Andrei Osterman Archives - Sanford Burnham Prebys

Tag: Andrei Osterman

Institute News

Gut microbiome repair in children with severe acute malnutrition

AuthorScott LaFee
Date

October 2, 2024

child being spoon fed with family in background

Child malnutrition remains an alarming and appalling scourge.

In 2022, according to the World Health Organization, 148 million children in the world under 5 years were too short for their age (stunting) and another 45 million were too thin for their height (wasting) due to inadequate diet and nutrition.

Researchers around the world, including Andrei L. Osterman, PhD, professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys, have been investigating potential remedies, in particular some of the consequences of malnutrition, such as disturbed metabolism and immune/gut function.

In a new paper published October 2, 2024 in Science Translational Medicine, the multi-institutional team (including Osterman and colleagues at SBP) describe an interventional diet that essentially repairs the gut microbiome in children with moderate to severe acute malnutrition.

They conducted a three-month randomized controlled trial of a specialized food supplement in 12- to 18-month-old Bangladeshi children living in rural and urban slums with moderate acute malnutrition who had already been treated in hospital for severe acute malnutrition. The supplement, called microbiota-directed complementary food or MDCF-2, contains chickpea flour, peanut flour, soy flour, green banana, sugar, soybean oil and a vitamin-mineral premix, a formulation designed to promote the growth of therapeutic gut bacteria and improve the overall health and balance of the gut microbiome.

They found that MDCF-2 improved weight-for-age better than the traditional ready-to-use supplementary food (RUSF) used by relief agencies and others, which is composed of more traditional ingredients like rice, lentil, sugar, soybean oil and skimmed milk powder mixed with vitamins and minerals.

When excluding children unable to continue study participation due to severe flooding during the trial, the study authors also reported improvement of stunting at a faster rate. They tied these improvements in children’s health to Prevotella copri–associated metabolic changes.

P. copri (recently renamed as Segatella copri) is a bacterium found abundantly in the human gastrointestinal microbiome. Past studies have reported both positive and negative associations with health and disease. In the former, for example, healthy bacterial colonization of the gut has been positively correlated with conditions like inflammation, insulin resistance and diarrhea. It appears to be a major player in regulating dietary metabolism.

The bacterium is more common in non-Westernized populations consuming a diet rich in plants—the bacterium’s source of nutrients. In Western populations, it is associated with consumption of fruits and vegetables.

Genomic reconstruction of the metabolic potential of P. copri strains positively associated with infants’ health improvement confirmed their unique ability to utilize a large repertoire of plant-derived polysaccharides comprising MDCF-2 diet.

“This study can be viewed as a test of the generalizability of the efficacy and mechanism of action of MDCF-2 in acutely malnourished children,” said Osterman. “The main findings include the demonstration of significantly higher efficacy of MDCF-2 vs RUSF with respect to the improvement of (weight) growth.

“The success of the treatment was also manifest by beneficial changes in microbiome composition and by global changes of a range of serum protein biomarkers associated with healthy development.”

The findings, he said, also provide proof-of-concept that improving gut microbial health can be achieved using therapeutic nutrition and offers further guidance on how best to use microbiota-directed complementary foods.

Institute News

Dodging AI and other computational biology dangers

AuthorGreg Calhoun
Date

August 13, 2024

Programming in a Petri Dish - AI series graphic

Sanford Burnham Prebys scientists say that understanding the potential pitfalls of using artificial intelligence and computational biology techniques in biomedical research helps maximize benefits while minimizing concerns

ChatGPT, an artificial intelligence (AI) “chatbot” that can understand and generate human language, steals most headlines related to AI along with the rising concerns about using AI tools to create false “deepfake” images, audio and video that appear convincingly real.

But scientific applications of AI and other computational biology methods are gaining a greater share of the spotlight as research teams successfully employ these techniques to make new discoveries such as predicting how patients will respond to cancer drugs.

AI and computational biology have proven to be boons to scientists searching for patterns in massive datasets, but some researchers are raising alarms about how AI and other computational tools are developed and used.

“We cannot just purely trust AI,” says Yu Xin (Will) Wang, PhD, assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys. “You need to understand its limitations, what it’s able to do and what it’s not able to do. Probably one of the simplest examples would be people asking ChatGPT about current events as they happen.”

(ChatGPT has access only to news information up to certain cutoff dates based on the training set of websites and other information used for the most current version. Thus, its awareness of current events is not necessarily current.)

