Injured Jellyfish Seek to Regain Symmetry

Self-repair is extremely important for living things. Get a cut on your finger and your skin can make new cells to heal the wound; lose your tail—if you are a particular kind of lizard—and tissue regeneration may produce a new one. Now, Caltech researchers have discovered a previously unknown self-repair mechanism—the reorganization of existing anatomy to regain symmetry—in a certain species of jellyfish.

The results are published in the June 15 online edition of the journal Proceedings of the National Academy of Sciences (PNAS).

Many marine animals, including some jellyfish, can rapidly regenerate tissues in response to injury, and this trait is important for survival. If a sea turtle takes a bite out of a jellyfish, the injured animal can quickly grow new cells to replace the lost tissue. In fact, a jellyfish-like animal called the hydra is a very commonly used model organism in studies of regeneration.

But Caltech assistant professor of biology Lea Goentoro, along with graduate student Michael Abrams and associate research technician Ty Basinger, were interested in another organism, the moon jellyfish (Aurelia aurita). Abrams, Basinger, and Goentoro, lead authors of the PNAS study, wanted to know if the moon jellyfish would respond to injuries in the same manner as an injured hydra. The team focused their study on the jellyfish's juvenile, or ephyra, stage, because the ephyra's simple body plan—a disk-shaped body with eight symmetrical arms—would make any tissue regeneration clearly visible.

To simulate injury—like that caused by a predator in the wild—the team performed amputations on anesthetized ephyra, producing animals with two, three, four, five, six, or seven arms, rather than the usual eight. They then returned the jellyfish to their habitat of artificial seawater, and monitored the tissue response.

Although wounds healed up as expected, with the tissue around the cut closing up in just a few hours, the researchers noticed something unexpected: the jellyfish were not regenerating tissues to replace the lost arms. Instead, within the first two days after the injury, the ephyra had reorganized its existing arms to be symmetrical and evenly spaced around the animal's disklike body. This so-called resymmetrization occurred whether the animal had as few as two limbs remaining or as many as seven, and the process was observed in three additional species of jellyfish ephyra.

"This is a different strategy of self-repair," says Goentoro. "Some animals just heal their wounds, other animals regenerate what is lost, but the moon jelly ephyrae don't regenerate their lost limbs. They heal the wound, but then they reorganize to regain symmetry."

There are several reasons why symmetry might be more important to the developing jellyfish than regenerating a lost limb. Jellyfish and many other marine animals such as sea urchins, sea stars, and sea anemones have what is known as radial symmetry. Although the bodies of these animals have a distinct top and bottom, they do not have distinguishable left and right sides—an arrangement, present in humans and other higher life forms, known as bilateral symmetry. And this radial symmetry is essential to how the jellyfish moves and eats, first author Abrams says.

"Jellyfish move by 'flapping' their arms; this allows for propulsion through the water, which also moves water—and food—past the mouth," he says. "As they are swimming, a boundary layer of viscous—that is, thick—fluid forms between their arms, creating a continuous paddling surface. And you can imagine how this paddling surface would be disturbed if you have a big gap between the arms."

Maintaining symmetry appears to be vital not just for propulsion and feeding, the researchers found. In the few cases when the injured animals do not symmetrize—only about 15 percent of the injured animals they studied—the unsymmetrical ephyra also cannot develop into normal adult jellyfish, called medusa.

The researchers next wanted to figure out how the new self-repair mechanism works. Cell proliferation and cell death are commonly involved in tissue regeneration and injury response, but, the team found, the amputee jellyfish were neither making new cells nor killing existing cells as they redistributed their existing arms around their bodies.

Instead, the mechanical forces created by the jellyfish's own muscle contractions were essential for symmetrization. In fact, when muscle relaxants were added to the seawater surrounding an injured jellyfish, slowing the animal's muscle contractions, the symmetrization of the intact arms also was slowed down. In contrast, a reduction in the amount of magnesium in the artificial seawater sped up the rate at which the jellyfish pulsed their muscles, and these faster muscle contractions increased the symmetrization rate.

"Symmetrization is a combination of the mechanical forces created by the muscle contractions and the viscoelastic jellyfish body material," Abrams says. "The cycle of contraction and the viscoelastic response from the jellyfish tissues leads to reorganization of the body. You can imagine that in the absence of symmetry, the mechanical forces are unbalanced, but over time, as the body and arms reorganize, the forces rebalance."

To test this idea, the team collaborated with coauthor Chin-Lin Guo, from Academia Sinica in Taiwan, to build a mathematical model, and succeeded in simulating the symmetrization process.

In addition to adding to our understanding about self-repair mechanisms, the discovery could help engineers design new biomaterials, Goentoro says. "Symmetrization may provide a new avenue for thinking about biomaterials that could be designed to 'heal' by regaining functional geometry rather than regenerating precise shapes," she says. "Other self-repair mechanisms require cell proliferation and cell death—biological processes that aren't easily translated to technology. But we can more easily apply mechanical forces to a material."

