Do Men Have Higher Genetic Risk of Melanoma?

A study led by researchers at Universitat Jaume I de Castellón has identified one of the genetic causes underlying the higher rate of melanoma in men. The results have been published in Biology of Sex Differences.

The Genetics of Skin Cancer and Human Pigmentation (Melanogen) research group, led by lecturer Conrado Martínez-Cadenas at the Universitat Jaume I de Castellón (UJI), has studied the differences between men and women in terms of pigmentation (eye, hair and skin) and sun response, i.e. history of sunburn, and the presence irregular moles and freckles caused by sun exposure. This study was carried out in collaboration with Dr. Gloria Ribas' research group at Incliva Biomedical Research Institute. It involved 1,057 people in total, some 52% of which were melanoma patients from hospitals in Castellón, Valencia, Madrid and Bilbao.

"The study included 384 genetic variants and six physical characteristics. The results show that, with the same genetic variability, men tend to have lighter skin pigmentation and a worse response to the effects of ultraviolet rays," Martínez-Cadenas tells us.

Estrogen enhances sun protection

Skin cancer is determined both by environmental factors, such as sun exposure, and other genetic factors. People with light skin or eyes and blonde or red hair have a 20 to 30 times greater chance of getting skin cancer that darker skinned people, who tan easily.

Meanwhile, several studies have shown that female hormones promote the production of melanin, the pigment that protects the skin from the sun. Indeed, "estrogen could be the reason why women have a darker skin tone, even when the genotypes of both sexes are the same, meaning that their risk of skin cancer is lower. So much so that skin cancer is much more prevalent in men," explains Bárbara Hernando, fellow researcher at the Melanogen research group and coauthor of the study.

This study on melanoma in Spain grew out of a previous study, where results "showed that men tend to have lighter eyes than women with the same genetic variety," Martínez-Cadenas adds.

Additional forensic uses

Research into the genetics of skin pigmentation is important for understanding human biology and evolution, as well as the biology of skin cancer. By identifying genetic factors that influence melanoma risk, we can study this kind of cancer in more detail. But beyond this, other studies carried out at the Melanogen group show that introducing the factor 'sex' in the eye colour prediction model developed for forensic purposes "significantly improves the success rate in identifying a suspect (or victim) from a biological sample found at a crime scene, for instance," Martínez-Cadenas explains.

Prevention is key to the fight against melanoma

The sheer number of factors involved in melanoma mean that treatments to cure it have not made much progress in recent years. Prevention is therefore the most effective weapon: "the best way to prevent melanoma is to limit exposure to the sun when UV radiation is at its peak, and to use sunscreen -at least factor 30- when outdoors" (Bárbara Hernando). Self-examination and regular visits to the specialist, especially if we detect irregular moles or freckles with uneven colouration, or which are larger than six millimetres in diameter, "are essential to preventing this disease," she concludes.

Three main lines of research are developed at the Melanogen research group at the Universitat Jaume I, led by Conrado Martínez-Cadenas. The first explores the genetic basis of human susceptibility to melanoma and other skin cancers. The second focuses on the molecular mechanisms and intracellular signalling pathways involved in the genesis and progression of skin cancer, both melanoma and non-melanoma (basal cell and squamous cell carcinomas). The third addresses the genetic, hormonal and environmental factors involved in the development of benign pigmented lesions: freckles, nevus, solar lentigo, melasma, etc.

Metastatic prostate cancer cases skyrocket: More lax screening rather than more aggressive disease?

The number of new cases of metastatic prostate cancer climbed 72 percent in the past decade from 2004 to 2013, reports a new Northwestern Medicine study. The report considers whether a recent trend of fewer men being screened may be contributing to the rise, or whether the disease has become more aggressive -- or both.

The largest increase in new cases was among men 55 to 69 years old, which rose 92 percent in the past decade. This rise is particularly troubling, the authors said, because men in this age group are believed to benefit most from prostate cancer screening and early treatment.

In addition, the average PSA (prostate-specific antigen) of men who were diagnosed with metastatic prostate cancer in 2013 was 49, nearly double that for men diagnosed in 2004 with an average PSA of 25, indicating a greater extent of disease at diagnosis.

The blood level of PSA, a protein produced by cells of the prostate gland, is often elevated in men with prostate cancer.

"One hypothesis is the disease has become more aggressive, regardless of the change in screening," said senior study author Dr. Edward Schaeffer, chair of urology at Northwestern University Feinberg School of Medicine and Northwestern Medicine. "The other idea is since screening guidelines have become more lax, when men do get diagnosed, it's at a more advanced stage of disease. Probably both are true. We don't know for sure but this is the focus of our current work."

