How to put nanoparticles to work in drug development, April 7, 2010, by Kelly Rae Chi – Nanoparticles are increasingly found in drug development. Researchers are using them in designing treatments for tumors, infections, and brain diseases, as well as for imaging techniques that enhance visualization of molecular-scale events in brain tissue and culture dishes. But so far, says biochemist Michael Sailor of the University of California-San Diego, the technology for designing nanoparticles “is kind of like where we were when we were building Model T cars.”

Creating nanoparticles—which are usually between 1 and 100 nanometers long and made from a variety of materials—and putting them to work within complex biological systems can be quite a challenge and it’s not something scientists, especially newbies, do alone. Rather, the field of medical nanotechnology requires expertise from material scientists, engineers, and biologists, says Sailor. There are a number of parameters to play with. For example, researchers might see that they can alter their particles’ shapes and sizes through simple changes to their preparation steps. These can lead to better targeting to the right organs, or extended release of a drug. Alternatively, scientists might be able to combine two less-than-stellar nanoparticle techniques to create a synergistic system. Maybe they’ll need to create an entirely new nanoparticle, ideally one that’s biodegradable if you eventually plan to use it in humans. These challenges require patience, but if done right, the quantity of nanoparticles produced can be easily scaled up.

The Scientist spoke with four researchers on the cutting edge of nanoparticle design. Here’s what they said about the challenges and opportunities nanoparticles bring to drug development.

Shape Shifting

Project: Designing nanoparticles to treat infectious diseases

User: Padma Devarajan, Professor of Pharmaceutical Sciences and Technology, University of Mumbai, India

Problem: The spleen, a potential target in treating diseases such as splenic tuberculosis, AIDS, and malaria, receives only about 15% of nanoparticles injected into the bloodstream. That’s because nanoparticles are rapidly cleared by immune cells within the liver before they reach the spleen. Devarajan wanted to create particles that bypassed the liver.

Solution: Her group stumbled onto a solution in 2008 when they were attaching the antibiotic drug doxycycline to lipid–polymer nanoparticles. By simply increasing the concentration of glycerol monostearate during the process of mixing together the nanoparticles with the drug, they produced two seemingly different types of particles that behaved differently: One lingered in the liver, as expected, but the other bypassed the liver and collected in the spleen. A closer look revealed that the nanoparticles targeting the spleen were irregularly shaped and made with greater concentrations of glycerol monostearate, whereas the ones in the liver were spherical. Data from their work and other labs suggested that the particles’ shape determined whether they targeted the spleen (J Biomed Nanotech 4:359–66, 2008).

They then tagged the nanoparticles with a radiolabeled dye and observed their biodistribution in vivo. They found high splenic uptake in rats, rabbits, and especially dogs, whose spleen-to-liver uptake ratio was nearly 6, compared to 0.5 for the original preparation (J Pharm Sci Jan 20, 2010 Epub ahead of print). “We are currentlyᅠevaluating methods to standardize the process,” Devarajan says.

Considerations: In the past 2 years, scientists have shown that shape plays an important part in nanoparticle design. Devarajan says researchers should try tweaking simple steps in their nanoprecipitation protocols to see whether it helps targeting. Stick with simple, inexpensive methods: “When I am looking at a drug or therapy I should have something that could be scaled up easily; otherwise, it’s no use,” she notes.

Cooperative Particles

Project: Nanoparticle design for cancer diagnosis and therapy

User: Michael Sailor, Professor of Chemistry and Biochemistry, University of California–San Diego

Problem: Heating a tumor has shown some potential in treating cancer, but as a therapy it is somewhat nonspecific and inefficient. One approach is to use radiowaves, but small tumors do not convert the waves into heat efficiently. “You can get the tumor hot but not hot enough to kill it,” Sailor says.

In a separate project, Sailor and his team found that when they inject worm-shaped nanoparticles with magnetic properties—called magnetic nanoworms—or liposomes containing tumor-targeting chemistry, relatively few of these particles actually made it to the tumor. His group needed a way to improve the specificity of their nanoparticles.

