A Brave New Era: Emerging Biotechnologies Are Changing Pediatric Care

Hansa Bhargava, MD; Daniel L. Kraft, MD

Disclosures

March 31, 2016

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Emerging Biotechnologies: Stem Cells and Cord Blood

Hansa Bhargava, MD: I'm Dr Hansa Bhargava, medical editor at WebMD and medical advisor for Medscape. We are talking with Dr Daniel Kraft about how research is changing trends in pediatrics. Dr Kraft, tell us about yourself.

Daniel L. Kraft, MD: I'm an adult/pediatric hematologist/oncologist trained at Massachusetts General Hospital and Stanford School of Medicine. I chair the medicine department at Singularity University. I'm the founder and chair of a program called Exponential Medicine, in which we look at the convergence of technologies from stem cell biology to 3D printing and robotics, and how they are affecting healthcare in the realm of diagnostics, therapy, research, and beyond.

Dr Bhargava: Let's talk about stem cell research. The promises of stem cell-based cancer therapies are tantalizing. Recent research has indicated that cord blood constituents can help with such conditions as eczema and rheumatoid arthritis. Parents are bombarded by private cord blood banks urging them to purchase "insurance policies" against life-threatening diseases. What's the current state of stem cell therapies, and how should clinicians advise parents?

Dr Kraft: My clinical focus has been pediatric bone marrow transplantation, which is a form of stem cell therapy. Cord blood transplants, in some cases, are supplanting the traditional bone marrow transplant procedure. For most individuals, however, you can find a match in the existing cord blood or bone marrow transplant registry, so banking your child's cord blood is not clearly indicated. The American Academy of Pediatrics and other organizations don't recommend it. If you are a rare ethnic mix or have a child in your family who is at risk for a particular disease, it's reasonable to use a cord bank. If you can afford to do it, then there isn't a downside.

The cutting edge of stem cell transplantation is blending it with some new gene therapies. Gene therapy has been promised for a long time. Now with CRISPR/Cas and other biotechnologies coming together, we can take a child with sickle cell disease, thalassemia, or another genetic disorder; remove some bone marrow stem cells; do gene therapy to replace the single gene that is malfunctioning; and transplant bone marrow back to the patient, to reboot the blood and immune system. The genetic defect will be corrected, resulting in a long-term cure. That has been done in a small number of patients in clinical trials, but in the next decade, this will become the norm for treating such diseases as thalassemia, sickle cell anemia, possibly HIV, and other disorders.

Stem cell therapy and hematopoietic transplantation are long-standing therapies that are becoming very interesting and may be applied not only in eczema, but in other, more severe autoimmune diseases as well.

Gene Editing: CRISPR/Cas

Dr Bhargava: Will CRISPR/Cas technology become more accurate?

Dr Kraft: It's the hot new biotechnology of the day—it's still early, but it's going to move into the clinic pretty quickly. The implications are dramatic, ranging from ethical issues and the challenges of "designer babies" to how to modify children and adults who have genetic disorders. We need to keep our eye on this and be careful how we regulate it. Genetic engineering has a dark side as well, but it has tremendous promise to achieve long-term cures for serious diseases at much lower costs.

Dr Bhargava: Could we even fight Zika that way?

Dr Kraft: For Zika, we might use the new world of synthetic biology. We're now in the era of genomics, with a $1000 genome sequencing cost that will soon be a $100 genome. We can also print DNA. We'll be entering an era when I can email you a vaccine for Zika or Ebola, and you can print that protein locally, or in your own body through messenger RNA-based therapies.

As we start to blend the world of gene therapies and biology "sequencing-omics," we're going to have dramatic new techniques for personalized and precision-based medicine to match specific diseases or infectious agents.

Dr Bhargava: We're talking about preventing diseases, infection control, cancer therapies, and many other possibilities?