“I see a misconception where some people think that AI is so intelligent that you can just throw data at an AI model and it will figure it all out by itself,” says Andrei Osterman, PhD, vice dean and associate dean of curriculum for the Graduate School of Biomedical Sciences and professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys.

Yu Xin (Will) Wang, PhD

Yu Xin (Will) Wang, PhD, is an assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys.

“In many cases, it’s not that simple. We can’t look at these models as black boxes where you put the data in and get an answer out, where you have no idea how the answer was determined, what it means and how it is applicable and generalizable.”

“The very first thing to focus on when properly applying computational methods or AI methods is data quality,” adds Kevin Yip, PhD, professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and director of the Bioinformatics Shared Resource. “Our mantra is ‘garbage in, garbage out.’”

Andrei Osterman, PhD

Andrei Osterman, PhD, is a professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys.

Once researchers have ensured the quality of their data, Yip says the next step is to be prepared to confirm the results.

“Once we actually plug into certain tools, how can we actually tell whether they are doing a good job or not?” asks Yip. “We cannot just trust them. We need to have ways to validate either experimentally or even computationally using other ways to cross-check the findings.”

Yip is concerned that AI-based research and computational biology are moving too fast in some cases, contributing to challenges reproducing and generalizing results.

“There are so many new algorithms, so many tools published every day,” adds Yip. “Sometimes, they are not maintained very well, and the investigators cannot be reached when we can’t run their code or download the data they analyzed.”

For AI and computational biology techniques to continue their rapid development, it is important for the scientific community to be responsible, transparent and collaborative in sharing data and either code or trained AI models so that studies can be reproduced to enhance trust as these fields grow.

Privacy is another potential breeding ground for mistrust in research using AI algorithms to analyze medical data, from electronic health records to insurance claims data to biopsied patient samples.

“It is completely understandable that members of the public are concerned about the privacy of their personal data as it is a primary topic I discuss with colleagues at conferences,” says Yip. “When we work with patient data, there are very strict rules and policies that we have to follow.”

Yip adds that the most important rule is for scientists to never re-identify the samples without proper consent, which means using algorithms to predict which patient provided certain data.

Kevin Yip, PhD

Kevin Yip, PhD, is a professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys.

Ultimately for Yip, using AI and computational methods appropriately—within their limitations and without violating patients’ privacy—is a matter of professional integrity for the owners and users of these emerging technologies.

“As creators of AI and computational tools, we need to maintain our code and models and make sure they are accessible along with our data. On the other side, users need to understand the limitations and how to make good use of what we create without overstepping and claiming findings beyond the capability of the tools.”

 “This level of shared responsibility is very important for the future of biomedical research during the data revolution.”

Programming in a Petri Dish, an 8-part series

How artificial intelligence, machine learning and emerging computational technologies are changing biomedical research and the future of health care

  • Part 1 – Using machines to personalize patient care. Artificial intelligence and other computational techniques are aiding scientists and physicians in their quest to prescribe or create treatments for individuals rather than populations.
  • Part 2 – Objective omics. Although the hypothesis is a core concept in science, unbiased omics methods may reduce attachments to incorrect hypotheses that can reduce impartiality and slow progress.
  • Part 3 – Coding clinic. Rapidly evolving computational tools may unlock vast archives of untapped clinical information—and help solve complex challenges confronting health care providers.
  • Part 4 – Scripting their own futures. At Sanford Burnham Prebys Graduate School of Biomedical Sciences, students embrace computational methods to enhance their research careers.
  • Part 5 – Dodging AI and computational biology dangers. Sanford Burnham Prebys scientists say that understanding the potential pitfalls of using AI and other computational tools to guide biomedical research helps maximize benefits while minimizing concerns.
  • Part 6 – Mapping the human body to better treat disease. Scientists synthesize supersized sets of biological and clinical data to make discoveries and find promising treatments.
  • Part 7 – Simulating science or science fiction? By harnessing artificial intelligence and modern computing, scientists are simulating more complex biological, clinical and public health phenomena to accelerate discovery.
  • Part 8 – Acceleration by automation. Increases in the scale and pace of research and drug discovery are being made possible by robotic automation of time-consuming tasks that must be repeated with exhaustive exactness.
Institute News

Scripting their own futures

AuthorGreg Calhoun
Date

August 8, 2024

Programming in a Petri Dish - AI series graphic

At Sanford Burnham Prebys Graduate School of Biomedical Sciences, students embrace computational methods to enhance their research careers

Although not every scientist-in-training will need to be an ace programmer, the next generation of scientists will need to take advantage of advances in artificial intelligence (AI) and computing that are shaping biomedical research. Scientists who understand how to best process, store, access and employ algorithms to analyze ever-increasing amounts of information will help lead the data revolution rather than follow in its wake.

