The expanding ecosystem of microbiome startups

More funding and another powerful pharma backer have entered the microbiome space, showing that at least some investors and pharma execs believe the field can begin converting preclinical ideas into valid human therapies.

Finch Therapeutics

Somerville, Massachusetts-based Finch Therapeutics announced a new agreement with Takeda Pharmaceuticals on Wednesday, a solid endorsement of its sophisticated bioinformatics platform.

Along with oncology and central nervous system disorders, gastrointestinal diseases are one of Takeda’s three therapeutic pillars. As part of the deal, Takeda will pay an upfront $10 million for exclusive worldwide rights to FIN-524, an investigational drug for ulcerative colitis, and any follow-on products for irritable bowel diseases (IBDs). Ulcerative colitis is a form of IBD in which the immune system attacks the lining of the large intestine.

Finch’s science taps into the high-potential, highly-unpalatable concept of a fecal transplant. It involves transferring a microbiota rich stool sample from a healthy individual into someone with severe gut dysbiosis.

It’s a smart approach, given how little we know about the many thousands of microbial strains that occupy our guts. Instead of adding them to a therapy one-by-one, scientists can take a sample ecosystem that is already known to work. Finch then has a feedback loop in place to determine how patients responded to the different donor cultures.

“By working from clinically annotated datasets of donor and patient microbiota before and after fecal transplantation, we can look for the patterns in changes to the patients’ microbiota associated with targeted clinical outcomes,” said Finch CEO Mark Smith in an email forwarded by a company representative.

It underscores how variable our microbiomes are, whether we’re healthy, sick, or somewhere in between.

Smith cited a 70-patient randomized control trial of fecal transplants performed at McMaster University (Moayyedi et al, 2015). Five donors were used in the study, but just one, Donor B, had a demonstrably large therapeutic effect. Without Donor B, the study would have failed.

Just how much Kombucha was Donor B drinking? And how do we learn from the strength of that participant’s microbiota? Finch is working to answer the latter.

Azitra

While gut bacteria and the microbiome are often used interchangeably, our microscopic citizens really populate our entire body, including the skin. That’s the target for Farmington, Connecticut-based Azitra.

Azitra announced on Wednesday that it had closed a $2.9 million Series A venture round led by Bios Partners. With earlier seed funding, including from Peter Thiel’s Breakout Labs program, the startup has raised $3.75 million to date.

Rather than brewing a complex bacterial concoction, Azitra has identified one key bacteria strain for its lead candidate, AZT-01, to be applied as a cream to affected skin. In its cross-hairs for treatment are eczema, rare genetic skin diseases, and more everyday cosmetic applications such as dry skin.

In an email forwarded by a company representative, Azitra Cofounder and CSO Travis Whitfill said the microbial treatment isn’t just a band-aid — it could address an underlying cause.

“Studies have repeatedly shown that these patients have an imbalanced microbiome, and in the case of eczema, they often have an overgrowth of Staph aureus. There is also evidence that our strain of bacteria can kill some strains of Staph aureus, which is one of the reasons we chose it as a chassis,” Whitfill said.

Applied topically, the good bacteria can colonize the area and begin correcting the dysbiosis.

Photo: spawns, Getty Images

Researchers created a menstrual cycle on a chip, paving the way for innovative cancer research

Researchers from Northwestern produced EVATAR, a modular system designed to replicate hormone signaling in the human menstrual cycle. Photo: Northwestern University Feinberg School of Medicine

Researchers have been looking for better ways to study human biology. Cells in a dish don’t capture the body’s complexity and generally don’t live that long. Recent advances in 3D organoids often fall short on their own. But now, researchers at Northwestern University Feinberg School of Medicine have developed a modular system that incorporates all the necessary organ types to replicate hormone signaling in the human menstrual cycle.

Called EVATAR (a combo of avatar and Eve), the system’s various modules contribute 3D models of human fallopian tube, uterus, cervix, liver and mouse ovary tissue. Microfluidics transfer a universal medium that acts like blood and carries hormonal and other signals between tissues. This communal approach produces a better model.

“They were sharing all this media and releasing factors that were propagating each other,” said Julie Kim, research professor and co-author on the team’s Nature Communications paper in a phone interview. “They survived better and responded to hormones better – more so than if they were alone in a static environment. These different cultures together in this microfluidic platform are able to survive for a whole menstrual cycle, 28 days, which is a long time for cells to grow in culture.”

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The effort pulled in experts on each tissue type – Kim’s lab focused on the uterus. Draper laboratory helped engineer the various connected boxes. Because we don’t take out healthy human ovaries, researchers used mouse ovaries, but even that was a win.

“The mouse estrus cycle is only four days long,” said Kim. “But by putting it in a dish and stimulating with hormones, like FSH and LH, we got 14 days of estrogen and 14 days of progesterone.”