And the impact of mechanical forces on development is being increasingly studied in a variety of organisms, Goentoro says. "Recently, mechanical forces have been increasingly found to play a role in development and tissue regulation," she says. "So the symmetrization process in Aurelia, with its simple geometry, lends itself as a good model system where we can study how mechanical forces play a role in morphogenesis."

These results are published in a paper titled "Self-repairing symmetry in jellyfish through mechanically driven reorganization." In addition to Abrams, Basinger, Goentoro, and Guo, former SURF student William Yuan from the University of Oxford was also a coauthor. Jellyfish were provided by the Cabrillo Marine Aquarium and the Monterey Bay Aquarium. John Dabiri, professor of aeronautics and bioengineering, provided discussions and suggestions throughout the study. Abrams is funded by the Graduate Research Fellowship Program of the National Science Foundation.

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Senior Spotlight: Phoebe Ann

Caltech's class of 2015 is group of smart, creative, and curious individuals. They are analytical thinkers, performers, researchers, engineers, athletes, and leaders who are ready to apply the lessons they have learned from Caltech's rigorous academic environment and the unique experiences they had as part of this close-knit community to pursue future challenges. 

We talked to two of these graduates, Phoebe Ann and Justin Koch, about their years at Caltech and what will come next.

Other graduates share their stories in videos posted on Caltech's Facebook page.

Watch as they and their peers are honored at Caltech's 121st commencement on June 12 at 10 a.m. If you can't be in Pasadena, the ceremony will be live-streamed at http://www.ustream.tv/caltech. You may also follow the action and share your favorite commencement moments on Facebook, Twitter, and Instagram by using #Caltech2015 in your tweets and postings.

Phoebe Ann

Major: Biology and English
House: Lloyd
Hometown: Irvine, California

Why did you originally decide to come to Caltech?

I was attracted by the small class size, and I've found to this day that it is one of Caltech's strongest advantages. Caltech is also extremely supportive of a student's individual endeavors, as demonstrated by the numerous awards and programs that promote independent research, volunteer work, or extracurricular interest projects. The most significant example of this is the Caltech Y, through which I was able to learn how to implement a personal idea or passion into a tangible program that my fellow students and I can all enjoy.

Were you involved in extracurricular activities at Caltech?

My most significant extracurricular activities were implemented through the Caltech Y. My proudest accomplishments were organizing alternative spring break trips to New York for Hurricane Sandy relief and to Costa Rica for community construction. Prior to Caltech, I had never traveled independently, let alone led a group of students to a foreign country. These activities were absolutely crucial to developing myself into an effective community member and future physician.

What were your most memorable experiences?

Aside from my Caltech Y activities, my most memorable experiences were interactions with my fellow Lloydies during freshman year. It was an exciting time of realizing my similarities and differences with others, as well as my ability to function without sleep.

What did you not know about Caltech that you learned after being here?

I did not know how hard Caltech pushed its students. I struggled tremendously upon arriving at Caltech because I was intimidated by all the students who seemed "naturally" intelligent. But Caltech forced me to just shut up and get to work. And when all was said and done, I was able to accomplish so much more than I had ever imagined.

What will you be doing after Caltech?

I will be studying medicine at Feinberg Medical School at Northwestern University in Chicago. After, I would like to be a surgeon or a pediatrician, depending on how well I can maintain a work-life balance.

Any words of advice to incoming students?

Join the Caltech Y! It is critical not only to find a work-life balance outside of the house system, but also to ground your scientific endeavors in a broader purpose: to serve and better your local, national, and international community.

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Diversity Retreat at Caltech

In September 2013, Caltech, UC Berkeley, UCLA, and Stanford University founded a new consortium—the California Alliance for Graduate Education and the Professoriate (AGEP)—to support underrepresented minority graduate students in the STEM fields of mathematics, the physical sciences, computer science, and engineering. The Alliance, launched through a grant from the National Science Foundation, was created to address the fact that minority students enter STEM fields in disproportionately low numbers and that, as a group, their progress slows at each step in their academic careers.

This April, Caltech was host to "The Next Generation of Researchers," the Alliance's second annual retreat. The retreats are designed to bring together graduate students, postdoctoral fellows, research scientists, and faculty from the four institutions and national labs in California for mentoring and network-building opportunities.

We recently spoke with Joseph E. Shepherd (PhD '81), dean of graduate studies and the C. L. "Kelly" Johnson Professor of Aeronautics and professor of mechanical engineering, about AGEP, the recent retreat, and Caltech's diversity initiatives.

 

What was Caltech's motivation for entering into the California Alliance, and what has the program accomplished so far?

Caltech joined the Alliance to encourage underrepresented minorities to pursue academic careers in mathematics, physical science, computer science, and engineering fields. We seek to not only diversify our own campuses (Caltech, Berkeley, Stanford, and UCLA) but also contribute to diversity throughout the nation.

During the first year, the Alliance members identified participants at the four campuses. We have conducted two retreats—the first at Stanford University in 2014 and the second at Caltech. Graduate students, postdoctoral scholars, and faculty gathered at these retreats and learned about opportunities and challenges for underrepresented minority students transitioning from graduate studies to a career as a faculty member.