Solution: Sailor’s group, in collaboration with Sangeeta Bhatia at the Massachusetts Institute of Technology and Erkki Ruoslahti at the Burnham Institute for Medical Research in La Jolla, Calif., came up with a new two-pronged approach to improve specificity of nanoparticles. The first step is injecting a gold nanorod, which accumulates in tumor blood vessels and makes the tumor more sensitive to laser heating than surrounding healthy tissue. The laser heat then changes the chemical composition of the tumors, making them express p32 receptors, a sign that the cells are stressed.

In the second step they injected a different type of nanoparticle—either magnetic nanoworms or liposomes loaded with the cancer chemotherapy drug doxorubicin and decorated with a nine-amino acid peptide called LyP-1, which is known to bind to p32 receptors. The particles were drawn to the tumors more readily when they were heated, and thus chemically altered, than when they weren’t, according to the group’s in vivo mouse studies (PNAS 104:981–86, 2010). “By separating the functions of two nanoparticles we could do better [reducing tumor size] than either of those two alone,” Sailor says.

Considerations: The applicability of gold nanorods for tumor targeting is limited to near-surface tumors like skin cancer, but Bhatia’s group has since found that attaching a substrate for an enzyme found in tumors to the nanorod in the first step keeps it in the body longer and improves its access to tumors.

Cleaving Chitosan

Project: Designing nanoparticles for extended-release drug delivery to the eye

User: Hong-Ru Lin, Professor of Chemical and Materials Engineering, Southern Taiwan University, Tainan

Because of its versatile chemistry, chitosan is an increasingly popular nanoparticle choice for carrying drugs, vaccines, and DNA.

Problem: In 2005, Lin’s group began altering nanoparticle drug carriers in eye drops to treat diseases like glaucoma. They created a nanoparticle containing a combination of chitosan, which is a linear polysaccharide, and polyacrylic acid (PAA). The group found that the drug pilocarpine, an established treatment for glaucoma, takes 315 minutes to clear out of the eye. In contrast, commercial drops containing pilocarpine take 90 minutes (J Biomater Sci Polym Ed 18:205–21, 2007).

But there was one issue with the chitosan-PAA mix when they tested it in a culture dish of tear-like solution and in rabbits: When it hit a physiological pH of 7.4, the nanoparticles tended to precipitate. Lin’s group needed a way to improve the solubility.

Solution: Chitosan is a large molecule, which affects its solubility. When Lin’s group cleaved strings of polysaccharides with a hydrogen peroxide solution, the smaller version of the molecule still bound PAA. An in vivo study showed that the more soluble, modified nanoparticle delivered the drug at the same rate as the nonmodified one.

Lin showed the nanoparticles’ loading efficiency—the percentage of drug that attaches to the nanoparticle—is roughly 70%. “In nanoparticle research, that’s considered high,” Lin says.

Considerations: Because of its versatile chemistry, chitosan is an increasingly popular nanoparticle choice for carrying drugs, vaccines, and DNA. There are several published methods for assembling chitosan nanoparticles. If you’re still running into problems with precipitation, tweak reaction time, hydrogen peroxide concentration or temperature. (Lin used a 2M H2O2 solution, a reaction time of 2 hours, and a reaction temperature of 60 °C.) Higher temperatures degrade the electrostatic bonds within a chitosan molecule, causing an increase in the molecule’s size.

As chitosan–PAA nanoparticles are nontoxic and biodegradable, they can be used for oral delivery. And because the pH of the gastrointestinal tract is lower than the physiological pH, you won’t need to modify chitosan.

Penetrating Mucus

Project: Designing nanocarriers that penetrate human mucus barriers

User: Justin Hanes, Professor of Ophthalmology, Johns Hopkins University, Baltimore, Md.

Problem: Human mucus is about 2000-fold more viscous than water and turns over quickly, making the administration of nanoparticles through the eyes, nose, intestines, and cervix a long-standing challenge in drug development. “When you look at the viscosity, you might think it’s impossible,” says Hanes.

In 2007, his group described a latex nanoparticle that could penetrate the barrier. The key component was its outer coating of polyethylene glycol (PEG), a nontoxic material commonly used in pharmaceuticals (PNAS 104:1482–87). But having solved one problem, they created two others: their inner latex particles could not release drugs, and they are not degraded by the human body.

Human mucus is about 2000-fold more viscous than water.