The research led to a lot of firsts, such as new 3D models for uterus and cervix, but it’s the applications that are generating the team’s excitement. EVATAR could enhance their ability to study many conditions, such as fibroids, endometriosis and endometrial cancer.

“If we could study tumors long-term in a microfluidic system, then we could see how tumors respond to progestin and see if we can use these types of platforms as mini clinical trials for compounds that can affect these diseases,” said Kim.

The project was spawned by NIH efforts to create a “body-on-a-chip.” The agency solicited proposals for a variety of tissues – cardiovascular, kidney, bowel – though, according to Kim, reproductive tissue was notably absent. The Northwestern team took that as a source of motivation.

Teresa Woodruff (director of the Women’s Health Research Institute and senior author on the paper) said we need a reproductive tract,” said Kim.

Their work is part of a major push to find better models to study human biology, test drugs for safety and efficacy and ultimately personalize care. Companies like Hµrel, Ascendence Bio and Tissuse have developed organs on chips. Others, like Organovo and BioBots, are creating or enabling 3D tissue printing.

Still, there’s lots more to do. The Northwestern group will be working on a male counterpart to EVATAR and there are other tissues that could improve their female model.

“We have only a couple of cell types in the endometrium,” says Kim. “There are more types that play an important role. If we put in blood vessels, immune cells and other cell types, we could see the tissue differentiate and eventually bleed.”

The DNA of depression: Australia launches 20,000-person genomics study

Why do some people respond to antidepressant medications, while others gain no symptom relief at all?

That’s just one of many million-dollar questions that confound drug developers and healthcare providers working in the field of mental health. The unknowns complicate clinical trials, treatment decisions, and of course, greatly impact patients.

In an effort to shine some light into the gray skies of depression, Australia has launched a 20,000-person genomics study, funded by the government’s National Health and Medical Research Council.

The resulting data and findings will feed into an international study of 200,000 individuals with depression, the largest-ever undertaking in the field.

It’s just what the doctor ordered.

According to a recent report by the World Health Organization (WHO), depression is now the leading cause of disability worldwide. As of 2015, some 322 million individuals were afflicted — roughly the population of the United States. Global prevalence has soared close to 20 percent in the last decade alone.

In a 2014 Nature article, Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, called for a large-scale genomics study of over 100,000 patients to bring the field up to speed.

“Progress in other disorders, such as autism and schizophrenia, suggest that the best hope for insights is to identify specific genetic variants associated with the disease,” Hyman wrote. “However, success in depression will require studies of much larger collections of human DNA samples than in other diseases if statistically significant signals are to come through.”

As part of the Australian study, volunteers 18-years and older will be asked to complete a 15-minute online survey. Based on their responses, they may then be asked to submit a saliva sample for genomic analysis. The sample will be sequenced and screened for hundreds of DNA variants through a process known as ‘genome-wide association scans’ (GWAS). The investigators are particularly interested in patients who have taken medications for the disease.

Genomic studies could unlock information about why some individuals – and families – have a greater likelihood of developing depression. The data could inform new drug development and ensure the right patients are recruited into the right trials.

It could also help explain the variable response individuals have to antidepressant medications — a burgeoning field known as pharmacogenomics. Such tests help guide what therapies and doses may work best.

Mayo Clinic startup OneOme has a panel that includes information on what psychotropic drugs, including antidepressants, could be well-tolerated based on the individual’s genetic makeup. Several genes relate to antidepressant efficacy, including HTR2A/GRIK4 and SLC6A4.

“There is a clear need in the psychiatric space for objective biomarkers that allow healthcare providers to tailor treatment – and that’s where pharmacogenomics comes in,” said OneOme CEO Paul Owens in an email forwarded by a company representative. “Since genetic factors account for up to 95 percent of drug-response variability, pharmacogenomics can help physicians identify which psychiatric drugs may work best for individual patients, before they even take them.”

While pharmacogenomics holds wide potential, a lot more information is needed to effectively treat mental illnesses the first time around. Owen also noted that the medical community has been slow to capitalize on the knowledge that does exist.

“Unfortunately, the education and understanding of genomics – let alone pharmacogenomics in routine medical practice – is still in its infancy stage,” he said.

There is a long way to go, but a 200,000-person genomics study is a good place to start. As Hyman wrote in nature, a basic understanding of the biology is still lacking.

“Failures to improve efficacy reflect continued ignorance of the molecular mechanisms of depression,” he said, then noted later on; “The investments will be well worth it.”

Photo: phototechno, Getty Images

Biden at AACR: “What a difference a year makes”

Former U.S. Vice President Joe Biden speaks at a signing ceremony for the 21st Century Cures Act  

Former Vice President Joe Biden took the stage at the American Association for Cancer Research (AACR) annual meeting on Monday, with a speech titled ‘The Beau Biden Cancer Moonshot: Progress and Promise.

