#Resistance is futile Cisplatin is given a chemotherapy drug to more than half of all cancer patients. The drug kills cells very effectively by damaging nuclear DNA but if tumors become resistant to cisplatin they often grow back.
A new study from MIT and the University of Toronto offers a possible way to overcome that resistance.
The researchers found that when cisplatin was delivered to cellular structures called mitochondria DNA in this organelle was damaged leading to cancer cell death.
Moreover the mitochondrial-targeted drug could overcome cisplatin resistance. These results suggest that the mitochondria can be an important target for platinum-based drugs says Robert Radford an MIT postdoc
and an author of a paper describing the findings in the Oct 31 online edition of the journal Biology & Chemistry.
Senior authors of the new paper are Stephen Lippard the Arthur Amos Noyes Professor of Chemistry at MIT and a member of MIT's Koch Institute for Integrative Cancer Research and Shana
Kelley a professor of biochemistry and pharmaceutical sciences at the University of Toronto. Lead authors are Simon Wisnovsky who received his Phd from the University of Toronto and MIT alumnus Justin Wilson Phd 13.
This is the first study to isolate the effects of a platinum drug in mitochondria and we were intrigued very to observe that the DNA damage caused by this drug outside of the nucleus were highly toxic Kelley says.
Overcoming resistancecisplatin which contains the metal platinum was approved to treat ovarian and testicular tumors in 1978
and is used now for many other cancers including lung and bladder. The drug forms crosslinks in DNA creating blockages that interfere with a cell s ability to read
or replicate its genome. If enough of these blockages form the cell undergoes a type of programmed cell suicide called apoptosis
. However questions remain about cisplatin s effects in other parts of the cell Radford says.
To help figure that out the researchers created a form of cisplatin targeted to go to mitochondria cell organelles that generate energy.
These structures have their own DNA inherited only from the mother which is essential for mitochondrial function.
Because mitochondria are involved in apoptosis the researchers wanted to see whether they could induce cell death by targeting MITOCHONDRIAL DNA particularly in cells that are already resistant to regular cisplatin.
The researchers also showed that the cells were dying through apoptosis and not some less-controlled form of cell death.
There are other ways for a cell to die besides apoptosis. You want a therapeutic agent to induce programmed cell death
The new targeted molecule is designed an elegantly platinum complex says Paul Dyson a professor of chemistry at the École Polytechnique Fédérale de Lausanne who was not part of the research team.
From metals to drugsthe researchers now hope to explore mitochondrial-targeted cisplatin s potential use as a chemotherapy drug by testing it in animals.
They also plan to try targeting cisplatin and other metal-based drugs to different parts of cells
Cisplatin and a handful of other platinum drugs are the only metal-based drugs now approved for human use
but researchers around the world are working on other types of metal-based drugs. People are interested really in using metals as therapeutics
but they re difficult to control and elucidating the cellular targets of metal-based drugs is challenging
because they can interact with so many different biomolecules Radford says. By targeting specific cellular organelles with the same therapeutic molecules we can learn a lot about how the cells respond to a given compound
and what cellular consequences metal-based drugs elicit. The research was funded by the National Cancer Institute the Canadian Institute of Health and a David H. Koch Graduate Fellowship s
#3q: Don Boroson on NASA s record-breaking use of laser communications Last week NASA announced that the Lunar Laser communication Demonstration (LLCD) on its Lunar Atmosphere
and Dust environment Explorer (LADEE) spacecraft had made history by using a pulsed laser beam to transmit data over the 239000 miles from the moon to Earth at a record-breaking data-download speed of 622 megabits per second (Mbps). This download speed is more than six times faster than the speed achieved by the best
radio system ever flown to the moon. LLCD also demonstrated a data-upload speed of 20 Mbps on a laser beam transmitted from a ground station in New mexico to the LADEE spacecraft in lunar orbit;
this speed is 5000 times faster than the upload speed of the best radio system sent to the moon.
which was developed by MIT Lincoln Laboratory researchers led by Don Boroson a laboratory fellow in MIT LL s Communication systems Division.
The beam-stabilization system on the space terminal is based on inertial sensors which can be scaled to work even at the most distant planets.
And the ground receiver is based on arrays of small inexpensive telescopes that are coupled fiber to highly efficient superconducting nanowires a photon counting technology that was brought to its high state of maturity by joint MIT and Lincoln Lab teams.
Why is this work important? A: It is agreed generally that present-day science and exploration missions to deep space are constrained by the amount of data they can get back to Earth.