“I think the way to do biology is very different from just a decade or so ago,” says Kevin Yip, PhD, a professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and the director of the Bioinformatics Shared Resource. “Looking back, I could not have imagined playing much of a role as a data scientist, and now I see that my peers and I are at the core of the whole discovery process.”

In 2017, bioinformatics experts suggested in Genome Biology that graduate education programs should focus on teaching computational biology to all learners rather than just those with a special interest in programming or data science. The authors noted that the changing nature of the life sciences required researchers to respond in kind. Teams of scientists must be able to formulate algorithms to keep pace and detect new discoveries obscured within oceans of data too vast to parse with prior methods.

“I think most people now would agree that data science and the use of computational methods—AI included—are indispensable in biology,” says Yip. “To use these approaches to the greatest effect, computational biologists and bench laboratory scientists need to be trained to speak a common language.”

Kevin Yip, PhD

Kevin Yip, PhD, is a professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys.

When Yip joined Sanford Burnham Prebys in 2022, he was tasked with directing a course on computational biology for the Institute’s Graduate School of Biomedical Sciences.

“We believe that the new generation of graduate students needs to have the ability to understand what algorithms are and how they work, rather than just treating those tools as black boxes,” says Yip. “They may not be able to invent new algorithms right out of the course, but they’ll be better equipped to participate in collaborative projects.”

Andrei Osterman, PhD

Andrei Osterman, PhD, is a professor in the Immunity and Pathogenesis
Program at Sanford Burnham Prebys.

Yip’s work developing the course has been well-received by graduate students based on their evaluations of the class.  

“I loved the computational biology course,” says Katya Marchetti, a second-year PhD student in the lab of  Karen Ocorr, PhD, and the recipient of an Association for Women in Science scholarship.

“It was so helpful to learn skills that I could immediately see incorporating into my own research. I’m so glad I had this course. I know for a fact that I will need this knowledge and experience to be successful in whatever comes after my PhD. The people who have these skills objectively do better in postdoctoral fellowships or in the biotechnology industry.”

Yip and his fellow faculty members in the graduate school see an opportunity to further expand their approach to computational biology and data science topics.

“In the current course, students learn to use computational methods to analyze transcriptomics data,” says Andrei Osterman, PhD, vice dean and associate dean of Curriculum for the Graduate School and a professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys. “This is very useful hands-on training, but not advanced enough for some students.”

“We are seeing students with a computer science background coming into our graduate program,” notes Yip. “We are thinking about adding a new elective course for students who want to go beyond what our current class is offering.”

Graduate education is quickly evolving at Sanford Burnham Prebys and throughout the biomedical research community to match the demands of an era defined by effectively integrating computation and biology.

“Mutual understanding among data scientists and biologists is very important for where research is heading,” says Yip. “We will keep improving our training to set our students up for success.”

Katya Marchetti

Katya Marchetti is a second-year PhD student at Sanford Burnham Prebys.

Programming in a Petri Dish, an 8-part series

How artificial intelligence, machine learning and emerging computational technologies are changing biomedical research and the future of health care

  • Part 1 – Using machines to personalize patient care. Artificial intelligence and other computational techniques are aiding scientists and physicians in their quest to prescribe or create treatments for individuals rather than populations.
  • Part 2 – Objective omics. Although the hypothesis is a core concept in science, unbiased omics methods may reduce attachments to incorrect hypotheses that can reduce impartiality and slow progress.
  • Part 3 – Coding clinic. Rapidly evolving computational tools may unlock vast archives of untapped clinical information—and help solve complex challenges confronting health care providers.
  • Part 4 – Scripting their own futures. At Sanford Burnham Prebys Graduate School of Biomedical Sciences, students embrace computational methods to enhance their research careers.
  • Part 5 – Dodging AI and computational biology dangers. Sanford Burnham Prebys scientists say that understanding the potential pitfalls of using AI and other computational tools to guide biomedical research helps maximize benefits while minimizing concerns.
  • Part 6 – Mapping the human body to better treat disease. Scientists synthesize supersized sets of biological and clinical data to make discoveries and find promising treatments.
  • Part 7 – Simulating science or science fiction? By harnessing artificial intelligence and modern computing, scientists are simulating more complex biological, clinical and public health phenomena to accelerate discovery.
  • Part 8 – Acceleration by automation. Increases in the scale and pace of research and drug discovery are being made possible by robotic automation of time-consuming tasks that must be repeated with exhaustive exactness.
Institute News