“What a difference a year makes,” he said in his opening remarks, streamed live by AACR.

Some 15 months after the Cancer Moonshot’s launch and one year after his first AACR keynote speech, there was a lot to report back to the Washington, D.C., crowd. What a difference a year makes, indeed.

There’s a movement.

Biden is not the leader of the cancer moonshot. He’s the inspiration.

“Look, I don’t have the answers,” he said. “But you all possess the potential to generate these answers.”

Trained as a lawyer, Biden educated himself about cancer after his son, Beau, was diagnosed with a brain tumor. He later passed away. That experience didn’t give him the expertise to navigate medicine’s way to a cure. It made him passionate about it, in a way that he can serve as a focal point for the necessary people to come together.

Silicon Valley showed up, politicians on both sides of the aisle, and Nobel laureates.

“I got a call from the chairman of the board of IBM,” Biden said. “Did I want Watson, the supercomputer, to partner with the department of defense and the VA?” 

With unprecedented data sharing and collaboration, the National Cancer Institutes launched the Genomic Data Commons to pool the information garnered through The Cancer Genome Atlas (TCGA), a database of 14,000 individuals’ genomic and health records. It has now expanded to 30,000 genomes.

Amazon called, Biden said, and agreed to open its cloud-computing platform for scientists using these massive databases. Since June, the data has been accessed 80 million times by researchers around the world.

Public support has been overwhelming. There is hope once again.

“You’ve lighted a fire under the public,” he said. “They’re beginning to believe again.”

There’s a cultural shift.

“For decades, we thought we could tackle cancer one discipline at a time,” Biden told the audience of cancer experts.

It’s not enough. Cancer uses every tool, system, and pathway at its disposal. The science community needs to meet each of those mechanisms head on, by uniting immunologists, virologists, geneticists, data scientists, chemical, biological and computer engineers and more. That’s happening, Biden said. The age of individual achievements in science is over.

Since its launch, the Cancer Moonshot has seeded at least 80 new collaborations. Many government-related projects have begun, he said, bringing together unlikely partnerships between the likes of NASA and the Department of Veterans Affairs.

There’s success in Washington.

In December, Congress passed the 21st Century Cures Act, which authorized an additional $6.3 billion in funding over seven years for health-related research, including $1.8 billion earmarked for cancer specifically.

Biden had the privilege to preside over the Cures Act, he said, which achieved remarkable bipartisan support.

With the passing of the Act, Republican Senator Mitch McConnell stood up to propose that the cancer initiative takes the name of Biden’s late son. The Beau Biden Cancer Moonshot.

“Those things don’t happen very much these days,” he recalled with a lot of emotion in his voice. “There is genuine, genuine bipartisan support.”

By this stage, the speech was starting to speak to something much more than the Cancer Moonshot. Late in the Obama administration, both sides had come together to pass something worthwhile.

“This is what [the American people] expect their government to do,” Biden said.

Oh, what a difference a year makes.

One year on, President Trump has taken the White House and is outlining major cuts to the NIH, the EPA — to the entire scientific field.

“The message sent out a few weeks ago in the President’s budget is counter to this hope and the progress we’ve made,” the 47th vice president of the United States told the audience.

He didn’t hold back.

“On the cusp of saving and extending lives for Americans, the President of the United States is not only not doubling-down on our investment, he’s proposing Draconian cuts.”

Funding would be set back 15 years, Biden said. By one estimate, new grant funding would be cut by 90 percent, given the multi-year commitments that the NIH has already made.

The ex-VP doesn’t believe the budget blueprint will pass Congress. However, the message it sends has already done a world of harm, communicating that science is not valued or worthy in the United States.

What a difference a year makes.

For Biden, the Cancer Moonshot was always about two things. It needed to inject urgency into the biomedical march towards a cure while also shifting the culture towards more collaboration, passion, and hope.

“You can not turn back the clock,” he said.

Not on his watch anyway.

Photo: MANDEL NGAN, AFP/Getty Images

All things new: Gritstone Oncology unveils its cancer vaccine roadmap at AACR

Gritstone Oncology splashed onto the scene in late-2015, with a $102 million Series A that hinted at some lofty goals for cancer immunotherapy.

Some 18-months later, the team is presenting the first of its data in a poster session at the American Association for Cancer Research (AACR) annual meeting, which kicked off in Washington, D.C., on Saturday.

It’s the company’s first big reveal. So what have they got?

Enough to shoot for an IND filing and human trials in the middle of next year, said Cofounder, President, and CEO Andrew Allen.

The poster outlines three concepts, each with supporting data. Combined, Allen said they close the loop on what the company is trying to achieve: A model for predicting tumor-specific neoantigens that can be used to trigger a robust T-cell immunotherapy response. The initial target is lung cancer.

What does that all mean?

