Researchers from Princeton Universitys Department of Molecular Biology have identified a small RNA molecule that helps maintain the activity of stem cells in both healthy and cancerous breast tissue. The study, which will be published in the June issue of Nature Cell Biology, suggests that this "microRNA" promotes particularly deadly forms of breast cancer and that inhibiting the effects of this molecule could improve the efficacy of existing breast cancer therapies.

Stem cells give rise to the different cell types in adult tissues but, in order to maintain these tissues throughout adulthood, stem cells must retain their activity for decades. They do this by "self-renewing" dividing to form additional stem cells and resisting the effects of environmental signals that would otherwise cause them to prematurely differentiate into other cell types.

Many tumors also contain so-called "cancer stem cells" that can drive tumor formation. Some tumors, such as triple-negative breast cancers, are particularly deadly because they contain large numbers of cancer stem cells that self-renew and resist differentiation.

To identify factors that help non-cancerous mammary gland stem cells (MaSCs) resist differentiation and retain their capacity to self-renew, Yibin Kang, the Warner-Lambert/Parke-Davis Professor of Molecular Biology, and colleagues searched for short RNA molecules called microRNAs that can bind and inhibit protein-coding messenger RNAs to reduce the levels of specific proteins. The researchers identified one microRNA, called miR-199a, that helps MaSCs retain their stem-cell activity by suppressing the production of a protein called LCOR, which binds DNA to regulate gene expression. The team showed that when they boosted miR-199a levels in mouse MaSCs, they suppressed LCOR and increased normal stem cell function. Conversely, when they increased LCOR levels, they could curtail mammary gland stem cell activity.

Kang and colleagues found that miR-199a was also expressed in human and mouse breast cancer stem cells. Just as boosting miR-199a levels helped normal mammary gland stem cells retain their activity, the researchers showed that miR-199a enhanced the ability of cancer stem cells to form tumors. By increasing LCOR levels, in contrast, they could reduce the tumor-forming capacity of the cancer stem cells. In collaboration with researchers led by Zhi-Ming Shao, a professor at Fudan University Shanghai Cancer Center in China, Kang's team found that breast cancer patients whose tumors expressed large amounts of miR-199a showed poor survival rates, whereas tumors with high levels of LCOR had a better prognosis.

Kang and colleagues found that LCOR sensitizes cells to the effects of interferon-signaling molecules released from epithelial and immune cells, particularly macrophages, in the mammary gland. During normal mammary gland development, these cells secrete interferon-alpha to promote cell differentiation and inhibit cell division, the researchers discovered. By suppressing LCOR, miR-199a protects MaSCs from interferon signaling, allowing MaSCs to remain undifferentiated and capable of self-renewal.

The microRNA plays a similar role during tumorigenesis, protecting breast cancer stem cells from the effects of interferons secreted by immune cells present in the tumor. "This is a very nice study linking a normal and malignant mammary gland stem cell program to protection from immune modulators," said Michael Clarke, the Karel H. and Avice N. Beekhuis Professor in Cancer Biology at Stanford School of Medicine, Institute of Stem Cell Biology and Regenerative Medicine, who first discovered breast cancer stem cells but was not involved in this study. "It clearly has therapeutic implications for designing strategies to rationally target the breast cancer stem cells with immune modulators."

Toni Celi-Terrassa, an associate research scholar in the Kang lab and the first author of the study, said, "This study unveils a new property of breast cancer stem cells that give them advantages in their interactions with the immune system, and therefore it represents an excellent opportunity to exploit for improving immunotherapy of cancer."

"Interferons have been widely used for the treatment of multiple cancer types, Kang said. "These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway."

Other authors on the paper were Daniel Liu, Abrar Choudhury, Xiang Hang, Yong Wei, Raymundo Alfaro-Aco, Rumela Chakrabarti, Christina DeCoste, Bong Ihn Koh and Heath Smith of the Department of Molecular Biology at Princeton University; Jose Zamalloa of the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics at Princeton University; and Yi-Zhou Jiang, Jun-Jing Li and Zhi-Ming Shao of the Department of Breast Surgery at Fudan University Shanghai Cancer Center and the Department of Oncology at Shanghai Medical College, Fudan University.

This work was supported by a Susan G. Komen Fellowship to Toni Celi-Terrassa (PDF15332075) and grants from the Brewster Foundation, the Breast Cancer Research Foundation, the U.S. Department of Defense (BC123187) and the National Institutes of Health (R01CA141062) to Kang's laboratory.

Read the rest here:
Study identifies RNA molecule that shields breast cancer stem cells from immune system - Princeton University

In two different studies, US scientists have succeeded in creating the stem cells which produce blood.

Both studies published in Nature are concerned with making haematopoietic stem cells (HSCs), which are found inside the bone marrow and can divide to generate each of the many types of blood cell.

In the first study, a team at the Daley laboratory at Boston Childrens Hospital, Massachusetts, took human embryonic stem cells or iPS(induced pluripotent stem) cells. They exposed these cells to developmental chemicals called cytokines, and also identified seven transcription factor genes associated with HSCs and introduced them into these stem cells using a viral vector. The resulting cells were not identical to natural HSCs, but appeared to perform the same function: mice injected into the leg bone with the cells, subsequently developed human blood cells of various types in the bone marrow and circulation.

In the second study, the team led by scientistsat Weill Cornell Medical College in New York bypassed the iPSCs stage entirely. They isolated cells from the blood vessel lining of adult mice and inserted four transcription factor genes, again using a virus. They grew these cells on material derived from the human umbilical cord which provided factors to guide development into HSCs.

Again, the cells produced once transplanted into mouse recipients were able to produce mature blood cells, including in mice which were genetically modified to lack an immune system.

Generating replacement HSCs from a patient's own cells, through either method, could allow a therapy to be tailored to an individual. Dr Ryohichi Sugimura at the Daley Lab, a lead author of the first paper, said: 'This step opens up an opportunity to take cells from patients with genetic blood disorders, use gene editing to correct their genetic defect and make functional blood cells. This also gives us the potential to have a limitless supply of blood stem cells and blood by taking cells from universal donors. This could potentially augment the blood supply for patients who need transfusions.'

An article in Nature, co-written by Dr Carolina Guibentif at the Wellcome Trust and MRC Cambridge Stem Cell Institute in Cambridge, discussed the findings, referring to the production of HSCs in the laboratory as a 'long-sought goal of stem-cell biology'. Dr Guibentif, who was not involved in either study, toldThe Independent:'People have been trying to do this for 20 years unsuccessfully. This is the first time they have got cells that can self-renew and give rise to all sorts of blood cells, so of course its a big step towards the goal, but we are not quite there yet.'

But she also cautioned that such generated cells could be a cancer risk:'Many of the transcription factors used in the current studies have also been implicated in the initiation of leukaemia.'