Objective omics

AuthorGreg Calhoun
Date

August 1, 2024

Programming in a Petri Dish - AI series graphic

Although the hypothesis is a core concept in science, unbiased omics methods may reduce attachments to incorrect hypotheses that can reduce impartiality and slow progress

Biological techniques that study the entire landscape of a sample’s genes or proteins—genomics or proteomics, respectively—help scientists discover new results without becoming too narrowly focused on what they predicted would happen. Although some scientists pursuing studies with this wider lens have been accused of going on “fishing expeditions,” many researchers counter that they now are able to investigate their hypotheses without missing other important results.

“I am a major proponent of omics, and especially unbiased omics,” says Sanju Sinha, PhD, an assistant professor in the Cancer Molecular Therapeutics Program at Sanford Burnham Prebys. “If someone now doesn’t show me unbiased results, it deeply bothers me. If every experiment only shows results from one pathway, it’s concerning and increases my skepticism about the study.”

An omics approach differs from traditional hypothesis-driven research in that it includes a comprehensive perspective about the phenomenon a scientist is studying and what might be causing it.

Sinha Lab

The Sinha Lab

“Unbiased omics look at the global picture of how everything is changing,” explains Sinha. “If you’re looking at genetic factors, you present all 20,000 genes and how they change, rather than just one pathway and maybe 10 genes.”

Sanju Sinha, PhD

Sanju Sinha, PhD, is an assistant professor in the Cancer Molecular
Therapeutics Program at  Sanford Burnham Prebys.

This method reflects the dynamic nature of biomedical research.

“Biomedical research is currently experiencing a period of accelerating and metamorphic discoveries fueled by unparalleled technologies that generate enormous amounts of data that, in turn, spur and spawn avenues of new inquiry and questions previously unimagined,” says David A. Brenner, MD, president and CEO of Sanford Burnham Prebys.

“An effective and successful biomedical researcher in the 21st century requires input from different disciplines that previously were not part of standard practice or the scientific method.”

Sinha agrees. “People used to work in small silos. They could work on the same biological pathway for 30 years.” The new model, he said, is quickly shifting to more multidisciplinary, team-based science where experts from many fields collaborate to make the most of new technology and the rich data it can provide.

Some teams employing these omics approaches have been criticized for conducting aimless studies due to the lack of traditional hypotheses. Sinha is quick to defend against these claims.

“I don’t mind these so-called fishing expeditions. I like to say that there are only two kinds of science: applied science and not-yet-applied science. Fishing expeditions are valuable if the data is made available and other scientists can make discoveries with it for years to come.”

“We should remember that fishing expeditions in biomedical research have done a great service to humanity.”

The hypothesis is not an endangered species destined to be replaced by unbiased omics approaches. On the contrary, omics experiments can often be kick-starters that help scientists generate new hypotheses to explore.

A team of scientists at Sanford Burnham Prebys and their collaborators are using an omics technique called resistomics to develop a new class of antibiotics effective against a drug-resistant pathogen.

In a paper published on January 3, 2024 in Nature, a multi-institutional team including  Andrei Osterman, PhD, a professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys, with colleagues at  Roche—the Swiss-based pharmaceutical/healthcare company—and others, describe a novel class of small-molecule-tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against carbapenem-resistant  Acinetobacter baumannii  (CRAB).

The World Health Organization and the Centers for Disease Control and Prevention have both categorized multidrug-resistant  A. baumannii as a top-priority pathogen and public health threat.

In the study, Osterman and colleagues applied an experimental evolution approach to help identify the drug target (the LPS transporter complex) of a new class of antibiotics—a macrocyclic peptide called Zosurabalpin—and elucidate the dynamics and mechanisms of acquired drug resistance in four distinct strains of A. baumannii. 

Andrei Osterman, PhD

Andrei Osterman, PhD, is a professor in the Immunity and Pathogenesis program at Sanford Burnham Prebys.

They used an integrative workflow that employs continuous bacterial culturing in an “evolution machine” (morbidostat) followed by time-resolved, whole-genome sequencing and bioinformatics analysis to map resistance-inducing mutations. 