Schaeffer also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The paper will be published July 19 in Prostate Cancer and Prostatic Diseases, a journal from Nature.

Schaeffer's research team analyzed information from the National Cancer Data Base. It included 767,550 men from 1,089 facilities nationwide who had been diagnosed with prostate cancer between 2004 and 2013.

Over the past decade, there has been a substantial reduction in the number of men being screened for prostate cancer and an associated decline in the overall number of new cases of prostate cancer being reported.

"The fact that men in 2013 who presented with metastatic disease had much higher PSAs than similar men in 2004 hints that more aggressive disease is on the rise," Schaeffer said. "If I were a patient, I would want to be vigilant. I firmly believe that PSA screening and rectal exams save lives."

If a patient is diagnosed with localized prostate cancer that is aggressive, treatment can be curative. If men present with metastatic prostate cancer, treatments are not curative and only slow disease progression. Most patients with metastatic prostate cancer eventually die from the disease.

"There could be a significant increase in prostate cancer death rates if more people are diagnosed with metastatic disease, because treatments can only slow progression, it's not curable," Schaeffer said.

The study measured the total number of cases of metastatic prostate cancer, not the incidence, for example, of cases per 100,000. In addition, metastatic disease began rising in 2008, before the change in screening recommendations from the U.S. Preventive Services Task Force. Thus, investigators said, they can't definitively link the increased cases to reduced screening alone.

Three percent of those included in the study had metastases, which means prostate cancer cells had spread to other parts of their bodies by the time the cancer was diagnosed. The number of cases of metastatic prostate cancer in 2013 (2,890) was 72 percent greater than that in 2004 (1,685). In middle-aged men 55 to 69 years old, the number rose 92 percent from 702 new cases in 2004 to 1,345 in 2013.

"The results indicate that screening guidelines and treatment need to be refined based on individual patient risk factors and genetics," said lead author Dr. Adam Weiner, a Feinberg urology resident. "This may help prevent the growing occurrence of metastatic prostate cancer and potential deaths associated with the disease. This also can help minimize overdiagnosing and overtreating men with low-risk prostate cancer who do not need treatment."

"This will be particularly critical for population health economics in the U.S., considering the added cost of care for metastatic prostate cancer and an aging constituency whose population over the age of 65 will double to over a projected 80 million by the year 2050," Schaeffer noted.

How New HIV Drugs Lock Virus in Immaturity

A new type of HIV drug currently being tested works in an unusual way, scientists in the Molecular Medicine Partnership Unit, a collaboration between EMBL and Heidelberg University Hospital, have found. They also discovered that when the virus became resistant to early versions of these drugs, it did not do so by blocking or preventing their effects, but rather by circumventing them. The study, published online today in Science, presents the most detailed view yet of part of the immature form of HIV.

HIV, the virus that causes AIDS, comes in two forms: immature and mature. The immature form is assembled inside an infected person's cells. After an immature virus particle has left the cell, it has to change into the mature form before it can infect other human cells. A new group of drugs that inhibit this maturation is currently undergoing clinical trials, but so far it was unclear how exactly these drugs act.

To go from immature to mature, HIV has to cut the connections between its main building blocks, and rearrange those pieces. John Briggs' lab at EMBL and Hans-Georg Kräusslich's lab at Heidelberg University Hospital looked at a particularly important cutting point. It connects building blocks known as the capsid protein and the spacer peptide 1, and if it is not cut, the virus cannot mature. The scientists used a combination of cryo-electron tomography and subtomogram averaging to reveal exactly what this part of the immature form of HIV looks like in 3D. They found that the cutting site is hidden in a position where the virus' cutting machinery can't sever it. So for the virus to mature, the structure first has to change, to expose that cutting point.

"When we looked at the virus with one of these inhibitor drugs on it, we found that the inhibitor doesn't prevent the cutting machinery from getting in, as you might expect," says Florian Schur, who carried out the work in Briggs' lab. "Rather, the drug locks the immature virus structure in place, so that it can't be cut."

When the new inhibitor drugs were first developed, scientists found that HIV viruses with certain mutations in their genetic sequence were unaffected by the drugs -- they were resistant. Having determined what the cutting point looks like and how the drugs act, Briggs and colleagues are now able to understand the effects of those mutations.