Read the original post:
Blood stem cells produced in the lab for the first time - BioNews

From just a bit of genetic information, a human embryo develops into a complete person. So humans have a limited ability to regrow body parts.

If you cut the leg off a salamander, it grows back. Humans, however, can't manage the trick. The reasons are far from simple, and to some extent are still a bit of a mystery.

"We actually regenerate really well; our epidermis, for example," David Gardiner, professor of developmental and cell biology at the University of California, Irvine, told Live Science, referring to the top layer of skin. "Our gut lining, we can regenerate bits and pieces. But we don't regenerate these more complex structures."

Gardiner has studied salamander regeneration for decades, seeking the underlying mechanism of the superpower. Human regeneration, he said, is likely still in the future, but not too far off it's possible one of his current graduate students or postdoctoral researchers will crack it, and limb regeneration will be a part of the medical toolkit. [11 Body Parts Grown in the Lab]

That's because, in theory, regrowing a human limb should be possible. In skin, for instance, if the cuts aren't deep, there will be no scarring due to the healing process that regenerates skin cells. It's also possible for humans to regenerate the very tips of the fingers if the cells under the fingernails are still intact. Bones will knit together if you rejoin the pieces, say, with a screw or a cast. Human livers can also grow to fill the space and rebuild some of the structure that was damaged.

But limb regeneration (of the kind salamanders do) is more than just replacing tissue. For a limb to regenerate, you need bone, muscle, blood vessels and nerves. There are adult stem cells, a kind of undifferentiated cell that can become specialized, that regenerate muscle, but they don't seem to activate. "You can regenerate blood vessels and even nerves," Gardiner said. "But the whole arm can't [regrow]."

Stphane Roy, director of the laboratory for tissue regeneration in vertebrates at the University of Montreal, noted that skin, liver and bone don't regenerate in the same sense that salamanders do it.

"Humans can only replace the superficial layer of skin, (which is, in fact, a continuous process referred to as homeostasis)," he said in an email. "Most of the dust in a house is dead skin cells that we lost."

"Liver is also quite different than limb regeneration in salamanders," Roy said. "Liver regeneration is really compensatory hyperplasia, which means that what is left will grow in size to compensate for what is lost." So the liver tissue that is there will grow larger, but if the entire liver were lost, it couldn't regenerate.

"What has been lost will not regrow, and hence you cannot re-amputate the liver, as opposed to limbs in a salamander, which can be amputated multiple times and each time a new limb will regenerate." [11 Surprising Facts About the Skeletal System]

Gardiner, however, said humans build entire organ systems in the womb; from just some genetic information a human embryo develops into a complete person in nine months. So there is a limited ability to regrow things, and that makes evolutionary sense humans have to be able to heal, he said.

On top of that, the underlying genetic machinery in a human and a salamander is not that different, even though our last common ancestor diverged during the Devonian period, some 360 million years ago. "There's no special genes for regeneration," Gardiner said. "There are these steps they go through and at least one of those steps doesn't work in humans."

To regrow a limb, the cells need to know where they are are they at the very tip of a limb by the fingers, or are they at the elbow joint? and they need to build the right structures in the right order. Salamanders do have certain genes that are "turned off" in humans, Gardiner said. Perhaps those genes enable regeneration, or at least help control the process. Something in humans' evolutionary past selected against expressing those genes the way salamanders do. Nobody knows what that something was, he said.

In 2013, an Australian scientist, James Godwin, at Monash University may have solved part of that mystery. He found that cells, called macrophages, seem to prevent the buildup of scar tissue in salamanders. Macrophages exist in other animals, including humans, and are part of the immune system. Their function is to stop infections and cause inflammation, which is the signal to the rest of the body that repair is needed. Salamanders lacking macrophages failed to regenerate their limbs, and instead formed scars.

Gardiner said Godwin's work was a step toward understanding limb regeneration. Ordinarily salamanders don't develop scar tissue at all. When a human tears a muscle or gets a deep-enough cut, damaging connective tissue, scar tissue forms. This scar tissue doesn't offer the same functionality as the original stuff.

"If I could get a salamander to scar that would really be something," Gardiner said, because that would shed light on the mechanism that makes humans unable to regrow a limb or organ. So macrophages might be part of the story, but not all of it.

The ability to "stay young" may add another insight into the mystery of limb regeneration. Mexican salamanders, called axolotls, or Ambystoma mexicanum, are neotenic, meaning they retain juvenile features into adulthood. This is why axolotls retain gills as they mature, whereas other salamander species don't.

Humans possess neoteny, too, which is why adults look more like our baby selves than is the case with other primates, and why we take longer to mature than, say, chimps do. There's some connection, perhaps, with neoteny and regeneration. Gardiner notes that younger people seem better able to heal than older ones.

In addition, researchers at Harvard Medical School found that a gene called Lin28a, which is active in immature animals (and humans), but shuts down with maturity, has a hand in enabling mice to regenerate tissue or at least to regrow the tips of their toes and ears. Once the animals were more than 5 weeks old, they weren't able to regrow those parts, even when Lin28a function was stimulated. Lin28a is part of the animal's control system for metabolism when stimulated, it can make an animal generate more energy, as though it were younger.

But the exact nature of the connection isn't understood yet. Whereas all salamanders can regenerate limbs, only axolotls are neotenic, Roy noted.

Salamanders, especially axolotls, can recruit stem cells to start regrowing limbs, and the kinds of cells that react to a wound site also appear connected to whether limbs can grow again. Gardiner was able to get salamanders to grow extra limbs by stimulating the growth of nerve cells in a wound site.

"It may have to do with a strong immune response, or the specific release of some growth factors, or a combination of both. It could be partly a question of biophysics: Salamander limbs are much smaller than humans; however, frogs cannot regenerate their limbs, so it may not be just a question of size," Roy said.

This mystery remains one at least for now.

Original article on Live Science.

Read this article:
Could Humans Ever Regenerate a Limb? - Live Science

May 17, 2017 Credit: CC0 Public Domain

Harvard Medical School researchers have mapped the interaction partners for proteins encoded by more than 5,800 genes, representing over a quarter of the human genome, according to a new study published online in Nature on May 17.

The network, dubbed BioPlex 2.0, identifies more than 56,000 unique protein-to-protein interactions87 percent of them previously unknownthe largest such network to date.

BioPlex reveals protein communities associated with fundamental cellular processes and diseases such as hypertension and cancer, and highlights new opportunities for efforts to understand human biology and disease.

The work was done in collaboration with Biogen, which also provided partial funding for the study.

"A gene isn't just a sequence of a piece of DNA. A gene is also the protein it encodes, and we will never understand the genome until we understand the proteome," said co-senior author Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology and chair of the Department of Cell Biology at Harvard Medical School. "BioPlex provides a framework with the depth and breadth of data needed to address this challenge."