In 2014, the Alliance established a postdoctoral scholar fellowship program, accepted applications in the fall, and is in the process of finalizing awards for this coming academic year (2015–16). The Alliance has also accepted applications for the mentor-matching program through which graduate students can visit faculty at Alliance institutions to learn about opportunities and faculty careers in specific research areas.

 

AGEP programs are funded by the NSF. What are they hoping to achieve through these programs?

The AGEP programs were originated at NSF as a response to the recognition of the obstacles that underrepresented minority students faced in graduate education and advancing to faculty careers. These issues are highlighted in "Losing Ground," a 1998 report of a study led by Dr. Shirley Malcom, director of Education and Human Resources Programs of the American Association for the Advancement Science. Dr. Malcolm is a Caltech trustee and was a featured speaker at our 2015 retreat.

 

What are we doing at Caltech to support underrepresented minority students in the graduate sciences, and has anything at Caltech changed as a result of our involvement in this consortium?

The Caltech Center for Diversity has a number of programs that support various segments of our student population, and we are increasing the number of underrepresented minority postdoctoral scholars at Caltech.

In collaboration with several offices across the campus, we are developing and maintaining a strong network focused on outreach, recruitment, matriculation, and the eventual awarding of degrees to underrepresented minorities in the campus' graduate programs.  

Specifically, the Office of Graduate Studies, the Center for Diversity, and the Center for Teaching, Learning, and Outreach focus on programming that creates access to resources, builds community, and leverages relationships to help to address the challenges highlighted in the AGEP program, including facilitated discussion groups that address issues of inclusion and equality, various graduate student clubs that promote cultural awareness and community education, and an annual "Celebration of Excellence" reception to recognize student successes and the efforts of staff, faculty, and students who promote equity and inclusion on campus.

In addition, the graduate recruitment initiative coordinated by the Office of Graduate Studies works to ensure that the campus is able to recruit at underrepresented minority STEM-focused conferences and research meetings around the United States, and encourages graduate student ambassadorship and provides opportunities for underrepresented minority graduate students to network across national professional communities with similar research and academic interests.

 

What can we do better?

Encourage greater diversity in graduate admissions by identifying and recruiting underrepresented minority graduate students and ensuring that every student thrives at Caltech. Encourage more of the current underrepresented minority students and postdoctoral scholars at Caltech to take advantage of the professional development opportunities in the Alliance and facilitate their transition to the next stage of their academic careers. Provide more professional development opportunities for all Caltech students and postdoctoral scholars to learn about academic careers.

 

What was the goal of this year's annual retreat?

One goal was to promote introductions and discussion among students, postdoctoral scholars, and faculty at the Alliance schools. In addition to informal meetings between participants, we held a number of roundtables and panel discussions on topics such as knowing what to expect of grad school, the postdoctoral experience, and, in general, life as a researcher and faculty member. Our retreat highlighted the research between done by faculty, students, and postdoctoral scholars in the Alliance by holding a poster session that enabled the participants to learn about each other's research activity. The retreat participants learned about some of the exciting research being done in protein design at Caltech from the other featured speaker, Steve Mayo (PhD '88), Caltech's William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering and Bren Professor of Biology and Chemistry.

 

Who were participants in this year's retreat, and what do you think they gained from the program?

There were a total of 111 attendees: 40 percent were faculty, 42 percent were graduate students, 8 percent postdoctoral scholars, and the remainder were staff members, including some from JPL and Sandia National Laboratory.

The participants were recruited by the Alliance leadership at each university. The student participants gained the opportunity to network with scientists and faculty at other Alliance institutions, learned about academic careers and postdoctoral scholar opportunities, and were able engage in wide-ranging discussions about careers in science. The faculty and staff participants were able to provide information and advice to students as well as learn about prospective postdoctoral scholars and faculty members.

In addition, a total of 18 faculty from Caltech participated out of a total of 43 faculty members who attended from all four Alliance universities. The faculty at Caltech are very positive about this program, and we are encouraged by the high level of participation.

 

Were the sessions specifically focused on the particular needs of underrepresented groups?

The focus of the Alliance is on helping young people from diverse backgrounds to consider and succeed in academic careers in science. Many of the issues that contribute to success or failure in academic science careers do not depend on the particular perspective or background of a prospective postdoctoral scholar or professor. The pathway to the professoriate and the mechanics of succeeding in an academic career are far from obvious, particularly for students with disadvantaged backgrounds as well as those who are the first in their family to obtain a college degree or consider a career in science. One of the important roles of the Alliance retreat is in providing information about the many career aspects to which our student participants are exposed early enough in their careers so that it may make a difference. 

