target for antidepressant medication. They looked for changes in DNA methylation in glucocorticoid response elements within this gene. Response elements are sequences of DNA that bind to specific transcription factors and regulate transcription of genes. In this case, glucocorticoid response elements are bound by glucocorticoid hormones and their receptors to regulate expression of the gene containing the response element. They found changes in DNA methylation in these specific elements of the specific FKBP5 gene in Jewish Holocaust survivors and their children, but not in other Jewish people of similar age. This observed change in DNA methylation of the FKBP5 gene was in the opposite direction in parents and offspring, yet we do not yet have an explanation as to why this change would be different in parents and offspring. Thus, it is actually impossible to say from the results of this paper if these epigenetic changes are due to direct effects of stress and high glucocorticoid levels (or other shared environmental factors) or to inheritance of epigenetic marks.

Let’s say a woman or girl lived through the Holocaust. She and her eggs were exposed to high glucocorticoid levels, and other effects, due to stress. If a woman was pregnant during this time, she, her eggs and her in utero daughters’ eggs were exposed. So that’s 2, and possibly, 3 generations directly exposed to the stress. Until you get to the 4th generation, there is still a possibility of direct exposure. It might be epigenetic, but it is also possible that it’s still a result of direct exposure. Changes must be observed in the generation the great-grandchildren to definitively say that they are epigenetically inherited and not a result of direct exposure. In general, the great-grandchildren are the first generation that was definitely not directly exposed to the stressor. However, in this case, they looked at preconception stress, so looking at the 3rd generation (grandchildren) would be sufficient to differentiate between epigenetic inheritance and direct exposure.

This paper only looks at parents and their children. So the eggs that produced ALL those children were directly exposed (since females are born with all their eggs) to the trauma. It’s possible that high glucocorticoid levels directly affect the methylation of FKBP5 in the eggs as well in cells of the parent. The discussion of the paper itself goes into this, but the article overlooked this point and it’s a really important point to understand if you are interested in epigenetic inheritance.

From the discussion section of the paper:

“The main finding in this study is that Holocaust survivors and their offspring have methylation changes on the same site in a functional intronic region of the FKBP5 gene, a GR binding sequence in intron 7, but in the opposite direction. To our knowledge, these results provide the first demonstration of transmission of preconception stress effects resulting in epigenetic changes in both exposed parents and their offspring in adult humans. Bin 3/site 6 methylation was not associated with the FKBP5 risk-allele, and could not be attributed to the offspring’s own trauma exposure, their own psychopathology, or other examined characteristics that might independently affect methylation of this gene. Yet, it could be attributed to Holocaust exposure in the F0.

It is not possible to infer mechanisms of transmission from these data. It was not possible to disentangle the influence of parental gender, including in utero effects, since both Holocaust parents were survivors. Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring, but blood samples will not permit ascertainment of gamete dependent transmission. What can be detected in blood samples is parental and offspring experience-dependent epigenetic modifications. Future prospective, longitudinal studies of high risk trauma survivors prior to conception, during pregnancy and postpartum may uncover sources of epigenetic influences.”

The paper reports evidence that the epigenetic effects of stress and trauma can be seen in both parents and offspring. However, there are a lot of variables that may cause similar epigenetic changes in parents and offspring. Further studies are needed to really know what the mechanism of these shared epigenetic marks are, before we can confidently assert that the epigenetic changes observed in parents and offspring are due to epigenetic inheritance. As with all good science, this paper answers a question while, at the same time, raising additional questions for future research.

This article was originally published on The Sound of Science blog in August 2015.

Development On the Fly: An Interview with Dr. Thomas Gregor

By John McLaughlin

 

Thomas Gregor is a biophysicist and Professor at Princeton University. His Laboratory for the Physics of Life uses both Drosophila melanogaster and Dictyostelium discoideum as model systems to understand developmental processes from a physical perspective.

 

Could you briefly describe your educational path from undergraduate to faculty member at Princeton?

TG: As an undergraduate, I studied physics in Geneva, and then moved into theoretical physics and math. I came to Princeton, initially for a theoretical physics PhD; I switched during my time here to theoretical biophysics and then realized that it makes sense to combine this with experiments. I ended up doing a PhD between three complementary disciplines. My main advisor was Bill Bialek, a theoretical physicist. My other two were David Tank, an experimental neuroscientist, and Eric Wieschaus, a fly geneticist. So I had both experiment and theory, from a biological and a physical side. I then went to Tokyo for a brief post-doc, during which I continued in that interface. But I changed model organisms: I switched from a multicellular, embryonic system to looking at populations of single cells [the social amoeba Dictyostelium discoideum]. As a physicist you’re not married to model organisms. When I came back to start my lab at Princeton in 2009, I kept both the fly and the amoeba systems.

 

What is the overall goal of your lab’s research program?

TG: Basically, to find physical principles behind biological phenomena. How can we come up with a larger, principled understanding that goes beyond the molecular details of any one particular system? I mostly look at genetic networks and try to understand their global properties.

 

Do you think the approaches of biologists and physicists are very different, and if so are they complementary?

TG: I’m driven by the physical aspects of things, but I’m also realistic enough to see what can now be done in biological systems, in terms of data collection and what we can test. To find the overlap between them is kind of an art, and I think that’s where I’m trying to come in.

 

Do you have any scientific role models who have shaped how you approach science?