"This project is an atlas of human protein interactions, spanning almost every aspect of biology," said co-senior author Steven Gygi, professor of cell biology and director of the Thermo Fisher Center for Multiplexed Proteomics at Harvard Medical School. "It creates a social network for each protein and allows us to see not only how proteins interact, but also possible functional roles for previously unknown proteins."

Bait and prey

Of the roughly 20,000 protein-coding genes in the human genome, scientists have studied only a fraction in detail. To work toward a description of the entire cast of proteins in a cell and the interactions between themknown as the proteome and interactome, respectivelya team led by Harper and Gygi developed BioPlex, a high-throughput approach for the identification of protein interplay.

BioPlex uses so-called affinity purification, in which a single tagged "bait" protein is expressed in human cells in the laboratory. The bait protein binds with its interaction partners, or "prey" proteins, which are then fished out from the cell and analyzed using mass spectrometry, a technique that identifies and quantifies proteins based on their unique molecular signatures. In 2015, an initial effort (BioPlex 1.0) used approximately 2,600 different bait proteins, drawn from the Human ORFeome database, to identify nearly 24,000 protein interactions.

In the current study, the team expanded the network to include a total of 5,891 bait proteins, which revealed 56,553 interactions involving 10,961 different proteins. An estimated 87 percent of these interactions have not been previously reported.

Guilt by association

y mapping these interactions, BioPlex 2.0 identifies groups of functionally related proteins, which tend to cluster into tightly interconnected communities. Such "guilt-by-association" analyses suggested possible roles for previously unknown proteins, as these communities often commingle proteins with both known and unknown functions.

The team mapped numerous protein clusters associated with basic cellular processes, such as DNA transcription and energy production, and a variety of human diseases. Colorectal cancer, for example, appears to be linked to protein networks that play a role in abnormal cell growth, while hypertension is linked to protein networks for ion channels, transcription factors and metabolic enzymes.

"With the upgraded network, we can make stronger predictions because we have a more complete picture of the interactions within a cell," said first author Edward Huttlin, instructor of cell biology at Harvard Medical School. "We can pick out statistical patterns in the data that might suggest disease susceptibility for certain proteins, or others that might suggest function or localization properties. It makes a significant portion of the human proteome accessible for study."

Launching point

The entire BioPlex network and accompanying data are publicly available, supporting both large-scale studies of protein interaction and targeted studies of the function of specific proteins.

Although the network serves as the largest collection of such data gathered to date, the authors caution it remains an incomplete model. The current pipeline expresses bait proteins in only one cell type (human embryonic kidney cells) grown under one set of conditions, for example, and distinct interactions may occur in different cell types or microenvironments.

As the network increases in size and more human proteins are used as baits, scientists can better judge the accuracy of each individual protein interaction by considering its context in the larger network. Isolating the same protein complex several times, each time using a different member as a bait, can provide multiple independent experimental observations to confirm each protein's membership. Moreover, by using prey proteins as bait, many protein interactions can be observed in the opposite direction as well. Both of these scenarios greatly reduce the likelihood that particular interactions were identified due to chance. The team continues to add to BioPlex, with a target goal of around 10,000 bait proteins, which would cover half of the human genome and would further increase the predictive power of the network.

"We certainly aren't seeing all the interactions, but it's a launching point. We think it's important to continue to build this map, to see how much of it is reproduced in other cell types under different conditions, to see whether the interactions are similar or dynamic," Gygi said. "Because whether you're interested in cancer or neurodegenerative disease, basic development or evolutionary fitnessyou can make new hypotheses and learn something from this network."

Explore further: Facebook for the proteome

More information: Architecture of the human interactome defines protein communities and disease networks, Nature (2017). nature.com/articles/doi:10.1038/nature22366

Journal reference: Nature

Provided by: Harvard Medical School

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May 18, 2017 Researchers have found that a cancer therapy may prompt a type of immune cell called a macrophage (illustrated above) to attack cancer. Credit: Sciencepics/Shutterstock

Antibodies to the proteins PD-1 and PD-L1 have been shown to fight cancer by unleashing the body's T cells, a type of immune cell. Now, researchers at the Stanford University School of Medicine have shown that the therapy also fights cancer in a completely different way, by prompting immune cells called macrophages to engulf and devour cancer cells.

The finding may have important implications for improving and expanding the use of this cancer treatment, the researchers said.

A study describing the work, which was done in mice, was published online May 17 in Nature. The senior author is Irving Weissman, MD, professor of pathology and of developmental biology. The lead author is graduate student Sydney Gordon.

PD-1 is a cell receptor that plays an important role in protecting the body from an overactive immune system. T cells, which are immune cells that learn to detect and destroy damaged or diseased cells, can at times mistakenly attack healthy cells, producing autoimmune disorders like lupus or multiple sclerosis. PD-1 is what's called an "immune checkpoint," a protein receptor that tamps down highly active T cells so that they are less likely to attack healthy tissue.

How cancer hijacks PD-1

About 10 years ago, researchers discovered that cancer cells learn to use this immune safeguard for their own purposes. Tumor cells crank up the production of PD-L1 proteins, which are detected by the PD-1 receptor, inhibiting T cells from attacking the tumors. In effect, the proteins are a "don't kill me" signal to the immune system, the Stanford researchers said. Cancer patients are now being treated with antibodies that block the PD-1 receptor or latch onto its binding partner, PD-L1, to turn off this "don't kill me" signal and enable the T cells' attack.

"Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy," said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. "While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved."

What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. "Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer," Gordon said.

Similar to anti-CD47 antibody

This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients.

As it stands, it's unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies.

The practical implications of the discovery could be important, the researchers said. "This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component," Gordon said.

Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. "In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place," Weissman said. "Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient."

Explore further: Potential new cancer treatment activates cancer-engulfing cells

More information: Sydney R. Gordon et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity, Nature (2017). DOI: 10.1038/nature22396

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Cancer immunotherapy may work in unexpected way - Medical Xpress

Harvard Medical School researchers have mapped the interaction partners for proteins encoded by more than 5,800 genes, representing over a quarter of the human genome, according to a new study published online in Nature on May 17.

The network, dubbed BioPlex 2.0, identifies more than 56,000 unique protein-to-protein interactions87 percent of them previously unknownthe largest such network to date.

Get HMS news here

BioPlex reveals protein communities associated with fundamental cellular processes and diseases such as hypertension and cancer, and highlights new opportunities for efforts to understand human biology and disease.

The work was done in collaboration with Biogen, which also provided partial funding for the study.

A gene isnt just a sequence of a piece of DNA. A gene is also the protein it encodes, and we will never understand the genome until we understand the proteome, said co-senior author Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology and chair of the Department of Cell Biology at HMS. BioPlex provides a framework with the depth and breadth of data needed to address this challenge.

This project is an atlas of human protein interactions, spanning almost every aspect of biology, said co-senior author Steven Gygi, professor of cell biology and director of the Thermo Fisher Center for Multiplexed Proteomics at HMS. It creates a social network for each protein and allows us to see not only how proteins interact, but also possible functional roles for previously unknown proteins.