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Students Try Their Hand at Programming DNA

In a new class called Design and Construction of Programmable Molecular Systems (BE/CS 196a), taught this term by Assistant Professor of Bioengineering Lulu Qian, undergraduate and graduate students in computer science, computation and neural systems, and bioengineering came together to study a new intersection of their fields: biomolecular computation. "Molecular programming is a really young research field that only has a couple of decades of history," said Qian, introducing the class's final project presentations on Friday, June 5. "But it offers a huge potential for transforming all molecular sciences into information technology."

In recent years, in order to "program" synthetic DNA sequences to accomplish a diverse range of functions, bioengineers have begun to take advantage of their ability to predict how DNA strands interact, exchange their binding partners, and fold.

Over the course of 10 weeks, three student teams in BE/CS 196a had the chance to specialize in one of the possibilities afforded by this technology. Working in the wet lab—a lab where biochemical materials can be handled in test tubes of liquids—one group attempted to simulate rudimentary neural networks that recognize the presence or absence of DNA strands, each representing information about four Caltech undergrad houses. Another designed molecules to compute multistep logic functions that implement two particular "transition rules" involved in a famous conjecture concerning a theoretical model of computation called "cellular automata."

Students in the third group designed DNA "origami." In DNA origami, a technique first developed at Caltech, DNA molecules automatically fold into prescribed shapes that may contain patterns of attachment sites—like a smiley face or a miniature circuit board—based on the molecules' designated sequence.

As used by Qian's students, junior Aditya Karan, a computer science major, and first-year bioengineering graduate student James Parkin, the process begins with a single-strand loop of DNA—the genome of virus M13, which has over 7,000 nucleotides. "Staples" made of matching sequences are used to connect specific points on the loop, so that these points are pulled together, causing the loop to fold into the desired shape. The team focused their efforts on manipulating a set of microscopic square tiles of DNA. In one experiment they created complex patterns on the surface of the squares; in another they designed the tiles to form heart-shaped arrays consisting of 11 tiles of four distinct types.

Although complete control of molecular systems is a long way off, these technologies offer what is essentially a programming language capable of interfacing with a biochemical environment. DNA folding, for example, could be used to design microscopic "boxes" that open and release a therapeutic drug only under certain chemical conditions on the surface of or inside specific type of cells. "What has kind of amazed us is how much we can get done with just DNA," says Parkin. "With DNA, we can design complicated things from scratch. We can't do that with proteins yet."

As Qian notes, programming molecular systems is an area "full of imagination and creativity."

"That's why I want to share these adventures with Caltech students," she says.

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Biology, With a Beat

This term, students in Biology 1—Principles of Biology—were offered a novel alternative to the traditional final exam: the opportunity to create a two-to-four-minute video explaining some aspect of biology in an interesting, entertaining and, yes, musical way.

Bi 1 is a large lecture course for nonmajors and, for most of them, as close as they will come to biology during their undergraduate career. As the class's instructor, Dianne Newman, professor of biology and geobiology, explains, "It's almost an absurd challenge. How do you teach biology in a substantive and engaging way in 10 weeks to students whose primary interests lie elsewhere?"

Newman found at least one way to meet that challenge. "I have a mid-session break in my class because it's an hour and a half long," says Newman. "After 45 minutes, I show a short video that relates to the content of my lecture just to break things up, to give students a chance to stretch and reengage." One day in April, Professor Newman showed a rap video on Hox gene development created by Stanford students. "The Hox genes are regulatory genes in eukaryotes that are critical for development," says Newman. "It was such a clever video. And so, off the cuff, I said to my Bi 1 students, 'These Stanford kids are pretty good. If any of you can come up with something equally outstanding, I'll give you an automatic A in the class.'"

After class, to Newman's surprise, a student came up to ask exactly what the rules were for this automatic A. If they did a video, could they skip the midterm? Could they skip the final? What about the assignment requiring students to write a hypothesis-driven paper on a topic of their choice? Disarmed, Newman promised she would soon send the class an email that would explain it all. She reflected on the idea and then laid out the rules for the Bi 1 video challenge: an automatic A on just the final exam, but only if the video adhered to a stringent set of rules regarding originality, scientific content, and aesthetic value.

Newman was skeptical anyone would take on the challenge, but in the end, six videos were submitted. All were screened on June 4, the last day of class. All of the students in the class were given clickers to vote on each video—giving it an A, B, or C, based on how well the video fulfilled the criteria. Newman promised to take their votes into consideration as she made her decisions about the adequacy of each video. Newman further enlisted some special A-list guests to attend the showing and give their reactions: Harry Gray, the Arnold O. Beckman Professor of Chemistry and founding director of the Beckman Institute; Jonas Peters, the Bren Professor of Chemistry; Cindy Weinstein, vice provost and professor of English; and Bil Clemons, professor of biochemistry. As an added surprise to the students, President Thomas Rosenbaum stopped in for the viewing.

Student videos covered a range of topics, from photosynthesis to metabolism to respiration, and employed a variety of styles, with each video showcasing the unique personalities and creative talents of their creators. Tyler Perez (freshman, planetary science) and Nicholas Meyer (freshman, physics), for example, created a video titled "A Rap about GFP" (GFP, or green fluorescent protein, is used as a marker to visualize protein localization and gene expression). Perez notes that the main challenge was not having a dedicated cameraman, creating the need for "planning the shots beforehand, setting up the tripod, running to the scene to do the acting/dubbing, running back to check the shot, move the camera, repeat."