TG: The three that I mentioned: Bialek influenced me in the types of questions that speak to me; Tank had a very thorough experimental approach that taught me how to make real, physics-style measurements; and Wieschaus brought a lot of enthusiasm and knowledge of the system.

 

Your lab has been studying developmental reproducibility and precision, in the patterning of the fly Drosophila melanogaster. In a 2014 paper1, you showed that levels of the anterior determinant bicoid mRNA vary by only ~9% between different embryos. This is a very similar value to the ~10% variation in Bicoid protein levels between embryos, which you demonstrated several years earlier2. So it seems that this reproducibility occurs even at the mRNA level.

TG: Before going into this, the general thought in the field is that things were very noisy initially, and as the developmental path goes along it becomes more refined and things become more precise. This paper basically asked whether the precision is inherited from the mother, or the embryo needs to acquire it. Because the fluctuations in mRNA, from the mother, completely mimic the fluctuations in protein that the zygote expresses, that told us that the mother lays the groundwork, and passes on a very reproducible pattern. So there’s no necessity for a mechanism that reduces fluctuations from the mRNA to the protein level.

 

Continuing on the theme of precision: in a separate paper from the same year3, your lab showed that the wing structure among different adult flies is identical to within less than a single cell width. Did you have any prior expectations going into this study, and did the results surprise you?

TG: Before looking at the wing, I had kind of made up my mind. I had first seen single cell precision in patterning of gene expression boundaries in the embryo. But I also knew that it’s always better to make a measurement first, and it seems that things are much more precise and reproducible in biology than we think, given the idea of “sloppiness” that we have.

 

Do you think that a high level of reproducibility is a general feature of development, or varies widely among different types of species?

TG: It’s a philosophical question in a way, because I haven’t looked. I think what we found in the embryo is not special to the fly; specific mechanisms for getting there might be unique to the fly. For instance, we have also shown in a recent paper from 2013 that transcription is just as noisy in flies as it is in bacteria, hugely noisy. So, physical mechanisms like temporal and spatial averaging seem enough to reduce the high ubiquitous noise that transcription has to the very fine, reproducible patterns that you see in the fly. The specific mechanisms that reduce noise will be very different from species to species, but I think overall the fact that development is precise and reproducible is something we may one day be able to call a principle.

 

If you could make any changes to scientific institutions, such as the current funding system, journal peer review, etc. what would they be?

TG: One thing that might be nice is if we didn’t have to fund graduate students for the first five years of their career; it would be nice to have more streamlined training grants, not only for U.S. but also international graduate students. And so, graduate students wouldn’t have to worry. They should be free to choose a school based on their scientific interests.

For peer review in journals, the problem is the sheer volume of output is becoming so high. One way to keep a peer review system, is either to pay the reviewers money, or to put everything on the bioRxiv [bio archive is a pre-print server for the life sciences] and let some other means determine how to evaluate a paper. I don’t read papers from looking at the top journals’ table of contents every week, I read them because I see people talk about it on Twitter, or my colleagues tell me I should look at that paper, or because I hear about the work in a talk and decide to see what else the guy is doing.

A lot of people are advocating the new metrics – citations, citation rates, H-index – which are so dependent on the particular field and not necessarily a good measure of impact. In 100 years, are we going to look more at those papers than the ones that currently get very few citations? We don’t know. I don’t think the solution is out there yet.

 

Do you have any advice for young scientists – current PhD students or post-doctoral fellows – for being successful in science?

TG: My advice would be to focus on one very impactful finding. If it’s very thorough and good science, it will be seen. Also, nothing comes from nothing. You need to put in the hours if you want to get a job in academia. And I think that’s one of the ways to measure a good scientist, because knowledge in experimental science comes from new, good data.


What are some future goals of your lab’s research?

TG: We’ve been looking at the genetic network in the fly embryo, trying to understand properties of that network. Medium term, we want to incorporate a slightly different angle, which is looking at the link between transcriptional regulation and the 3D architecture of the genome. In the living embryo, we want to look at how individual pieces of DNA interact, and how that influences transcription and eventually patterning. In the longer term, I don’t know yet; I just got tenure, so I need to sit back. Everything is open. That is what’s nice about being a physicist; you’re not married to your biological past so much.

 

In your opinion, what are the most exciting developments happening in biology right now, whether in your own field or elsewhere?

TG: It’s definitely the fact that so many different disciplines have stormed into biology, making it a very multidisciplinary science. I think it makes the life sciences a very vibrant, communal enterprise. Hopefully the next decades will show the fruits of those interactions.

 

This question is asked very often: How do you balance your lab and family life?

TG: When you start thinking about having a family in science, things become much more complicated. Since I’ve had children, my workload went down a lot. My wife is also a scientist, and for her it’s much harder because she’s not yet tenured. As much as people look at the CV and see how many high-profile papers you have, they should also look at it and see your family and life situation. And for women in science, despite all the efforts that have been made, I don’t think we’re there yet.

 

References

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  1. Petkova, MD et al. Maternal origins of developmental reproducibility. Current Biology. 2014. 24(11).
  2. Gregor, T et al. Probing the limits to positional information. Cell. 2007. 130(1).
  3. Abouchar, L et al. Fly wing vein patterns have spatial reproducibility of a single cell. J R Soc Interface. 2014. 11(97).

[/ordered_list]