HMS scientists are mapping interaction networks throughoutthe human proteome. Edward Huttlin, instructorin cell biology, explains. Video: Elizabeth Cooney

Bait and prey

Of the roughly 20,000 protein-coding genes in the human genome, scientists have studied only a fraction in detail. To work toward a description of the entire cast of proteins in a cell and the interactions between themknown as the proteome and interactome, respectivelya team led by Harper and Gygi developed BioPlex, a high-throughput approach for the identification of protein interplay.

BioPlex uses so-called affinity purification, in which a single tagged bait protein is expressed in human cells in the laboratory. The bait protein binds with its interaction partners, or prey proteins, which are then fished out from the cell and analyzed using mass spectrometry, a technique that identifies and quantifies proteins based on their unique molecular signatures. In 2015, an initial effort (BioPlex 1.0) used approximately 2,600 different bait proteins, drawn from the Human ORFeome database, to identify nearly 24,000 protein interactions.

In the current study, the team expanded the network to include a total of 5,891 bait proteins, which revealed 56,553 interactions involving 10,961 different proteins. An estimated 87 percent of these interactions have not been previously reported.

Guilt by association

By mapping these interactions, BioPlex 2.0 identifies groups of functionally related proteins, which tend to cluster into tightly interconnected communities. Such guilt-by-association analyses suggested possible roles for previously unknown proteins, as these communities often commingle proteins with both known and unknown functions.

The team mapped numerous protein clusters associated with basic cellular processes, such as DNA transcription and energy production, and a variety of human diseases. Colorectal cancer, for example, appears to be linked to protein networks that play a role in abnormal cell growth, while hypertension is linked to protein networks for ion channels, transcription factors and metabolic enzymes.

With the upgraded network, we can make stronger predictions because we have a more complete picture of the interactions within a cell, said first author Edward Huttlin, instructor of cell biology at HMS. We can pick out statistical patterns in the data that might suggest disease susceptibility for certain proteins, or others that might suggest function or localization properties. It makes a significant portion of the human proteome accessible for study.

Launching point

The entire BioPlex network and accompanying data are publicly available, supporting both large-scale studies of protein interaction and targeted studies of the function of specific proteins.

Although the network serves as the largest collection of such data gathered to date, the authors caution it remains an incomplete model. The current pipeline expresses bait proteins in only one cell type (human embryonic kidney cells) grown under one set of conditions, for example, and distinct interactions may occur in different cell types or microenvironments.

As the network increases in size and more human proteins are used as baits, scientists can better judge the accuracy of each individual protein interaction by considering its context in the larger network. Isolating the same protein complex several times, each time using a different member as a bait, can provide multiple independent experimental observations to confirm each proteins membership.

Moreover, by using prey proteins as bait, many protein interactions can be observed in the opposite direction as well. Both of these scenarios greatly reduce the likelihood that particular interactions were identified due to chance. The team continues to add to BioPlex, with a target goal of around 10,000 bait proteins, which would cover half of the human genome and would further increase the predictive power of the network.

We certainly arent seeing all the interactions, but its a launching point. We think its important to continue to build this map, to see how much of it is reproduced in other cell types under different conditions, to see whether the interactions are similar or dynamic, Gygi said. Because whether youre interested in cancer or neurodegenerative disease, basic development or evolutionary fitnessyou can make new hypotheses and learn something from this network.

This work was supported by the National Institutes of Health (HG006673, DK098285), Biogen and the Canadian Institutes of Health Research.

Co-authors on the study included Raphael J. Bruckner, Joao A. Paulo, Joe R. Cannon, Lily Ting, Kurt Baltier, Greg Colby, Fana Gebreab, Melanie P. Gygi, Hannah Parzen, John Szpyt, Stanley Tam, Gabriela Zarraga, Laura Pontano-Vaites, Sharan Swarup, Anne E. White, Devin K. Schweppe, Ramin Rad, Brian K. Erickson, Robert A. Obar, K.G. Guruharsha, Kejie Li and Spyros Artavanis-Tsakonas.

Read this article:
Social networking for the proteome, upgraded | HMS - Harvard Medical School (registration)

Adenosine triphosphate (ATP) performs many jobs in a cell. It carries energy, serves as a signaling molecule, and is the source of adenosine in DNA and RNA.

But cells contain far more ATPas much as 5 mM in the cytoplasmthan these known uses seem to require. That might be because ATP also can solubilize proteins, suggests a new study (Science 2017, DOI: 10.1126/science.aaf6846).

ATP has the general characteristics of a hydrotrope, an amphiphilic molecule that has both a hydrophilic and a hydrophobic component but does not assemble into structures such as micelles. Hydrotropes are used industrially to solubilize hydrophobic species in aqueous solution. The hydrophobic portion of hydrotropessuch as ATPs adenosinelikely interacts with the hydrophobic species, while the hydrophilic partsuch as ATPs triphosphateallows the species to stay in solution.

In the new work, a team led by Yamuna Krishnan of the University of Chicago and Anthony A. Hyman of the Max Planck Institute of Molecular Cell Biology & Genetics investigated the effects of ATP on the aggregation of several proteins. They found that ATP could prevent the aggregation of two proteins known to form amyloid clumps. For a third protein, ATP was further able to dissolve fibers of already aggregated protein. And ATP kept proteins in boiled egg white from aggregating.

Most healthy cell functions require that proteins remain soluble at enormous intracellular concentrations, without aggregating into pathogenic deposits, write Allyson M. Rice and Michael K. Rosen of the University of Texas Southwestern Medical Center in a perspective accompanying the paper. The cell may exploit a natural hydrotrope to keep itself in a functioning, dynamic state.

ATP may have also played an important role in the origin and evolution of life, Krishnan, Hyman, and colleagues note in their paper. Aggregation would have been a problem even for early biological macromolecules. ATP may have been coopted early in evolution to prevent such aggregation, even before the molecule became an energy carrier, the researchers suggest.

Originally posted here:
New role in cells suggested for ATP - Chemical & Engineering News

May 18, 2017 by James Badham A light micrograph shows individuals of aBotryllus schlossericolony that have arranged themselves into a star-shaped structure called asystem. Credit:Delany Rodriguez

At first glance, Botryllus schlosseri is pretty nondescript.

The small, transparent marine organism, abundant along California's coast, spends its life colonizing submerged surfacesboats, docks and even other animals. But the star ascidian or golden star tunicate, as B. schlosseri is commonly known, is more than just a humble hanger-on.

As an invertebrate closely related to humans, it has characteristics that are about to make it the focus of a multicampus research project aimed at placing the University of California (UC) at the forefront of vascular mechanics andby extensioncardiovascular disease, which is responsible for one in four deaths in the state.

