Spare time fun: protein structure analysis of mutations causing inheritable diseases

Most people I know would not consider protein structure analysis of mutations causing inheritable diseases “spare time fun”. Then again, most people I know don’t think I am like most people they know.

This week I’m a “single-dad”, since my wife is traveling. So my spare time right now is almost non existent. Nevertheless, the thought of mutating a Proline into a Glycine at position 22 intrigued me, so I spent a few minutes simulating it. Here is what I found out:

Method

The 3D-structure of my protein of interest was obtained from the UniProt database using Reprof. The structural information was obtained from the analysis of PDB: 3NIR. Annotations were obtained from UniProt entry CRAM_CRAAB.

Amino Acids

I was interested in the mutation of a Proline into a Glycine at position 22.

The figure below shows the schematic structures of the original (left) and the mutant (right) amino acid. The backbone, which is the same for each amino acid, is colored red. The side chain, unique for each amino acid, is colored black.

 mutates into 

Each amino acid has its own specific size, charge, and hydrophobicity-value. The original wild-type residue and newly introduced mutant residue differ in these properties: the mutant residue is smaller than the wild-type residue, while the wild-type residue is more hydrophobic than the mutant residue.

Variants

A mutation to “S” was found at this position, which differs from the mutation I was simulating. The effect of this variant is annotated as: In isoform SI.

Conservation

The wild-type residue is not conserved at this position. Another residue type was observed more often at this position in other homologous sequences. This means that other homologous proteins exist with that other residue type than with the wild-type residue in my protein sequence, but the other residue type is not similar to my mutant residue. Therefore, the mutation is possibly damaging.

Domains

This residue is part of an interpro domain named: Thionin IPR001010

The mutated residue is located on the surface of a domain with unknown function. The residue was not found to be in contact with other domains of which the function is known within the used structure. However, contact with other molecules or domains is still possible and might be affected by this mutation.

Amino Acid Properties

The wild-type and mutant amino acids differ in size. The mutant residue is smaller than the wild-type residue. This will cause a possible loss of external interactions.

The hydrophobicity of the wild-type and mutant residue differs. The mutation might cause loss of hydrophobic interactions with other molecules on the surface of the protein.

Images

Overview of the protein in ribbon-presentation. The protein is coloured by element; α-helix=blue, β-strand = red, turn=green, and random coil=cyan.

Overview of the protein in ribbon-presentation. The protein is coloured grey, the side chain of the mutated residue is coloured magenta and shown as small balls.

Close-up of the mutation. The protein is coloured grey, the side chains of both the wild-type and the mutant residue are shown and coloured green and red respectively.

Close-up of the mutation (seen from a slightly different angle). The protein is coloured grey, the side chains of both the wild-type and the mutant residue are shown and coloured green and red (not show from this angle) respectively.

Close-up of the mutation (seen from a slightly different angle). The protein is coloured grey, the side chains of both the wild-type and the mutant residue are shown and coloured green and red respectively.

Movies

Close-up of the mutation. Both the wild-type and mutant side chain are shown in green and red respectively. The rest of the protein is show in grey.

Close-up of the mutation, same colours as animation 1. The animation shows alternating the wild-type side chain and the mutant side chain.

Citation

Protein structure analysis of mutations causing inheritable diseases. DOI: 10.1186/1471-2105-11-548. PubMed: 21059217.

DHVF, participating in a collective art performance, and meetings in Oxford Science Park

The last couple of weeks in October I went to Valencia to attend the Digital Health Venture Forum, where I received the Best Presentation Award.

After spending a few days with my family and my Spanish team, and participating in an art installation by the SuperFlex collective on the 25th, I returned to London.

October 27 I went to the beautiful Oxford Science Park to have a couple of business meetings.

Exponential Medicine Conference San Diego day 4

Tuesday, October 11th, was day four, and last, at the Exponential Medicine Conference in San Diego.

Some of the talks I enjoyed the most:

Exponential Thinking & Future Predictions: Ray Kurzweil Co-founder & Chancellor, Singularity University

Exponential Entrepreneurship:

  • Zayna Khayat, PhD Lead, MaRS Health and Director, MaRS EXCITE
  • Stephanie Marrus, MBA Entrepreneurship Center Director, UCSF

Investing In The Future: Vinod Khosla Founder, Khosla Ventures

Visualizing the Future of Medical Education, from VR to the OR:

  • Stefano Bini, MD Professor of Orthopedics, UCSF
  • Stephen Swensen Medical Director- Leadership and Organization Development, Mayo Clinic

Synthesis- From Imagination to Innovation to Impact
Kevin Wildenhaus, PhD Behavioral Science Lead: Janssen Disease Interception Accelerator, Johnson & Johnson

And right after that, I left for the airport.

Here you can see more photos from the event.

Exponential Medicine Conference San Diego day 3

Monday, October 10th was day 3 at the Exponential Medicine Conference San Diego.