“This comprehensive mapping of the drug-resistance landscape yields valuable insights for a variety of practical applications,” says Osterman, “from therapy optimization via genomics-based assessment of drug resistance/susceptibility of bacterial pathogens to a rational development of novel drugs with minimized resistibility potential.”

Programming in a Petri Dish, an 8-part series

How artificial intelligence, machine learning and emerging computational technologies are changing biomedical research and the future of health care

  • Part 1 – Using machines to personalize patient care. Artificial intelligence and other computational techniques are aiding scientists and physicians in their quest to prescribe or create treatments for individuals rather than populations.
  • Part 2 – Objective omics. Although the hypothesis is a core concept in science, unbiased omics methods may reduce attachments to incorrect hypotheses that can reduce impartiality and slow progress.
  • Part 3 – Coding clinic. Rapidly evolving computational tools may unlock vast archives of untapped clinical information—and help solve complex challenges confronting health care providers.
  • Part 4 – Scripting their own futures. At Sanford Burnham Prebys Graduate School of Biomedical Sciences, students embrace computational methods to enhance their research careers.
  • Part 5 – Dodging AI and computational biology dangers. Sanford Burnham Prebys scientists say that understanding the potential pitfalls of using AI and other computational tools to guide biomedical research helps maximize benefits while minimizing concerns.
  • Part 6 – Mapping the human body to better treat disease. Scientists synthesize supersized sets of biological and clinical data to make discoveries and find promising treatments.
  • Part 7 – Simulating science or science fiction? By harnessing artificial intelligence and modern computing, scientists are simulating more complex biological, clinical and public health phenomena to accelerate discovery.
  • Part 8 – Acceleration by automation. Increases in the scale and pace of research and drug discovery are being made possible by robotic automation of time-consuming tasks that must be repeated with exhaustive exactness.
Institute News

A potential new weapon against a deadly, drug-resistant bacterial pathogen

AuthorScott LaFee
Date

January 8, 2024

Acinetobacter baumannii (CRAB)

Carbapenems are a class of highly effective antibiotics that are often used to treat severe bacterial infections. They are usually reserved for known or suspected bacterial infections resistant to other drugs.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is, as the name suggests, impervious to carbapenems; and it has become a major global pathogen, particularly in hospital settings and conflict zones. No new antibiotic chemical class with activity against A. baumannii has successfully emerged in more than 50 years.

In a paper published January 3, 2024, in Nature, a multi-institutional team including Andrei Osterman, PhD, at Sanford Burnham Prebys, with colleagues at Roche—the Swiss-based pharmaceutical/healthcare company—and others, describe a novel class of small-molecule tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. Osterman’s lab provided critical data and discoveries related to the drug target and mapping of drug-resistant mutations.

Developing a new class of antibiotics effective against CRAB is critical. The bacterium is resistant to nearly all antibiotics and is difficult to remove from the environment. It poses a particular health threat to hospitalized patients and nursing home residents, with an estimated mortality rate in invasive cases of 40–60%.

The World Health Organization and the Centers for Disease Control (CDC) have both categorized multidrug-resistant A. baumannii as a top-priority pathogen and public health threat.

In the new study, Osterman and colleagues applied an experimental evolution approach to help identify the drug target (the LPS transporter complex) of a new class of antibiotics—a macrocyclic peptide called Zosurabalpin—and elucidate the dynamics and mechanisms of acquired drug resistance in four distinct strains of A. baumannii.

They used an integrative workflow that employs continuous bacterial culturing in an “evolution machine” (morbidostat) followed by time-resolved, whole-genome sequencing and bioinformatics analysis to map resistance-inducing mutations.

In addition to a mechanistic understanding (crucial from a regulatory perspective), the new information also helped reveal the drug-binding site. A related paper in the same issue experimentally verified the findings.

“This comprehensive mapping of the drug-resistance landscape yields valuable insights for a variety of practical applications,” says Osterman, “from therapy optimization via genomics-based assessment of drug resistance/susceptibility of bacterial pathogens to a rational development of novel drugs with minimized resistibility potential.”

A commentary in Nature said the research was “cause for cautious celebration” and urged further development.

Institute News

Sanford Burnham Prebys research plays a key role in developing microbiome-directed complementary food to help save malnourished children

AuthorScott LaFee
Date

January 4, 2024

A Bangladeshi mother and child in the Nutritional Rehabilitation Unit of the International Centre for Diarrhoeal Disease Research Hospital in Dhaka.

Among the consequences of childhood malnutrition is the underdevelopment of their gut microbiomes, critical to human health, from innate immunity to appetite and energy metabolism.