UC has awarded Megan Valentine, an associate professor in UCSB's Department of Mechanical Engineering, and partners at UCLA and UC Irvine with $300,000 for a pilot project that is part of the UC Multi-Campus Research Programs and Initiatives (MRPI). The awards provide two years of seed funding for collaborations that show promise in terms of launching pioneering cross-disciplinary research that strengthens UC's position as a leading public research university, supports innovative graduate student research, informs public policy and benefits California residents.

"This is a really strong area for UC and something we have a lot of pride of ownership in, but the campuses could be better linked," Valentine said. "These interdisciplinary initiatives from the UC Office of the President play an important role in cultivating relationships within and across campuses. We're very grateful for this opportunity to leverage system-wide resources and expertise."

Valentine, her key UCSB collaborator, Anthony De Tomaso, an associate professor in UCSB's Department of Molecular, Cellular, and Developmental Biology, and colleagues at the two other UC campuses will focus their research on the star ascidia's vascular mechanics and mechanobiology. The latter is an emerging field of science focused on how physical forces and changes in the mechanical properties of cells and tissues contribute to development, cell differentiation, physiology and disease.

The project focuses specifically on vascular mechanics, whichdespite the invertebrate's close evolutionary relationship to humanshas not been studied previously in this context. "A lot of the discoveries we've made in terms of what proteins are important for vasculature in humans appear also to be relevant in this model," Valentine said. "It has completely untapped potential for discovery."

"The biology of Botryllus is fascinating and allows novel approaches in a number of fields, from immunology to stem cell biology and regeneration," said De Tomasco, whose lab has studied the animal for HOW LONG. "However, this new project on vascular biology is potentially groundbreaking, as it joins the unique anatomy and accessibility of the blood vessels to powerful visualization techniques. That allows us to directly manipulate and characterize global responses at a resolution not available in other model organisms."

The star ascidian has a simple but unique anatomy, with the vasculature located externally. When it is treated with a drug that disrupts collagen crosslinkinganother of its valuable characteristics is that it responds to drugs that humans also respond toit retracts the vascular structure in a process clearly visible through an optical microscope and even to the naked eye.

"So we get this immediate visual readout from a live organism," Valentine explained. "We can go in and manipulate the vessels: stretch them or apply forces with the goal of understanding what's happening mechanically. The drug does not affect the blood vessels directly; it affects the matrix in which they sit, softening it. And when the vasculature receives that softening signal, it retracts. We want to dig into the details of how organisms sense force and how they receive and process mechanical signals and turn that information into other cell functionsthat's not something that we understand. Then we need to connect that to the broader context of human vascular biology."

The long-term goal is to use the project to establish an infrastructure and then to secure longer-term funding and form a consortium of biologists and engineers to investigate how blood vessels know when to grow and shrink and how to control those decisions to fight human diseases such as cardiovascular disease, macular degeneration and cancer.

The project also seeks to understanding of the role of phagocytes, cells that protect an organism by ingesting harmful foreign entities, cells and tissues that are no longer needed. "In this case, as those vessels are retreating and you're losing all the blood vessel volume, those cells have to go somewhere, and phagocytes play a role in destroying them," Valentine explained. "There are a lot of open questions about exactly how that works. And because the vasculature is on the outside in this system, we have a lot of opportunities for imaging and for other analysis, so maybe we can get to the heart of that question."

Student training is another key component of the MRPI Awards, and UCSB undergraduate and graduate students who are trained in engineering will have the opportunity to work with colleagues at UCI and UCLA who have expertise in such areas as conventional animal model studies, as well as conducting human clinical trials.

Undergraduate students in a new class for summer 2017 will spend three weeks doing discovery-based research at UCSB and three weeks learning bioinformatics at UCLA. "The coolest thing about this system is that it is so accessible; you can touch the blood vessels with your fingers," De Tomaso said. "Because the retraction of the vasculature also occurs quicklytaking only 16 hoursstudents can rapidly learn many experimental processes. There is so much low-hanging fruit experimentally that they will actually be able to do brand-new science."

MRPI projects build connections among UC campuses while taking advantage of specific characteristics unique to each one. "In Santa Barbara, because of our location, we understand ocean resources and what we can learn from studying ocean organisms," Valentine said. "It will be powerful if we can share our ocean experience with the other campuses that don't have those resources. In a 10 campus system, you don't need every campus to have expertise in every area. We should be specialized, but then we should also recognize that as part of the UC system, we can leverage all of the other campuses in really unique ways."

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Researchers probe a unique marine animal for insights into human vascular system - Phys.Org

May 17, 2017 Researchers have identified a speedy protein that plays an important role in the cell division process called meiosis. Credit: SCIEPRO/Science Photo Library

Researchers have shown that a recently identified protein, called Speedy A, plays an essential role in the early stages of meiosisa special type of cell division that produces sperm and egg cells.

In meiosis, a single cell divides twice, producing four cells, known as sperm or egg cells, which contain half the genetic information of the original cell. When a sperm fertilizes an egg, the resultant embryo contains a full set of chromosomes. In the early stages of meiosis, chromosomes residing in the nucleus undergo a process called recombination, which involves the exchange of genetic material that leads to genetic diversity.

"Recombination can only happen when the ends of the chromosomes, called telomeres, are attached to the nuclear envelope," explains Philipp Kaldis of the A*STAR Institute of Molecular and Cell Biology.

Kaldis, in collaboration with Kui Liu of Sweden's University of Gothenburg, and colleagues in China and the US, wanted to understand how chromosomal telomeres attach to the nuclear membrane or 'envelope', during meiosis.

Using immunofluorescent staining of mouse spermatocytes, they found that a protein called Speedy A is localized to telomeres. Speedy A is a member of the Speedy/RINGO protein family, which activate cyclin-dependent kinase 2 (Cdk2), an important cell division-related protein which is also localized to telomeres, but whose role in meiosis is not fully understood.

The researchers then bred mice that were deficient in the gene for Speedy A and found that mice lacking Speedy A were infertile, similar to mice that were previously bred lacking Cdk2.

By comparing telomerenuclear envelope attachment in mice with and without Speedy A, the team found that a specific portion of the Speedy A protein, called its RINGO domain, facilitated binding to Cdk2. Speedy A also bound to telomeres via its N terminus (the end that has a free amine group) and this, together with the RINGO domain, form Speedy A's 'telomere localization domain', which the researchers believe mediates the initial binding of chromosomal telomeres to the nuclear envelope.

Speedy A's other end, the C terminus (which has a free carboxyl group), is responsible for activating Cdk2 and is unlikely to affect telomere attachment to the nuclear membrane. Speedy A may also recruit Cdk2 to telomeres and later activate it together with other cyclins. Activated Cdk2 may then help regulate chromosome movements along the nuclear envelope.

"Our work is basic research, but you wonder whether a man with fertility defects may have defects associated with Cdk2 and Speedy A," says Kaldis. The team's "ultimate goal is to develop treatments for males with fertility issues," he says.