Mars landers and orbiters gather much more information in the form of images for example than they can send back over the huge distance Mars is as much as 1000 times farther from Earth than the moon despite the incredible development of NASA s radio-based
It has been known for years that laser communications have the potential to deliver much higher data rates and use smaller space terminals than radio-based systems.
and power on their spacecraft for the much higher data return they can get. Q:
Then the Laboratory did the more detailed full-system design the detailed design of the three modules that make up the space terminal and the detailed design of the primary ground terminal.
and delivered these various parts to the spacecraft and to the ground site. Finally we designed
The work pens up a new avenue for optical manipulation of quantum states of matter,
the Lawrence C. 1944) and Sarah W. Biedenharn Associate professor of Physics and senior author of a paper published this week in Science.
They demonstrated the existence of a quantum-mechanical mixture of electrons and photons, known as a Floquet-Bloch state, in a crystalline solid.
electrons move in a crystal in a regular, repeating pattern dictated by the periodic structure of the crystal lattice.
Victor Galitski, a professor of physics at the University of Maryland who was involved not in this research,
says, he importance of this work is difficult to overestimate. He says it pens new avenues not only for optical control of topological states,
changing it from a conductor to a semiconductor just by changing the laser beam polarization. Normally, to produce such dramatic changes in a material properties,
the Sun Jae Professor of Mechanical engineering at MIT. hat pretty much a description of what the ankle is.
Hogan and his colleagues in the Newman Laboratory for Biomechanics and Human Rehabilitation have measured the stiffness of the ankle in various directions using a robot called the nklebot.
Electrodes record the angular displacement and torque at the joint, which researchers use to calculate the ankle stiffness.
as if pressing on a gas pedal. The joint is weaker when tilting from side to side,
and therapists better understand the physical limitations caused by strokes and other motor disorders. The researchers report their findings in the journal IEEE Transactions on Neural Systems and Rehabilitation Engineering.
and Hermano Krebs from MIT and Mohammad Rastgaar Aagaah from Michigan Technological University. A robotic walking coach Hogan and Krebs
Typically during the first few sessions, the robot does most of the work moving the patient ankle back and forth and side to side, loosening up the muscles, ind of like a massage,
Hogan says. The robot senses when patients start to move their ankles on their own, and adapts by offering less assistance. he key thing is,
Many other robotic therapies are designed to do most of the work for the patient in an attempt to train the muscles to walk.
leaving little room for patients to move on their own. asically you can fall asleep in these machines,
Hogan says. hat wee trying to do with machines in therapy is equivalent to helping the patients,
as well as surface electrodes attached to the ankle four major muscles. The robot was connected to a video display with a pixelated bar that moved up and down
the ankle was least stiff a finding that suggests this direction of movement is most vulnerable to injury.
Eric Perreault, a professor of biomedical engineering and physical medicine and rehabilitation at Northwestern University, says the group findings present the first insight into how muscle activation alters the ankle mechanical properties over its normal range of motion,
hich are highly relevant to many ankle injuries including the common ankle sprain. n intriguing extension of this work is that it may be possible to train individuals to activate their ankle musculature in a way that helps reduce the chance of injury,
who did not participate in the research. more immediate benefit of the study is that it presents a method for quantifying the impact of existing rehabilitation therapies on the mechanical properties of the ankle.
Understanding the mechanics of the ankle in healthy subjects may help therapists identify abnormalities in patients with motor disorders.
For now, the team will continue its work in rehabilitation, using the Anklebot to train patients to walk
what s called supervised machine learning: They re trained on sample recordings that a human has indexed indicating
You can know something about the identity of a person from the sound of their voice so this technology is keying in to that type of information says Jim Glass a senior research scientist at MIT s Computer science and Artificial intelligence Laboratory (CSAIL) and head
To create a sonic portrait of a single speaker Glass explains a computer system will generally have to analyze more than 2000 different speech sounds;
A new algorithm that determines who speaks when in audio recordings represents every second of speech as a point in a three-dimensional space.
In prior work Najim Dehak a research scientist in the Spoken language Systems Group and one of the new paper s co-authors had demonstrated a technique for reducing the number of variables required to describe the acoustic signature of a particular speaker
To get a sense of how the technique works imagine a graph that plotted say hours worked by an hourly worker against money earned.
Stephen Shum a graduate student in MIT s Department of Electrical engineering and Computer science and lead author on the new paper found that a 100-variable i-vector a 100-dimension approximation of the 120000-dimension space was an adequate
According to Patrick Kenny a principal research scientist at the Computer Research Institute of Montreal i-vectors were devised originally to solve the problem of speaker recognition or determining whether the same speaker features on multiple recordings.