Although malnourished children gain some weight and grow better when fed a nutrient-rich diet, they do not catch up to their well-fed counterparts—and their gut microbiomes do not recover.

In a 2021 clinical trial, researchers at Washington University School of Medicine showed how a newly designed therapeutic food—a unique mix of peanuts, bananas and other foods dubbed microbiome-directed complementary food, or MDCF—more effectively nourished healthy gut microbial communities than standard dietary supplements.

Now, with bioinformatics support from Andrei L. Osterman, PhD, professor in the Immunity and Pathogenesis and Cancer Metabolism and Microenvironment programs at Sanford Burnham Prebys  and his colleagues Dmitry Rodionov, PhD, and Alex Arzamasov, the multi-institutional scientific team has published new research that identifies and describes the bioactive elements of microbiome-directed food.

“These are naturally occurring carbohydrate structures that could, in theory, be recovered in large quantities from the by-product streams of food manufacturing and be used to produce prebiotics,” said senior study author Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor at Washington University.

“We also have identified the microbes that process these food components, and in theory, there is potential for the organisms themselves to be part of a therapeutic intervention in children completely lacking these beneficial gut microbes.”

Osterman’s lab contributed bioinformatics analyses of 1,000 new metagenomically assembled genomes, or MAGs, representing the gut microbiomes of healthy Bangladeshi infants. The analyses included genome-based inference of the presence or absence in these MAGs of functional metabolic pathways for 106 major nutrients and intermediary metabolites.

“These predictions enabled the assessment of the microbiome-wide representation or enrichment of dietary carbohydrate utilization capabilities across numerous biospecimens from a randomized, controlled trial of MDCF in Bangladeshi children with moderate acute malnutrition,” said Osterman.

“The analyses helped elucidate glycan components of MDCF metabolized by bacterial taxa that are positively associated with healthy weight growth. The knowledge will help guide the therapeutic use of current MDCF and enable development of new formulations.”

Childhood undernutrition is a global scourge. In 2020, an estimated 149 million children under the age of 5 had stunted growth (low height for age), and 45 million exhibited stunting (low weight for height). More than 30 million children worldwide have moderate, acute malnutrition.

Undernutrition and its consequences are the leading causes of disease and death for children in this age range. An estimated 3 million children die each year due to poor nutrition and hunger.

Institute News

Sanford Burnham Prebys and Roche fight back against antibiotic resistance

AuthorMiles Martin
Date

December 8, 2021

Brown and orange illustration of different shapes of bacteria

Researchers from Sanford Burnham Prebys have teamed up with prominent drug developer Roche Pharma to learn how bacteria develop antibiotic resistance.

Their new results, published in the journal mBio, are one piece of a long-standing collaboration between the two organizations, the goal of which is to mitigate the growing threat of antibiotic resistance by developing more “irresistible” drugs and by helping improve antibiotic prescribing practices.

“The emergence of antibiotic resistance is inevitable for any single drug, new or old. It’s only a question of time,” says senior author Andrei Osterman, PhD, a professor at Sanford Burnham Prebys. “But the precise time is different for every drug and every microbe, so studying when and how resistance to antibiotics evolves gives us powerful information for improving antibiotic treatment.”

Antibiotic resistance develops rapidly

When a patient is treated with antibiotics, most individual bacteria die, but a few cells will survive, usually as a lucky consequence of a random genetic mutation. These survivors go on to multiply into a whole new population of antibiotic-resistant bacteria.

“The development of antibiotic resistance is a strictly Darwinian process, very similar to evolution in larger organisms,” says Osterman. “The difference is that in bacteria, it happens much more rapidly, which makes antibiotic resistance one of the most pressing challenges facing medicine today.” 

Although the speed at which evolution occurs in bacteria makes antibiotic resistance a threat, the researchers were also able to take advantage of this speed to study its development. The team cultured three species of bacteria in a morbidostat, a device that allows bacteria to grow continuously over multiple generations while being dosed with antibiotics. Although theirs was not the first morbidostat device, the team designed a new, more effective version of the system for their experiments.

“It’s like an evolution machine, letting us watch the development of antibiotic resistance in real time and in an environment that more accurately models what happens to bacteria in a clinical setting than other approaches,” says Osterman. “This gives us a clearer and more comprehensive view of resistance than we’ve ever had before.”

Different bacteria develop resistance differently

By observing the bacteria’s evolution in the morbidostat and sequencing their genomes as they evolved, the researchers found that all three species had a similar pattern of resistance development. However, they also found subtle differences in the ways certain genes were expressed, particularly those that help bacteria remove toxins, a critical process in developing resistance.