Solution: Keeping the outer coating of PEG, Hanes’ group developed a new type of inner particle composed largely of polysebacic acid (PSA), which traps therapeutic agents inside. They chose PSA because it has a unique degradation profile that provides steady release that can be tweaked from hours to weeks, and because it is efficient at encapsulating pH-sensitive drugs.

In a recent study, the group showed that the new particles can be loaded with several different cancer drugs, and that a single dose of drug-loaded particles limited tumor growth in a mouse model of lung cancer for up to 30 days (Biomaterials 31:339–44, 2010).

Considerations: Hanes’s group has patented its method, but Hanes says he’s happy to give pointers to researchers who are interested in making their own PSA-PEG nanoparticles. He suggests sticking with low-molecular-weight PEG and applying a thick coat of it. He finds that if the coating is made of high-molecular-weight PEG or if it isn’t sufficiently applied, the nanoparticle will get caught in the mucus.

Read more: Sizing up Nanoparticles – The Scientist – Magazine of the Life Sciences

Pill police: This capsule, which wraps around a standard pill capsule, includes

 a microchip and a tiny antenna etched from silver ink to track when and if the

pill was taken.   Credit: University of Florida

A new smart pill could let doctors know when patients have taken their medicine


MIT Technology Review, April 8, 2010, by Jennifer Chu  –  The medicine cabinet of the future could help make sure patients take their medications on time via a myriad of smart technologies. There are already pill bottles that wirelessly report to a computer when a cap has been opened, and devices for automatically dispensing medicine at the right time, and for reminding patients to take their meds.

Now researchers at the University of Florida have engineered a smart pill with a tiny antenna and microchip that could signal when it has made it into a patient’s stomach–reporting to a cell phone or computer that she has taken her medicine. Their design is the latest of several high-tech pill-reporting efforts to improve patient adherence and provide accurate reporting.

The prototype pill is composed of a standard pill capsule, wrapped in a thin label etched in silver nano-ink, comprising an antenna. The team also outfitted the label with a tiny microchip, which can be loaded with sensors to detect measurements like body temperature or pH levels. Both the antenna and microchip communicate with an external transmitter, which researchers say could be fashioned into a wearable device such as a wristband. The transmitter sends low frequency pulses into the body; the pill’s antenna tunes into the transmitter’s specific frequency, and sends pulses back, along with data collected from the microchip, potentially including the time when the patient ingested the pill, and the type of pill taken.

Daniel Touchette, assistant professor of pharmacy practice at the University of Illinois at Chicago, studies the use of technology to improve patient compliance. “With tuberculosis or mental illness, where you want to make sure they’re taking the meds, this system would make sure people are taking their meds, and potentially cut down on nursing time,” says Touchette, who was not involved in the research.

Such smart pills could also help pharmaceutical companies test new drugs. Currently, the main way companies can keep track of whether subjects take a given drug or placebo is through patient diaries, which can be easily doctored to skew a drug trial’s results. To counter this, companies test the drug on very large populations of subjects in order to get statistically relevant results, which can get expensive.

Rizwan Bashirullah, assistant professor of electrical and computer engineering at the University of Florida, says pills that report back when ingested could significantly improve a drug trial’s accuracy, and potentially cut costs. He and his colleagues have spun off a company, eTect, to further develop the smart pill system and market it to pharmaceutical companies.

“The vision for this would be to create something you could stick on a capsule on a large scale manufacturing basis,” says Bashirullah. “The same way you do a label on a Tylenol pill, we’re envisioning a printing system where they print thousand of pills a second.”

Bashirullah says one big advantage of the smart pill is that it doesn’t require an onboard battery. Instead, the pill’s antenna picks up the transmitter’s low frequency energy. The team has so far tested the smart pill in models that simulate the electrical properties of a human body. They were able to find a low frequency signal that elicited a response from the pill’s antenna within a few milliseconds.

Maysam Ghovanloo, assistant professor of electrical and computer engineering at Georgia Institute of Technology, has designed a similar smart pill that contains a tiny magnet. A magnetic necklace worn by a patient creates a magnetic field only when it detects the magnetized pill in the digestive tract. And a company called Proteus Biomedical has designed a smart pill tagged with a chemical that reacts with stomach acid to produce an electrical signal that can be transmitted to an external receiver.