Dr Kraft: From the pediatric hematologist/oncologist's point of view, we are still giving broad-based toxins to patients to cure them. Soon, every tumor is going to be sequenced, sometimes repeatedly. Many tumors have a lot of heterogeneity. We're going to apply machine learning. IBM's Watson has already been applied to lung cancer to determine the right cocktails of drugs that are already on the market (or sometimes are used off-label) to—like we do with infectious diseases—treat a cancer and modify the therapy over time to react to mutations. Hopefully, we're entering an era of truly precision-based oncology, when using viruses and other designer drugs to match a patient's particular set of mutations will improve long-term outcomes and, in some cases, achieve cures.

Dr Bhargava: What is the timeline for the changes that you have mentioned?

Dr Kraft: Right now, you can send a tumor biopsy sample to companies that mine the data from sequencing and suggest therapeutics to the oncologist. We're seeing the advent of true cancer immunotherapy. The PD1 inhibitors being used in lung, pancreatic, and colon cancer are starting to enter the pediatric realm as well, and in some cases, positively affect diseases that have been characterized by low rates of long-term survival.

We are going to see a blend of these therapies. There is no magic bullet, and no cure for cancer. We're going to learn that every cancer is heterogeneous, like autism and Alzheimer disease. In some cases of lung cancer, for example, there are thousands of molecular subtypes. Across the healthcare spectrum, we're going to redefine disease at the molecular level and find specific drugs or cocktails that apply only to that individual.

'Spit in a Tube' Technology

Dr Bhargava: The dramatic decrease in the cost of whole-exome sequencing has led some experts to predict that we might see widespread use of pre-prescription genotyping, maternal serum cell-free DNA fetal screening, and gene sequencing as standard practice. Do you see widespread gene sequencing and genomic therapies for children coming in the near future?

Dr Kraft: Absolutely. Today, you can spit in a tube and drop it in the mail for $100 and get 2.5 million or more base pairs analyzed—single-nucleotide polymorphisms (SNPs)—from such companies as 23andMe, which has huge implications for prevention, screening, and therapeutics. Take pharmacogenomics alone: How your genes influence what statin or antiseizure medication you might take can be determined from a $100 saliva sample analyzed for SNPs. The genome is no longer $1000; the price of sequencing is dropping at twice the rate of Moore's law. In a few years, it will be $100 or maybe even $10, which has dramatic implications.

When you see a patient, you will no longer treat according to population-based risk. You will know the patient's specific risk for certain diseases and how the patient responds to certain drugs. It's going beyond the "omics." There are many ethical issues to consider. Watch the 1997 movie Gattaca—it's a good example.

Enter the "Omes"

Dr Kraft: We're now in the area of other "omes," such as the proteome. We used to order a "chem 20" test (the comprehensive or basic metabolic panel [BMP], which we can still order), but we will eventually have a "chem 10,000" test. We're going to have thousands of data points, and we will see the data points move between normality and disease and be able to detect diseases early. Not to mention the microbiome, which you can now sequence for less than $100.

We know now, for example, that children born by cesarean section (C-section) have a very different microbiome compared with children born vaginally, which may predispose them to obesity and type 2 diabetes. Nature Medicine recently published an study[1] of vaginal microbiome transplants in babies following C-sections, which cost almost nothing.

We're learning that the microbiome increases the risk for obesity, inflammatory bowel disease, and maybe even psychiatric disorders. The field of "omics" is exploding. These analyses are becoming much cheaper and more accessible. Soon we will be able to do them at the point of care, like a quick test for infectious disease. Is that a virus or bacteria? How are you going to treat it, based on very specific information at the point of care for a very low cost?

Dr Bhargava: Here is an issue that comes up for some clinicians: When a patient spits in a tube for analysis and the results are positive for certain illnesses, who provides guidance for that patient? Is that an issue that you're worried about?

Dr Kraft: We're entering the era of the empowered, engaged patient who owns his or her healthcare data and takes some responsibility for them. There is no way that we're going to have enough genetic counselors to sit down with every patient.

Materials that provide guided pathways through genomics mean that you understand, before you take the test, what the test means. One test might be for the risk of developing Huntington chorea or Alzheimer disease. Another test might guide the right therapeutics for asthma, cardiovascular disease, or diabetes. We need to blend these and be smart without being fearful.