Like Neon Therapeutics and The Parker Institute for Cancer Immunotherapy, Gritstone is targeting neoantigens. These are mutations that arise “de novo” in a given cancer — they’re not otherwise found in the human genome.

As an immunotherapy target, they offer two major benefits: They’re foreign to the immune system and they’re not found in healthy tissue.

By comparison, traditional lung cancer targets such as ALK or EGFR have been present in the body since early development. They may be overexpressed in cancer cells, but the immune system has over time learned to tolerate them as “self.” That’s not a good platform for triggering a T-cell attack. Conversely, if the immune system was activated against those receptors, some healthy tissue would be hit.

Neoantigens are next-level personalized medicine, with next-level logistical challenges.

Predicting cancer neoantigens

Given the recurrent failures in cancer vaccine development, Gritstone is taking a two-pronged approach that verifies that specific neoantigens are truly being expressed on cancer cells.

“For success here, you’ve got to do two things well,” Allen said. “You’ve got to predict neoantigens well because that’s a big part of the problem. And then you’ve got to deliver them in a way that is going to drive large numbers of highly active T-cells.”

The first half of the puzzle is being pieced together by a team of around twenty, working in a facility in Cambridge, Massachusetts. The resulting data also make up the first findings in Gritstone’s AACR poster. The company asked whether the predictive modeling can be out-sourced.

Lung cancer has a high mutational burden, Allen explained — there are on average around 300 genomic changes. Of those, only around 1 percent will be truly novel neoantigens. It’s a drop in the ocean that is easily missed when a generalized approach to tumor profiling is deployed. Third-party labs that look for standard receptor targets typically omit between 20-25 percent of the mutations, Allen said. In some patients, 50-60 percent of the mutations are lost. Scientists need better data to build a cancer vaccine that works.

Zooming in on lung cancer, the Cambridge crew have extensively characterized hundreds of real tumor samples using DNA and RNA sequencing, mass spectrometry and deep learning.

Deep learning fast-tracks the process and removes the limitations of current thinking, Allen explained. It’s pure mathematics: it doesn’t apply the researcher’s biases and hypothesis and it’s not limited by our imagination.

“You’re saying, let me look for associations in a completely unconstrained way,” he said.

Those associations are then iteratively tested, to be rejected or strengthened. It eventually leads to a model that can predict from the sequence alone, which of those mutations will create peptides or antigens that will be presented on the tumor cell surface.

Andrew Allen, cofounder, president and CEO of Gritstone Oncology

Andrew Allen, cofounder, president and CEO of Gritstone Oncology

“Our estimate, when we test ourselves on fresh data, is that we’re operating at something like ten-fold better than the public domain approach that many of our competitors are using,” Allen said.

Therein lies the second segment of findings in the AACR poster, which asked if Gritstone’s in-house approach is effective. It seems it is. In the future, its scientists can sequence fresh tumor biopsies to accurately predict what mutated peptides could be targeted.

Rallying the immune response

The second challenge with cancer vaccines is learning how to weaponize the neoantigens to ensure the immune response doesn’t fall flat.

“Our model doesn’t necessarily predict antigens, it predicts whether a peptide will be presented by an HLA class 1 molecule on the cell surface,” Allen noted. “To be an antigen, you also have to stimulate a T-cell response.”

A West Coast team of around 30 is working on this problem in Gritstone’s headquarters in Emeryville, California.

Lessons on how to make a successful cancer vaccine, Allen said, could not be found in the cancer vaccine field. Not a lot has worked. Instead, Gritstone looked to the field of infectious diseases. Certain viruses, such as Malaria, are able to bury themselves deep within cells, he said. That necessitates a robust CD8 T-cell response — the kind Gritstone is hoping to produce.

“What was striking to us was that so many people were using viruses as a vector for delivering the antigens, in order to get these really effective T-cell responses. And so that’s the path that we’ve pursued,” he explained. 

It led to the third component of the poster. The company took the isolated peptides and some HLA-matched T-cells and asked; can they prime a T-cell response to a given neoantigen in vitro. Can they show that it does register an immune response?

They could.

“So that’s really closing the loop and obviously suggesting that, were this to be a patient that we were predicting and making a vaccine,” Allen said. “We have identified an antigen that should in principle be able to make good T-cells in response to the vaccine that may have the potential to kill the tumor.”

The company can connect a DNA mutation to an altered protein and show that it is processed and presented as an altered peptide. Gritstone may be the first to connect those dots in lung cancer, he said.

An eventual vaccine would be given in combination with an immune modulator, such as a PD-1 inhibitor , setting the immune system up for an optimal anti-tumor response.

It’s all theory for now, but Gritstone’s integrated use of deep learning and bioinformatics is broadening the basic theories the human mind can generate.

Photo: Esben_H, Getty Images

Why is clinical research so messed up and how can it be fixed?