Rachael Morton (freshman, computer science) and Roohi Dalal (freshman, physics and history) described details about the nuclei of differentiated cells to the tune of Taylor Swift's "Blank Space" in a video they called "Enucleated Space." Morton recalls spending "a few interesting afternoons walking around campus in formal wear, lugging around cameras while lip syncing, as confused-looking tour groups and classmates passed by."

Ashwin Balakrishna (freshman, electrical engineering) and Kelly Woo (freshman, electrical engineering) collaborated on "Photosynthesis," rapping out lyrics like "ATP synthase she the center of it all/I got H+ gradient and now it comes into call" (inspired by Drake's rap video for "Energy"). Woo says, "As corny as this sounds, shooting this video really allowed me to slow down and appreciate how beautiful our campus is."

This may sound like a lot of fun and only a little science, but the Caltech faculty reviewers were impressed. "I'm a little prouder to be a professor at Caltech today," Peters said.

Harry Gray, after viewing the video on respiration created by Ashwin Hari (freshman, computer science) and Hanzhi Lin (freshman, computer science), humorously noted, "I've been studying respiration for a long time, but I learned more in this video than I have in 30 years. I hope you guys will make a lot more videos. I'm going to come to all of them so I don't have to spend all that time reading stupid journals."
 

While reviewing freshman Tara Shankar's (freshman, computer science) video, "Metabolism, Let's Break it Down," Jonas Peters tried to recruit the computer science major to chemistry. He even offered a powerful incentive: "If Professor Newman doesn't give you an A on the final for this video, you can take any course in CCE [the Division of Chemistry and Chemical Engineering], and we will give you an A."

After the last video was shown, Peters, on a more serious note, drew students' attention to all the opportunities that they—as nonmajors in biology—could bring to biology from their very different "corners of the campus."

"Professor Newman's enthusiasm for the class was mirrored by the joie de vivre of the students, who sang, danced, and rapped their way through the central themes of Bi 1," says Weinstein. "Seeing students bring such intelligence, creativity, and downright fun to their studies reminds us of the rewards that come to teachers who inspire."

So did these students earn their prize, the opportunity to spend another afternoon singing and dancing their way across campus while their fellow Bi 1 students grind out their final? The jury—a one-woman jury named Dianne Newman—is still out, but it looks as though the Bi 1 video challenge will be finding its way onto her next Bi 1 syllabus.

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Screening Cells for a Cure

A powerful partnership leads to advances in islet-cell transplants to treat diabetes

Living with type 1 diabetes today is typically manageable thanks to advancements in medical technology. However, some patients still confront severe complications, from extreme hypoglycemia that can lead to diabetic coma to long-term effects, such as blindness, nerve damage, and kidney failure. In some cases, type 1 diabetes can be life-threatening, and in all cases, it is currently incurable.

But there is hope, fostered by a collaboration between Caltech and its neighbor in Duarte, City of Hope. Established in 2008 with a $6 million gift from an anonymous donor, the Caltech-City of Hope Biomedical Research Initiative provides seed grants to accelerate the development of basic scientific research and its translation into applications ranging from new pharmaceuticals to medical devices to treatment methods. The partnership was formalized—and further strengthened—in 2014, when the two institutions signed a memorandum of understanding, encouraging researchers to collaborate and share resources.

Leadership from Caltech and City of Hope and members of the public celebrated the partnership at a special event on May 13. More than 70 attendees gathered in Caltech's Beckman Institute Auditorium to learn about progress in fighting diabetes.

"The benefits of the deepening relationship between our two institutions emerged clearly in the evening's events," says Caltech President Thomas F. Rosenbaum, holder of the Sonja and William Davidow Presidential Chair and professor of physics. "Our increasing set of research interactions is making great strides in translating fundamental science to advance human health."

To date, the initiative has funded 28 endeavors led by teams of Caltech and City of Hope investigators—early-stage research projects that might not have moved forward if they had had to rely on traditional funding sources.

"The more we work together, the more we enable discovery," says City of Hope president and CEO Robert Stone. "Saving lives today and tomorrow—that's what this collaboration is about."

One encouraging development for people facing uncontrolled type 1 diabetes comes in the form of a simple surgery. The procedure takes healthy, functioning pancreatic islets—clusters of cells that contain insulin-producing beta cells—from an organ donor and transplants them into a patient's liver. Doctors at City of Hope have already performed the surgery on a limited number of patients and have seen promising results.

While islet transplantation eventually may lead to a cure for diabetes, challenges remain in making it practical. Once islets have been donated, for example, how can they be isolated and kept functional? How do researchers distinguish good islets from bad without wasting the good ones during testing?

Through the Caltech-City of Hope Biomedical Research Initiative, researchers and clinicians are working hand-in-hand to answer these important questions.