Ghovanloo says both these competing designs employ relatively passive external receivers. “The burden is on the pill to announce and identify itself,” says Ghovanloo. In contrast, the University of Florida’s design relies more on the external transmitter to send signals, searching for the presence of a pill.

“The question is, how much energy can you store in that wristwatch to be sufficient,” says Ghovanloo. “If they resolve that issue, the advantage would be the simplicity and small size of the pill.”

As a power solution, Bashirullah says the system could be paired with other technologies, such as automated reminders from cellphones that could momentarily turn on the external transmitter to search for the presence of a pill.

“It has to be integrated with other technologies,” says Bashirullah. “There’s certainly going to be power constraints, and that’s something we’re looking at now.”

U.S. Department of Health and Human Services


Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

For Immediate Release: Wednesday, April 7, 2010


The more obese a woman is when she becomes pregnant, the greater the likelihood that she will give birth to an infant with a congenital heart defect, according to a study conducted by researchers at the National Institutes of Health and the New York state Department of Health.

The researchers found that, on average, obesity increases a woman’s chance of having a baby with a heart defect by around 15 percent.  The risk increases with rising obesity. Moderately obese women are 11 percent more likely to have a child with a heart defect, and morbidly obese women are 33 percent more likely.

“The current findings strongly suggest that by losing weight before they become pregnant, obese women may reduce the chances that their infants will be born with heart defects,” said Alan E. Guttmacher, M.D., acting director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH Institute that conducted the study.

Congenital heart defects are the most common type of birth defect, affecting 8 in every 1,000 newborns. ( These defects consist of a number of problems in the structure of the heart and range from minor to life threatening.

Previous studies have shown that maternal obesity during pregnancy is associated with complications for mothers and infants ( Obesity increases the risk for pregnancy-induced hypertension, preeclampsia (a serious form of hypertension during pregnancy), gestational diabetes, and cesarean delivery.  Infants born to women who were obese during pregnancy are themselves at increased risk for overweight and type II diabetes later in life.  Previous research by NICHD scientists and others has also shown an association between maternal obesity and birth defects, such as neural tube defects — serious malformations of the spinal column.  In the United States, 1 in 5 women are obese at the beginning of pregnancy.

The findings were published online in the American Journal of Clinical Nutrition.  The study’s first author was James L. Mills, M.D., M.S., at the NICHD’s Division of Epidemiology, Statistics and Prevention Research.  Other authors of the study were James Troendle, Mary R. Conley and Tonia Carter, also of the Division of Epidemiology, Statistics and Prevention Research, and Charlotte M. Druschel, of the New York State Congenital Malformations Registry.

“The trend is unmistakable: the more obese a woman is, the more likely she is to have had a child with a heart defect,” Dr. Mills said.

Overall, previous studies on maternal obesity and congenital heart defects were inconclusive, with some suggesting a link and others finding no association.

To conduct the current study, the researchers analyzed data in the New York State Congenital Malformations Registry, a repository of case reports on children born with birth defects in New York state, excluding New York City. Using 1.53 million births that took place in the state over the course of 11 years, the researchers compared the records of mothers of 7,392 of children born with major heart defects to those of more than 56,000 mothers of infants born without birth defects.

The researchers calculated the mothers’ body mass index (BMI), a measure of an individual’s proportion of body fat to her height. A normal BMI is 18.5 to 24.9; overweight is 25 to 29.9 and obese is 30 and above.

The obese mothers were 15 percent more likely than mothers with normal BMI to have children with heart defects. Women classified as morbidly obese — with a BMI of 40 or higher — were 33 percent more likely than women with normal BMI to have children with heart defects.

The risk of heart defects increased sharply at a BMI of 30 and was progressively higher with each increase in BMI.

On average, women who were overweight but not obese had no increased risk. However, the researchers saw the chances of having a child with a congenital heart defect increase for obese women, and increase sharply for morbidly obese women.

The study examined records of infants after they had been born and for this reason it cannot conclusively prove that obese women who lose weight before they conceive will reduce their infants’ risks of heart defects.  For conclusive proof, a study would need to enroll obese women who were not yet pregnant, follow those who succeed in losing weight before conceiving, and then determining the frequency of heart defects among the children subsequently born to them.  However, until such a study can be conducted, the researchers believe it is reasonable to assume that attaining a healthy weight before conception will reduce the risk for heart defects.