"Rather than stopping the drug from binding, the virus becomes resistant through mutations that destabilise the immature structure," says Kräusslich. "This allows it to rearrange and be cut even when the drug is in place."

The researchers would now like to probe the virus and the inhibitor drugs in even greater detail, to understand exactly how the drugs attach themselves to the viral proteins, and potentially gather data that could help to search for better drugs -- or to design them.

The method used in this study -- combined cryo-electron tomography and subtomogram averaging -- enables scientists to study structures inside irregular viruses like HIV, or within cells. In essence, the scientists use an electron microscope to obtain a 3D image of the sample -- in this case, whole HIV-1 particles. They then identify all the copies of the object they want to study -- all the instances of the capsid protein-spacer peptide 1 cutting point -- and use software to rotate the 3D image of each copy so that they are all facing the same way. By repeating this procedure with thousands of images, the scientists can obtain an accurate picture. With this approach, researchers can study such samples without having to purify them in a test-tube, which means that they see them in their real state. The EMBL scientists' work now proves that the method can provide the level of detail that is crucial to understanding how molecular machines work and to informing drug design.

Synthetic biology used to limit bacterial growth and coordinate drug release

Researchers at the University of California San Diego and the Massachusetts Institute of Technology (MIT) have come up with a strategy for using synthetic biology in therapeutics. The approach enables continual production and release of drugs at disease sites in mice while simultaneously limiting the size, over time, of the populations of bacteria engineered to produce the drugs. The findings are published in the July 20 online issue of Nature.

UC San Diego researchers led by Jeff Hasty, a professor of bioengineering and biology, engineered a clinically relevant bacterium to produce cancer drugs and then self-destruct and release the drugs at the site of tumors. The team then transferred the bacterial therapy to their MIT collaborators for testing in an animal model of colorectal metastasis. The design of the therapy represents a culmination of four previous Nature papers from the UC San Diego group that describe the systematic development of engineered genetic clocks and synchronization. Over the years, the researchers have employed a broad approach that spans the scales of synthetic biology.

The new study offers a therapeutic approach that minimizes damage to surrounding cells.

"In synthetic biology, one goal of therapeutics is to target disease sites and minimize damage," said UC San Diego bioengineering and biology professor Jeff Hasty. He wondered if a genetic "kill" circuit could be engineered to control a population of bacteria in vivo, thus minimizing their growth. "We also wanted to deliver a significant therapeutic payload to the disease site."

In order to achieve this, he and his team synchronized the bacteria to release bursts of known cancer drugs when a bacterial colony self-destructs within the tumor environment. The use of bacteria to deliver cancer drugs in vivo is enticing because conventional chemotherapy doesn't always reach the inner regions of a tumor, but bacteria can colonize there. Importantly, the researchers observed that the combination of chemotherapy and the gene products produced by the bacterial circuit consistently reduced tumor size.

"The new work by Jeff Hasty and team is a brilliant demonstration of how theory in synthetic biology can lead to clinically meaningful advances," said Jim Collins, a professor at MIT who is known as a founder of the field of synthetic biology. "Over a decade ago during the early days of the field, Jeff developed a theoretical framework for synchronizing cellular processes across a community of cells. Now his team has shown experimentally how one can harness such effects to create a novel, clinically viable therapeutic approach."

Limiting the bacterial population

In order to observe the bacterial population dynamics, the researchers designed custom microfluidic devices for careful testing before investigations in animal disease models. Consistent with the engineering design, they observed cycling of the bacterial population that successfully limits overall growth while simultaneously enabling production and release of encoded cargo. When the bacteria were equipped with a gene that drives production of a therapeutic, the synchronized lysis of the bacterial colony was shown to kill human cancer cells. It is the first engineered gene circuit in synthetic biology to achieve these objectives.

"In this paper, we describe a circuit that contains a gene that codes for a small molecule that can diffuse between cells and can turn on genes," said Omar Din, the paper's lead author and a UC San Diego Jacobs School of Engineering bioengineering Ph.D. student in Hasty's research group. "Once the population grows to a critical size -- a few thousand cells -- there's a high-enough concentration of that molecule present in the cells to cause mass transcription of the genes behind the promoter."

The molecule, AHL, is known to coordinate gene expression across a colony of bacterial cells. Once on, the genes driven by the promoter are also activated, including the AHL-producing gene itself. Thanks to this positive feedback loop, the more AHL accumulates, the more it is produced. Because AHL is small enough to diffuse between cells and turn on the promoter in neighboring cells, the genes activated by it would also be produced in high amounts, leading to a phenomenon known as quorum sensing. Bacteria use quorum sensing to communicate with each other about the size of their population, and regulate gene expression accordingly. Scientists have used this natural ability of bacteria extensively as a tool.