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More information: Zhaowei Tu et al. Speedy ACdk2 binding mediates initial telomerenuclear envelope attachment during meiotic prophase I independent of Cdk2 activation, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1618465114

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A more detailed understanding of cell divisions giving rise to sperm and egg cells could lead to infertility treatments - Medical Xpress

Life stories from Annette Gordon-Reed, Martin Karplus, Joseph Nye, E.O. Wilson, and many more, in the Experience series.

In 1960s Silicon Valley Pamela Silver came of age part math nerd, part rebel, absorbing the spirit of both time and place. Think space race. Think Grateful Dead.

She set out on her scientific career without a plan, propelled by an aptitude for math, an interest in science, and a love of the sometimes frenzied life of the laboratory. That love fueled groundbreaking work on how proteins make their way from the cytoplasm of a cell into the nucleus, a process called nuclear localization. Decades and many discoveries later, the same passion helped establish her as a leader in the fledgling field of synthetic biology.

Silver was recently named a fellow of the American Academy of Arts and Sciences. She is the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology.

Q: Lets start at the beginning. You grew up in Atherton, Calif., in Silicon Valley?

A: [My parents] were both psychotherapists, and it made for an interesting childhood. I think they must have met here [in Boston] and then they moved to the Bay Area probably right after the war, late 40s, early 50s. And my father became one of the founders of the Palo Alto Medical Clinic; it was one of the first group practices, sort of soup-to-nuts. [He] was also on the Stanford faculty. They moved to California right at the beginning of the rapid growth of Silicon Valley. We lived in Atherton before it was the richest town in the world. It was kind of cool, these old estates, built by James Flood and his children big mansions and big land. They were just starting to subdivide it. Our house was one of the first ranch-style homes. It was already kind of upper class, but I didnt realize that at the time; it was just where we lived.

Q: You never do when youre a kid. You just grow up in your surroundings.

A: The roads were still dirt. The Flood granddaughters still lived there and had horses, so we could walk around and feed the horses. It all seemed very idyllic to me, I guess if I think back on it, which I do more and more. My parents were very high-level thinkers and very intelligent. That obviously set the tone in our household, maybe a little overdoing it. My sister was actually 10 years older, so it was more like I was an only child.

Q: Is your sister your only sibling?

A: Yes. My parents did get divorced. We were not a tightknit family but more highly dysfunctional. And in retrospect that was OK in terms of my own independence and things like that.

At that time in Silicon Valley, everything was very science-oriented. How do we promote science in schools it was all about the space race and stuff like that. I apparently had precocious math ability. Some on my fathers side of the family had an inclination to mathematics. He nurtured this. He taught me how to play Go when I was 6. Chess, maybe, but Go? Really?

I won an IBM math contest when I was in junior high, but nobody was pushing me. My parents were so preoccupied with themselves, they just wanted to make sure that I didnt do anything bad.

Q: I read that you got a slide rule as a prize?

A: Yeah, that was the prize. What a hoot. It wasnt just any slide rule. My slide rule had a beveled edge, so the slider thing was here and you could still use it as a straight edge. What an amazing slide rule. Ive never been able to find one like it. I also loved homework. I would beg the teachers in elementary school to give me homework, partly because I think it was a way to get lost from the family dysfunction and also it was just interesting.

Q: What about your early schools?

A: I went to the public high school, which was nearby, for a year. Then my parents sort of decided that I wasnt getting the right education. They sent me to a local all-girls high school called Castilleja. Its one of the few all-girls high schools left. It didnt seem to emphasize science very much. The times were very disruptive. There was a lot of protest and the Vietnam War, and there you are in the all-girls school. It was a bit odd.

Q: You said it wasnt heavy on science. Was your interest in

A: My interest was independence. I have to say I was kind of a wild kid in high school. Lets be honest, there was a fair amount of recreational drug-taking and going to the Fillmore Auditorium I was heavily into the music of the times. The Grateful Dead were still kind of a local band and we were big fans it was a big part of the local culture. Bob Weir grew up nearby, and they used to practice locally. Even when we were kids, we would go listen to them. They would play at local parks and pizza parlors.

The great thing about my school is that the teachers took a personal interest in me. I had one teacher that thought I was a good writer. No idea why. The Palo Alto Times the school was in Palo Alto would have a student from each school write columns, and so she assigned me to be the reporter for Castilleja. So I really got into that. Then there was this whole culture around personal computers and electronic hacking. There were so many wacky things going on, and even as teenagers we were very much part of that. Not clear how the parents felt about it.

Q: What about college?

Castilleja was very much a college prep school. I applied to Stanford and Yale, but my real top choice was UC Santa Cruz, which is where I ended up going. I knew from the start that I wanted to do science, so the other good thing was that there werent very many course requirements or grades. I took as many advanced placement tests as possible, so I wouldnt have to take anything but science classes, which probably made my whole undergraduate experience very warped. I started as a math major, maybe, then went to physics, and then ended up in chemistry. One thing I wanted to do, which Santa Cruz was very big on, was independent research, and so as fast as possible I just wanted to get into that, and I did.

Q: Where did your initial interest in science come from?

A: I would say its a combination of this uber-intellectual family life and also the school system, for sure. There were science contests and endless science projects, and my father fed that a little bit. I remember, in first grade, he brought a dissected cat to the class, because he was an M.D. Hed take me to the hospital all the time. A lot of our family friends were somehow connected to either the medical or engineering [fields]. My father used to play poker with [Nobel Prize-winning chemist] Linus Pauling, and one of my first job interviews in high school was at his institute. Other fathers gave me early programmable personal calculators for homework.

Q: So, youre in college, and youre wending your way from math to physics to chemistry. How did that go?

A: The math part I dont remember much about. Physics was transient also. What I realized about myself was that I wanted to do experiments. So I think I ended up in chemistry because of the opportunity to do experiments. Im sure it was a product of people I met and knew and things like that teachers but also I always was kind of a rebel. Everyone was majoring in psychology, that was the thing. There was just no way I was going to do what everyone else did.

Q: No temptation, given your parents background?

A: Absolutely none. Zero. Med school off the table. Forget it. College was meeting up with just crazily interesting people. And Santa Cruz was just idyllic. Youd go off in the woods and the trees and surfing oh, and sailing. Big deal, sailing. Probably the one thing that I got out of that was being on the sailing team and having something organized in my life. So that was different and fun.

Our whole goal was to make the engineering of biology faster, cheaper, and more predictable. Lets say we succeed. So then what? Do we have the perfect planet? Is everything wonderful? Is there misuse? Im thinking about things I dont know the answer to.

Q: Are you still a sailor?

A: Yeah, its [in the picture] right behind you. Thats my boat.

Mostly I worked in the lab a lot. I liked the lab culture. I liked the all-night thing and feeling like you belonged and you were working on something. I really liked that part of it. I just characterize my life as not having a plan. And people say to me: But youre at Harvard, howd that happen? It just kind of happened. Im not saying that was a good thing or a bad thing, but I do compare it to these kids now who start out so early with a plan. I am glad I had time to explore and be kind of a dreamer.