“It’s like three remakes of the same movie by three different directors, and their comparison gives us a wealth of information to guide the development and use of antibiotics,” says Osterman. 

Understanding resistance is critical to reducing its harm

Working with Roche, the team has completed similar studies on several other classes of antibiotic drugs, which is helping Roche identify promising candidates for antibiotics that are less prone to resistance.

And because antibiotic resistance is often not assessed in drug candidates until years into the process, using resistance to screen for drug candidates this way could save the biomedical industry millions of dollars and help patients benefit from effective drugs sooner.

“A completely ‘irresistible’ drug is a holy grail, something we can never truly achieve,” says Osterman. “But some drugs are less resistible than others, and our methods allow us to figure out which is which in a systematic way.”

In addition to helping develop new drugs, the researchers claim that their findings are easily translatable to the clinic, where doctors can use detailed knowledge of resistance to select optimal drug combinations with less likelihood of failure due to resistance.

“We are moving away from trial-and-error approaches in medicine and moving toward being able to predict exactly what drugs will work best for each patient,” says Osterman. “It is going to take time, effort and money to make this happen, but it will all be worth it if we’re able to alleviate the threat of antibiotic resistance and help save lives, which I’m confident can be done.”

Institute News

How microbes shape human health: an interview with Andrei Osterman

AuthorMiles Martin
Date

October 7, 2021

Sanford Burnham Prebys Professor Andrei Osterman, PhD

In his work on the human microbiome, Sanford Burnham Prebys professor Andrei Osterman, PhD, has shown how the organisms living within us can be leveraged to boost human health for a humanitarian cause – the plight of malnourished children. 

Describe your research aimed to improve the gut microbiome in malnourished children.
In infants, it’s been well-established that conditions of severe poverty and food insecurity cause a delayed development of gut microbes, and that this results in stunted growth, numerous syndromes, and even death. My team has been collaborating with researchers at Washington University in St. Louis to develop foods that are designed to enhance the microbiome, and we’ve found that these can actually work to correct some of these pathologies. 

One study involved introducing microbes from undernourished Bangladeshi children into the guts of mice. When these mice were then fed a typical Bangladeshi diet, they exhibited a weaker immune response to the oral cholera vaccine. More importantly, this poor response could be repaired by establishing a more normal gut microbiome in the mice and providing them supplements to boost these microbes’ propagation.

What else can we learn from this research that could be applied more broadly?
From a humanitarian perspective, the progress we’ve made is so valuable that there is no question we will continue the work. But studying the microbiome in infants, regardless of their food security, can also provide us with new insights into the importance of the microbiome in human health. 

In a more recent study with collaborators from University of California San Diego and University of Southern California, we found that adding corn syrup to infant formula can enhance the populations of beneficial microbes they might otherwise have gotten from breast milk. 

We hope this is the first of many studies we work on with this team, because the transition of infants from breast milk or formula to conventional foods is thought to be the most drastic example of how the microbiome changes with diet. Studying infants and their diets at this early point in life could help reveal fundamental truths that we’ll be able to translate to other syndromes related to the microbiome in children and adults worldwide, regardless of food security. 

And this isn’t just speculation. Another study with the team in St. Louis used the same methods as the malnutrition study to develop supplementary foods, called “fiber snacks,” to correct microbiome imbalances in people with obesity. One might think that obesity would be the total opposite of malnutrition, but the microbiome is a key player in both. 

More broadly, gut microbes are already the most well-studied part of the human microbiome, and the list of health associations with these microbes extend well beyond the digestive tract, even into the immune system, affecting the risk for diseases like cancer or diabetes. There’s also a growing body of evidence that suggests that gut microbes can have a direct effect on the brain. For example, the microbiome is being studied closely in connection to autism spectrum disorder, since many people on the spectrum experience concurrent gastrointestinal syndromes.

What would you say is important to know for people not familiar with the subject?
We need to acknowledge that our body and many of its problems have a huge microbiome component. The human body is a complex organism, and we are still learning how the microbiome influences and is influenced by different health conditions. The next step is to incorporate the role of the microbiome into the design of new diagnostics and therapeutics—because this undoubtedly influences their effectiveness. We can’t ignore this aspect of our biology, and the time is ripe to improve our understanding of it and leverage it to our advantage. Moving forward, this is going to help us solve so many problems—from issues we’ve already started looking at like obesity and malnutrition, all the way through to problems we aren’t even aware of yet. 