“If a woman is obese, it makes sense for her to try to lose weight before becoming pregnant,” Dr. Mills said. “Not only will weight loss improve her own health and that of her infant, it is likely to have the added benefit of reducing the infant’s risk for heart defects.”

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.  For more information, visit the Institute’s Web site at <>.


The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <>., April 7, 2010, by Alla Katsnelson  –   As the story goes, the Cambridge-based epigenetic therapeutics company Epizyme was born on a summer California day in 2007, during an annual scientific retreat held by MPM Capital, a life science venture fund.

Each year, the bicoastal investment company hand picks a group of academic scientists to present their work around a chosen theme. That year’s theme was “new modalities for cancer,” and one of the speakers was Yi Zhang, a biochemist and biophysicist at the University of North Carolina at Chapel Hill. He was studying a number of enzymes that modify histones—the protein spools around which DNA winds—and the dysregulation of these enzymes in cancer.

Zhang told the room that it was the start of a new era in drug discovery, and that epigenetic therapies—which target not genes themselves, but enzymes regulating how and when those genes are transcribed—would soon take the drug discovery world by storm. He described the success of a drug called Zolinza, which takes the brakes off silenced genes by inhibiting a type of enzyme called histone deacetylase (HDAC); Zolinza was bought by Merck for an estimated $145 million in 2004, and was approved to treat cutaneous T-cell lymphoma the year before. Other epigenetic enzymes could be targeted to create less toxic and more specific therapies.

There were entire classes of new druggable targets waiting to be discovered, he said, including those in a class he studied, called histone methyltransferases (HMTs), which regulate gene expression by adding methyl groups to selected lysine or arginine residues on histones. His lab had linked two HMT enzymes—EZH2 and hDOT1—to specific solid cancers and leukemia, respectively, and had proof-of-concept data showing that it was possible to interfere with their activity. Cancer “is just the beginning,” he recalls telling the audience that day. “Everything has risks, but if you don’t invest now, if you wait until the whole field becomes mature, you’ll be too late.”

Almost every pharma company has an internal program in epigenetics, or a strong interest in partnering with an epigenetics biotech.

It wasn’t Zhang’s first presentation to venture capitalists. Until then, he’d gotten interest but no real backing; this time, “he brought the house down,” says Kazumi Shiosaki, managing director of MPM and CEO of Epizyme, who was at the retreat. After a few months of intensive meetings, Epizyme launched with the joint backing of MPM and Silicon Valley stalwart Kleiner Perkins Caufield & Byers, raising $14 million in its first round of funding. Last December, the company brought in an additional $40 million in venture capital cash. As a Howard Hughes Medical Institute Investigator, Zhang can’t be in the direct employ of a company, so he is Epizyme’s cofounder and a scientific advisory board member. The company is starting by targeting HMTs.

Company Funding Details
Epizyme (US) $14 million in venture capital funding from MPM and KMPG in 2008; an additional $40 million last December Founded in 2008. Focusing on targets against HMT.
Constellation (US) $32 million in venture capital funding from Third Rock and others in 2008 Founded in 2008. Working on targets against HMT and HDM.
CellCentric (UK) February 2010 licensing deal with Takeda Pharmaceuticals potentially worth more than $200 million Founded in 2004. Developing targets against HMT, HDM and ubiquitin-related enzymes.
EpiTherapeutics (Denmark) DKK 34 million ($6 million) from investors and government grants Founded in 2008. Focusing on targets against HMT and HDM.
Chroma Therapeutics (UK) $53 million in Series C financing, 2006; $23 million in Series D financing, 2009 Founded in 2001. Next-generation HDAC inhibitor for cancer in Phase 1 trials; an undisclosed chromatin target for cancer and other HDAC inhibitors for inflammation in lead optimization.
ValiRX (UK) Publicly traded since 2006 Founded in 2006. Developing diagnostics that recognize cancer-associated epigenetic changes, and two gene-modifying drug compounds in early testing.
Celgene Corporation (US) Publicly traded since 1987 Founded 1986. In 2008 acquired Pharmion, developer of demethylating agent Vidaza, approved in 2004 to treat blood disorders called myelodysplastic syndromes. In 2010 acquired Gloucester Pharmaceuticals, developer of Istodax, an HDAC inhibitor approved in 2009 to treat cutaneous T-cell lymphoma.
MethylGene (Canada) Publicly traded since 2004 Founded 1995. Focus on kinase and HDAC inhibitors; three current HDAC inhibitors in Phase I and Phase 2 testing for cancer, fungal infection, and (in collaboration with EnVivo Pharmaceuticals) neurodegenerative diseases.
Cellzome (UK/Germany) March 2010 deal with GlaxoSmithKline potentially worth $654 million Founded in 2000. Recent interest in epigenetics targeting HDACs and HMTs.