At the event, researchers told the story and explained the science behind their project. Fouad Kandeel, chair and professor in the Department of Clinical Diabetes, Endocrinology, and Metabolism at City of Hope, and his colleague, Kevin Ferreri, associate research professor in the Division of Developmental and Translational Diabetes and Endocrine Research, have been working on islet cell transplantation as a treatment for their patients with type 1 diabetes. Yet existing methods of selecting islets took too much time, involved too much labor, and used up too many islets.

That is where the Caltech partners came in. Yu-Chong Tai, the Anna L. Rosen Professor of Electrical Engineering and Mechanical Engineering, and Hyuck Choo, assistant professor of electrical engineering and medical engineering, invented a novel device that can screen individual islets. The microfluidic platform accurately determines the health of an islet sample by applying glucose and measuring the sample's reaction. In less than a year, the team has designed a proof-of-concept platform.

Once the device is perfected, Choo believes the team will be able to easily scale it up and even use its technology to help overcome other clinical challenges.

"This is the perfect opportunity for medical engineering at Caltech," says Choo. "We want to create technology-based solutions to large-scale societal health issues, like diabetes."

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Urging Caution During a Genomic Revolution: A Conversation with David Baltimore

Earlier this year, an elite group of scientists and ethicists—including Nobel Laureate David Baltimore, president emeritus and Robert Andrews Millikan Professor of Biology at Caltech—convened in Napa, California, to discuss the scientific, medical, legal, and ethical implications of genome engineering technology.

Such technologies—chief among them a now-widespread genetic tool known as CRISPR-Cas9, known colloquially as "DNA scissors"—allow scientists to make precise edits to the genome, or the entire genetic script, of an organism. By essentially rewriting genomes, researchers can, in weeks rather than years, create animal strains that mimic human diseases to test new therapies; easily knock out genes in the cells of animals and humans to test their function; and even change DNA sequences to correct genetic defects. Such edits can be made in both body cells and in germ-line cells (sperm and eggs), to alter heritable genes.

We recently spoke with Baltimore about these new technologies and the issues they raise.

 

What was your motivation for participating in this conversation in January about the uses of genome engineering technology?

I was most concerned about the ability to carry out germ-line modifications of humans using this technology. Other issues came up—modification of the general biosphere, somatic gene therapy as opposed to heritable gene therapy—but I think those things are less concerning at the moment.

 

What is the big issue with human germ-line modification?

The big issue is how simple it is, at least conceptually, to modify cells—embryonic stem cells as well as somatic cells. The major concern is the potential for off-target effects: If you carry out the germ-line modification of a gene that you have identified as of concern, how do you know that, somewhere else in the genome, there hasn't been an alteration which you didn't plan to do but that has occurred anyway? Most of the genome is not coding—it doesn't code for anything. So you wouldn't necessarily see a protein change. But that change would become heritable generations into the future. You want to be pretty sure that that is not happening.

We know that people have put a lot of effort into minimizing such off-target effects. Whether they have been minimized enough is a very important safety consideration.

 

Are you and your colleagues concerned about the potential for using this technology to create "designer" babies?

I think the thing to do is to distinguish between the long-term concern about modifications that are heritable but made for reasons that are "cosmetic," and a situation in which a modification is made in order to ameliorate a serious human disease.

The example that I find most compelling is Huntington's disease. It involves a mutation in the genome that most people don't carry; the few people who do carry it suffer very serious deleterious consequences that only become apparent with age. Ridding the genome of that modified gene seems to me to be an unalloyed good. Therefore, the question becomes, do you need to use genome alteration technology to accomplish that end or is there some other way to accomplish that? But the end seems to me to be something almost everybody would agree is a good.

 

But there are situations that are not that clear-cut . . .

Exactly. You go from, on one side, Huntington's disease, and on the other side, the desire for a more intelligent child. One is easy, it can be fixed by changing a single gene. The other is much more complicated. Intelligence certainly isn't determined by a single gene. It is multigenic—the result of many genes. One is a pretty straightforward medical decision; the other is an issue which is very culturally bound. So those are the two poles, and then there is everything in between.

 

For the in-between situations, that is just a judgment call?

Yes, it is a judgment call.

 

Who makes the decisions in those cases?                                                                   

Society, in the end, will make those decisions. The problem that I think everybody has with it is that although society has the ability to make decisions like that, it is a big world. And you could imagine things being done in other jurisdictions, where we don't have control.

 

How do we manage that?

My personal thought is that the best we can do is to make absolutely unambiguous the consensus feeling of society. Because the scientific community is an international community, we do have the ability to at least provide moral guidelines.

Any kind of modification that involves something as elusive as intelligence is a long way off. We don't understand it well enough to make modifications today, and so to an extent we are trying to establish a framework that will serve the world well into the future. That is a big order, and whether an international meeting can grapple with anything as profound as that, we will see.

 

Where do you see this technology in 10 years? 100 years?