So college is ending. I heard about this graduate school thing, and maybe I should apply. Id heard of two chemistry programs that I thought would be, for some reason, good. One was Berkeley and one was Harvard. Those were my only two grad school applications. I remember somehow deciding that I didnt want to go to grad school, though. I forget why. My father had died. I just didnt feel right. I had no money, and so I decided, maybe Ill just get a job. It was all complicated with boyfriends and husbands and lots of stuff. I did get a job at a startup chemical company, literally in Silicon Valley. It was across the street from Hewlett-Packard, really in the thick of it.

Q: So how did you end up going back to graduate school?

A: With my then-spouse, I moved to Los Angeles. The short story is thats how I ended up going to UCLA for grad school. Id actually spent an extra year at Santa Cruz doing this protein structure work, so I bargained with UCLA. If I could pass the equivalent of their qualifying exam, could I not take any classes and therefore finish my Ph.D. as fast as possible? I passed it, and so I got my Ph.D. in three years. I had a very supportive adviser who said you should just get your Ph.D. really fast. It was a good experience.

Q: How was choosing Harvard for a postdoc different from not choosing it for grad school?

A: Maybe there was finally an element of careerism starting to emerge. All these guys at UCLA were super young hotshots, and they had all come from Stanford and Harvard. So there was probably an element of hey, I can do that.

At the same time, my adviser kept trying to push me, which just was perfect for me. He kept saying, try to do something where you set up your own research program. I did formulate a question in my mind of what I thought I wanted to solve. That was the question of how do things proteins and RNAs move between the nucleus and the cytoplasm? I had some hypotheses about this, so I approached a couple of faculty here.

One was well known for letting people come to do whatever they wanted, so I went there. But I spent the summer before at Cold Spring Harbor. I went there to take the yeast course, which was a big deal then. That was just a total eye-opener.

Q: Learning how to manage and use yeast as an experimental organism, essentially?

A: Yes, but it was also about learning how to think as a geneticist, and it was just transformative for me. In many ways being at Cold Spring Harbor was amazing. Being in this community of scientists where it had that kind of 24-hour science-is-the-big-thing, interesting people to talk to left and right. Id never seen anything like it. Youre just kind of away from all your responsibilities. It was just very magical and crazy, and I thought, jeez, this is how it should be.

So when I got back to Boston, I started working in the lab Id chosen. And I met people in Mark Ptashnes lab, which was kind of a happening place. There was a lot of energy.

I realized that I was initially not in the right lab nothing wrong with it, it just wasnt right for me. So I went to Mark, and I said, I have this idea, and Ive thought more about it. I think I could test it better using yeast. And he was starting up this yeast group. So I joined Marks lab, and it was an amazing experience. The people there were just insanely smart. I mean, there were ups and downs, for sure, and some of those people could fight like dogs. It was either politics or science. It was just a crazily intense environment and I solved my problem. I discovered how proteins have a sequence that targets them into the nucleus, and that was one of the first examples of that. And I really did it on my own.

[At the end of the postdoc] everyone else seemed to have a plan. I said, hey, if this whole nuclear localization thing doesnt work out, Ill do something else. I did not have the Im-going-to-be-a-professor-for-sure mentality at all. I remember picking a couple schools that I thought I might actually go to if they offered me jobs, places that had openings. It was a very short list. One was Harvard. And one was Yale. One was Princeton. And one was Cornell.

I had interviews everywhere. I did not think about gender bias back then. I really did not. There were times I realized in college I was the only woman in the class. I just never felt anything [sexist] until I went on those job interviews and there were almost no women faculty mostly dinners with all guys. Then I had an offer at Princeton. And then at Yale. Princeton was sort of: Were growing, were new. And I thought, well, that sounds interesting. And I went to Princeton but did not stay for long.

Q: You went to Dana-Farber Cancer Institute and were there for a while, right?

A: Yeah. I was hired in BCMP [Biological Chemistry and Molecular Pharmacology], and Chris Walsh was the chair. And he essentially saved my scientific life. I always say they took a risk on me. Many people said something like, Oh my God, youre going to go to Harvard? Theyre so mean. Its going to be horrible. It was the antithesis of all those things super-supportive and they wanted me.

Q: So you were here as an associate professor?

A: Based at Dana-Farber. My full appointment was in BCMP. It was back in the old days, when getting tenure took forever. The agreement was that when I was hired, they would start the process. And back then, the process sometimes took two to three years. So I had to sweat it a bit, but I had good friends there and good support. Ive been blessed with regard to funding for my research, so far. I was worried being at Dana-Farber would be odd for me as a basic scientist, but it turned out it was fabulous. I was worried I wouldnt get grad students. That turned out not to be true got great students, great postdocs. And I continued to work on cell biology combined with molecular biology, and then it expanded into what you loosely might call systems biology.

And my work had some cancer overtones to it in that we did discover we did a small molecule screen where we discovered small molecules where, in principle, we could decipher the mechanism by which they would revert cancer cells away from cancer.

Q: How did you transition from Dana-Farber to what was then the new Department of Systems Biology at Harvard Medical School?

A: My own research was transitioning. I was taking a more systems-wide view of the cell biological problems I was working on. And also I was starting to feel like it was a time in my life where I was looking to change.

It was a really good time for Dana-Farber. They were starting to get a handle on making targeted drugs for cancer, the kinase inhibitors. And I felt good about Dana-Farber, that they were going in a good direction, that they were closer to real cancer cures. But I wasnt sure that my work was still a good fit. It had been so I mean that in a positive way.

The other thing that happened that was probably more consequential was that my now-husband, Jeff Way, who works here at the Wyss Institute, was helping a friend of ours start a new institute in Berkeley. He met a young postdoc there named Drew Endy and they became good friends. Drew had come from civil engineering, I think, and [he was] thinking about where biology should go. And then he came here this was in the early 2000s, late 1990s and started this group at MIT. It was bioengineers, computer scientists, and included me as the token real biologist. And that became the Synthetic Biology Working Group.

It was nearby, so I could go over there a lot. I became pretty engaged in that. Then, simultaneously, Marc Kirschner [of Harvard] was starting this new department [of systems biology]. Marc asked me if I wanted to be part of this department.

Q: And this was in around 2004, right?

A: Right. It was fun to be around new people, new ideas, and also I was given the charge of starting the new grad program.

Q: Lets talk about the grad program and your thoughts on graduate education.

A: Ive had a ton of grad students, and I watched them matriculate and turn into scientists. Id been thinking a lot about it and what that meant, and also this engagement with MIT was giving me a different perspective. One idea was it shouldnt be that you come to grad school and just take a bunch of classes. You come to grad school to do research. They should engage in research soon and they would get custom mentoring. Also, we tried to attract students from a diversity of areas. They could come from computer science or math. So they didnt necessarily have to have a biology background.