I would argue that we need to start in the clinic and embrace "omics" data and make them part of the workflow. If you want to prescribe a particular drug, it would be great to know the patient's pharmacogenetic type to make an informed, smart decision, whether you are managing hypertension or diabetes.

Dr Bhargava: The biome you mentioned with C-section vs vaginal delivery has been in the news. Sometimes, patients get this information and decide to act on it before doctors can advise them. For example, there was a method called "vaginal seeding" for babies who were born by C-section, because their mothers were afraid that the infants weren't getting the benefits of a vaginal delivery. What can we do as physicians to advise these parents?

Dr Kraft: We're still learning. It used to take 17 years from publication to standard of care for treating such diseases as ulcers, for example. Now we are in an era of crowdsourced medicine. A parent can go online and find other new parents who may have done vaginal seeding or a microbiome transplant and get an idea of how it works. We're going to start crowdsourcing patient-driven clinical trials. That's already happening.

Microbiome transplant simulates what would happen in a vaginal delivery and isn't super high-risk. If it's a study of certain drugs or other interventions, then we need to be more careful. There is a new opportunity to shift how trials are done and how we learn, and engage the consumer, the parent, and the patient in the discovery process.

Self-sequencing and Sharing

Dr Bhargava: What about the controversial use of the at-home genetic sequence test? The US Food and Drug Administration (FDA) requested one company to stop marketing the test, although they have given approval for a test that covers one or two syndromes now. Although it's not marketed for use in children, do you think some families will choose direct-to-consumer genetic testing? What happens if they get a result that says "Your child is at risk for cancer" (or Alzheimer disease, or autism), and they take matters into their own hands?

Dr Kraft: As parents (and we are both parents), we want to optimize our children's future, and having our children's genetic information can enable us to be proactive. If someone is at high risk of developing cardiovascular disease or a certain form of cancer, we can provide guidance for screening, diets, or other lifestyle considerations early in life that can have a significant impact later in life.

Knowledge can be power, but we're still at an early stage where some of the knowledge isn't clear. There is low-hanging fruit, such as risks for certain diseases, and pharmacogenomics. You can now take your data to consumer websites, upload them, and determine your ability for certain sports. The ethical issues presented in the movie Gattaca are relevant here, but if we want to be informed about healthcare, then using that information is going to be increasingly powerful.

Dr Bhargava: Does it make sense for the companies that are developing these cutting-edge technologies that help patients realize what they are at risk for to reach out to their physicians as well? Is there a way that they can communicate with physicians about the diagnoses that the consumers will be given?

Dr Kraft: It's a partnership. If I come to you with my genome on a disk drive, it's hard for you to act on it. It's going to be more integrative if you prescribe a genome, microbiome, or proteome. You look at the data with the patient and family, and you guide decisions based on the data. We're going to need artificial intelligence and machine learning to sort through all of the data. Companies are now building app stores for your genome.

As thousands, and then millions of people are fully sequenced, we'll start to learn. We're already starting to see kids with rare genetic defects sequenced for free and put into a database so that we can continue to learn. It's not just one side with the consumer having this genetic information, but not the clinician. It's a matter of combining this information—of "unsiloing" it among electronic medical records (EMRs), hospital systems, and pharmaceutical companies, and eventually moving to (in some cases) crowdsourced participatory healthcare.

Dr Bhargava: Sharing the information between the patient and physician will lead to better therapy for all of us.

Dr Kraft: Sharing is caring. What if you had a share button in the hospital? You could opt to share your EMR (deidentified) data. That can dramatically improve outcomes, because today, we're still waiting for the double-blind, placebo-controlled trial, which is the old way. The future is going to be practice-based medicine. I'm going to look for other patients in the EMR who have the same genetics as my patient. Their outcomes will be much more specific to my patient.

Dr Bhargava: It sounds like all of this information is going to lead to better medicine, and we'll all be able to access better medicine, both physicians and patients.

Dr Kraft: Information is power. We are still in the early stages of integrating this exponential explosion of genomics and other clinical information. It has huge implications for shifting the practice of healthcare from prevention to diagnostics to therapy.

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