For me the highlights were:

Bold Innovation: Peter Diamandis, MD Co-Founder, Singularity University and Founder & Chair, XPRIZE

Redesigning Care: Tony Young, PhD FRCS National Clinical Director for Innovation, NHS England

Bakul Patel, MBA Associate Director of Digital Health, Food and Drug Administration/Center for Devices and Radiological Health

Getting the xMED Scrubs Photo on the Beach, with an awesome drone:

The Brain and Beyond

  • Divya Chander, MD PhD Anesthesiologist/Neuroscientist, Stanford University
  • Arshya Vahabzadeh, MD Psychiatrist, Harvard Medical School
  • Anthony Bossis, PhD Clinical Assistant Professor- Department of Psychiatry, NYU School of Medicine

Off the Planet, Remote Medicine: Scott Parazynski, MD Managing Director, Apogee Interests & 5 Time NASA Astronaut (Retired)

Security & Privacy Threats in Healthcare (And What to Do About It): Marc Goodman, Resident futurologist at the FBI, Policy Law and Ethics Faculty Chair, Singularity University and Founder, FutureCrimes

The day ended with dinner on the beach, and a beach party, with bonfire and drum circle.

Award and Exponential Medicine Conference San Diego day 2

Sunday, October 9th, was day two at Exponential Medicine Conference in San Diego.

Some of the highlights were:

From ‘Omics to Action

  • Moira Gunn, PhD Host, NPR’s Biotech Nation
  • Larry Smarr, PhD Professor, UCSD and Director, Calit2
  • George Poste, DVM PhD FRS Chief Scientist, Complex Adaptive Systems Initiative- Arizona State University

Mobile, Connected, Digital Health

  • David Albert, MD Founder, AliveCor
  • Stanley Shaw, MD PhD Co-Director, MGH Center for Assessment Technology & Continuous Health
  • Bakul Patel, MBA Associate Director of Digital Health, Food and Drug Administration/Center for Devices and Radiological Health
  • Ulrik Wisløff Professor: Faculty of Medicine, Norwegian University of Science and Technology

Innovating at Scale: John Mattison, MD CMIO and Assistant Medical Director, Kaiser Permanente

Connecting the Dots: Mark Hyman, MD Chairman, Institute for Functional Medicine

Future of Intervention

  • Catherine Mohr, MD Vice President of Strategy, Intuitive Surgical
  • Tippi MacKenzie, MD Professor of Pediatric Surgery, UCSF
  • Amir Szold, MD Chairman, Technology Committee: European Society for Endoscopic Surgery
  • Olivia Hallisey Grand Prize Winner, 2015 Google Science Fair

Disrupting Clinical Practice: Todd Huffman Founder & CEO, 3Scan

Future of Cancer

  • Marty Tenenbaum, PhD Founder, Cancer Commons and Chairman & Founder/Chairman, CommerceNet
  • Sangeeta Bhatia, MD PhD, Director of Laboratory for Multiscale Regenerative Technologies, MIT
  • David Roberts, MBA, Former Special Agent, Business and Technology Disruption Expert

IMG_20161009_121012
The other cool thing that happened on day 2 is that I received an award: the Precision Medicine Impact Challenge Award launched by the White House Initiative on Precision Medicine and awarded by the State of California, presented by Elizabeth Baca, MD MPA, from the California Governor’s Office.
IMG_20161009_133001

Exponential Medicine Conference San Diego day 1

Saturday, October 8th, I attended day 1 of the Singularity University Exponential Medicine Conference in San Diego at the amazing Hotel Del Coronado.

The event was organized mainly by Will Weisman and the incomparable Daniel Kraft, MD (whom I met last year at the London Stock Exchange), both from Singularity University.

The Conference was fully packed with activities. Morning activities started at 7am and included Yoga, Meditation, Art, and Beach Run. Evening activities changed every day, and included things like Team Collaboration & Innovation Games, Gadget & S’mores Bar, Music & Magic at the Bar, UnConference, or Silent Disco.

There was also an expo area called The Innovation Lab, where innovative companies showcased their latest and greatest.

But, without a doubt, the most important part of the conference was the extremely interesting and thought-provoking speakers and subjects. Day 1 included, amongst many others:

  • Blockchain: Rajeev Ronanki – Principal, Deloitte Consulting; and Mariya Filipova – Healthcare Transformation, Deloitte Consulting

  • From Big Data to Actionable Information: Leroy Hood, PhD – President & Co-Founder, Institute for Systems Biology; Senior Vice President & Chief Science Officer, Providence Health & Services

We ended up the day with a beachside dinner under the stars.

 

Re-designing a NASA interface

interface

I am interested in many things. One of the main ones is technology. And within technology, software development to view telemetry data in different ways, within the same application.

Answering NASA’s call to help contribute to the exploration of the solar system, I got access to their next-generation mission control framework being developed at the NASA Ames Research Center in Silicon Valley being used for mission planning and operations in the lead up to the Resource Prospector mission, and at NASA’s Jet Propulsion Laboratory to view data from the Curiosity Rover.

Although I do not have much “spare time”, I have been tinkering with composing and modifying screen layouts, bringing together various telemetry objects and other object types in a single screen, following some basic design principles, as outlined in a book I have read recently: Designing for Emerging Technologies – UX for Genomics, Robotics and the IoT, by Jonathan Follett (Editor) published by O’Reilly.