The other thing I encouraged was collaborative projects, so you could have, for example, two advisers. A lot of students took us up on that. That would increase collaboration amongst the faculty through the students.

It goes to the idea that the students are empowered and theyre helping define their education. It was about getting a mix of faculty across the University from different disciplines, not just the Medical School. Have a big umbrella. I liked that component of it. We got a significant number of applicants, and they were just amazing; they were some of the top students in the country. And then it stayed that way, and we got these interesting, quirky students. Im not running it anymore. Its still a great program.

Q: During this period, you were starting to focus more on synthetic biology, right?

A: Right.

Q: So tell me a little bit about that. You were at the meetings at MIT. Were you coming to understand the potential of looking at biology as modular, that it could be engineered in a rational way once you figured it all out?

A: The modularity of biology was something that resonated for me, because it was the essence of much of my work in molecular biology. I had done things like take parts of proteins and fuse them to other proteins and show they could move to the nucleus in the cell. So thats one essence of modularity. I was primed to think about it that way. I dont know if I called it synthetic biology or anything, but it was very much in my wheelhouse.

Q: Lets talk about your lab. What do you consider milestones?

A: Well, the first one was programming yeast to sense radiation. You can build sensors, but we wanted to build cells that not only sensed, but remembered. That was one of our first successes: building predictable circuits in yeast.

Q: How do you get a cell to remember?

A: There are a lot of different ways. Our way was to use transcriptional control, which is regulating how genes are made. One theme of our research is to draw from what we know about nature and try to apply that to practical problems. What nature tends to do with transcription is to use different kinds of feedback control that can either be positive or negative. So we took advantage of that. If you have a signal, instead of just having one burst, [we engineered it to] keep itself going, so it has this continuous feedback control. Thats a process used by nature that we deployed in our work.

Q: So exposure to radiation would trigger a process that

A: Yes. Imagine it triggers a pulse and something happens, and then that promotes a more sustained response over time.

Q: And that sustained response is the memory?

A: We call that the memory, yes. Memory of course means a lot of things to a lot of people, especially in neurobiology. So were using the term memory in a loose way here.

Q: And without this, the cell would respond and then stop?

A: And stop, yes.

Q: So youd be able to look at it and say, since this process is ongoing, something happened in

A: That it happened sometime in the past. My overall dream, which I think were close to achieving, is not only would something happen in the past, but a cell then could count and tell you when it happened, so it would be a true computer. And it would tell you when it happened and then ultimately do something. That doing of something, hopefully, could be something practical, like emit a signal that tells you there are poisonous chemicals somewhere or that theres a pathogen, or produce a therapeutic on-demand at the right time. We havent gotten there, but, at the time of me getting involved in synthetic biology, that was the overarching dream. Now weve taken a lot of different side paths.

We have this paper coming out in a few weeks about sensing inflammation in the gut. That, of course, is a huge problem in general. Theres no good treatment and its a chronic disease. Many people suffer from it. So we can create intestinal bacteria that will report on inflammation. Now the question is, can we get them to make a therapeutic for it? Thats one of the examples of the dream getting close to reality.

Q: Another project youve worked on is the bionic leaf.

A: Its super exciting. There are just so many opportunities here at Harvard, sometimes you look back and you say, oh my God, this thing happened. I was working on cyanobacteria, which are one of the simplest organisms that do photosynthesis, and we had engineered them to make hydrogen. We were believers in the hydrogen economy, which kind of didnt turn out so well. It might come back someday.

I got invited to be part of the Harvard University Center for the Environment, and Dan Schrag, the director, introduced me to Dan Nocera at the holiday party. Dan Nocera he had just moved [to Harvard], and he said something like, Ive been trying to meet you. Ive got this artificial leaf. It makes hydrogen. And I responded with, Ive got these bacteria, and theyll eat hydrogen and fix CO2. It was like two synergistic personalities; it just clicked.

Q: Looking ahead in synthetic biology 10 years from now what do you think will be most important?

A: In the perfect world, I would say on-demand drugs would be a big deal, whether that be protein-based drugs, cell-based drugs, or chemicals. For example, a friend of mine who is a professor at Stanford has made yeast that will make opiates. Think about the consequences of that. One is economic and the other is to make designer opiates that get rid of some of the bad things about them. I think thats just an example of the power of biology to make things weve never seen before.

We are at a tipping point around DNA synthesis. Its not yet cheap enough where a grad student could say, Im going to build a whole new organism. We need another kind of technological leap.

Our whole goal was to make the engineering of biology faster, cheaper, and more predictable. Lets say we succeed. So then what? Do we have the perfect planet? Is everything wonderful? Is there misuse? Im thinking about things I dont know the answer to. How do you find the genetically engineered organisms [released into the environment]? How do you respond quickly to a pandemic? These are things I think we are poised to do well. Can we make a vaccine in a day? Can we figure out what a pandemic is in a few hours? That really fits the bill of faster, cheaper.

How do we marry the coming firestorm of AI with synthetic biology? There was a time when young people wanted to work on molecular biology. That was the cool thing. AI is the cool thing now. Hundreds of undergrads at MIT want to take Intro AI. So we have to capture that imagination and meld it with synthetic biology.

Q: Do you look at young women in science today and think about how things are either different or the same as when you were coming up?

A: There are still a lot of males in charge and, as you get higher up the food chain, you start to notice different things. There are still times Im the only woman in the room. I have my one activism thing, where if I see meetings with no women speakers, I write a letter. I have some things that I call out, like science advisory boards with no women. So I make a pest of myself every now and then, but so do a lot of other people.

But about the trainees that is something I think were all worried about. Its a complicated problem. It feels like its harder to get women applicants and have them stick with it. I try to encourage the women in my own group. But at the same time, they have to make choices that make them happy. There just still arent a lot of women at the top. How much impact does it have if youre a younger woman and you dont see women in [leadership]?

If Harvard holds a symposium, it should never be all male. Any topic theres no reason. These, to me, are cheap, simple fixes. You should never have posters for conferences that have all males. That costs you almost no money. So I think there are lots of things you can do that dont require major investments that send signals that are positive.

Q: They say that science is at least partly about failure and learning from failure. Do you have advice on how you deal with failure?

A: Its very hard to say to someone, Look, its just not working. So I try to do it early and then say, Lets move on. Why dont you work on this thing that is working for a while so you can feel what its like to have something work, and then maybe thatll get you a paper or chapter in your thesis. Then you can go back to something riskier.

But at the same time, I like to encourage people to be risk takers, because if you dont take risks, youre not going to get anywhere. So there has to be some balance. I will say its the thing I most lose sleep over. Forget not getting grants and all that. Its the people you worry about you want everyone to succeed. At my stage, this is not about me anymore. Its about them.

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Harvard's Pamela Silver recalls journey from Silicon Valley to synthetic biology - Harvard Gazette