And just as Zhang predicted, less than three years after his speech to MPM, almost every major pharmaceutical company has an internal program in epigenetics, or a strong interest in partnering with a new crop of biotech companies starting to make their mark on the space. This February, a UK company called CellCentric, which works on HMTs, histone demethylases (HDMs, which remove methyl groups from histones), and a third class, ubiquitin-related enzymes, signed the first major pharma licensing deal—potentially worth more than $200 million—to develop compounds for targets beyond HDACs. In March, an Anglo-German company called Cellzome targeting HDACs and HMTs announced a partnership with GlaxoSmithKline with an upfront payment of $45 million, potentially worth $654 million with milestones, using its technology to identify epigenetic drugs for immunoinflammatory diseases.

“I think the speed with which we’ve gotten to the pharmaceutical industry has been very quick,” says Mark Levin, a partner at Boston-based life science investment firm Third Rock Ventures, who helped found Constellation Pharmaceuticals, another Boston epigenetics company that launched with similarly strong venture backing to Epizyme.


Zolinza wasn’t the first FDA-approved epigenetic drug. A few years before, the agency had okayed two others of a different class, chemotherapy agents that also inhibit DNA methylation, to treat blood diseases called myeloplastic syndromes. But the drug has become something of an epigenetics poster child, and paved the way for the field. “I think HDACs have proven that it’s doable [to produce a drug that targets epigenetic processes],” says Will West, CEO of CellCentric. But while several pharma companies and biotechs continue to pursue HDAC inhibitors, only one other HDAC inhibitor, Istodax, developed by Gloucester Pharmaceuticals (acquired by Celgene this year), has been approved since.

“The epigenome regulates transcription, so eventually, epigenetics can be targeted for almost any kind of disease.” —Yi Zhang

HDAC inhibitors have been plagued with toxicity because they target general processes in a cell, such as apoptosis and differentiation. These processes play a special role in tumor cells, but since the drugs aren’t aiming at a specific disease-causing process such as a mutation, they also damage some normal cells, causing significant side effects. Specific HDACs also aren’t known to play a causative role in disease—for example, they don’t seem to be overexpressed in cancer cells, says Kristian Helin, chief scientific officer of EpiTherapeutics, a Danish company founded last year. “There’s no biological evidence that [HDACs] are involved in a particular form of cancer,” he says.

“On the other hand, methyltransferases have amazing specificity,” says Zhang. There are multiple amino acids that become methylated, and each methylation site is regulated by a particular HMT. The hope, he says, is to identify how mutations cause cancer by upregulating specific methyltransferases, and develop compounds to block those specific enzymes. “We have much better genetic evidence” than with HDACs, says Helin, who is also the director of the Biotech Research and Innovation Center at the University of Copenhagen, including accumulating data on how specific HMTs change in specific cancers. “And that means when you work on the chemicals, you know what types of tumors you want to see efficacy in.”

One of the things that got both scientists and investors excited about these targets is that there are multiple classes of enzymes to explore, says Levin, who founded Millennium Pharmaceuticals, one of the first genomics biotechs, in 1993. That means that within a single class, researchers will be able to apply the biology learned about one enzyme to its cousins, which may show more specificity for that disease or others, says Mark Goldsmith, Constellation’s president and CEO. In total, there are about 10 known classes of enzymes that regulate gene expression by modifying histones. Newer, second-generation epigenetics-based biotechs—such as CellCentric, EpiTherapeutics, Epizyme, and Constellation—are largely focusing on HMTs, as well as HDMs. The primary attraction of these classes is that they are large, constituting about 75 enzymes in total, and that there is good evidence for their deregulation in various diseases. “You have to start somewhere, but I have no doubt that this [search] will be expanded to all the classes [of chromatin modifiers],” says Zhang.