From left: Dr. Michael Kolodziej of Flatiron Health, Dr. Gregg Shepard of Tennessee Oncology, Dr. James Hamrick of Flatiron Health, Dr. Cary Presant of City of Hope Medical Center, Melissa Pool of the Center for Cancer and Blood Disorders

Dr. Michael Kolodziej was set to moderate a talk on developing a new infrastructure for conducting clinical trials with cancer patients. Instead, the former lead of Aetna’s oncology program and currently national medical director for New York-based health IT company Flatiron Health took his seat, looked at the panel, and then announced to the crowd he was renaming the talk.

“Why is clinical research so messed up?” he asked. “And how can we fix it?”

Kolodziej’s made his presentation, which included four other oncology experts, during the Association of Community Cancer Center’s 43rd annual meeting in Washington D.C. this week. But the reason for changing the name of this talk to the two questions Kolodziej asked quickly became apparent to the audience. After all, there’s no point in talking about a new infrastructure for clinical trials without first tackling their current troubles.

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Narrow eligibility criteria, financial feasibility, and the impediment of sheer geography are three problems that repeatedly reared their heads during the 45-minute discussion.

For Melissa Pool, a registered nurse and clinical research director at the Center for Cancer and Blood Disorders near Dallas, the geography angle was an early sticking point, especially in a state that’s as large as Texas.

“The difficulties we have are getting clinical trials out to rural communities,” she said.

Dr. Cary Presant of the City of Hope Medical Center near Los Angeles, Calif., added that part of the current challenge of conducting clinical trials is just finding appropriate trials workable at particular community sites. Presant’s group currently has about four sites with two staff at each prepared to do clinical trials. But financial feasibility remains a question in a way it isn’t for a hospital or large medical center that has the full-time staff and the resources to conduct trials.

“We find that the amount of discretionary funds to be able to do clinical trials is rapidly diminishing,” Presant said. “Unless you have a large practice, clinical trials might be a loss leader.”

There’s also something to be said about finding the perceived “perfect patient” to participate oncological trials.

“At the point of care of enrolling patients, the number one barrier is the availability of a trial to fit that patient and narrow eligibility criteria,” said Dr. Gregg Shepard of Tennessee Oncology, a large oncology group with about 100 physicians.

Of course, the whole point of conducting clinical trials is to test the efficacy of new drugs or treatments, which might be a boon to cancer patients willing to take risks in the course of their treatment programs.

But it’s often more difficult to enroll most cancer patients in clinical trials. Present said many drug companies want patients without comorbidities or without prior cancer. Most cancer patients do have comorbidities that they are treating in tandem with their cancer.

The overarching problem, it seems, is that clinical trials in their current state aren’t exactly representative of the population of people in the U.S. who have cancer.

Where there does appear to be some hope for the future of clinical trials is in the continuing digitization of health, something that Dr. James Hamrick, a practicing physician with Kaiser Permanente Georgia and senior medical director for Flatiron Health touched on. The data that doctors enter at the point of care, the routine that goes into all cancer patient encounters, can be harnessed to guide clinical trials. This can be done in a retrospective way — by gathering patient data in the aggregate, and then analyzing it to get a real-time, big-picture sense of cancer care in the U.S. It can also be done in a prospective way, by using the data to inform whether eligibility criteria of future trials should be loosened.

“It’s one of the promises of the digitization of healthcare,” Hamrick said. “It’s also part of the implicit bargain we make with patients when we click away on computers in the exam room with patients. There’s an assumption that the data we’re putting into the computer is going somewhere and being used to help other cancer patients.”

Using medical data will never replace the randomized clinical trial, Hamrick said. But with data, doctors in the future can stay one step ahead of trials by understanding who among their patients would be eligible for them. In a talk filled with important examinations of problems, the angle on healthcare data provided a spot of hope for reforming how clinical trials are done in the future.

Photo: From left: Dr. Michael Kolodziej of Flatiron Health, Dr. Gregg Shepard of Tennessee Oncology, Dr. James Hamrick of Kaiser Permanente, Dr. Cary Presant of City of Hope Medical Center, Melissa Pool of the Center for Cancer and Blood Disorders

Photo: Andrew Zaleski

Gore joins ViaCyte’s quest for a functional type 1 diabetes cure

A cure for type 1 diabetes has been “just around the corner” for decades now — or so patients have been told. But the moonshot mission has been rough.

ViaCyte knows this well after years 18 years of R&D. With every step of progress, a new mountain of challenges looms. The company puts its head down and troubleshoots through, with backing from private investors, pharma partners, the California Institute for Regenerative Medicine (CIRM) and the Juvenile Diabetes Research Fund (JDRF).

On Wednesday, the San Diego, California-based company announced a new partner; W. L. Gore & Associates, the multi-billion dollar manufacturer of medical and non-medical fabrics and devices, including the iconic GORE-TEX. If Gore can contribute some materials expertise, one more problem could get solved.