Din used quorum sensing as an engineering tool to synchronize the cells and then added a kill gene that causes cells to break open (lyse) when a bacterial colony grows to a threshold. After the mass self-destruction event, a few cells remain to repopulate the colony and the resulting population dynamics are cyclical.

"The lysis circuit was originally conceived for use as an aquatic biosensor, but it subsequently became clear that an exciting application could be the coordinated release of drugs when bacteria lyse in vivo," Hasty said.

Watch a video showing the programmed cycles of bacterial drug delivery.

Finding the right drug combination

Next, the researchers needed to find the right drug for delivery by the bacteria. They tested three different therapeutic proteins that had been shown to shrink tumors. The tests showed that the proteins were most effective when combined. They placed the genes responsible for these proteins in the circuit along with the lysis gene. They then conducted experiments with HeLa cells that showed enough protein was produced to kill cancer cells.

The testing of the therapy in mice was carried out by UC San Diego bioengineering alumnus Tal Danino while he was a postdoctoral researcher in Sangeeta Bhatia's research group at MIT. Danino is now a professor at Columbia University.

The bacteria were first injected into mice with a grafted subcutaneous tumor. This mouse model was used to visualize the bacterial population in vivo and observe their dynamics. The result was a decrease in tumor size. Danino then used a more advanced mouse model with liver metastases, where bacteria were fed to the mice. After testing a combination of the engineered bacteria and chemotherapy with this model, the researchers found that the combined therapy prolonged survival of the mice over either therapy administered alone. The researchers note that this new approach has not yet cured any mice. They did find that the therapy led to around a 50 percent increase in life expectancy, but it's difficult to anticipate how this would translate to humans. Taken together, the experiments in mice establish a proof-of-principle for using the tools of synthetic biology to engineer 'tumor-targeting' bacteria to deliver therapeutic proteins in vivo.

Developing a strategy

The new Nature paper shows the use of quorum sensing to limit bacterial population growth and release drugs. In previous Nature papers, the Hasty lab has shown how engineered cellular oscillations can be coordinated within a bacterial colony and even between thousands of interacting colonies.

"This paper describes a highly innovative strategy employing synthetic biology to weaponize bacteria," said Bert Vogelstein, Director of the Ludwig Center at Johns Hopkins University and pioneer in the field of cancer genomics. "The authors show that these bacteria can be used to slow the growth of tumors growing in mice. Though much further work will be required to make this therapy applicable to humans, it's just the kind of new, forward-thinking approach that we desperately need if we are to more effectively combat cancer."

Next possible steps include investigating the natural presence of bacteria in tumors and then engineering these bacteria for use in vivo and using multiple strains of bacteria to form a therapeutic community.

"Additionally, we are currently investigating methods for maintaining the circuit inside bacteria," said Din. "Since the proteins produced by the circuit put a burden on the bacteria, the bacteria are prone to mutate these genes. Additionally, there is a selection pressure to get rid of the plasmids which harbor the genes comprising the circuit. Thus, one of our future research aims is to identify strategies for stabilizing the circuit components in bacteria and decreasing their susceptibility to mutations."

Ancient feces provides earliest evidence of infectious disease being carried on Silk Road

An ancient latrine near a desert in north-western China has revealed the first archaeological evidence that travellers along the Silk Road were responsible for the spread of infectious diseases along huge distances of the route 2,000 years ago.

Cambridge researchers Hui-Yuan Yeh and Piers Mitchell used microscopy to study preserved faeces on ancient 'personal hygiene sticks' (used for wiping away faeces from the anus) in the latrine at what was a large Silk Road relay station on the eastern margins of the Tamrin Basin, a region that contains the Taklamakan desert. The latrine is thought to date from 111 BC (Han Dynasty) and was in use until 109 AD.

They found that eggs from four species of parasitic worm (helminths) were present: roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura), tapeworm (Taenia sp.), and Chinese liver fluke (Clonorchis sinensis).

Chinese liver fluke is a parasitic flatworm that causes abdominal pain, diarrhea, jaundice and liver cancer. It requires well-watered, marshy areas to complete its life cycle. Xuanquanzhi relay station was located at the eastern end of the arid Tamrin Basin, an area that contains the fearsome Taklamakan Desert. The liver fluke could not have been endemic in this dry region.