What are the next steps for you and your team?
What we’re really interested in now is exploring new genomic technologies that are starting to revolutionize the field. The latest development is something called MAG genomics, short for metagenomically assembled genomes. This involves looking at the big picture, sequencing DNA from the whole microbiome at once in a way that is much faster and of much better quality than we’ve ever been capable of before. It’s like the difference between watching a movie on a clunky pixelated monitor from the 80’s and seeing that same movie on an HD monitor. Methods like this are moving us into a new paradigm in biomedical research, one that may be more complex, but also one that has the potential to substantially improve health outcomes for people around the world.

Institute News

Vitamin A deficiency has an outsize impact on gut microbes

AuthorSusan Gammon
Date

May 30, 2017

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Deficiencies in vitamins and minerals are a major global health threat, affecting two billion people worldwide. Scientists have extensively studied how human biology is affected by imbalances in vitamins and minerals, also known as micronutrients. But much less is known about the effects of micronutrient deficiencies on gut microbes, which also play important roles in human health and disease.

Sanford Burnham Prebys Medical Discovery (SBP) researchers provided an important contribution to a new study, which addressed this gap in knowledge by comparing the effects of deficiencies in vitamin A, folate, iron, and zinc on gut bacteria in mice. As reported May 17th in Science Translational Medicine, vitamin A deficiency had the largest effect on bacterial community structure and gene activity, increasing the abundance of Bacteroides vulgatus, a species previously associated with host growth.

“The current study provides preclinical evidence supporting the concept that the treatment of micronutrient imbalances needs to be considered from the perspective of not only the human host, but also the host’s gut microbiota,” says study co-author Andrei Osterman, PhD, a professor at SBP.

Hidden hunger

Micronutrients enable the body to produce enzymes, hormones and other molecules essential for proper growth and development. The human body doesn’t need a large amount of these substances, but the consequences of their absence are severe. In particular, imbalances in iron, zinc, folate and vitamin A represent a pressing global public health problem, disproportionately affecting children and pregnant women who live in low-income countries.

To examine the effects of iron, zinc, folate and vitamin A deficiencies on gut microbes, Osterman teamed up with senior study author Jeffrey Gordon, M.D, a professor at Washington University School of Medicine. They first colonized mice with a large and diverse community of human gut bacterial strains. Next, they subjected the mice to a diet oscillation, which began with a micronutrient-sufficient diet, followed by a diet that lacked one of the four micronutrients under investigation, followed by a return to the original diet.

By sequencing microbial RNA and DNA in fecal samples, the researchers examined the effect of diet on the bacterial community structure and gene activity. Surprisingly, they found that vitamin A deficiency had the most profound effect, significantly increasing the abundance of B. vulgatus. Repletion of vitamin A in the diet decreased the abundance of this bacterial species, which has been positively associated with host growth in mouse models of postnatal human gut microbiota development.

Reassessing supplements

Currently, the World Health Organization recommends high-dose vitamin A supplementation for infants and children in high-risk areas, for good reason. Deficiency in vitamin A, which plays important roles in vision, growth, and immune function, is a significant public health problem in more than half of all countries. It is the leading cause of preventable blindness in children and increases the risk of disease and death from severe infections. In pregnant women, vitamin A deficiency causes night blindness and may increase the risk of maternal mortality.

Although adequate levels of vitamin A are crucial for survival, some evidence suggests that micronutrient supplementation can actually cause health problems. The new findings add to these concerns, raising the worrying possibility that vitamin A supplementation might have the unintended consequence of inhibiting the growth of infants and children. But for now, there is not enough evidence to conclude that vitamin A imbalances influence host growth through their effects on B. vulgatus.

“However, our results provide a rationale and a preclinical method for examining whether current vitamin A dosing regimens, and by extension other critical micronutrients, have unintended and deleterious effects on the developing gut microbiota of undernourished children, whose healthy growth such treatments are intended to promote,” Osterman says.

Institute News

Targeting gut microbes may help malnourished children grow

Authorjmoore
Date

March 7, 2016

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Malnutrition in infants and young children can have major life-long impacts—deficiencies in important nutrients stunt growth and impair development. Although aid organizations have developed fortified meals to make up for these deficiencies, they don’t completely compensate for the lack of nutrition. Now scientists know why malnourished children might not benefit as much as they should from added nutrients in their diet. Continue reading “Targeting gut microbes may help malnourished children grow”