The partnership centers around ViaCyte’s flagship islet replacement therapy. 

Type 1 diabetes (aka juvenile diabetes) is an autoimmune disease. It accounts for around 5 percent of all diabetes cases. Some 95 percent are caused by so-called adult-onset diabetes, which is a longer-term metabolic disorder.

While genetic and environmental factors are believed to play a role, the ultimate trigger for type 1 diabetes is not known. At some point, the immune system incorrectly recognizes beta cells in the pancreas as foreign or threatening. It begins systematically destroying them and with that, the ability of the body to produce insulin.

Insulin is the key that allows glucose to enter cells. Without insulin, glucose builds up in the bloodstream while cells are effectively being starved. For decades, patients have replaced the missing insulin with a synthetic version. Yet dosing is problematic. Too little insulin and the blood glucose levels rise; too little and the patient becomes hypoglycemic — a potentially fatal condition if the individual isn’t revived with a readily available source of sugar.

Patients must manage this life or death balancing act for the remainder of their days.

ViaCyte hopes to remove the uncertainty with its PEC-Encap combination product. It comprises PEC-01 pancreatic progenitor (stem cell precursor) cells packaged in an immune-protective device called the Encaptra Cell Delivery System. 

Once implanted under the skin, the PEC-01 cells further mature into insulin-producing ‘islets’ — beta cells included.  Blood can flow in and out of the device, allowing the cells to register blood glucose in real time and produce an appropriate amount of insulin in response. 

To preserve the biological package, ViaCyte has been fine-tuning its transplant device, which CEO Paul Laikind likens to a tea bag.

“In the case of PEC-Encap it’s a semi-permeable membrane that is really the active component of the device,” Laikind said in a phone interview. “That membrane is sized such that oxygen, nutrients, glucose, and even proteins can move freely back and forth across the membrane surface. But it is also sized such that cells cannot. So none of the immune cells of the host are able to penetrate and communicate with the cells inside, so to speak, or directly access the cells in the device. And none of the cells inside the device are able to exit.”

That separation is critical for staving off the two-pronged immune response waiting to neutralize the cells.

Once triggered, the immune system of diabetes patients will forever be geared towards destroying beta cells. That’s the autoimmune component. The second issue is the natural immune rejection that occurs when cells or tissues containing foreign DNA are introduced into a transplant patient. ViaCyte uses stem cells derived from an embryo, which triggers this kind of reaction.

Finding a balance between cell preservation and efficacy is hard. According to Laikind, ViaCyte had progressed into Phase 1/2 trials with the PEC-Encap, but after treating around 20 patients it identified an issue with vascularization.

The membrane doesn’t allow the components of blood vessels to pass through — they’re too big. Yet the cells need nutrients and oxygen to survive.

“When it engrafts, what we need is that vascular network to set down on the outside of the device,” Laikind said.

That’s why Gore’s expertise in medical devices is needed.

Another product being forwarded by the ViaCyte is a straight transplant of insulin-producing cells. The patient would need to take immune-suppressing medications indefinitely to protect the introduced cells. According to Laikind, the side effect profile of this approach is better suited to patients who struggle to maintain stable blood glucose levels or for the 10-40 percent of patients who have hypoglycemia unawareness. In the latter cases, the individuals are unaware their blood sugar is dropping and thus, can’t halt their descent into hypoglycemia.

Beyond ViaCyte, other companies are attempting to break into the field.

Novo Nordisk, the world’s largest manufacturer of diabetes drugs, has signaled its intent to move into stem cell therapies. Another company, Semma Therapeutics, is eying up clinical trials, having developed a method for efficiently producing beta cells en masse.

Both are several steps behind ViaCyte, which is a blessing and a curse for the San Diego team. The company has raised millions as the flag bearer for a lasting therapy for type 1 diabetes. But it is also the first to encounter unforeseen challenges in the field. It’s those challenges that continue to stall any chance of a cure. For now, at least.

Photo: Hero Images, Getty Images

Some of the most exciting (and scary) aspects of machine learning that you may not know about

The decibel of chatter around artificial intelligence is rising to the point where many are inclined to dismiss it as hype. It’s unfair because while certain aspects of the technology are a long way away from becoming mainstream tech, like self-driving cars, it’s a fascinating topic. After listening to a talk recently by Dr. Eric Horvitz, Microsoft Research managing director, I can appreciate that the number of applications being conceived around the technology is only matched by the ethical dilemmas surrounding it. But in both cases, they are much more varied than what typically dominates the conversation about AI.

For fans of the ethical roads less traveled in AI, Horvitz offered a fair few items for his audience to consider at the SXSW conference last week that alternated between hope for the human condition and fear for it. Although I previously highlighted some of the healthcare applications he discussed, there are plenty of issues he raised that one day could be just as relevant to healthcare. I have included a few of them here.