Still a “work in progress”, but I hope my contributions help.

Talking to Prof. Church about machine learning applied to genomic research

During my flight to Boston I read “Regenesis”, the interesting genomic science book by Professor George Church, which was a gift from my friend Dr. Raminderpal Singh.

George, Raminder and Jorge 2016 Boston

On Wednesday evening I had a very interesting conversation in Boston with both of them. Neither of them needs an introduction in the genomics world, but for those of you outside the field:

  • Raminder is Vice-president at Eagle Genomics and Advisor at Kanteron Systems. He was previously Genomic Medicine Strategy Lead at IBM, where he was responsible for the Watson Genomics project.
  • George is a bestselling author, Professor of Genetics at Harvard Medical School and Professor of Health Sciences and Technology at Harvard and MIT. His PhD led to the first genome sequence and contributed to nearly all “next generation” DNA sequencing methods.

Since George’s lab work revolves around chip-DNA-synthesis, gene editing, stem cell engineering, super-resolution, molecular computing, dark matter and similar subjects, and since he has PhD students from Harvard, MIT, Boston U., and Cambridge, during the conversation I could not resist the opportunity and I asked him about de novo computational discovery of motifs.

It is an idea I had a few weeks ago while sailing from Saint Petersburg to Helsinki: what if we apply machine learning/intelligence (whether Random Forests or Hierarchical Temporal Memory) algorithms, or even better quantum computing, to look for sequence motifs (nucleotide or amino-acid sequence pattern) to help us predict and engineer structural motifs (chain-like biological molecules)? We could begin with those related to binding and folding, which could lead to an exponential advance in the field of information storage and synthetic biology. But that would be only the beginning. The possibilities and implications could be really far fetching. It would overflow the SFLD 😉

In a nutshell (graphical silly example), it would make it much easier to go from this:
to this:

And not only describe it, but also understand it and facilitate its application in de-novo engineering.

There are already over 100 software programs which try to do this programmatically (MEME, EXTREME, AlignAce, Amadeus, CisModule, FIRE, Gibbs Motif Sampler, PhyloGibbs, SeSiMCMC, ChIPMunk, Weeder, SCOPE, MotifVoter, MProfiler…). Weirauch et al. evaluated many in a 2013 benchmark. But what I am proposing is a lot more powerful, versatile, and quick than anything done before (as far as I know).

He mentioned some of the research work his wife (Harvard Professor Ting Wu, whom I also met in Boston) is currently involved in around Super-resolution imaging for chromatin folding, and evolutionary conservation, and told me “your idea is really interesting”.

Honestly, I usually can care less about what others think of my ideas (I’m a scientist, I value evidence and data, not “beliefs” or “judgements”) but I personally admire and respect his work, and agree with his views, specially on sharing knowledge and human genome editing, so his comment made my day and encouraged me to further pursue that hypothesis… someday. Right now in my spare time I am redesigning a multi-sensors data stream interface for NASA (pro-bono, unrequested… but that’s my idea of fun!).

Festival of Genomics Boston

June 28 and 29 I attended, along with my friend John Memarian, President & CCO of my company Kanteron Systems, the Festival of Genomics Boston, as a Microsoft Genomics Group partner.

Although the show was small, it was a great opportunity to network with industry and academic experts (from Harvard Professors to Illumina executives) and learn.

From scientific posters to the latest sequencing technologies, from robotic arms to genomics experiments in space, it was great #geekfun.

Invited to Microsoft Research Cambridge workshop: Computing in Cancer

May 27 I was invited to participate in the “Computing in Cancer Workshop” organized by Microsoft Research in Cambridge.

It was a great opportunity to network, meet with colleagues and other researchers, and especially to learn a lot.

The fascinating lectures were:

  • Antonio Criminisi (Principal Researcher, Microsoft Research): Machine Learning for Medical Image Analysis
  • Jasmin Fisher (Senior Researcher, Microsoft Research): Virtual Models of Cancer
  • Giles Maskell (President, Royal College of Radiologists): Current problems in diagnostic radiology
  • Fiona Gilbert (Head of the Department of Radiology, University of Cambridge)
  • Dennis Wang (Senior Bioinformatics Scientist, AstraZeneca): Predicting drug combinations and biomarkers of response: a crowd-sourced solution
  • Florian Markowetz (University of Cambridge, CRUK Cambridge Institute): Quantifying patterns of tumour evolution
  • Francesca Buffa (Associate Professor, Department of Oncology, University of Oxford): In-silico systems biology and functional genomics approaches to accelerate biomarker discovery
  • Hoifung Poon (Researcher, Microsoft Research): Machine Reading for Cancer Panomics
  • Raj Jena (Academic Consultant Clinical Oncologist, Cambridge University Hospitals): Computing for Radiation Oncology – from cell culture to the clinic
  • Bertie Gottgens (Professor of Molecular Haematology, University of Cambridge): Defining Cell States and Regulatory Networks using Single Cell Genomics