So far though, epigenetics companies have explored little beyond cancer. “The epigenome regulates transcription, so eventually, epigenetics can be targeted for almost any kind of disease,” says Zhang. “I think [indications beyond cancer are] still a few years behind, but there is a lot of literature just starting to develop,” agrees Levin.

Despite the field’s optimism, researchers and companies realize how little they still know about pulling therapies out of epigenetics. “There’s a great deal of work to be done to biologically characterize these targets and understand the consequences” of selectively inhibiting gene-modifying enzymes, stresses Goldsmith. It’s hard not to wonder whether the promise of epigenetic drugs is as overhyped as the promise of drugs based on genomics, which have delivered a disappointing yield, concede Levin and other proponents of genomic therapies. The race for epigenetic drugs beyond HDAC inhibitors has barely left the starting line, with most companies still optimizing leads or just entering preclinical testing. Still, says Helin: “A drug takes 10–15 years to develop from scratch. There’s not much you can do about it.”

Read more: An Epic Search – The Scientist – Magazine of the Life Sciences

For decades, scientists studying evolution have relied on fossil records and animal morphology to painstakingly piece together the puzzle of how animals evolved. Today, growing numbers of scientists are using DNA evidence collected from modern animals to look back hundreds of millions of years to a time when animals first began to evolve. One of those leading the charge is molecular biologist Sean Carroll.

Carroll’s research focuses on the way new animal forms have evolved, and his studies of a wide variety of animal species have dramatically changed the face of evolutionary biology. Using genetics and the tools of molecular biology, he is looking back to the dawn of animal life some 600 to 700 million years ago. It is so long ago that there are virtually no fossils or other physical clues to indicate what Earth’s earliest animals were like.

“Evolution encompasses all of biology—it is our big picture,” Carroll said. “When I was a student, we had a grand picture of animal evolution from the fossil record, but no knowledge whatsoever of how new animal forms arose. That is the mystery that I want to tackle.”

Carroll’s studies have uncovered evidence that an ancient common ancestor—a worm-like animal from which most of the world’s animals evolved—had a set of “master” genes to grow appendages, such as legs, arms, claws, fins, and antennas. Moreover, Carroll noted, these genes were operational at least 600 million years ago and are similar in all animals, from humans to vertebrates, insects, and fish. What is different, however, is the way these genes are expressed, leading some animals to develop wings, and others to grow claws or feet.

“We found the same mechanism in all the divisions of the animal kingdom,” Carroll noted. “The architecture varies tremendously, but the genetic instructions are the same and have been preserved for a very long period of time.”

Carroll is also probing the common fruit fly, Drosophila melanogaster, to elucidate how genes control the development and evolution of animal morphology, or form. This innovative approach to studying evolution has led scientists to a more detailed understanding of how animal patterns and diversity evolve.

By analyzing the genetic origin of the decorative spots on a fruit fly wing, Carroll has discovered a molecular mechanism that helps to explain how new patterns emerge. The key appears to lie in specific segments of DNA, rather than genes themselves, that dictate when during development and where on an insect’s body proteins are produced to create spots or other patterns.

The same molecular mechanism is likely at work in other animals, including humans, and helps to explain the pattern of stripes on a zebra or the technicolor tail of the peacock. Carroll and his colleagues chose to study the evolution of the wing spot on fruit flies because it is a simple trait with a well-understood evolutionary history. While ancient fruit fly species lack spots, some species have evolved spots under the pressure of sexual selection. The wing spots offer a survival advantage to males, who depend on the decorations to “impress” females to choose them in the mating process.

The discovery is important because it provides critical evidence of the way that animals evolve new features to improve their chances of reproductive success and survival. “We now have convincing proof that evolution occurs when accidental mutations create features such as spots or stripes that impart an advantage for attracting mates, hiding from or confusing predators, or gaining access to food,” Carroll explained. “These accidents are then preserved as small changes in the DNA.”

Dr. Carroll is also Professor of Molecular Biology, Genetics, and Medical Genetics at the University of Wisconsin–Madison.