That is a good distinction—10 years versus 100 years. The latter is very hard to think about, because we have really no idea what scientific advances are going to be made in the next 100 years. About all we can be sure of is that they will be impressive and maybe revolutionary, and will present us with a very different technological landscape in which these questions will evolve.

In 10 years, we certainly are likely to know the outline of what we are likely to see, and it is not going to be a whole lot different from what we are seeing today. I would guess that in 10 years, we would understand multigenic traits better than we do now. I do suspect that people will be gratified that at this time we began the basic considerations, because the problems will get more difficult rather than easier.

 

Forty years ago, you were one of the organizers of the influential Asilomar Conference on Recombinant DNA, which laid out voluntary guidelines for the use of genetic engineering—the same type of guidelines you and your colleagues are advocating for now with genome engineering. What was the original inspiration for convening the Asilomar Conference?

It was the advent of recombinant DNA technology that drew our attention. We all worked in the biological sciences. We recognized that recombinant DNA technology was a game changer because it was going to allow scientific investigation of the questions that heretofore had been unavailable. In some ways, many of us had designed our careers around the inability to do this kind of work, and, suddenly, we were going to be able to do things that we had only previously dreamed about, if we had considered them at all.

But at the same time, there seemed to be potentially problematic aspects to it, in particular the ability to modify organisms, mainly microbial organisms, in ways that could have given the organisms the ability to be a danger to human health.

Actually, we simply did not know whether that was a realistic concern or not. As we talked to other people, we discovered that no one knew. So it seemed like a good idea to take a breather and to give consideration to these concerns of potential hazards in an international meeting that would be convened in the United States.

 

Was there some thought that if you tried to self-regulate you could avoid governmental regulation?

It wasn't a matter of avoiding governmental regulation. It was that we thought that we—the scientific community—were uniquely capable of putting in perspective these new capabilities. The answer might have been to have legislation. In fact, as our thinking progressed, we realized that the very best situation would be to avoid legislation because legislation is very hard to undo. We wanted to be sure we would have the flexibility to respond to inevitably changing scientific perspectives.

 

In retrospect, do you think Asilomar was a success?

It worked out very close to how we hoped it would. That is, as we learned more, we became more comfortable with the technology; as we investigated potential hazards, we saw less and less reason to be concerned; and we had a built-in flexibility in the system to allow it to evolve in the context of newer understanding.

 

Are you aware of any situations where scientists did not follow the rules?

To my knowledge, that has never happened.

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Urging Caution During a Genomic Revolution: A Conversation with David Baltimore
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Amgen and Caltech Establish Partnership in Health Sciences

Caltech and Amgen have joined forces in the pursuit of foundational discoveries in the biological sciences through a multifaceted new partnership spanning research, graduate student training, and shared resources.

"The work we do is built upon the foundation of basic discoveries in biology," says Alexander Kamb (PhD '88), Amgen's senior vice president of Discovery Research. "We look forward to strengthening and extending this foundation through our connection with Caltech."

Caltech received its first gift from Amgen in 1981, just one year after the company was formed. Over the past three decades, Amgen has provided support for a variety of educational programs and investigations at Caltech. Today, Amgen has grown to be one of the world's leading independent biotechnology companies, and it has now entered into a collaborative research agreement for joint investigations with Caltech that will leverage the two institutions' strengths in discovery, and translational and clinical science.

Under the terms of the new agreement, Amgen will fund up to five research projects per year for three years. Bridging the divisions of Chemistry and Chemical Engineering, Biology and Biological Engineering, and Engineering and Applied Science, the projects will focus on large- and small-molecule drug discovery, drug-delivery devices, and diagnostic technologies. Amgen will also provide support for Amgen Graduate Student Fellows in Caltech's interdisciplinary Graduate Program in Biochemistry and Molecular Biophysics.

In addition to fellowship and research support, Amgen has chosen Caltech as its first partner to access the Amgen Biology-Enabling Resource, a searchable database comprising more than 1,000 items, including molecules, peptides, antibodies, and engineered cell lines acquired through years of discovery efforts. Amgen will have no claim to ownership of intellectual property to discoveries that may ensue. Over time, Amgen will extend access to other research institutions and, as specific materials are depleted, add others to the catalog.

This comprehensive agreement with Amgen exemplifies Caltech's commitment to building strategic partnerships to optimize the Institute's capabilities and help solve pressing problems for the benefit of the public. This and other such relationships with corporations, government agencies, non-governmental organizations, and other institutions, focus on transferring technology from Caltech's campus to industry.

"Each industry collaboration has a unique scope and focus, but all share a goal of transforming new research findings into applications that will benefit society," explains Caltech Vice Provost, Mory Gharib, the Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering. "The hope is that the Caltech–Amgen partnership will enable our teams to swiftly convert laboratory discoveries into therapeutics or devices that will improve patients' lives."

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Yeast Protein Network Could Provide Insights into Human Obesity

A team of biologists and a mathematician have identified and characterized a network composed of 94 proteins that work together to regulate fat storage in yeast.