Interpreting facial expressions

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The idea of machine learning being applied to make people more connected to each other improve in subtle ways our communication skills is fascinating to me. One example used was a blind man conducting a meeting and receiving auditory cues on the facial expressions of his audience. The idea is to provide more insight on the people around him so he can have a better sense of how the points he raised are perceived beyond what the people in the meeting actually say. In a practical way, it gives him an additional layer of knowledge he wouldn’t have otherwise and makes him feel more connected to others.

The ethical decisions of self-driving cars

As exciting as the prospect of self-driving cars is, Horvitz called attention to some of the still unresolved, important questions of how they would perform in an accident or when trying to avoid an accident. What decisions would the computer make when, say a collision with a pedestrian is likely and the car has to make a split-second choice? Does it preserve the life of the driver or the pedestrian, if it comes to that?  What responsibility does the manufacturer have?  What values will be embedded in the system? How should manufacturers disclose this information?

Horvitz slide

A slide that was part of Dr. Eric Horvitz’s talk at SXSW this year.

Adversarial machine learning

One fascinating topic addressed in the talk was how machine learning could be used with negative intent —referred to as adversarial machine learning. It involves feeding a computer information that changes how it interprets images, words, and how it processes information. In one study, a computer that was fed images of a stop sign could be retained to interpret those images as a yield sign. That has important implications for self-driving cars and automated tasks in other sectors.

Another facet of adversarial machine learning is the use of information tracking individuals’ Web searches, likes and dislikes shared in social networks and the kinds of content they tend to click on and using that information to manipulate these people. That could cover a wide swathe of misdeeds from manipulation through fake Tweets designed by neural networks in the personality of the account holder to particularly nasty phishing attacks. Horvitz noted that these AI attacks on human minds will be an important issue in our lifetime.

“We’re talking about technologies that will touch us in much more intimate ways because they are the technologies of intellect,” Horvitz said.

Appling AI to judicial sentencing software

Although machine learning for clinical decision support tools is an area of interest in healthcare to help identify patients at risk of readmission or to analyze medical images for patterns and anomalies, it’s also entering the realm of judicial sentencing. The concern is that these software tools that some states permit judges to use in determining sentencing include the bias of their human creators and further erode confidence in the legal system. ProPublica drew attention to the issue last year.

Wrestling with ethical issues and challenges of AI

Although he likened the stage of AI development to the first airplane flight by the Wright Brothers at Kittyhawk, North Carolina which was 20 feet off the ground and lasted all of 12 seconds. But the risk and challenge of many technologies is that a certain point it can progress far faster than anyone can anticipate. This is why there’s been a push to wrestle with the ethical issues of AI rather than address them after the fact in a reactive way, such as Partnership on AI. Eight years ago, Stanford University set up AI100, an initiative to study AI for the next 100 years. The idea is that the group will study and anticipate how the effects of artificial intelligence will impact every aspect of how people work and live.

Photo: Andrzej Wojcicki, Getty Images

Google’s life-prolonging moonshot Calico partners with C4 Therapeutics

If you haven’t heard of Calico, that’s by design. The mysterious biotech spun out of Google (now Alphabet) in 2013, with a mission to unravel the biological mechanisms of aging.

C4 Therapeutics, on the other hand, is focused on protein degradation. Its aim is to develop therapies “for patients with life-threatening and life-impairing conditions.”

On Thursday, the two companies announced a five-year collaboration to move possible age- and/or cancer-related therapies into the clinic.

The joint statement was the first mention of ‘aging’ on C4T’s website. Why does that matter? It offers insight into how Calico – aka the California Life Company – plans to realize its moonshot mission.

In a nutshell, there’s no miracle elixir on the horizon. The idea is to prevent disease, not prolong life. That will a require an ongoing series of medical “interventions,” the term used on the company’s website. Based on Calico’s previous agreement with the personal genetics company AncestryDNA, it looks like the interventions will also be highly personalized.

Protein degradation fits in as a tool for prolonging death from diseases such as cancer.

In an email forwarded by a company representative, C4T President and CSO Andrew Phillips said Calico contacted the company in 2016 to discuss a partnership. As part of the agreement, C4T will contribute its expertise to the discovery and validation of small molecule “protein degraders” that can reduce disease-causing proteins in the body.

How central is protein production to the maintenance of human health? Very, Phillips said.

“Overall homeostasis of proteins (the balance of protein synthesis and protein degradation) is of great importance to normal health. In some cases, an excess of a protein can be central to disease (e.g. overexpression of an oncogenic protein) and in other cases, erroneous protein degradation can result in disease (e.g. the teratogenic effects of thalidomide.) Many neurodegenerative disorders also provide examples of misbalanced synthesis and degradation of proteins.”

It’s also notable that the contract clearly separates the research and discovery obligations (C4T), from the clinical development and any possible commercialization, which would be handled by Calico.