In fact, based on the current prevalence of the Chinese liver fluke, its closest endemic area to the latrine's location in Dunhuang is around 1,500km away, and the species is most common in Guandong Province -- some 2,000km from Dunhuang.

Researchers from the University of Cambridge's Department of Archaeology and Anthropology, who conducted the study, suggest that the traveller infected with this liver fluke must have journeyed an enormous distance, and suggest the discovery provides the first reliable evidence for long distance travel with an infectious disease along the Silk Road.

The findings are published today in the Journal of Archaeological Science: Reports.

"When I first saw the Chinese liver fluke egg down the microscope I knew that we had made a momentous discovery," said Hui-Yuan Yeh, one of the study's authors. "Our study is the first to use archaeological evidence from a site on the Silk Road to demonstrate that travellers were taking infectious diseases with them over these huge distances."

The Silk Road (or Silk Route) came to prominence during the Han Dynasty in China (202 BC -- AD 220) as merchants, explorers, soldiers and government officials journeyed between East Asia and the Middle East/Mediterranean region.

Researchers have previously suggested that diseases such as bubonic plague, anthrax and leprosy might have been carried by ancient travellers along the legendary trading route, as similar strains have been found in China and Europe.

"Until now there has been no proof that the Silk Road was responsible for the spread of infectious diseases. They could instead have spread between China and Europe via India to the south, or via Mongolia and Russia to the north," says study lead Piers Mitchell.

The Cambridge team worked alongside Chinese researchers Ruilin Mao and Hui Wang from the Gansu Institute for Cultural Relics and Archaeology, who originally excavated the ancient latrine and relay station in Ganzu Province.

The stop was a popular one on the Silk Road with travellers staying there and government officials using the facility to change their horses and deliver letters. While excavating the latrine, the Chinese team found the personal hygiene sticks with cloth wrapped round one end.

Added Mitchell: "Finding evidence for this species in the latrine indicates that a traveller had come here from a region of China with plenty of water, where the parasite was endemic. This proves for the first time that travellers along the Silk Road really were responsible for the spread of infectious disease along this route in the past."

Real reason turtles have shells: Burrowing tool

A recent study on the oldest proto turtle, Eunotosaurus (left), suggests the broadening of the ribs in turtles was initially an adaptation for burrowing to escape the extremely arid environment of South Africa 260 million years ago. Later the ribs were incorporated into the modern protective turtle shell as found in Pelusios (right).

Credit: Luke Norton

It is common knowledge that the modern turtle shell is largely used for protection. No other living vertebrate has so drastically altered its body to form such an impenetrable protective structure as the turtle. However, a new study by an international group of paleontologists suggests that the broad ribbed proto shell on the earliest partially shelled fossil turtles was initially an adaptation, for burrowing underground, not for protection. Paleontologist Tyler Lyson from the Denver Museum of Nature & Science is among the scientists that helped make this discovery.

"Why the turtle shell evolved is a very Dr. Seuss-like question and the answer seems pretty obvious -- it was for protection," said Dr. Lyson, lead author of Fossorial Origin of the Turtle Shell, which was released today by Current Biology. But just like the bird feather did not initially evolve for flight, the earliest beginnings of the turtle shell was not for protection but rather for digging underground to escape the harsh South African environment where these early proto turtles lived."

The early evolution of the turtle shell had long puzzled scientists. "We knew from both the fossil record and observing how the turtle shell develops in modern turtles that one of the first major changes toward a shell was the broadening of the ribs," said Dr. Lyson. While distinctly broadened ribs may not seem like a significant modification, it has a serious impact on both breathing and speed in quadrupedal animals. Ribs are used to support the body during locomotion and play a crucial role in ventilating the lungs. Distinctly broadened ribs stiffen the torso, which shortens an animals stride length and slows it down, interfering with breathing.

"The integral role of ribs in both locomotion and breathing is likely why we don't see much variation in the shape of ribs," said Dr. Lyson. "Ribs are generally pretty boring bones. The ribs of whales, snakes, dinosaurs, humans, and pretty much all other animals look the same. Turtles are the one exception, where they are highly modified to form the majority of the shell."

A big breakthrough came with the discovery of several specimens of the oldest (260- million-year-old) partially shelled proto turtle, Eunotosaurusafricanus, from the Karoo Basin of South Africa. Several of these specimens were discovered by two of the study's coauthors, Drs. Roger Smith and Bruce Rubidge from the University of Witwatersrand in Johannesburg. But the most important specimen was found by a then 8-year-old South African boy on his father's farm in the Western Cape of South Africa. This specimen, which is about 15 cm long, comprises a well preserved skeleton together with the fully articulated hands and feet.