"Removal of any one of the proteins results in an increase in cellular fat content, which is analogous to obesity," says study coauthor Bader Al-Anzi, a research scientist at Caltech.

The findings, detailed in the May issue of the journal PLOS Computational Biology, suggest that yeast could serve as a valuable test organism for studying human obesity.

"Many of the proteins we identified have mammalian counterparts, but detailed examinations of their role in humans has been challenging," says Al-Anzi. "The obesity research field would benefit greatly if a single-cell model organism such as yeast could be used—one that can be analyzed using easy, fast, and affordable methods."

Using genetic tools, Al-Anzi and his research assistant Patrick Arpp screened a collection of about 5,000 different mutant yeast strains and identified 94 genes that, when removed, produced yeast with increases in fat content, as measured by quantitating fat bands on thin-layer chromatography plates. Other studies have shown that such "obese" yeast cells grow more slowly than normal, an indication that in yeast as in humans, too much fat accumulation is not a good thing. "A yeast cell that uses most of its energy to synthesize fat that is not needed does so at the expense of other critical functions, and that ultimately slows down its growth and reproduction," Al-Anzi says.

When the team looked at the protein products of the genes, they discovered that those proteins are physically bonded to one another to form an extensive, highly clustered network within the cell.

Such a configuration cannot be generated through a random process, say study coauthors Sherif Gerges, a bioinformatician at Princeton University, and Noah Olsman, a graduate student in Caltech's Division of Engineering and Applied Science, who independently evaluated the details of the network. Both concluded that the network must have formed as the result of evolutionary selection.

In human-scale networks, such as the Internet, power grids, and social networks, the most influential or critical nodes are often, but not always, those that are the most highly connected.

The team wondered whether the fat-storage network exhibits this feature, and, if not, whether some other characteristics of the nodes would determine which ones were most critical. Then, they could ask if removing the genes that encode the most critical nodes would have the largest effect on fat content.

To examine this hypothesis further, Al-Anzi sought out the help of a mathematician familiar with graph theory, the branch of mathematics that considers the structure of nodes connected by edges, or pathways. "When I realized I needed help, I closed my laptop and went across campus to the mathematics department at Caltech," Al-Anzi recalls. "I walked into the only office door that was open at the time, and introduced myself."

The mathematician that Al-Anzi found that day was Christopher Ormerod, a Taussky–Todd Instructor in Mathematics at Caltech. Al-Anzi's data piqued Ormerod's curiosity. "I was especially struck by the fact that connections between the proteins in the network didn't appear to be random," says Ormerod, who is also a coauthor on the study. "I suspected there was something mathematically interesting happening in this network."

With the help of Ormerod, the team created a computer model that suggested the yeast fat network exhibits what is known as the small-world property. This is akin to a social network that contains many different local clusters of people who are linked to each other by mutual acquaintances, so that any person within the cluster can be reached via another person through a small number of steps.

This pattern is also seen in a well-known network model in graph theory, called the Watts-Strogatz model. The model was originally devised to explain the clustering phenomenon often observed in real networks, but had not previously been applied to cellular networks.

Ormerod suggested that graph theory might be used to make predictions that could be experimentally proven. For example, graph theory says that the most important nodes in the network are not necessarily the ones with the most connections, but rather those that have the most high-quality connections. In particular, nodes having many distant or circuitous connections are less important than those with more direct connections to other nodes, and, especially, direct connections to other important nodes. In mathematical jargon, these important nodes are said to have a high "centrality score."

"In network analysis, the centrality of a node serves as an indicator of its importance to the overall network," Ormerod says.

"Our work predicts that changing the proteins with the highest centrality scores will have a bigger effect on network output than average," he adds. And indeed, the researchers found that the removal of proteins with the highest predicted centrality scores produced yeast cells with a larger fat band than in yeast whose less-important proteins had been removed.

The use of centrality scores to gauge the relative importance of a protein in a cellular network is a marked departure from how proteins traditionally have been viewed and studied—that is, as lone players, whose characteristics are individually assessed. "It was a very local view of how cells functioned," Al-Anzi says. "Now we're realizing that the majority of proteins are parts of signaling networks that perform specific tasks within the cell."

Moving forward, the researchers think their technique could be applicable to protein networks that control other cellular functions—such as abnormal cell division, which can lead to cancer.

"These kinds of methods might allow researchers to determine which proteins are most important to study in order to understand diseases that arise when these functions are disrupted," says Kai Zinn, a professor of biology at Caltech and the study's senior author. "For example, defects in the control of cell growth and division can lead to cancer, and one might be able to use centrality scores to identify key proteins that regulate these processes. These might be proteins that had been overlooked in the past, and they could represent new targets for drug development."

Funding support for the paper, "Experimental and Computational Analysis of a Large Protein Network That Controls Fat Storage Reveals the Design Principles of a Signaling Network," was provided by the National Institutes of Health.

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Tuesday, May 26, 2015 to Friday, May 29, 2015
Center for Student Services 360 (Workshop Space) – Center for Student Services

CTLO Presents Ed Talk Week 2015

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