Even as a series of interventions, proving a therapy or therapies can slow aging or increase lifespans is a battle unto itself. Calico’s all-star cast of scientists from the fields of medicine, drug development, molecular biology, genetics, and computational biology, will all be needed to develop any possible drugs and chart a clinical course forward.

It’s a big undertaking, but they don’t plan to do it alone. The bulk of the content on the company’s scant website is dedicated to future collaborations.

“We are most interested in external opportunities at the research and early development stage within these areas of focus,” it reads, highlighting conditions that often occur alongside aging: oncology, neurodegeneration, chronic inflammation and metabolic dysfunction.

“We also believe that, in some cases, programs focused on patients with rare diseases may present unique opportunities to explore aging biology in the context of therapeutic development,” the website states.

Along with C4T, deals have been hashed out with QB3, the Broad Institute, AbbVie2M and the Buck Institute for Research on Aging. Each represents a small puzzle piece that adds to an incomplete picture of how Calico plans to realize its moonshot.

Photo: John Sullivan, Getty Images 

Here’s the latest entrant in the Internet of Things in healthcare market

The Breg Flex sensor device and mobile app for remote virtual rehabilitation

Physical therapy is a big part of orthopedic care, and as the era of bundled payments take hold, albeit with a pause here and there, virtual rehab is poised to take off.

Traditional widget makers are sensing an opportunity in this trend. Take Breg, the sports medicine manufacturer and distributor based in Carlsbad, California.

At the recently-concluded annual meeting of the American Academy of Orthpaedic Surgeons (AAOS), Breg executives were showing off a new sensor-device connected to a mobile app that can guide patients through their daily exercise routine following orthopedic surgery.

This is the first time the company has forayed into the digital health, Internet of Things space, confirmed Brad Lee, president and CEO, in a booth interview last week where demos of the Breg Flex system were being presented. Lee said the impetus for the product dates back seven years ago when the company underwent a strategic shift.

“Rather than focusing on the widgets we provide to an orthopedic caregiver, [we wanted to] focus on managing the pain points in their world in the orthopedic episode,” Lee said.

As providers are moving to a value-based system in healthcare, accelerated by alternative payment models especially in joint replacement, hospitals have scrambled to understand where you can take costs out. Everyone has landed squarely on post-acute care — once the joint replacement procedure is complete. One item on the cost chopping block is physical therapy.

“We are actively moving toward online physical therapy programs and our goal is to eliminate physical therapy for hips, only use in knees when we need it …,” said Richard Iorio, a hip and knee surgeon at NYU Langone Medical Center, at a panel discussion on orthopedic bundled payments last week at AAOS.

And that’s exactly where Breg’s Flex system fits in.

“This product Flex was developed for the post-surgical rehabilitation segment of the episode.”

Here’s what the product incorporates: A chargeable Bluetooth wireless sensor, worn by patients to track progress with prescribed PT exercises with a companion mobile app.

The sensor and app work in concert to record range-of-motion that is key to better clinical outcomes. The data is also shared in real time with providers such that clinicians can tweak exercise protocols. The interactive patient app has a virtual avatar that guides patients through exercises. The system can also collect patient-reported outcomes that are key to getting reimbursed for certain orthopedic procedures such as joint replacement under bundled care programs.

Lee explained that Breg Flex also works with the electronic medical record of a practice or a hospital.

“The entire recording of the rehabilitation episode is now documented in the patient’s history seamlessly,” he added.

Breg Flex is FDA-exempt because it simply monitors and tracks and does not offer clinical decision support.

In that context, the device is different from other virtual rehab programs on the market such as Reflexion Health’s Vera virtual rehab program. The San Diego-based company uses the Microsoft Kinect gaming console and the Vera avatar to guide patients through their at-home exercise regimen. The system received FDA clearance in 2015.

But like Breg, other companies also seem to feel that FDA clearance to use a digital product for remote physical therapy is not needed. Zimmer-Biomet, the Indiana company that holds the largest market share in hip and knee replacements acquired the RespondWell virtual rehab program that is also not FDA-cleared.

Aside from regulatory clearance that distinguishes companies in the field, another characteristic serves as a point of distinction. Companies like Jintronics and Reflexion Health use the Kinect platform thereby tying joint replacement patients to a console or a TV to do their daily rehab. All Breg Flex needs is a cell phone, or tablet and a sensor-device.

“We are measuring range of motion in the rehab process with a high degree of accuracy in a remote location that doesn’t require to be tethered to any other technology except the sensors on your knee and a phone, which is not a huge burden,” Lee said.

In other words, patients can be out and about, and still get their rehab done.

While that may be a distinguishing factor, the virtual rehab space is getting crowded with several companies vying to win. But Breg’s CEO shrugged it off.

“There is a huge market and there will be a lot of good players in the space,” he said.

Photo: Breg Inc.