It s really an order of magnitude less than the recordings that are used in text-dependent speech recognition. What was completely not obvious
I think that was the significant contribution of Stephen s work k
#Schizophrenia linked to abnormal brain waves Schizophrenia patients usually suffer from a breakdown of organized thought often accompanied by delusions or hallucinations.
For the first time MIT neuroscientists have observed the neural activity that appears to produce this disordered thinking. The researchers found that mice lacking the brain protein calcineurin have hyperactive brainwave oscillations in the hippocampus
Mutations in the gene for calcineurin have previously been found in some schizophrenia patients. Ten years ago MIT researchers led by Susumu Tonegawa the Picower Professor of Biology
and Neuroscience created mice lacking the gene for calcineurin in the forebrain; these mice displayed several behavioral symptoms of schizophrenia including impaired short-term memory attention deficits and abnormal social behavior.
In the new study which appears in the Oct 16 issue of the journal Neuron Tonegawa
and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics at MIT s Picower Institute for Learning and Memory recorded the electrical activity of individual neurons in the hippocampus of these knockout mice
These replays occur in association with very high frequency brainwave oscillations known as ripple events. In mice lacking calcineurin the researchers found that brain activity was normal as the mice ran the course
Furthermore the firing of the place cells was augmented abnormally and in no particular order indicating that the mice were not replaying the route they had just run.
This pattern helps to explain some of the symptoms seen in schizophrenia the researchers say.
We think that in this mouse model we may have some kind of indication that there s a disorganized thinking process going on says Junghyup Suh a research scientist at the Picower Institute
This mutant mouse doesn t seem to have that kind of replay of a previous experience.
Other authors are Heydar Davoudi and Matthew Wilson the Sherman Fairchild Professor of Neuroscience at MIT and a member of the Picower Institute.
when a person (or mouse) is resting between goal-oriented tasks. When the brain is focusing on a specific goal
However this network is hyperactive in schizophrenic patients before and during tasks that require the brain to focus
Further studies of these mice could help reveal more about the role of the default mode network in schizophrenia Tonegawa says.
Compilers are computer programs that translate high-level instructions written in human-readable languages like Java or C into low-level instructions that machines can execute.
Most compilers also streamline the code they produce, modifying algorithms specified by programmers so that theyl run more efficiently.
Sometimes that means simply discarding lines of code that appear to serve no purpose. But as it turns out,
compilers can be overaggressive, dispensing not only with functional code but also with code that actually performs vital security checks.
At the ACM Symposium on Operating systems Principles in November, MIT researchers will present a new system
that automatically combs through programmerscode, identifying just those lines that compilers might discard but which could, in fact, be functional.
commercial software engineers have downloaded already Stack and begun using it, with encouraging results. As strange as it may seem to nonprogrammers or people
and compilers should remove it. Problems arise when compilers also remove code that leads to ndefined behavior
. or some things this is obvious, says Frans Kaashoek, the Charles A. Piper Professor in the Department of Electrical engineering and Computer science (EECS).
f youe a programmer, you should not write a statement where you take some number and divide it by zero.
You never expect that to work. So the compiler will just remove that. It pointless to execute it anyway,
because there not going to be any sensible result. Defining moments Over time, however, ompiler writers got a little more aggressive,
Kaashoek says. t turns out that the C programming language has a lot of subtle corners to the language specification,
and there are things that are undefined behavior that most programmers don realize are undefined behavior. A classic example
explains Xi Wang, a graduate student in EECS and first author on the new paper, is the assumption that
if a program attempts to store too large a number at a memory location reserved for an integer,
the computer will lop off the bits that don fit. n machines, integers have a limit,
Seasoned C programmers will actually exploit this behavior to verify that program inputs don exceed some threshold.
According to Wang, programmers give a range of explanations for this practice. Some say that the intent of the comparison an overflow check is clearer
while the wraparound check works fine with unsigned integers integers that are always positive it is,
according to the C language specification, undefined for signed integers integers that can be either positive or negative.
The fine print Complicating things further is the fact that different compilers will dispense with different undefined behaviors:
but prohibit other programming shortcuts; some might impose exactly the opposite restrictions. So Wang combed through the C language specifications
and identified every undefined behavior that he and his coauthors Kaashoek and his fellow EECS professors Nickolai Zeldovich and Armando Solar-Lezama imagined that a programmer might ever inadvertently invoke.