"I want to thank Kobus Snyman and shake his hand because without Kobus both finding the specimen and taking it to his local museum, the Fransie Pienaar Museum in Prince Albert, this study would not have been possible," said Dr. Lyson.

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Story Source:

The above post is reprinted from materials provided by Denver Museum of Nature & Science.

Scientists program cells to remember and respond to series of stimuli

Synthetic biology allows researchers to program cells to perform novel functions such as fluorescing in response to a particular chemical or producing drugs in response to disease markers. In a step toward devising much more complex cellular circuits, MIT engineers have now programmed cells to remember and respond to a series of events.

These cells can remember, in the correct order, up to three different inputs, but this approach should be scalable to incorporate many more stimuli, the researchers say. Using this system, scientists can track cellular events that occur in a particular order, create environmental sensors that store complex histories, or program cellular trajectories.

"You can build very complex computing systems if you integrate the element of memory together with computation," says Timothy Lu, an associate professor of electrical engineering and computer science and of biological engineering, and head of the Synthetic Biology Group at MIT's Research Laboratory of Electronics.

This approach allows scientists to create biological "state machines" -- devices that exist in different states depending on the identities and orders of inputs they receive. The researchers also created software that helps users design circuits that implement state machines with different behaviors, which can then be tested in cells.

Lu is the senior author of the new study, which appears in the 22 July issue ofScience. Nathaniel Roquet, an MIT and Harvard graduate student, is the paper's lead author. Other authors on the paper include Scott Aaronson, an associate professor of electrical engineering and computer science, recent MIT graduate Ava Soleimany, and recent Wellesley College graduate Alyssa Ferris.

Long-term memory

In 2013, Lu and colleagues designed cell circuits that could perform a logic function and then store a memory of the event by encoding it in their DNA.

The state machine circuits that they designed in the new paper rely on enzymes called recombinases. When activated by a specific input in the cell, such as a chemical signal, recombinases either delete or invert a particular stretch of DNA, depending on the orientation of two DNA target sequences known as recognition sites. The stretch of DNA between those sites may contain recognition sites for other recombinases that respond to different inputs. Flipping or deleting those sites alters what will happen to the DNA if a second or third recombinase is later activated. Therefore, a cell's history can be determined by sequencing its DNA.

In the simplest version of this system, with just two inputs, there are five possible states for the circuit: states corresponding to neither input, input A only, input B only, A followed by B, and B followed by A. The researchers also designed and built circuits that record three inputs, in which 16 states are possible.

For this study, the researchers programmed E. coli cells to respond to substances commonly used in lab experiments, including ATc (an analogue of the antibiotic tetracycline), a sugar called arabinose, and a chemical called DAPG. However, for medical or environmental applications, the recombinases could be re-engineered to respond to other conditions such as acidity or the presence of specific transcription factors (proteins that control gene expression).

Gene control

After creating circuits that could record events, the researchers then incorporated genes into the array of recombinase binding sites, along with genetic regulatory elements. In these circuits, when recombinases rearrange the DNA, the circuits not only record information but also control which genes get turned on or off.

The researchers tested this approach with three genes that code for different fluorescent proteins -- green, red, and blue, constructing a circuit that expressed a different combination of the fluorescent proteins for each identity and order of two inputs. For example, when cells carrying this circuit recieved input A followed by input B they fluoresced red and green, while cells that recieved B before A fluoresced red and blue.

Lu's lab now hopes to use this approach to study cellular processes that are controlled by a series of events, such as the appearance of cytokines or other signaling molecules, or the activation of certain genes.

"This idea that we can record and respond to not just combinations of biological events but also their orders opens up a lot of potential applications. A lot is known about what factors regulate differentiation of specific cell types or lead to the progression of certain diseases, but not much is known about the temporal organization of those factors. That's one of the areas we hope to dive into with our device," Roquet says.

For example, scientists could use this technique to follow the trajectory of stem cells or other immature cells into differentiated, mature cell types. They could also follow the progression of diseases such as cancer. A recent study has shown that the order in which cancer-causing mutations are acquired can determine the behavior of the disease, including how cancer cells respond to drugs and develop into tumors. Furthermore, engineers could use the state machine platform developed here to program cell functions and differentiation pathways.