Stack, in effect, compiles a program twice: once just looking to excise dead code, and a second time to excise dead code and undefined behavior.
but not the first and warns the programmer that it could pose problems. The MIT researchers tested their system on several open-source programs.
In one case, the developers of a program that performs database searches refused to believe that their code had bugs,
. i sent them a one-line SQL statement that basically crashed their application, by exploiting their orrectcode,
Mattias Engdegård, an engineer at Intel, is one of the developers who found Stack online
while recovering from surgery or takes certain medications. There is no fast and easy way to diagnose these clots which often remain undetected until they break free
and cause a stroke or heart attack. However new technology from MIT may soon change that:
The noninvasive diagnostic described in a recent issue of the journal ACS Nano relies on nanoparticles that detect the presence of thrombin a key blood-clotting factor.
Such a system could be used to monitor patients who are at high risk for blood clots says Sangeeta Bhatia senior author of the paper and the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical engineering and Computer science.
but existing blood tests are not consistently able to detect the formation of new clots says Bhatia who is also a senior associate member of the Broad Institute and a member of MIT s Koch Institute for Integrative Cancer Research
and Institute for Medical Engineering and Science (IMES). Lead authors of the paper are Kevin Lin a graduate student in chemical engineering and Gabriel Kwong a postdoc in IMES.
Other authors are Andrew Warren a graduate student in Health Sciences and Technology (HST) and former HST postdoc David wood.
Sensing thrombinblood clotting is produced by a complex cascade of protein interactions culminating in the formation of fibrin a fibrous protein that seals wounds.
The last step of this process the conversion of fibrinogen to fibrin is controlled by an enzyme called thrombin.
Bhatia and her colleagues developed their new test based on a technology they first reported last year for early detection of colorectal cancer.
which is an injectable nanoparticle and made it a thrombin sensor. The system consists of iron oxide nanoparticles
which the Food and Drug Administration has approved for human use coated with peptides (short proteins) that are specialized to interact with thrombin.
After being injected into mice the nanoparticles travel throughout the body. When the particles encounter thrombin the thrombin cleaves the peptides at a specific location releasing fragments that are excreted then in the animals urine.
Once the urine is collected the protein fragments can be identified by treating the sample with antibodies specific to peptide tags included in the fragments.
The researchers showed that the amount of these tags found in the urine is directly proportional to the level of blood clotting in the mice s lungs.
In the previous version of the system reported last December in Nature Biotechnology the researchers used mass spectrometry to distinguish the fragments by their mass.
However testing samples with antibodies is much simpler and cheaper the researchers say. Rapid screeningbhatia says she envisions two possible applications for this kind of test.
One is to screen patients who come to the emergency room complaining of symptoms that might indicate a blood clot allowing doctors to rapidly triage such patients
Another application is monitoring patients who are at high risk for a clot for example people who have to spend a lot of time in bed recovering from surgery.
Bhatia is working on a urine dipstick test similar to a pregnancy test that doctors could give patients
when they go home after surgery. If a patient is at risk for thrombosis you could send them home with a 10-pack of these sticks
and say Pee on this every other day and call me if it turns blue she says.
The technology could also be useful for predicting recurrence of clots says Henri Spronk an assistant professor of biochemistry at Maastricht University in The netherlands.
High levels of activation markers have been related to recurrent thrombosis but they don t have good sensitivity or specificity.
Through application of the nanoparticles if proven well-tolerated and nontoxic alterations in the normal low levels of physiological thrombin generation might be detected easily says Spronk who was not part of the research team.
Bhatia plans to launch a company to commercialize the technology with funding from MIT s Deshpande Center for Technological Innovation.
Other applications for the nanoparticle system could include monitoring and diagnosing cancer. It could also be adapted to track liver pulmonary
and kidney fibrosis Bhatia says. The research was funded by the Koch Institute Frontier Research Fund the Kathy and Curt Marble Cancer Research Fund the Mazumdar-Shaw International Oncology Fellows Program the Burroughs Wellcome
Fund and the Deshpande Center r
#Creating a permanent bacteria barrier Any medical device implanted in the body attracts bacteria, proteins, and other microbes to its surface, causing infections and thrombosis (blood clotting) that lead to hundreds of thousands of deaths annually.
Devices can be coated with antibiotics, blood thinners, and other agents but these eventually dissolve, limiting their longevity and effectiveness.
Now, Semprus Biosciences, a startup co-founded by two MIT alumni Christopher Loose Phd 7
and CEO David Lucchino MBA 6 is developing a novel biomaterial for implanted medical devices that permanently barricades these troublesome microbes from the device surface.
The biomaterial is a nonleaching polymeric sulfobetaine (polysb) that when applied to a medical device, sprouts a thicket of polymers that attract water,
creating an impenetrable barrier for microbes. Its chemical makeup also mimics that of cells important to homeostasis,
potentially reducing the body natural rejection of implanted devices. asically, wee developed a long-lasting solution that blocks negative consequences in the body by making devices look more like the human body, Loose says.
The application of polysb to catheters yields a significant reduction in the buildup of protein, mammalian cells,
and microbes on a device surface, compared with unmodified catheters. This has potential to reduce blood clots and infection
and improve overall patient health, the cofounders say. The technology was described in a paper published last year in the journal Science Translation Medicine,
co-authored by Loose, Lucchino, MIT Institute Professor Robert Langer, and other researchers. Based on Loose work at MIT,
the biomaterial has positioned Semprus as a fast-growing biotech firm in Kendall Square. In its six years, the startup seed-funded, in part,
by the MIT $100k Entrepreneurship Competition has earned millions of dollars in private and federal funding. In 2012, Semprus sold to a medical device-manufacturing giant for an amount that could reach $80 million.
As a wholly owned subsidiary the Semprus team continues developing the technology. Semprusfirst commercial product based on the biomaterial, Semprus Sustain technology,
is designed specifically for venous catheters and recently earned clearance from the Food and Drug Administration as a medical device deemed safe and effective for commercial distribution in the United states. It also recently received designation as a product meeting European union standards of health, safety,
and environmental protection. Addressing an nmet needthe Semprus story began in Langer lab, where Loose,
a chemical engineering Phd student, was charged with developing medical devices that could permanently be inserted in the body without triggering an immune response in other words,
creating medical devices that ooked more human, Loose says. Loose developed a means of applying naturally occurring antibiotics,
called antimicrobial peptides found in bacteria and human sweat on medical devices. These peptides would puncture bacteria that came near,
and microbes would have trouble developing resistance to them. In 2007, Loose was named one of 5 innovators under 35by MIT Technology Review for this innovation.
Seeing commercial potential, Langer a chemical engineer, bioengineer, and famed MIT entrepreneur layed matchmakerbetween Loose and Lucchino,
who had worked previously for Polaris Ventures Partners and was, at the time, an Alfred P. Sloan Fellow at the MIT Sloan School of management.
The two had an instant rapport Lucchino says and an ambition to commercialize Loose innovation.
So they ent to schoolon the medical device market, canvassing hospitals to meet patients and to talk with nurses and doctors about unmet clinical needs. e learned quickly that the most successful entrepreneurs are good listeners,
Lucchino says. e conducted our own istening tourto understand the problem, so we could develop the most strategic business and technology solution.
They found many patients suffering from chronic diseases such as diabetes, cancer, and heart disease and a lack of permanent oatingsfor medical implants that might help these patients.
Thus Loose says, they were ahead of the curve in addressing the nmet needof the medical devices market. e realized an unmet need that was going to grow over the next few years
and we were one of the first to have a solution to it, he says. verything starts with the unmet need.
In the Science Translation Medicine paper, the cofounders exposed polysb-modified catheters to blood for 60 days.
In vitro, the modified catheters on both their external and internal surfaces saw a 98 percent reduction in the accumulation of platelets and three types of white blood cells.
In vivo, the modified catheters showed a 99 percent reduction in thrombus accumulation, 50 percent less inflammation,
Through MIT network of entrepreneurs, investors, and lawyers, e were able to assemble a great team of advisers to refine our plans
and give us the momentum to go out and do financing, Lucchino says. Under Lucchino stewardship, Semprus secured $28. 5 million in venture capital financing and $2. 4 million in federal funding, primarily from the National Science Foundation
and grew from two to 40 employees. Lucchino says he owes some of his business acumen to his education at MIT Sloan,
which taught him a broad set of entrepreneurial skills in finance, business, and operations strategies. t was continuing to fertilize my entrepreneurial soil to get
me in the best position to succeed, Lucchino says. Today, the two entrepreneurs continue to mentor students
and give talks at MIT and Harvard Business school, sharing startup advice, or their ules of the roadsuch as knowing your technological and personal limitations, working with limited resources, being flexible to economic and other changes,
and, most importantly, teamwork. o one person builds a company alone, says Lucchino, who has served as guest lecturer at MIT Sloan. s your company grows
and there real value attached to what youe doing, you need to be able to trust the people youe working with.
Chris and I, as a team, made Semprus a success. The most important skill and functionality we have is trust. l
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